Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
ruxolitinib · 67 trials · 98 indications
≥75% improvement in facial Vitiligo Area Scoring Index.
HiSCR75 is defined as at least a 75% reduction from baseline in the total abscess and/or inflammatory nodule (AN) count with no increase from baseline in abscess or draining tunnel count.
Defined as achieving ≥ 75% improvement in Eczema Area and Severity Index (EASI) score from baseline.
GFS will be defined as the elapsed time between the date of transplant to Grade III-IV acute graft-versus host disease (GVHD), chronic GVHD requiring systemic immune suppression, or death by any cause.
EASI75 was defined as achieving a ≥75% improvement in the EASI score compared to the baseline score. The EASI scoring system is a validated scoring system that grades the physical signs of atopic dermatitis (AD) to provide a measure of AD severity (ranging from 0 to 72). The disease severity strata for the EASI are: 0 = clear; 0.1 to 1.0 = almost clear; 1.1 to 7.0 = mild; 7.1 to 21.0 = moderate; 21.1 to 50.0 = severe; 50.1 to 72.0 = very severe.
IGA-TS was defined as achieving an IGA score of 0 or 1 with a ≥2-grade improvement from baseline. The IGA is an overall eczema severity rating on a 0 to 4 scale. 0: clear; no erythema or induration/papulation, no oozing/crusting; there may be minor residual discoloration. 1: almost clear; may be trace faint pink erythema, with almost no induration/papulation, and no oozing/crusting. 2: mild; may be faint pink erythema, with mild induration/papulation and no oozing/crusting. 3: moderate; may be pink-red erythema with moderate induration/papulation and may be some oozing/crusting. 4: severe; may be deep or bright red erythema with severe induration/papulation and with oozing/crusting.
WI-NRS4 was defined as the percentage of participants achieving a ≥4-point improvement (reduction) in Worst-Itch Numeric Rating Scale (WI-NRS) score from baseline. The WI-NRS is a patient-reported outcome comprised of a single item rated on a scale from 0 ("no itch") to 10 ("worst imaginable itch"). Participants assessed their worst level of prurigo nodularis-related itch during the past 24 hours on a scale of 0 to 10. The WI-NRS score for baseline was determined by averaging the 7 daily WI-NRS scores before Day 1 (i.e., Days -7 to -1) for all by-visit summaries. The by-visit WI-NRS score for post-baseline visits was determined by averaging the 7 daily WI-NRS scores before the visit day. Participants with missing Week 12 data for any reason, including treatment discontinuation (due to development of atopic dermatitis lesions or any other cause), were defined as nonresponders.
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was considered drug related. An AE could therefore be any unfavorable or unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study cream. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first application of study cream and up to 30 days after the last application of study cream.
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it was drug related. A TEAE was defined as any AE either reported for the first time or the worsening of a pre-existing event after the first application of study cream and up to 30 days after the last application of study cream. The severity of AEs was assessed using Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) Grades 1 through 5. Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment not indicated. Grade 2: moderate; minimal, local, or noninvasive treatment indicated; limiting age-appropriate activities of daily living. Grade 3: severe or medically significant but not immediately life threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4: life-threatening consequences; urgent treatment indicated. Grade 5: fatal.
The IGA is an overall eczema severity rating on a 5-point scale ranging from 0 (clear skin) to 4 (severe disease). The score is based on an overall assessment of the degree of erythema, induration/papulation, and oozing/crusting. The IGA-TS is defined as an IGA score of 0 (clear skin) or 1 (almost clear skin) with ≥2 grade improvement from Baseline.
An F-VASI75 responder achieved at least 75% improvement from Baseline in F-VASI, measured by the percentage of vitiligo involvement (percentage of body surface area \[BSA\]) and the degree of depigmentation: 0% (no depigmentation), 10% (only specks of depigmentation), 25% (pigmented area exceeded depigmented area), 50% (depigmented and pigmented area was equal), 75% (depigmented area exceeded pigmented area), 90% (specks of pigment), or 100% (no pigment). The percentage of BSA (hand unit) vitiligo involvement was estimated to the nearest 0.1% by the Investigator using the Palmar Method. The Investigator used his/her hand to mimic the participant's hand size to evaluate the percentage of BSA vitiligo involvement. F-VASI was then derived by multiplying the values assessed for the vitiligo involvement by the percentage of affected skin for each site on the face and summing the values of all sites (possible range: 0-3; lower scores indicate increased improvement).
The IGA is an overall eczema severity rating on a 5-point scale ranging from 0 (clear skin) to 4 (severe disease). The score is based on an overall assessment of the degree of erythema, induration/papulation, and oozing/crusting. The IGA-TS is defined as an IGA score of 0 (clear skin) or 1 (almost clear skin) with ≥ 2 grade improvement from Baseline.
ORR was defined as the percentage of participants in each arm demonstrating a complete response (CR) or partial response (PR) based on chronic GvHD (cGvHD) disease assessments (National Institutes of Health Consensus Criteria) without the requirement of additional systemic therapies for an earlier progression, mixed response, or non-response. Scoring of response was relative to the organ score at the time of randomization. CR: complete resolution of all signs and symptoms of cGVHD in all evaluable organs without the initiation or addition of new systemic therapy. PR: improvement in at least one organ (e.g., improvement of 1 or more points on a 4- to 7-point scale, or an improvement of 2 or more points on a 10- to 12-point scale) without progression in other organs or sites, initiation, or addition of new systemic therapies.
Symptoms of polycythemia vera were assessed using a modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) electronic diary. Using the diary, patients rated the following symptoms on a scale from 0 (absent) to 10 (worst imaginable): tiredness, itching, muscle aches, night sweats, and sweats while awake. The total symptom score ranged from 0-50 and was calculated as the sum of the 5 symptom scores. A higher score indicates worse symptoms.
Primary response was defined as having achieved hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and Spleen Volume Reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32).
Spleen volume was assessed by magnetic resonance imaging (MRI) or by computed tomography (CT) scans if MRI was not suitable, and analyzed by a blinded central laboratory reader. Patients who withdrew, crossed over to ruxolitinib prior to the visit, or had a missing value at the visit were considered non-responders.
The Investigator's Global Assessment will be performed at study visits 2-6. The IGA is an instrument to rate the severity of the subject's global disease. This IGA is comprised of a 5-point scale of disease activity ranging from 0 to 4 as follows: 0: "clear," no erythema or scale 1. "almost clear," pink erythema without scale 2. "mild," pink erythema with scale 3. "moderate," red erythema with scale 4. "severe," purple/violaceous or hemorrhagic/crusted erythema OR hypertrophic/ verrucous scale Range of scores are 0-4 with higher scores indicating worse outcome.
The number of treated accelerated-phase and blast-phase MPN patients (primary cohort) that achieve a best response per 2013 International Working Group (IWG) criteria of either complete response (CR), Partial Response (PR), or complete response with incomplete recovery of counts (CRi), when treated with the combination of ruxolitinib with enasidenib within 6 cycles of combined therapy. Complete Response with incomplete recovery of counts (CRi) - complete remission (\<5% marrow blasts by morphology) with incomplete count recovery (platelet count \<100 x 10\^9\^/L and/or absolute neutrophil count \< 1 x 10\^9\^/L) Complete Response (CR) - full marrow recovery; full count recovery; resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH Partial Response (PR) - morphologic remission in the peripheral blood but not necessarily in the bone marrow; resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH
The number of premalignant breast cells in apoptosis at the time of diagnosis will be compared to the number of cells in apoptosis following treatment with 15 (+/- 5) days of ruxolitinib or placebo.
SGFS will be calculated from the time of transplant to onset of grade 3-4 acute GVHD or death censoring patients alive without grade 3-4 GVHD at last clinical assessment date. The SGFS rate together with 95% confidence interval at day 180 will be estimated by Kaplan-Meier method.
Relapse is defined as evidence of disease progression or recurrence based on Lugano criteria or confirmed by biopsy.
GRFS is a composite endpoint of survival without grade III-IV acute GVHD, systemic therapy-requiring chronic GVHD (cGVHD), relapse, or death. Will be evaluated using the Kaplan-Meier method, with median survival and probability of surviving to relevant time points reported with point estimates and 90% confidence intervals separately for each study cohort. Comparisons to Center for International Blood and Marrow Transplant Research (CIBMTR) patients will use log-rank tests.
Clinical Benefit Response (CBR):CBR is defined by improvements in clinical symptoms (fatigue, anorexia, fever and night sweats). Laboratory markers like Hemoglobin levels, weight change and lymph node size are included in the CBR. A CBR is considered positive if there is at least a 25% reduction in the size of the largest lymph node (measured by modified Cheson criteria), a significant improvement in at least one laboratory marker (e.g., hemoglobin), and improvement in at least one clinical symptom without worsening of others. Positive response: Relative to baseline, improvement in at least one of the criterion without worsening of any single criterion other than hemoglobin on two consecutive study visits. Negative response: Relative to baseline, worsening of any single criterion other than hemoglobin on two consecutive site visits or failure to achieve improvement for any criterion.
For Arm 1, in patients with Peripheral T-cell Lymphoma (PTCL), the primary objective will be complete response (CR) rate.
For Arm 2, in patients with Cutaneous T-cell Lymphoma (CTCL), the primary objective will be overall response rate (ORR)
OS is defined as the time from first treatment until the date of death from any cause at the end of the study. Participants who are lost to follow-up will be censored at the time of the last follow-up.
Day 28 response to treatment defined as complete (CR), very good partial (VGPR), or partial (PR) response without intervening therapy or death to ruxolitinib monotherapy. CR - All evaluable organs (skin, liver, GI tract) stage 0. For a response to be scored as CR, the patient must be in CR on the date of assessment and have had no intervening additional GVHD therapy. VGPR - Stage 0 liver and GI and residual stage 1 skin GVHD. For a response to be scored as VGPR, the patient must be in VGPR on the date of assessment and have had no intervening additional GVHD therapy. PR - An improvement by one or more stages in one or more organ involved with GVHD symptoms without worsening in others. For a response to be scored as PR, the patient must be in PR on the date of assessment and have had no intervening additional GVHD therapy.
The improvement of rash is defined on the physician global assessment score (PGA) and on the body surface area (BSA). PGA: measures the overall response to treatment as assessed by the physician; scale 0-4 Reduction of PGA (e.g. PGA 4 to PGA0) will be converted into percentage: decrease of PGA of 1 point on a scale from 0 to 4 shows a decrease of 25%, decrease of 4 points shows a decrease of 100%. This value (percentage of PGA decrease) will be combined with the reduction of BSA (percentage) and will result in the improvement of rash.
The Investigator's Global Assessment-Chronic Hand Eczema (IGA-CHE) is an instrument used to rate the severity of the participant's global CHE and is based on a 5-point scale ranging from 0 (clear) to 4 (severe) (1, almost clear; 2, mild eczema; 3, moderate eczema). IGA-CHE TS is defined as an IGA-CHE score of 0 (clear) or 1 (almost clear) with a ≥2-step improvement from Baseline.
The VNS is a patient-reported measure of vitiligo treatment success that has a 5-point scale. The participant was asked to respond to the following query: "Compared with before treatment, how noticeable is the vitiligo now? Responses: (1) more noticeable, (2) as noticeable, (3) slightly less noticeable, (4) a lot less noticeable, or (5) no longer noticeable. The baseline genital photograph was shown to the participant for reference. A VNS score of 4 or 5 can be interpreted as representing treatment success.
The mixed model repeated measure (MMRM) included the fixed effects of the treatment group (ruxolitinib 1.5% and vehicle cream), stratification factor (Baseline AN count of ≥3 to 4 or ≥5 to 10), visit, and visit-by-treatment interaction. Change from Baseline was calculated as the Week 16 value minus the Baseline value.
The Investigator's Global Assessment (IGA) is a modified global assessment tool to assess the severity of lesions. Grading was based on 0 (clear), 1 (almost clear), 2 (mild), 3 (moderate), and 4 (severe). IGA-TS response was defined as an IGA score of 0 or 1 with a ≥2-grade improvement from Baseline at Week 16.
ITCH4 response was defined as a ≥4-point improvement from Baseline in by-visit Itch Numeric Rating Scale (NRS) score. The Itch NRS is a daily participant-reported measure (24-hour recall) of the worst level of itch intensity. Participants rated itch severity of their lichen sclerosus by selecting a number from 0 (no itch) to 10 (worst imaginable itch) that best described the worst level of itch they experienced in the past 24 hours.
The EASI scoring system examines 4 areas of the body (head/neck, trunk, upper limbs, and lower limbs) and weights them for participants of at least 8 years of age. Each of the 4 body regions is assessed separately for erythema (E), induration/papulation/edema (I), excoriations (Ex), and lichenification (l) on a scale of 0 to 3 (0 = none, absent; 1 = mild; 2 = moderate; 3 = severe). Half scores are allowed between severities 1, 2, and 3. The final EASI score was obtained by weight-averaging these 4 scores and will range from 0 to 72; the severity strata are as follows: 0 = clear; 0.1 to 1.0 = almost clear; 1.1 to 7.0 = mild; 7.1 to 21.0 = moderate; 21.1 to 50.0 = severe; 50.1 to 72.0 = very severe. Specifically for the head and neck region, the EASI score ranges from 0 to 7.2 An EASI75 responder was defined as a participant achieving a 75% or greater improvement from Baseline in the EASI score for the head and neck.
The intensity of pruritus (itch) was recorded daily using the PP-NRS (24-hour recall period). Participants were asked to assign a numerical score representing their itch at the worst moment during the previous 24 hours on a scale of 0 to 10, with 0 being no itch and 10 being the worst itch imaginable. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Baseline was defined as the average of all non-missing PP-NRS scores reported during the 7-day run-in period.
Biologic response to 7-day run-in phase treatment, defined as a change in phosphorylated STAT3 (pSTAT3) expression from moderate/high positive (pSTAT3-positive) in pre-run-in phase sample to negative or weakly positive/equivocal (pSTAT3-negative) in post-run-in samples. pSTAT3 status was determined by evaluating the percent positive cells and the strength of staining (weak vs. strong/moderate) in relation to positive and negative controls. A T-score was calculated based on percent-stained cells and intensity of staining and interpreted as follows: Scores 0-4 are negative/weakly positive (pStat3 negative) and 5-8 are moderate/high positive (pStat3 positive). Hence, pStat3 negative indicates a biologic response or a decrease in pSTAT3 levels.
Defined as the percentage of participants demonstrating a complete response (CR), very good partial response (VGPR), or partial response (PR).
Subjects will be treated until disease progression or discontinuation criteria are met.
Spleen volume was measured using magnetic resonance imaging (MRI) or computed tomography (CT) scan. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. CT scans were performed if the participant was not a candidate for MRI. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for all visits for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred.
Spleen volume was measured using magnetic resonance imaging (MRI) or computed tomography (CT) scan. The MRIs were read in the central imaging laboratory. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the technique of least squares. MRI was the preferred method for obtaining spleen volume data. CT scans were performed if the participant was not a candidate for MRI. The CT scans were processed by the same central laboratory used for MRIs. The same method (MRI or CT) was used for all visits for a given participant unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurred.
Overall survival was measured as the length of time (in days) between the randomization date and the date of death.
Magnetic resonance imaging (MRI) of the upper and lower abdomen and pelvis was performed to assess spleen volumes. Computed tomography (CT) scan was performed if participant was not a candidate for MRI or if MRI was not readily available. MRI was performed with a body coil. Spleen volume was obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares. The MRI (or CT scan in applicable participants) was performed on the first or second day of the baseline period (ie, Day -7 or Day -6), and the site radiologist sent the scan to the central imaging laboratory that same day. The CT scans were processed by the same central laboratory used for MRIs.
Symptoms of myelofibrosis were assessed using a modified Myelofibrosis Symptom Assessment Form (MFSAF) Version 2.0 diary. Using the diary, patients rated the following symptoms on a scale from 0 (absent) to 10 (worst imaginable): night sweats, itching, abdominal discomfort, pain under ribs on left, feeling of fullness (early satiety), and muscle/bone pain. The total symptom score ranged from 0-60 and was calculated as the sum of the 6 symptom scores. A higher score indicates worse symptoms.
TEAE was defined as adverse events that began or worsened from baseline after the first administration of the study drug. Participants were analyzed based on the number of subjects who received a dose within the dose group. The percentages for each column are calculated using this N. Participants who had more than 1 event in an AE category (eg, treatment-related TEAE) are counted once at each dose level the event occurred.
Participants with platelet count between 50 and 100 × 10\^9/L at the screening and/or baseline visit were enrolled in the study. Thrombocytopenia is defined as a condition with low blood platelet count. Grade 4 thrombocytopenia was platelet count \< 25 × 10\^9/L. Participants were analyzed based on the number of subjects who received a dose within the dose group. The percentages for each column are calculated using this N. Participants who had more than 1 event in an AE category (eg, treatment-related TEAE) are counted once at each dose level the event occurred.
Hemorrhages were defined as any lower level terms by MedDRA included in the Standardized MedDRA Query (SMQ) for hemorrhage terms. Participants were analyzed based on the number of subjects who received a dose within the dose group. The percentages for each column are calculated using this N. Participants who had more than 1 event in an AE category (eg, treatment-related TEAE) are counted once at each dose level the event occurred.
The investigator graded OR according to the International Working Group for Myelofibrosis Research and Therapy criteria for treatment response. As bone marrow biopsies were not taken after baseline, the best achievable response was clinical improvement which required 1 of the following in the absence of progressive disease (PD): (1) A ≥ 2 g/dL increase in hemoglobin level or (2) either a palpable ≥ 50% reduction of splenomegaly of a spleen ≥ 10 cm at baseline or a spleen palpable at \> 5 cm at baseline becoming not palpable. PD required 1 of the following: (1) Progressive splenomegaly defined by the appearance of previously absent splenomegaly that was palpable at \> 5 cm below the left costal margin or a ≥ 100% increase in palpable distance for baseline splenomegaly of 5-10 cm or a ≥ 50% increase in palpable distance for baseline splenomegaly of \> 10 cm or (2) an increase in peripheral blood blast percentage to ≥ 20% that lasted for ≥ 8 weeks. Stable disease: None of the above.
Total Lesion Score is calculated as the sum of component scores for erythema (E), scaling (S), and thickness (T) of the study-treated lesions taken together. Each component consists of ratings of 0=none, 1=mild, 2=moderate, 3=marked, and 4=severe such that total lesion score can vary in value from 0 to 12. A negative change from Baseline indicates improvement.
A responder is defined as a patient with a complete response (negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow) or a partial response (≥ 50% reduction of serum M-protein and reduction in 24 h urinary M-protein by ≥ 90% or to \< 200 mg per 24 h).
Adverse events reported for the first time or worsening of a pre-existing event after first dose of study drug/treatment
The INCB018424 skin flux was estimated from the overall mean steady-state plasma concentrations for each subject in this study and the estimated systemic clearance of INCB018424 following oral-dose administration in another study.
The INCB018424 bioavailability was estimated from the overall mean steady-state plasma concentrations for each subject in this study and the estimated systemic clearance of INCB018424 following oral-dose administration in another study.
All observed INCB018424 plasma concentrations from Days 8, 15, 22, and 28 were averaged to obtain an overall mean exposure for each subject. Samples were taken pre-dose and approximately one hour post-dose.
The investigator assessed the severity of the clinical signs erythema, scaling, and thickness for each test site by using a 5-point scale from 0 (no evidence) to 4.0 (severe).
The total target lesion score was calculated by summing the scores for erythema, scaling, and thickness for that particular target lesion. The investigator assessed the severity of the clinical signs erythema, scaling, and thickness for each test site by using a 5-point scale from 0 (no evidence) to 4.0 (severe).
A TEAE is any AE either reported for first time or worsening of a pre-existing event after first dose of study drug.
The INCB018424 bioavailability will be estimated from the overall mean steady-state plasma concentrations for each subject in this study and the estimated systemic clearance of INCB018424 following oral-dose administration in another study. Bioavailability is defined as the proportion of a drug which enters the circulation when introduced into the body and so is able to have an active effect.
Proportion of patients achieving an Investigators Global Assessment (IGA) score of 0 or 1 with at least a 2-step improvement (IGA treatment success). The Investigator Global Assessment (IGA) will provide information of the overall disease. It is a 5-point scale: clear-1, almost clear-2, mild-3, moderate-4, and severe-5.
Hand Eczema Severity Index (HECSI) , a well-accepted and validated scoring system for disease activity. It incorporates both the extent and the intensity of the disease. Each hand is divided into five areas: fingertips, fingers (except the tips), palms, back of hands and wrists. Each area will be scored for extension and intensity of the six following clinical signs: erythema, induration /papulation, vesicles, fissuring, scaling, and edema; which are graded on the following scale: 0, no skin changes; 1, mild disease; 2, moderate and 3, severe. Data will be reported as a percent change in the HECSI score from baseline to week 12. The score ranges from 0-360.
DLTs will be determined for each subject as a binary variable indicating whether or not the subject experienced a DLT during Cycle 1
The maximum tolerated dose (MTD) combination is defined as the dose combination associated with a target probability of dose limiting toxicity (DLT) of 0.25. A dose-limiting toxicity is defined as the MTD with DLTs defined as any grade 3 non-hematologic toxicities despite maximal supportive care or any grade 4 hematologic toxicity. The MTD will be estimated using the time to event continual reassessment method (TITE-CRM). The TITE-CRM will use an empirical dose-toxicity model, with a sample size of 10. The dose-toxicity model is calibrated such that the method will eventually select a dose that yields between 16% and 34% DLT.
Progression free survival (PFS) will be measured every 3 cycles (9 weeks of treatment +/- 4 days). PFS will be defined as the time from patient registration until objective or disease progression or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression).
Ruxolitinib MTD in combination with paclitaxel 80 mg/m2 intravenously (IV) weekly is determined by the number of patients who have dose limiting toxicity (DLT). See DLT primary outcome measure for definition * If a DLT was observed in 0 of 3 patients in a cohort, then 3 patients were enrolled to the next cohort using a 5mg higher dose of ruxolitinib. * If a DLT was observed in 1 of 3 patients in a cohort, then 3 additional patients were added, and then if no further DLTs were observed, 3 patients were enrolled to the next cohort using a 5mg higher dose of ruxolitinib. * The MTD is identified as the level BELOW the cohort where DLT occurred in less than one third of patients within the cohort. * If no DLT's are observed, the MTD is not reached.
DLT: (a) grade \>2 non-hematologic, non-hepatic, organ toxicity not due to disease progression or another clearly identified cause except: alopecia of any grade; Grade 3 nausea, vomiting or diarrhea and grade 3 fasting hyperglycemia that resolves to grade\<2 within 3 days and 7 days, respectively, with our without optimal medical management; and grade 3 fasting hyperglycemia within 3 days of glucocorticoid use; (b) grade \>3 thrombocytopenia lasting more than 24 hours or associated with clinically significant bleeding; (c) grade \>3 neutropenia lasting \>4 days or accompanied with fever; (d) grade\>3 anemia; grade\>2 total bilirubin, aspartate and alanine aminotransaminase (AST and ALT), or alkaline phosphatase (ALP) lasting \> 72 hours except: with baseline grade 2 as a result of liver metastases then levels (ALP, AST, ALT) \>10x upper limit of normal is DLT; (e) delay in ability to administer paclitaxel more than 2 weeks due to toxicity.
Safety and efficacy of ruxolitinib when used in combination with decitabine. MTD is defined as the highest dose studied for which the incidence of (Dose Limiting Toxicities) DLT is at least 33%.
Safety and efficacy of ruxolitinib when used in combination with decitabine. DLTs will be defined as those adverse events occurring in the first 5 weeks after initiation of therapy that are not clearly related to disease.
Determine the recommended phase 2 dose of ruxolitinib in combination with a fixed dose of retifanlimab. The recommended phase 2 dose will be determined by assessment of the dose limiting toxicities during the first cycle of treatment.
Number of participants with TEAEs leading to dose interruption or discontinuation
Defined as any adverse event either reported for the first time or worsening of a pre-existing event after first application of study drug
Within each arm, patient-level toxicity events will be summarized by dose level, major organ category, and grade.
Determined by rate of side effects seen when combination is given
To assess the maximum tolerated dose (MTD) of ruxolitinib in combination with nivolumab in patients with relapsed/refractory Hodgkin lymphoma. (Phase I Only)
To evaluate the best Overall Disease Control (CR+PR+SD) at 3 months of nivolumab in combination with ruxolitinib at MTD in patients with relapsed/refractory Hodgkin lymphoma using the modified Lugano Classification "lymphoma response criteria to immunomodulatory therapy criteria" (LYRIC)1 (Phase II Only)
A TEAE is any adverse event (AE) either reported for the first time or worsening of a pre-existing event after first application of study drug.
MTD will be determined by measuring incidence of the dose-limiting toxicities (DLTs) per dose level, of ruxolitinib in combination with steroids and lenalidomide for MM patients currently with progressive disease.
Safety will be measured by counting the occurrence of adverse events throughout the study, graded via Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria
DLT was defined as the occurrence of any of the following treatment-related toxicities, occurring through Day 28: Any grade ≥ 2 hemorrhagic event ; Any grade thrombocytopenia requiring PLT transfusion; PLT count \< 25x109/L\*; Grade 4 neutropenia (absolute neutrophil count \< 0.5x109/L)\*; Grade ≥ 3 febrile neutropenia\*; Grade ≥ 2 total serum bilirubin with coincident direct bilirubin ≥ 0.5 mg/dL; Grade 3 non-hematologic toxicity for ≥ 7 consecutive days; Grade 4 non-hematologic toxicity. In the dose escalation stage in the core study period, the starting does in both strata was 5mg bid. Successive cohorts of newly enrolled patients received increasing doses of ruxolitinib until the Maximum Safe Starting Dose (MSSD) was determined. Initially, only patients with PLT counts 75-99 x10\^9/L (stratum 1) were allowed to be enrolled. Once safety was established in stratum 1 at the first 2 dose cohorts, eligible population was further expanded to patients with PLT counts 50-74 x10\^9/L (stratum 2).
Treatment-Emergent AEs are events occurring after first drug administration or worsened from baseline. Treatment-Related AEs are those with a definite, probable, possible or missing causality. A serious AE is a medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is a medical event requiring intervention to prevent 1 of the above. A severe or life-threatening AE is based on intensity, according to National Cancer Institute-Common Toxicity Criteria for Adverse Effects (NCI-CTCAE) v3.0.
Clinical improvement was defined according to the International Working Group Myelofibrosis Research and Treatment criteria, and required 1 of the following: 1. A ≥ 2 g/dL increase in Hemoglobin level or becoming transfusion independent; 2. Either a ≥ 50% reduction in palpable splenomegaly if spleen was ≥ 10 cm at Baseline or a spleen palpable at \> 5 cm at Baseline becomes not palpable; 3. A ≥ 100% increase in platelet count and an absolute platelet count of ≥ 50,000 x 10\^9/L or 4. A ≥ 100% increase in absolute neutrophil count (ANC) and an ANC of ≥ 0.5 x 10\^9/L.
* To establish the utility of using an increase in sBCMA levels \> 25% or IMWG criteria for disease progression to direct this therapeutic approach, TTP will be measured, where TTP is defined as a number of days between the start of treatment (cycle 1 day 1) and PD. PD is defined by either change in sBCMA (≥25% increase from its nadir levels) or by standard IMWG criteria (using sM-protein and SFLC assessments), whichever occurs first. PD will be confirmed by two consecutive tests. * Duration of response 1 (DOR1), defined as the time from the first response to progressive disease as determined by either changes in sBCMA or IMWG criteria (whichever occurs first) while patients are on ruxolitinib and methylprednisolone treatment * Duration of response 2 (DOR2), defined as the time from the first response to progressive disease as determined by standard IMWG criteria while patients on ruxolitinib, lenalidomide and methylprednisolone treatment
| Arm | Type | Description |
|---|---|---|
| Ruxolitinib 0.75 % Cream | EXPERIMENTAL | Participants received ruxolitinib 0.75% cream, applied topically to the affected area as defined in the protocol. |
| Ruxolitinib 1.5 % Cream | EXPERIMENTAL | Participants received ruxolitinib 1.5% cream, applied topically to the affected area as defined in the protocol. |
| Vehicle Cream | PLACEBO_COMPARATOR | Participants received vehicle cream, applied topically to the affected area as defined by the protocol. |
| Vehicle-controlled (VC) Period: Ruxolitinib (1.5% Cream) | EXPERIMENTAL | Study drug will be administered twice daily. |
| VC Period: Vehicle Cream | PLACEBO_COMPARATOR | Matching vehicle cream will be administered twice daily. |
| Disease Control (DC) Period: Ruxolitinib (1.5% Cream) | EXPERIMENTAL | Study drug will be administered twice weekly. |
| DC Period: Vehicle Cream | PLACEBO_COMPARATOR | Matching vehicle cream will be administered twice weekly. |
| DC Period: Open Label - Ruxolitinib (1.5% Cream) | EXPERIMENTAL | Study drug will be administered twice daily to treat Disease Exacerbations. |
| Open-label Extension (OLE) period: Ruxolitinib (1.5% Cream) | EXPERIMENTAL | Study drug will be administered twice daily. |
| Dose Finding Run-In Group 1: Tac/MTX/Ruxolitnib Dose 1 | EXPERIMENTAL | Tacrolimus/ methotrexate/ ruxolitinib (Tac/MTX/Rux) at the protocol defined doses. |
| Dose Finding Run-In Group 2: Tac/MTX/Ruxolitnib Dose 2 | EXPERIMENTAL | Tacrolimus/ methotrexate/ ruxolitinib (Tac/MTX/Rux) at the protocol defined doses. |
| Main Study Group A: Tac/MTX/Ruxolitnib | EXPERIMENTAL | Tacrolimus/ methotrexate/ ruxolitinib (Tac/MTX/Rux) at the protocol defined doses. |
| Main Study Group B: PTCy/Tac/MMF | ACTIVE_COMPARATOR | Post-transplant cyclophosphamide/ tacrolimus/ mycophenolate mofetil (PTCy/Tac/MMF) at the protocol defined doses. |
| VC Period: Ruxolitinib 1.5% Cream BID | EXPERIMENTAL | Participants received ruxolitinib 1.5% cream, applied topically to the affected areas as a thin film twice daily (BID) from Day 1 to Week 8 during the Vehicle Control (VC) Period. Participants applied cream BID to areas identified at Baseline even if the areas improved. |
| VC Period: Vehicle Cream BID | PLACEBO_COMPARATOR | Participants received vehicle cream, applied topically to the affected areas as a thin film twice daily (BID) from Day 1 to Week 8 during the VC Period. Participants applied cream BID to areas identified at Baseline even if the areas improved. |
| VC Extension Period/Escape Arm: Ruxolitinib 1.5% Cream BID | EXPERIMENTAL | Participants who applied ruxolitinib 1.5% cream during VC Period, continued applying ruxolitinib 1.5% cream topically to the affected areas as a thin film BID from Week 8 to 24 during the Vehicle Control Extension (VCE) Period. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. |
| VC Extension Period/Escape Arm: Vehicle Cream BID | PLACEBO_COMPARATOR | Participants who applied vehicle cream during the VC Period, continued applying vehicle cream as a thin film twice daily (BID) from Weeks 8 to 24 during the VCE Period. Participants applied cream BID to areas identified at Baseline even if the areas improved. Participants will be eligible to enter the ruxolitinib 1.5% cream open-label escape arm as defined in the protocol. |
| VC Extension Period: Ruxolitinib 1.5% cream open-label escape arm | EXPERIMENTAL | Participants received ruxolitinib 1.5% cream, applied topically to the affected areas as a thin film twice daily (BID) during the VCE Period. Participants applied cream BID to areas identified at Baseline even if the areas improved. |
| Vehicle Cream BID | PLACEBO_COMPARATOR | Participants apply ruxolitinib matching vehicle cream topically to the affected areas as a thin film twice daily (BID) for 12 weeks during the DBVC period. Participants who have completed the treatment during DBVC period will apply ruxolitinib 1.5% cream topically during the open label extension (OLE) period for up to 40 weeks. |
| Ruxolitinib 1.5% Cream | EXPERIMENTAL | Participants apply ruxolitinib 1.5% cream topically to the affected areas as a thin film BID for 12 weeks during the DBVC period. Participants who have completed the treatment during DBVC period will apply ruxolitinib 1.5% cream the open label extension (OLE) period for up to 40 weeks. |
| Ruxolitinib | EXPERIMENTAL | Ruxolitinib cream 1.5% twice daily (BID) during the continuous and LTS treatment period. |
| Ruxolitinib (1.5% Cream) | EXPERIMENTAL | Study drug will be administered twice daiily. |
| Ruxolitinib (0.75% cream) | EXPERIMENTAL | Study drug will be administered twice daily. |
| Double-Blind Period: Ruxolitinib cream 1.5% BID | EXPERIMENTAL | Participants applied ruxolitinib 1.5% cream twice daily (BID) for 24 weeks. |
| Double-Blind Period: Vehicle cream BID | PLACEBO_COMPARATOR | Participants applied matching vehicle cream BID for 24 weeks. |
| Treatment-Extension Period: Ruxolitinib cream 1.5% BID | EXPERIMENTAL | Participants who completed the Week 24 assessments with no safety concerns could continue into the 28-week Treatment-Extension Period. Participants who applied ruxolitinib cream 1.5% BID during the Double-Blind Period continued to apply ruxolitinib cream 1.5% BID for an additional 28 weeks in the Treatment-Extension Period. |
| Treatment-Extension Period: Vehicle cream to Ruxolitinib cream 1.5% BID | EXPERIMENTAL | Participants who completed the Week 24 assessments with no safety concerns could continue into the 28-week Treatment-Extension Period. Participants who applied vehicle cream BID during the Double-Blind Period applied ruxolitinib cream 1.5%m BID for 28 weeks in the Treatment-Extension Period. |
| Vehicle Control (VC) Period: Vehicle Cream BID | PLACEBO_COMPARATOR | Participants received ruxolitinib matching vehicle cream, applied topically to the affected areas as a thin film twice daily (BID) 8 hours apart from Day 1 up to Week 8. Participants applied cream BID to areas identified at Baseline even if the areas improved. |
| VC Period: Ruxolitinib 0.75% Cream BID | EXPERIMENTAL | Participants received ruxolitinib 0.75% cream, applied topically to the affected areas as a thin film BID 8 hours apart from Day 1 up to Week 8. Participants applied cream BID to areas identified at Baseline even if the areas improved. |
| Long-Term Safety (LTS) Period: Vehicle Cream to Ruxolitinib 0.75% Cream BID | EXPERIMENTAL | Participants who applied vehicle cream during the VC Period were randomized at Week 8 to apply ruxolitinib 0.75% cream, topically to the affected areas as a thin film BID as needed from Week 8 up to Week 52. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. |
| LTS Period: Vehicle Cream to Ruxolitinib 1.5% Cream BID | EXPERIMENTAL | Participants who applied vehicle cream during the VC Period were randomized at Week 8 to apply ruxolitinib 1.5% cream, topically to the affected areas as a thin film BID as needed from Week 8 up to Week 52. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. |
| LTS Period: Ruxolitinib 0.75% Cream BID | EXPERIMENTAL | Participants who applied ruxolitinib 0.75% cream during the VC Period, continued applying ruxolitinib 0.75% cream, topically to the affected areas as a thin film BID as needed from Week 8 up to Week 52. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. |
| LTS Period: Ruxolitinib 1.5% Cream BID | EXPERIMENTAL | Participants who applied ruxolitinib 1.5% cream during the VC Period, continued applying ruxolitinib 1.5% cream, topically to the affected areas as a thin film BID as needed from Week 8 up to Week 52. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. |
| LTS Period: Vehicle Cream to Ruxolitinib 0.75% Cream BID | EXPERIMENTAL | Participants who applied vehicle cream BID during the VC Period, were randomized to apply ruxolitinib 0.75% cream, topically to the affected areas as a thin film BID from Week 8 to 52 during the Long-term Safety (LTS) Period. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. |
| LTS Period: Ruxolitinib 0.75% Cream | EXPERIMENTAL | Arm description: Participants who applied ruxolitinib 0.75% cream during VC Period, continued applying ruxolitinib 0.75% cream topically to the affected areas as a thin film BID from Week 8 to 52 during the LTS Period. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. |
| LTS Period: Ruxolitinib 1.5% Cream | EXPERIMENTAL | Arm description: Participants who applied ruxolitinib 1.5% cream during VC Period, continued applying ruxolitinib 1.5% cream topically to the affected areas as a thin film BID from Week 8 to 52 during the LTS Period. Participants stopped treatment 3 days after lesions disappeared and restarted at the first sign of recurrence. |
| Best Available Therapy | ACTIVE_COMPARATOR | Best available therapy for the treatment period and extension period, with optional crossover to ruxolitinib after Cycle 6. |
| ruxolitinib and hydroxyurea (HU)-placebo | EXPERIMENTAL | - |
| HU and ruxolitinib-placebo | ACTIVE_COMPARATOR | - |
| ruxolitinib tablets | EXPERIMENTAL | Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg once a day (QD) to 25 mg BID based on safety and efficacy |
| Placebo | PLACEBO_COMPARATOR | Placebo tablets matching ruxolitinib were administered orally twice a day at a starting dose based on Baseline platelet count. Doses were titrated using the same guidelines as for active drug. Patients meeting certain protocol requirements detailed below were given the opportunity to cross over to ruxolitinib treatment. |
| Discoid lupus erythematosus | EXPERIMENTAL | Patients with discoid lupus erythematosus will be given ruxolitinib cream to be used twice daily for 12 weeks. |
| Patients with MPN | EXPERIMENTAL | Ruxolitinib and Enasidenib combination therapy |
| Cohort 1 (Feasibility) | EXPERIMENTAL | Patients will receive post-transplant cyclophosphamide 25 mg/kg on Days +3 and +4, tacrolimus, and ruxolitinib for GVHD prophylaxis. Ruxolitinib will be dosed as ruxolitinib IR 5 mg po qD (on fluconazole, 5 mg po BID not on fluconazole) starting Day -1 until Day +28 and neutrophil engraftment and then increase to ruxolitinib IR 5 mg po BID (on fluconazole,10 mg po BID not on fluconazole) for up to 12 months. Tacrolimus will be tapered after Day +90 per institutional guidelines. Patients will receive ruxolitinib up to Day 180 posttransplant. Ruxolitinib will be tapered over 2-3 months depending on the starting dose at time of taper. |
| Cohort 2 (dose expansion) | EXPERIMENTAL | Patients will receive post-transplant cyclophosphamide 25 mg/kg on Days +3 and +4, tacrolimus, and ruxolitinib for GVHD prophylaxis. Ruxolitinib will be dosed as ruxolitinib IR 5 mg po qD (on fluconazole, 5 mg po BID not on fluconazole) starting Day -1 until Day +28 and neutrophil engraftment and then increase to ruxolitinib IR 5 mg po BID (on fluconazole,10 mg po BID not on fluconazole) for up to 12 months. Tacrolimus will be tapered after Day +90 per institutional guidelines. Patients will receive ruxolitinib up to Day 365 post-transplant. Ruxolitinib will be tapered over 2-3 months depending on the starting dose at time of taper. |
| Treatment (ruxolitinib maintenance) | EXPERIMENTAL | Starting day +35 to day +120 post-SCT, patients receive ruxolitinib PO BID on days 1-30 of each cycle. Cycles repeat every 30 days for 1 year post-SCT, in the absence of disease progression or unacceptable toxicity. Patients undergo PET-CT scan and blood sample collection throughout the study. Patients may undergo bone marrow biopsy and/or tissue biopsy throughout the study, at time of progression. |
| Ruxolitinib plus Radiation and Temozolomide | EXPERIMENTAL | There will be two phases of drug administration: (1) Ruxolitinib and temozolomide will be administered "During Radiation Therapy" and (2) Maintenance phase after radiation therapy is complete. |
| Radiation and Temozolomide | ACTIVE_COMPARATOR | There will be two phases of drug administration: (1) Temozolomide will be administered "During Radiation Therapy" and (2) Maintenance phase after radiation therapy is complete. |
| Minnesota Standard Risk lower dose | EXPERIMENTAL | Patients receive lower dose ruxolitinib orally (PO) twice daily (BID) for 56 days then begin taper PO once daily (QD) for 1 week in the absence of disease progression or unacceptable toxicity |
| Minnesota Standard Risk higher dose | EXPERIMENTAL | Patients receive higher dose ruxolitinib PO BID for 56 days then begin taper PO BID for 1 week, followed by PO QD for 1 week in the absence of disease progression or unacceptable toxicity. |
| Minnesota High Risk | EXPERIMENTAL | Patients receive higher dose ruxolitinib PO BID for 56 days then begin taper PO BID for 1 week, followed by PO QD for 1 week in the absence of disease progression or unacceptable toxicity. Patients also receive systemic corticosteroid (methylprednisolone or similar) for a minimum of 3 days, then taper dose every 3-5 days in the absence of disease progression or unacceptable toxicity. |
| Experimental Intervention | EXPERIMENTAL | This study will be performed as one-arm with no comparator. |
| Treatment (ruxolitinib, dexamethasone, etoposide) | EXPERIMENTAL | During induction therapy, participants receive ruxolitinib orally (PO) twice daily (BID) plus de-intensified HLH-94 induction with dexamethasone PO or intravenously (IV) once daily (QD) or BID for 4 weeks and etoposide IV twice a week (BIW) for 2 weeks and then based on response, once a week (QW) for another 2 weeks in the absence of disease progression or unacceptable toxicity. After induction therapy, participants receive continuation therapy with ruxolitinib PO BID on days 1-28 of each cycle. Treatment repeats every 28 days for a total of up to 6 months after first administration of study drug in the absence of disease progression or unacceptable toxicity. |
| Vehicle | PLACEBO_COMPARATOR | Vehicle cream for 16 weeks followed by crossover to ruxolitinib cream 1.5% BID in a 16-week treatment extension period. |
| Ruxolitinib Cream | EXPERIMENTAL | Participants with non-segmental vitiligo with genital involvement will receive ruxolitinib 1.5% cream BID for up to 48 weeks |
| Double-blind Period: vehicle cream or Ruxolitinib cream 1.5% BID | EXPERIMENTAL | Participants will be treated with ruxolitinib cream 1.5% or vehicle cream twice a day (BID) in a double-blind fashion. |
| Open Label Extension: Ruxolitiib cream 1.5% | EXPERIMENTAL | Patients will be treated with Ruxoltinib cream 1.5% twice per day (BID) during the open label extension period. Participants who complete the double-blind period will continue into this open-label extension period for an additional 4 weeks of treatment. |
| Treatment Group : Ruxolitinib | EXPERIMENTAL | ruxolitinib cream 1.5% will be applied twice daily as a thin film. |
| Treatment (ruxolitinib) | EXPERIMENTAL | Patients receive ruxolitinib PO BID on days 1-28. Treatment repeats for up to 6 cycles (28 days each) in the absence of disease progression or unacceptable toxicity. |
| Paclitaxel (12weeks) | EXPERIMENTAL | Paclitaxel is administered weekly followed by standard Doxorubicin and Dyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively * 16 patients will be randomized from the Run-In 7 days of Ruxolitinib * The drug will be administered at a pre-determine dosage |
| Ruxolitinib with Paclitaxel (12weeks) | EXPERIMENTAL | Paclitaxel is administered with daily Ruxolitinib, followed by standard Doxorubicin and Cyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively * 16 patients will be randomized from the Run-In 7 days of Ruxolitinib * The drug will be administered at a pre-determine dosage |
| Ruxolitinib and Paclitaxel (12weeks) | EXPERIMENTAL | Paclitaxel is administered with daily Ruxolitinib, followed by standard Doxorubicin and Cyclophosphamide (AC) given every 2 weeks for 4 cycles preoperatively * 32 patients will be randomized from the Run-In 7 days of Ruxolitinib + Paclitaxel * The drug will be administered at a pre-determine dosage |
| Ruxolitinib in combination with corticosteroids | EXPERIMENTAL | Participants began oral administration of ruxolitinib at 5 mg twice daily (BID); if stable after the first 3 days of treatment, the dose could be increased to 10 mg BID. |
| Ruxolitinib plus background cancer therapy | EXPERIMENTAL | Study treatment for participants should be the same as the dosage from the parent study at the time the roll over protocol is initiated. Dose modifications are permitted. |
| Background cancer therapy alone | EXPERIMENTAL | Capecitabine and Regorafenib at the same dose provided in the parent study at the time of the rollover. |
| Ruxolitinib in combination with chemotherapy | EXPERIMENTAL | - |
| Capecitabine and ruxolitinib | EXPERIMENTAL | - |
| Capecitabine and placebo | PLACEBO_COMPARATOR | - |
| Ruxolitinib 5 mg | EXPERIMENTAL | Participants began administration with 5 mg ruxolitinib twice daily (BID) orally. Beginning at the Week 4 visit, doses of ruxolitinib could be increased in 5 mg once a day (QD) increments every 4 weeks every 4 weeks not to exceed a dose of 25 mg BID. |
| Ruxolitinib 25 mg SR/10, 15, or 20 mg IR | EXPERIMENTAL | Participants began administration with 25 mg ruxolitinib sustained release (SR) once daily (QD). After 8 weeks, if there was inadequate efficacy, the dose level could be titrated to 50 mg SR QD or 25 mg SR every other day (QOD) alternating with 50 mg SR QOD. At Week 16, participants transitioned to ruxolitinib 10, 15, or 20 mg immediate release (IR) orally twice daily. Participants who continued to demonstrate benefit in the opinion of the investigator could remain on ruxolitinib IR until the last participant completed Week 36 or the commercial availability of ruxolitinib IR, whichever was earlier; the dose received was based on platelet counts at the time of transition. |
| Ruxolitinib Phosphate 0.5% Cream | EXPERIMENTAL | Ruxolitinib phosphate 0.5% cream, applied topically, once daily from Day 1 to Week 12. |
| Ruxolitinib Phosphate 1.0% Cream | EXPERIMENTAL | Ruxolitinib phosphate 1.0% cream, applied topically, once daily from Day 1 to Week 12. |
| Ruxolitinib Phosphate 1.5% Cream | EXPERIMENTAL | Ruxolitinib phosphate 1.5% cream, applied topically, once daily from Day 1 to Week 12. |
| Ruxolitinib then Ruxolitinib + Dexamethasone | EXPERIMENTAL | Patients received ruxolitinib 25 mg orally twice daily (bid) in each treatment cycle of 28 days. For those patients who had disease progression at any time or stable disease for 3 cycles and did not meet a withdrawal criterion, or withdrew consent, then 40 mg of dexamethasone was added to ruxolitinib on Days 1 to 4, 9 to 12, and 17 to 20 of four 28-day cycles. After the 4th cycle, 40 mg of dexamethasone was administered only on Days 1 to 4 of each subsequent cycle. Patients could continue to receive monotherapy or combination therapy indefinitely as long as no withdrawal criterion was met, did not have progressive disease and were receiving some clinical benefit. |
| Group A | EXPERIMENTAL | Patients with active stable plaque psoriasis treated with topical cream application on lesions involving a small percent BSA. |
| Group B | EXPERIMENTAL | Patients with active stable plaque psoriasis treated with topical cream application on lesions involving a larger percent BSA than Cohort 1. |
| Group C | EXPERIMENTAL | Patients with active stable plaque psoriasis treated with topical cream application on lesions involving a larger percent BSA than Cohort 2. |
| Cohort A: INCB018424 Ruxolitinib 0.5% | EXPERIMENTAL | INCB018424 Ruxolitinib 0.5% vs vehicle applied once daily for 28 days |
| Cohort B: INCB018424 Ruxolitinib 1.0% | EXPERIMENTAL | INCB018424 Ruxolitinib 1.0% vs vehicle applied once daily for 28 days |
| Cohort C: INCB018424 Ruxolitinib 1.5% | EXPERIMENTAL | INCB018424 Ruxolitinib 1.5% vs vehicle applied twice for 28 days |
| Cohort D: 18424 Ruxolitinib vs Dovonex® calcipotriene | EXPERIMENTAL | INCB018424 up to 1.5% versus Dovonex® calcipotriene 0.005% cream applied BID for 28 days |
| Cohort E: 18424 Ruxolitinib vs Diprolene® AF betamethasone diproprionate | EXPERIMENTAL | INCB018424 up to 1.5% versus Diprolene ® AF betamethasone dipropionate 0.05% cream applied twice a day for 28 days |
| All Participants | EXPERIMENTAL | You are being asked to apply topical medication called Ruxolitinib cream to your skin at home twice daily. |
| Phase I | EXPERIMENTAL | Cohort 1) 5mg ruxolitinib, Cohort 2) 10mg ruxolitinib, Cohort 3) 15mg ruxolitinib |
| Phase II | OTHER | Cohort A) non-responders to Phase I regimen, Cohort B) responders to Phase I regimen |
| Ruxolitinib/Trastuzumab | EXPERIMENTAL | Jakafi (Ruxolitinib) and Trastuzumab (Herceptin) - 21 day cycle until disease progression |
| Phase I Dose Level 0: Paclitaxel + Ruxolitiniib 10 mg | EXPERIMENTAL | Paclitaxel 80 mg/m2 IV weekly + Ruxolitinib 10 mg orally twice daily for 4 cycles 1 cycle = 21 days Participants with stable disease or better will have the opportunity to continue on single agent 10 mg Ruxolitinib until disease progression, unacceptable toxicity or patient withdrawal. |
| Phase I Dose Level 1: Paclitaxel + Ruxolitiniib 15 mg | EXPERIMENTAL | Paclitaxel 80 mg/m2 IV weekly + Ruxolitinib 15 mg orally twice daily for 4 cycles 1 cycle = 21 days Participants with stable disease or better will have the opportunity to continue on single agent 15 mg Ruxolitinib until disease progression, unacceptable toxicity or patient withdrawal. |
| Phase I Dose Level 2: Paclitaxel + Ruxolitiniib 20 mg | EXPERIMENTAL | Paclitaxel 80 mg/m2 IV weekly + Ruxolitinib 20 mg orally twice daily for 4 cycles 1 cycle = 21 days Participants with stable disease or better will have the opportunity to continue on single agent 20 mg Ruxolitinib until disease progression, unacceptable toxicity or patient withdrawal. |
| Phase I Dose Level 3: Paclitaxel + Ruxolitiniib 25 mg | EXPERIMENTAL | Paclitaxel 80 mg/m2 IV weekly + Ruxolitinib 25 mg orally twice daily for 4 cycles 1 cycle = 21 days Participants with stable disease or better will have the opportunity to continue on single agent 20 mg Ruxolitinib until disease progression, unacceptable toxicity or patient withdrawal. |
| Myeloproliferative neoplasms | EXPERIMENTAL | In phase I, increasing doses of ruxolitinib in combination with decitabine at a dose of 20 mg/m2 daily intravenously over 5 days. An initial dose of ruxolitinib of 10 mg orally twice daily is anticipated with planned, dose escalations of 15 mg orally twice daily, 25 mg orally twice daily and 50 mg orally twice daily. The dose can also be de-escalated to 5mg orally twice daily if dose limiting toxicities (DLTs) are observed at the initial 10mg dose. Patients will receive ruxolitinib as a single agent for the first 7 days followed by the administration of decitabine on day 8 for a total of 5 consecutive days. Patients will continue ruxolitinib at the assigned dose through the first cycle and may reduce the dose for specified toxicity beginning with the second cycle. Patients in Phase II will start at the recommended phase II dose (RPTD) of ruxolitinib in combination with decitabine at a dose of 20 mg/m2 daily intravenously over 5 days. |
| ruxolitinib plus retifanlimab | EXPERIMENTAL | Combination of the Janus kinase 1/2 inhibitor ruxolitinib plus the programmed cell death protein-1 blocker retifanlimab. The study utilizes a standard 3+3 dose escalation design evaluating 2 dose escalation levels (15 mg and 20 mg orally twice daily) and 2 dose de-escalation levels (10 mg and 5 mg orally twice daily, if necessary) of ruxolitinib with fixed dose retifanlimab (500 mg intravenously every 4 weeks), followed by an expansion cohort at the recommended phase 2 dose. |
| Regimen 1: Ruxolitinib | EXPERIMENTAL | -Ruxolitinib at 5 mg twice per day (BID) beginning on Day -3 and continuing until Day 180 followed by a taper (duration of taper depends on dose of ruxolitinib at Day 180). Once a patient's counts have reached ANC ≥ 1.5 K/cumm, hemoglobin ≥ 9.0 g/dL, and platelets ≥ 50 K/cumm, ruxolitinib dosing will escalate to 10 mg BID. |
| Regimen 2: Ruxolitinib + Abatacept | EXPERIMENTAL | * Ruxolitinib at 5 mg twice per day (BID) beginning on Day -3 and continuing until Day 180 followed by a taper (duration of taper depends on dose of ruxolitinib at Day 180). Once a patient's counts have reached ANC ≥ 1.5 K/cumm, hemoglobin ≥ 9.0 g/dL, and platelets ≥ 50 K/cumm, ruxolitinib dosing will escalate to 10 mg BID. * In addition, patients will receive abatacept 10 mg/kg IV over 30 minutes on days +5, +14, +28, and +56. |
| Arm 1 (ruxolitinib, venetoclax) | EXPERIMENTAL | Patients receive ruxolitinib PO BID and venetoclax PO QD on days 1-28 of each cycle. Cycles repeat every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients may receive additional cycles of ruxolitinib and venetoclax at the discretion of the sponsor-investigator. Patients also undergo a skin punch biopsy and ECHO at screening and blood sample collection and bone marrow aspiration and biopsy throughout the study. (COMPLETE 04/04/2025) |
| Arm 2 (ruxolitinib,venetoclax, azacitidine) | EXPERIMENTAL | Patients receive ruxolitinib PO BID, venetoclax PO QD, and azacitidine IV or SC on days 1-7 of each cycle. Cycles repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo ECHO at screening and blood sample collection and bone marrow aspiration and biopsy throughout the study. |
| Phase I:Ruxolitinib and Nivolumab | EXPERIMENTAL | Participants will receive ruxolitinib at their assigned dose taken orally twice daily on a 28-day cycle combined with nivolumab 480 mg IV administered every 4 weeks (i.e. on Day 1 of a 28-day cycle) until disease progression, unacceptable toxicity, or for a maximum of 2 years. |
| Phase II: Ruxolitinib and Nivolumab | EXPERIMENTAL | Participants will receive ruxolitinib at 20mg orally twice daily on a 28-day cycle combined with nivolumab 480 mg IV administered every 4 weeks (i.e. on Day 1 of a 28-day cycle) until disease progression, unacceptable toxicity, or for a maximum of 2 years. |
| Cohort 1 | EXPERIMENTAL | Ruxolitinib phosphate cream 0.5%. |
| Cohort 2 | EXPERIMENTAL | Ruxolitinib phosphate cream 1.5%. |
| Cohort 3 | EXPERIMENTAL | Ruxolitinib phosphate cream 0.75%. |
| Cohort 4 | EXPERIMENTAL | Ruxolitinib phosphate cream 1.5%. |
| Cohort 5 | EXPERIMENTAL | Ruxolitinib phosphate cream 0.75%. |
| Cohort 6 | EXPERIMENTAL | Ruxolitinib phosphate cream 1.5%. |
| Rux Len and Steroid | EXPERIMENTAL | Ruxolitinib Oral Tablet \[Jakafi\] at 5mg, 10mg or 15mg BID, Lenalidomide Oral at 5mg or 10mg QD and Methylprednisolone Oral at 40mg QOD. (Dose varies during dose escalation portion of the study) |
| Rux and Steroid until progression, then add Len | EXPERIMENTAL | Subject will receive Ruxolitinib Oral Tablet \[Jakafi\] at 15mg BID, and Methylprednisolone at 40mg QOD until disease progression. Lenalidomide at 10mg QD will be added to the treatment (Ruxolitinib, Methylprednisolone) once disease progression was confirmed. |
| Expanded Eligibility Criteria | EXPERIMENTAL | Subject will receive Ruxolitinib Oral Tablet \[Jakafi\] at 15mg BID, Lenalidomide at 10mg QD, and Methylprednisolone at 40mg QOD until disease progression. |
| High-dose Ruxolitinib | EXPERIMENTAL | Subject will receive Ruxolitinib Oral Tablet \[Jakafi\] at 20mg BID and Methylprednisolone at 40mg QOD until disease progression. |
| Stratum -1 | EXPERIMENTAL | Participants with baseline Platelet counts of 75-99 x10\^9/L |
| Stratum -2 | EXPERIMENTAL | Participants with baseline Platelet counts of 50-74 x10\^9/L |
| Rux + Steroid | EXPERIMENTAL | Subject will receive Ruxolitinib Oral Tablet \[Jakafi\] at 15mg BID, and Methylprednisolone at 40mg QOD until disease progression. Lenalidomide at 10mg QD will be added to the treatment (Ruxolitinib, Methylprednisolone) once disease progression was confirmed. |
| Rux + Steroid + Len | EXPERIMENTAL | Ruxolitinib Oral Tablet \[Jakafi\] at 5mg, 10mg or 15mg BID, Lenalidomide Oral at 5mg or 10mg QD and Methylprednisolone Oral at 40mg QOD. (Dose varies during dose escalation portion of the study) |
| Name | Type | Description |
|---|---|---|
| Ruxolitinib Cream | DRUG | Ruxolitinib cream applied topically to the affected area as a thin film twice daily. |
| Vehicle Cream | DRUG | Matching vehicle cream applied topically to the affected area as a thin film twice daily. |
| Ruxolitinib | DRUG | The study cream will be applied topically as defined in the protocol for each period. |
| Tacrolimus (Tac) | DRUG | Tablet or intravenously (IV) |
| Methotrexate (MTX) | DRUG | Intravenously (IV) |
| Ruxolitinib (Rux) | DRUG | Tablet |
| Cyclophosphamide | DRUG | Intravenously (IV) |
| Mycophenolate mofetil (MMF) | DRUG | Tablet or intravenously (IV) |
| Vehicle | DRUG | Vehicle cream is a topical formulation applied as a thin film to affected areas. |
| Extracorporeal photopheresis (ECP) | DRUG | Best available therapy (BAT) will be selected by the investigator for each participant. BAT may not include experimental agents (ie, those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements. The BAT in this study will be among the following treatments currently used in this setting (no other types or combinations of BATs are permitted in this study). |
| Low-dose methotrexate (MTX) | DRUG | Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. |
| mechanistic Target of Rapamycin (mTOR) inhibitors (everolimus or sirolimus) | DRUG | Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. |
| Infliximab | DRUG | Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. |
| Rituximab | DRUG | Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. |
| Pentostatin | DRUG | Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. |
| Imatinib | DRUG | Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. |
| Ibrutinib | DRUG | Patients will receive BAT based on the Investigator's opinion, taking into account the manufacturer's instructions, labeling, subject's medical condition, and institutional guidelines for any dose adjustment. |
| Hydroxyurea (HU) | DRUG | Hydroxyurea (500 mg capsules) will be orally self-administered at the dose that the subject was receiving previously. The dose may be increased after 4 weeks and again after 8 weeks of therapy to optimize efficacy for subjects meeting prespecified criteria. |
| HU-placebo | DRUG | All placebo will be self-administered, and dosing will be the same as with the blinded dose. When adjustments are made to the ruxolitinib dose, the dose of HU-placebo will be adjusted concurrently. |
| Ruxolitinib-placebo | DRUG | All placebo will be self-administered, and dosing will be the same as with the blinded dose. When adjustments are made to the HU dose, the dose of ruxolitinib-placebo will be adjusted concurrently. |
| ruxolitinib tablets | DRUG | Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy |
| Best Available Therapy (BAT) | OTHER | Best Available Therapy (BAT) will be selected by the Investigator for each participant. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs in accordance with the protocol-defined requirements. |
| Placebo | DRUG | Matching placebo tablets were administered as oral doses in the same manner as active drug. |
| Enasidenib | DRUG | 50mg -100mg daily |
| Placebo (for Ruxolitinib) | DRUG | tablet (taken by mouth) |
| Myeloablative conditioning regimen | DRUG | Patients will receive a full-intensity myeloablative conditioning regimen. Allowed regimens include: * Flu/Bu(130 mg/m2/day x 4 days) * Flu/TBI (8-12Gy) * Flu/Bu/Thiotepa The addition of alemtuzumab or ATG is not allowed. |
| Hematopoietic Stem Cell Transplantation | PROCEDURE | Patients will undergo HCT |
| Tacrolimus | DRUG | Given PO |
| Positron emission tomography-computed tomography | PROCEDURE | Undergo PET-CT Scan |
| Bone Marrow Biopsy | PROCEDURE | Undergo bone marrow biopsy |
| Biopsy Procedure | PROCEDURE | Undergo tissue biopsy |
| Biospecimen Collection | PROCEDURE | Undergo blood sample collection |
| Pembrolizumab | DRUG | Pembrolizumab immunotherapy will be administered intravenously at 200 mg once every 21 days. Subjects will receive pembrolizumab for as long as the disease responds, up to a maximum of one year (or 17 cycles). Each cycle is 21 days long. |
| Temozolomide | DRUG | "During Radiation Therapy" phase: 75 mg/m\^2 will be self-administered PO once every day, starting on Day 1, for 6 weeks. Then there will be a 4-week break after radiotherapy is complete. "Maintenance" phase: Occurs thirty days (4 weeks) after receiving the last dose of radiotherapy. Temozolomide 150-200 mg/m\^2 will be self-administered PO BID, starting on Day 1 to Day 5 of each cycle for six cycles. Either phase: The dose may be reduced in the case of certain adverse events. |
| Radiation Therapy | RADIATION | Radiation will be administered every weekday (Monday to Friday) in 2 Gy fractions for 30 fractions during a 6-week period (60 Gy total). |
| Methylprednisolone | DRUG | Starting dose 2 mg/kg/d for at least three days, then taper Given IV or orally |
| Ruxolitinib Topical Cream | DRUG | Ruxolitinib cream will be applied topically twice daily on up to 20% of the body surface over 12 weeks in patients with lichenoid skin toxicity under anti PD1 treatment. |
| Etoposide | DRUG | Administered IV |
| Dexamethasone | DRUG | Administered PO or IV |
| Non-interventional Imaging | PROCEDURE | Participants undergo abdominal ultrasound and/or magnetic resonance imaging (MRI) |
| Research Biopsy | PROCEDURE | Bone marrow biopsy and lymph node biopsy will be obtained during screening and as clinically indicated throughout the trial. |
| Paclitaxel | DRUG | 80 mg/m2, IV (in the vein) weekly for 12 weeks. |
| Doxorubicin | DRUG | 60 mg/m2, IV (in the vein) every 14 days for 4 doses. |
| Prednisone or methylprednisolone | DRUG | Either oral prednisone or IV methylprednisolone may be used to begin corticosteroid treatment at the investigator's discretion. |
| Capecitabine | DRUG | Capecitabine at the same dose provided in the parent study at the time of the rollover. |
| Regorafenib | DRUG | Regorafenib at the same dose provided in the parent study at the time of the rollover. |
| Asparaginase Erwinia Chrysanthemi | DRUG | - |
| Cytarabine | DRUG | - |
| Leucovorin Calcium | DRUG | - |
| Mercaptopurine | DRUG | - |
| Methotrexate | DRUG | - |
| Pegaspargase | DRUG | - |
| Prednisone | DRUG | - |
| Thioguanine | DRUG | - |
| Vincristine Sulfate | DRUG | - |
| Placebo Cream | OTHER | Cream with no active drug |
| Ruxolitinib Phosphate | DRUG | Ruxolitinib phosphate cream |
| Ruxolitinib 25 mg | DRUG | Ruxolitinib was supplied as 5 and 25 mg tablets. |
| Dexamethasone 40 mg | DRUG | Dexamethasone was obtained commercially by Investigators in tablet strengths of 20 or 40 mg. |
| Ruxolitinib phosphate cream | DRUG | Ruxolitinib phosphate cream 0.5% |
| Dovonex® calcipotriene 0.005% | DRUG | Cream applied once or twice daily for up to 56 days. |
| Diprolene® AF betamethasone dipropionate 0.05% cream. | DRUG | Cream applied once or twice daily for up to 56 days |
| Carfilzomib | DRUG | Irreversible proteasome inhibitor |
| Trastuzumab | DRUG | 6 mg/kg every 3 weeks (cycle = 21 days). If no trastuzumab \> 28 days, patients will be initially re-loaded at 8 mg/kg, then 6 mg/kg. |
| Decitabine | DRUG | Decitabine is administered intravenously at a dose of 20 mg/m2 daily for 5 days. Subsequent cycles of decitabine may be administered at 4 week intervals as clinically tolerated. Decitabine treatment may be deferred for up to 2 weeks to allow recovery from non-hematologic toxicity during the first 6 cycles and up to 2 weeks thereafter for hematologic toxicities as well. The first treatment cycle will last 35 days and will be the evaluable period for DLTs and RPTD determination for patients enrolled in the phase I portion only. Subsequent treatment cycles will be 4-6 weeks in duration as defined by decitabine administration. |
| Retifanlimab | DRUG | Programmed cell death protein-1 blocker |
| Abatacept | DRUG | Abatacept is commercially available. |
| Azacitidine | DRUG | Given IV or SC |
| Bone Marrow Aspiration | PROCEDURE | Undergo bone marrow aspiration and biopsy |
| Echocardiography Test | PROCEDURE | Undergo ECHO |
| Punch Biopsy | PROCEDURE | Undergo skin punch biopsy |
| Questionnaire Administration | OTHER | Ancillary studies |
| Venetoclax | DRUG | Given PO |
| Vincristine | DRUG | Remission consolidation regimen: * 1.5 mg/m2 (maximum 2 mg) IV once per week on Days 15, 22, 43, and 50 Interim maintenance regimen: * 1.5 mg/m2 (maximum 2 mg) IV on Days 1, 11, 21, 31, and 41 Delayed Intensification regimen: * 1.5 mg/m2 (maximum 2 mg) IV on Days 1, 8, 15, 43, and 50 Maintenance Therapy: * 1.5 mg/m2 (maximum 2 mg) IV on Days 1, 29, and 57 |
| Methotrexate (Intrathecal Administration) | DRUG | Drug is given through a needle which is inserted in one of the spaces between the bones in the lower back (intrathecal \[IT\] administration). Remission consolidation regimen: * 15 mg on Days 1, 8, 15, and 22 Interim maintenance regimen: * 15 mg on Days 1 and 31 Delayed Intensification regimen: * 15 mg on Days 1, 29, and 36 Maintenance Therapy: * 15 mg on Day 1 * 15 mg on Day 29 (First 4 courses only) |
| Methotrexate (Intravenous Administration) | DRUG | Interim maintenance regimen: * 100 mg/m2 IV on Days 1, 11, 21, 31, and 41 |
| Methotrexate Oral Product | DRUG | Taken by mouth. Maintenance Therapy: * 20 mg/m2 weekly (on Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78) * Not given on Day 29 of first 4 courses (on days when IT Methotrexate is given\] |
| Nivolumab | DRUG | Nivolumab 480 mg IV every 4 weeks (Day 1) Until disease progression, unacceptable toxicity, patient refusal or a maximum of 2 years |
| Ruxolitinib Oral Tablet [Jakafi] | DRUG | Ruxolitinib will be administered on days 1-28 of the treatment cycle. |
| Lenalidomide | DRUG | Lenalidomide will be administered on Days 1-21 of the treatment cycle. |
Inclusion Criteria: * Aged 6 to \< 12 years at the time of signing the ICF. * Clinical diagnosis of nonsegmental vitiligo with depigmented area including ≥ 0.5% BSA on the face, ≥ 0.5 F-VASI, ≥ 3% BSA on nonfacial areas, ≥ 3 T-VASI. * Total body vitiligo area does not exceed 10% BSA. * Pigmented ha...
| Company | Ticker | Trials | Lead Phase | Drugs |
|---|---|---|---|---|
| Protagonist Therapeutics, Inc. | PTGX | 2 | PHASE3 | Rusfertide |
| Merck & Co., Inc. | MRK | 1 | PHASE3 | Bomedemstat |
| Disc Medicine, Inc. | IRON | 1 | PHASE2 | DISC-3405 |
| Prelude Therapeutics, Inc. | PRLD | 1 | PHASE1 | PRT12396 |
| Novartis AG Sponsored ADR | NVS | 1 | - | Undisclosed |