Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Ibrutinib · 30 trials · 38 indications
Time from randomization to the first occurrence of progression or relapse (determined using standard iwCLL guidelines), or death from any cause, whichever occurs first
per the RECIL criteria
TLS events are defined as follows: * Clinical TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) with the following exceptions: * For the purpose of TLS assessment during the Safety Run-in Period, only those increases in serum creatinine \> 1.0 mg/dL from pre-treatment baseline will be considered clinical TLS. * In participants with renal dysfunction at baseline (CrCl \< 60 mL/min), clinical TLS is defined as the presence of laboratory TLS plus either seizures, cardiac dysrhythmia, or death. * Laboratory TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) for laboratory TLS, that does not resolve within 72 hours despite protocol required management.
DLT: any Grade (Gr) 3 or higher non-TLS adverse event (AE) at least possibly related to study drug occurring during the DLT assessment period with the following clarifications: Non-Hematologic DLTs: Gr ≥3 nausea, vomiting or diarrhea uncontrolled despite maximum medical supportive care and persisting \>5 days; Gr 3 fatigue persisting \>7 days; Gr 3 infection is not a DLT, however an infection with lifethreatening consequences or requiring urgent intervention (Gr 4) was considered a DLT; Treatment delay of any study drug \>7 days for toxicity. Hematologic DLTs: Gr 3 neutropenia is not a DLT, however, Gr 4 neutropenia (ANC \<500/mm\^3) lasting for \> 7 days is a DLT; Gr 3 or 4 neutropenia complicated by fever ≥38.5°C or infection; Gr 4 thrombocytopenia (\<25,000/mm\^3) that persists for \> 7 days; Gr 3 or 4 thrombocytopenia associated with Gr 2 or greater bleeding; Gr 3 anemia is not a DLT, however, Gr 4 anemia is a DLT; Treatment delay of any study drug \>7 days for hematologic toxicity.
AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug. Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).
PFS is defined as the time from the date of randomization to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.
CR rate is defined as the percentage of participants with a CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
Response rate was defined as the percentage of participants who were responders. Responders were defined as participants who had a complete response (CR) or a partial response (PR) at 48 weeks without starting any subsequent therapy for cGVHD or having evidence of relapse of their underlying disease that was indication for transplant prior to response assessment at 48 weeks. Response was defined using the National Institutes of Health (NIH) Consensus Panel Chronic GVHD Activity Assessment (2014). Skin, mouth, liver, upper and lower gastrointestinal, esophagus, lung, eye, and joint/fascia are the organs or sites considered in evaluating overall response. CR is defined as resolution of all manifestations in each organ or site. PR is defined as improvement in at least 1 organ or site without progression in any other organ or site.
PFS is the time from the date of randomization to the date of the first documented evidence of disease progression (based on the Revised Response Criteria for Malignant Lymphoma \[Cheson 2014, Lugano Classification\]) or death from any cause, whichever occurs first. Participants who initiated subsequent anticancer therapy or missed two or more consecutive overall disease assessments were censored as described in the SAP. Estimated by Kaplan-Meier method.
PFS is defined as the time from the date of randomization until disease progression per RECIST 1.1 criteria assessed by investigator, or death from any cause, whichever occurs first.
OS, is defined as the time from date of randomization until date of death from any cause.
PFS was defined as time from the date randomization to the date of first IRC-confirmed disease progression (PD) or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. The primary analysis was performed after observing 94 PFS events as pre-specified in the study protocol. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 30 months (that is, the estimated percentage of participants with progression-free survival at Month 30) are presented.
PFS was defined as time from the date randomization to the date of first investigator-confirmed PD or date of death due to any cause, whichever occurred first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. Assessment of PD was conducted in accordance with the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria (Halleck et al) with the modification that treatment-related lymphocytosis in the absence of other signs or symptoms of disease progression was not considered progressive disease. As the median PFS was not reached in the experimental (IBR+OB) arm at the time of the analysis, Kaplan Meier landmark estimates of the PFS rate at 48 months (that is, the estimated percentage of participants with progression-free survival at Month 48) are presented.
PFS was defined as the time from date randomization to date of first IRC-confirmed disease progression (PD) assessed according to the modified VIth International Workshop on Waldenström's Macroglobulinemia (IWWM) criteria (National Comprehensive Cancer Network \[NCCN\] 2014) or death due to any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. As the median PFS was not reached in the Ibrutinib + Rituximab arm at the time of the analysis, Kaplan Meier landmark estimate of the PFS rate at 54 months (that is, the estimated percentage of participants with PFS at Month 54) is presented.
PFS is defined as the time from the date of randomization to the date of disease progression determined by the investigator or date of death from any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to disease progression (PD) or death. Estimated by Kaplan-Meier method.
The primary objective of this study was to evaluate the efficacy of Ibrutinib compared with Chlorambucil based on the independent review committee (IRC) assessment of PFS Progressive disease according to 2008 IWCLL guidelines was defined as: * Group A * Lymphadenopathy, increase ≥50% * Hepatomegaly, increase ≥50% * Splenomegaly, increase ≥50% * Blood lymphocytes, increase ≥ 50% over baseline * Group B * Platelets counts, decrease of ≥ 50% from baseline secondary to CLL * Hemoglobin, decrease of \> 2 g/dL from baseline secondary to CLL
Complete response rate (CRR), defined as the percentage of participants achieving a best overall response of complete response (CR) per the Revised Criteria for Response Assessment for Malignant Lymphoma following the Lugano classification (Cheson 2014), assessed by an Independent Review Committee (IRC).
Proportion of patients with VGPR to therapy within 24 cycles of therapy initiation. (VGPR is \>90% reduction in serum IgM from baseline)
Respiratory failure is defined as a clinical diagnosis of respiratory failure and initiation of one of the following therapies: endotracheal intubation and mechanical ventilation; OR extracorporeal membrane oxygenation; OR high-flow nasal cannula oxygen delivery (i.e., reinforced nasal cannula delivering heated, humidified oxygen with fraction of delivered oxygen ≥ 0.5 and flow rates of ≥ 30 L/min); OR non-invasive positive pressure ventilation; OR clinical diagnosis of respiratory failure with initiation of none of these measures only when clinical decision-making is driven solely by resource limitation.
DFS is defined as time from randomization date to MRD-positive relapse, or disease progression per investigator assessment (per 2008 International Workshop for Chronic Lymphocytic Leukemia \[IWCLL\] criteria \[Halleck et al\]) or death from any cause, whichever occurred first. 1-year DFS estimated using Kaplan-Meier method at 12 months landmark time.
CR/CRi rate is defined as the percentage of participants achieving a best overall response of complete response (CR), CR with incomplete blood count recovery (CRi) per 2008 IWCLL criteria (halleck et al.) on or prior to initiation of subsequent antineoplastic therapy or, if applicable, reintroduction of study treatment, whichever occurred earlier.
The primary efficacy endpoint of this study is mPFS. Progression free survival is defined as the time from the date of first dose of study treatment to confirmed disease progression or death from any cause, whichever occurs first.
To assess the number of participants who achieve an MRD negative complete response at the 2 months post last dose of FCR timepoint by 2008 IW-CLL criteria ( Hallek et. al). Participants will have a bone marrow biopsy procedure 2 months after completing combination therapy (Ibrutinib+ FCR) in tandem with a chest, neck, abdomen and pelvic PET CT scan. A central read of the PET CT scan will confirm a radiographic complete response, and the bone marrow pathology and morphology assessments will confirm morphological CR in the bone marrow, while MRD testing will be done by four-color flow cytometry on the bone marrow aspirate with a detection level of 10-4.
Number of subjects achieving the best overall responses of CR or PR prior to the initiation of the next line of antineoplastic therapy as assessed by investigator per the Cheson et al, 2007 criteria. Target lesions are measured by CT, unless MRI is used as the assessment modality for lesions in anatomical locations not amenable to CT. CR is defined as the disappearance of all evidence of disease. PR is defined as \>=50% decrease in the sum of the product of the diameters of up to 6 largest dominant masses.
ORR is defined as the proportion of subjects who achieved complete response (CR), partial response (PR). Response criteria are as outlined in the International Working Group Criteria for NHL, Cheson (2007), with disease assessments performed by an independent review committee (IRC). Per Cheson: CR is defined as disappearance of all evidence of disease. PR is defined as regression of measurable disease and no new sites.
The primary objective of this study is to evaluate the efficacy of ibrutinib in terms of ORR according to an Independent Review Committee (IRC). ORR based upon IRC assessment is the proportion of responders in the all treated population. Responders were subjects who achieved partial response (PR) or better, ie, complete response (CR), complete response with incomplete marrow recovery (CRi), nodule partial response (nPR) or PR, per IWCLL 2008 criteria with the clarification for treatment-related lymphocytosis.
The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator.
The maximum tolerated dose of Ibrutinib and Venetoclax as determined by number of DLTs observed. • If 0/3 DLT is observed, dose escalation will continue to the next upper dose level. • If ≥ 2/3 DLTs are observed, then the dose finding procedure will be terminated. • If 1/3 DLT is observed, then 3 additional patients will be enrolled in the same dose level. If no DLT is observed from the additional 3 patients, then dose escalation will continue to the next upper dose level. If any DLT is observed from the 3 additional patients, then the previously lower dose will be chosen as the MTD and the dose finding procedure will be terminated.
Number of participants on the recommended phase II dose level 2, with a partial or complete response, as determined by the revised Lugano Response Criteria for Non-Hodgkin Lymphoma,
Highest dose of ibrutinib from Phase 1 (420, 560, or 840 mg by mouth daily) that had fewer than two dose-limiting toxicities in its respective cohort
To define the clinical benefit rate (CBR = CR \[complete response\] + PR \[partial response\] + SD \[stable disease\] \> 6 months) of ibrutinib plus trastuzumab in patients with HER2-amplified, T-DM1-pretreated MBC
A DLT was defined as any Grade 3 (severe) or higher non-hematologic or Grade 4 (life-threatening) hematologic adverse event (AE) occurring during the DLT observation period that was considered to be at least possibly related to the study treatment (ibrutinib or drug combination).
PFS is defined as the time from the date of first dose of study treatment to the date of first documentation of progressive disease (PD) or date of death from any cause, whichever occurs first, regardless of the use of subsequent anti-cancer treatment. PD was defined in accordance with Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1. PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), and an absolute increase of ≥ 5 mm, or unequivocal progression of existing non-target lesions or the appearance of new lesions.
ORR is defined as the percentage of participants who have a best response of partial response (PR) or complete response (CR) to therapy in accordance with RECIST 1.1 criteria. CR: The disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Normalization of tumor marker level, if relevant. All lymph nodes must be non-pathological in size (\< 10 mm short axis). PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
The response criteria is measured based on the revised criteria for malignant lymphoma described by the International Working Group for NHL (Cheson 2014).
Number of participants with dose-limiting toxicities as a measure of safety profile to determine recommended dose of ibrutinib
Overall Response Rate is defined as the proportion of subjects who achieved complete response (CR) or partial response (PR). Response criteria are based on NIH cGVHD Response assessment (Pavletic 2006; Measurement of Therapeutic Response, ASBMT Web site).
Part-1: To determine the maximum tolerated dose (MTD) of the combination of ibrutinib and lenalidomide with dose adjusted EPOCH-R
Part 2 - Overall Response rate will be defined as the proportion of subjects who achieve either a Complete Response or a Partial Response according to the international Working Group Response Criteria for NHL as assessed by investigator.
The dose levels of lenalidomide were explored, and dose escalation of lenalidomide followed the 3+3+3 dose escalation schema. A Dose Level Review Committee evaluated safety data following completion of each dose observation period of the Phase 1b portion.
An adverse event (AE) is any untoward medical occurrence, which does not necessarily have a causal relationship with treatment. A serious AE is any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalization \> 24 hours or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an important medical event. AEs that started or worsened during the treatment-emergent period and all possibly related or related AEs were considered TEAEs. Related events were those that were considered possibly related or related to study drug per investigator's judgment. Events were graded per the national Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.03: Grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life-threatening; grade 5=death.
The ORR was defined as the percentage of participants who achieve either a partial response (PR) or complete response (CR), according to the Revised International Working Group Response Criteria for Malignant Lymphoma or Lugano Classification (Cheson 2014), as assessed by the investigator in response-evaluable population. The 95% confidence interval (CI) was calculated using the exact method.
-To evaluate the overall response (ORR) of ibrutinib in combination with carfilzomib and dexamethasone.
| Arm | Type | Description |
|---|---|---|
| I (Ibrutinib) | EXPERIMENTAL | Ibrutinib p.o. will be administered until occurrence of unacceptable toxicity, progression of CLL or end of trial, whichever occurs first. |
| VG (Obinutuzumab + Venetoclax) | EXPERIMENTAL | 12 cycles (q 28d): Obinutuzumab i.v. + Venetoclax p.o. will be administered for 6 cycles, followed by 6 additional cycles of Venetoclax alone |
| VI (Venetoclax + Ibrutinib) | EXPERIMENTAL | 15 cycles (q 28d): Ibrutinib p.o. + Venetoclax p.o. will be administered for a total of 12 cycles with a prior Ibrutinib monotherapy lead-in of 3 cycles |
| Ibrutinib/Rituximab | EXPERIMENTAL | All subjects meeting eligibility criteria will receive rituximab: 375 mg/m\^2 on days 1, 8, 15 and 22 on cycle 1. |
| Ibrutinib/Placebo | PLACEBO_COMPARATOR | Ibrutinib capsules (140 mg each) will be dosed at 560 mg once daily on a 28-day cycle on a continuous basis. Placebo capsules will be similarly dosed at 4 capsules daily. |
| Safety Run-in | EXPERIMENTAL | Participants with a low or high risk of TLS enroll into the open-label Safety Run-in Period to receive concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramp up to a target dose of 400 mg once daily over a 5-week period. |
| Randomization Phase: Ibrutinb + Venetoclax | EXPERIMENTAL | Participants randomized to ibrutinib and venetoclax for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax is discontinued after 104 weeks of treatment, regardless of response assessment. |
| Randomization Phase: Ibrutinib + Placebo | PLACEBO_COMPARATOR | Participants randomized to ibrutinib and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo is discontinued after 104 weeks of treatment, regardless of response assessment. |
| Treatment-naive Open-label Arm | EXPERIMENTAL | Participants are treated with ibrutinib 560 mg and venetoclax 400 mg, administered using the 5-week ramp-up schedule. |
| Ibrutinib + Prednisone | EXPERIMENTAL | Ibrutinib (420 mg) given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. The 420 mg dose was adjusted for cytochrome P450 \[CYP\] inhibitors or hepatic dysfunction as applicable. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses. |
| Placebo + Prednisone | PLACEBO_COMPARATOR | Placebo given orally once daily continuously starting on Week 1 Day 1 until cGVHD progression, progression of underlying malignancy, participant begins another systemic treatment for cGVHD or unacceptable toxicity. Prednisone 1 mg/kg/d given orally once daily continuously starting on Week 1 Day 1 until unacceptable toxicity or until participant is successfully tapered from the prednisone. Starting prednisone dose may be as low as 0.5 mg/kg/d if a participant cannot tolerate higher doses. |
| (Arm A) ibrutinib + rituximab | EXPERIMENTAL | Participants to receive 560mg of ibrutinib once daily and rituximab 375mg/m\^2 weekly x4 with maintenance. |
| (Arm B) placebo + rituximab | PLACEBO_COMPARATOR | Participants to receive placebo once daily and rituximab 375mg/m\^2 weekly x4 with maintenance. |
| Ibrutinib | ACTIVE_COMPARATOR | Ibrutinib daily in combination with: Nab-paclitaxel and gemcitabine |
| Placebo | PLACEBO_COMPARATOR | Placebo daily in combination with: Nab-paclitaxel and gemcitabine |
| IBR + OB | EXPERIMENTAL | Ibrutinib (IBR) given orally at a dose of 420 mg/day until progressive disease or unacceptable toxicity. Intravenous obinutuzumab (OB) given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until progressive disease or unacceptable toxicity. |
| CLB + OB | EXPERIMENTAL | Chlorambucil (CLB) given orally at a dose of 0.5 mg/kg body weight up to a total of 6 cycles on Days 1 and 15 of each cycle or until disease progression or unacceptable toxicity. Intravenous obinutuzumab given on Days 1 and 2 (100 mg on Day 1 and 900 mg on Day 2), 1000 mg on Days 8 and 15 of Cycle 1 and 1000 mg on Day 1 of each cycle up to 6 cycles or until disease progression or unacceptable toxicity. |
| Randomized Study (Ibrutinib + Rituximab) | EXPERIMENTAL | Ibrutinib: 420 mg (3 capsules x 140 mg) orally administered daily beginning from Day 1. Rituximab: 375 mg/m\^2 intravenous (IV) per package insert weekly for four consecutive weeks, followed by a second four-weekly rituximab course after a three-month interval. |
| Randomized Study (Placebo + Rituximab) | EXPERIMENTAL | Placebo: 3 capsules of placebo orally administered daily beginning from Day 1. Rituximab: 375 mg/m\^2 IV per package insert weekly for four consecutive weeks, followed by a second four-weekly rituximab course after a three-month interval. |
| Open-Label Substudy (Ibrutinib) | EXPERIMENTAL | Ibrutinib: 420 mg (3 capsules) orally administered daily beginning from Day 1. |
| Chlorambucil | EXPERIMENTAL | Participants who received chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) Days 1 and 15 of 28-day cycle up to 12 cycles in Study 1115. In Study 1116, participants had the option to crossover to next-line ibrutinib 420 mg/day after disease progression (PD). |
| Ibrutinib + Venetoclax | EXPERIMENTAL | Participants will receive Ibrutinib Dose A + Venetoclax in various doses until a target dose is reached, for up to 104 weeks, followed by Ibrutinib monotherapy. |
| Ibrutinib and Venetoclax | EXPERIMENTAL | The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. * Ibrutinib will be administered at a predetermined dose, once daily for 28 days * TLS Prophylaxis (Treatment to reduce risk of tumor lysis syndrome) prior to first dose of venetoclax (and for at least the first 2 weeks of treatment) * Venetoclax Cycle 2-24. PO daily, predetermined dosage ramp up during cycle 2. |
| Ibrutinib 420 mg + SOC | EXPERIMENTAL | 420 mg ibrutinib administered once daily as three hard gelatin capsules (140 mg each) with approximately 240 mL of water for up to 28 days and supportive care (standard-of-care, SOC) |
| Placebo + SOC | PLACEBO_COMPARATOR | Three hard gelatin placebo capsules administered once daily with approximately 240 mL of water for up to 28 days and supportive care (standard-of-care, SOC) |
| Fixed Duration (FD) Cohort: Open Label Ibrutinib + Venetoclax | EXPERIMENTAL | Participants receive 420 mg of single-agent ibrutinib for first 3 cycles followed by ibrutinib plus venetoclax combination treatment (ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule) for 12 cycles (a cycle is defined by 28 days) or until disease progression or unacceptable toxicity. |
| MRD Cohort/Confirmed Undetectable MRD (uMRD): Randomized to Ibrutinib (Blinded) | EXPERIMENTAL | Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD are randomized to receive ibrutinib 420 mg orally once daily on a continuous schedule until MRD-positive relapse, disease progression (PD), or unacceptable toxicity. After MRD-positive relapse or disease progression (PD) by iwCLL criteria, participants can reintroduce 400 mg venetoclax with a 5-week ramp up. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. |
| MRD Cohort/Confirmed uMRD: Randomized Placebo (Blinded) | PLACEBO_COMPARATOR | Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre-randomization phase). Participants with confirmed uMRD are randomized to receive placebo orally once daily on a continuous schedule until MRD-positive relapse, PD or unacceptable toxicity. If MRD-positive relapse or PD is confirmed after restaging per iwCLL criteria, participants can first reintroduce oral daily ibrutinib with the option of subsequently reintroducing 400 mg venetoclax with a 5-week ramp up, if subsequent disease relapse per iwCLL criteria occurs after ibrutinib reintroduction. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. |
| MRD Cohort/uMRD Not Confirmed: Randomized to Ibrutinib (Open-Label) | EXPERIMENTAL | Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre randomization phase). Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. In case of confirmed PD after restaging per iwCLL criteria, participants can continue ibrutinib and reintroduce venetoclax treatment. If venetoclax is to be reintroduced, venetoclax treatment is to continue at the dose of 400 mg/day for up to approximately 2 years (cumulative) until PD or unacceptable toxicity. |
| MRD Cohort/uMRD Not Confirmed: Randomized Ibrutinib + Venetoclax (Open-Label) | EXPERIMENTAL | Participants receive 420 mg of single-agent ibrutinib for the first 3 cycles followed by ibrutinib plus venetoclax combination treatment for at least 12 cycles (a cycle is defined as 28 days) prior to randomization (pre randomization phase). Participants with uMRD not confirmed are randomized to receive open-label ibrutinib 420 mg and venetoclax 400 mg orally once daily on a continuous schedule until PD or unacceptable toxicity. Venetoclax was allowed for administration up to 2 years cumulatively from first dose started in the pre-randomization phase to last dose in the randomization phase. |
| Ibrutinib+ Bortezomib+ Dexamethasone | EXPERIMENTAL | - |
| Main Study Arm 1 | EXPERIMENTAL | Subjects enrolled into this arm will receive ibrutinib continuously until disease progression or unacceptable toxicity. In addition, subjects will receive rituximab once weekly for four doses for the first four weeks of study treatment. |
| Exploratory Study Arm 2 | EXPERIMENTAL | Subjects enrolled into this arm will receive ibrutinib continuously as a single agent for the first eight weeks, then ibrutinib concurrently with rituximab once weekly for four doses. After the rituximab treatment, subjects will receive ibrutinib continuously until disease progression or unacceptable toxicity. |
| PCI-32765: 560 mg | EXPERIMENTAL | Treatment Group 1: Subjects received 560 mg of ibrutinib once daily, on a continuous basis. |
| PCI-32765: 840 mg | EXPERIMENTAL | Treatment Group 2: Subjects received 840 mg of ibrutinib once daily, on a continuous basis. |
| Phase I - Dose Level 0 | EXPERIMENTAL | Ibrutinib (capsule) - 420mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase I - Dose Level 1 | EXPERIMENTAL | Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase I - Dose Level 2 | EXPERIMENTAL | Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 600mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase I - Dose Level 3 | EXPERIMENTAL | Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 800mg Each medication is taken daily. Treatment cycles are 28 days long. |
| Phase II Dose | EXPERIMENTAL | The Phase II dose will be the maximum tolerated dose as determined in the Phase I portion. |
| Phase 1/2 | EXPERIMENTAL | Part A: Subjects ≥1 to \<12 years of age with moderate or severe cGVHD after failure of 1 or more lines of systemic therapy, will receive oral ibrutinib once daily to determine Recommended Pediatric Equivalent Dose (RPED). Part A Continuation: Subjects participating in Part A may continue receiving daily ibrutinib until the RPED is determined, at which time their dose may be adjusted to the RPED. Part B: Subjects ≥1 to \<12 years of age( upper age limit is \< 22 years) with moderate or severe cGVHD after failure of 1 or more lines of systemic therapy or with newly diagnosed moderate or severe cGVHD will be dosed at the RPED. Subjects ≥12 will be given 420mg orally ibrutinib once daily. |
| Trastuzumab plus Ibrutinib 560 mg | EXPERIMENTAL | In Phase I, starting dose of Ibrutinib will be 560 mg orally per day. 3 patients will be enrolled first. If none of these have DLTs, 3 new patients will be enrolled at the next higher Ibrutinib dose level (840 mg orally per day). If 1 of these 3 patients have a DLT, expand this arm to 6 patients. If 2 or more of these 6 patients have a DLT, enroll 3 patients in lower dose lever (420 mg). |
| Trastuzumab plus Ibrutinib 840 mg | EXPERIMENTAL | If no patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this higher dose is tolerated. |
| Trastuzumab plus Ibrutinib 420 mg | EXPERIMENTAL | If 2 or more patients in 560 mg arm have DLTs, this arm will be opened in Phase I to see how this lower dose is tolerated. |
| Phase II- Trastuzumab plus Maximum Tolerated Dose | EXPERIMENTAL | Maximum tolerated dose from Phase I will be used here in Phase II. |
| Cohort 1: Renal Cell Carcinoma (RCC) | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of everolimus to determine the recommended phase 2 dose (RP2D) of ibrutinib. (The RP2D was determined for each cohort separately.) Phase 2: Participants receive ibrutinib at the RP2D determined in phase 1b in combination with everolimus. |
| Cohort 2: Urothelial Carcinoma (UC) | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of paclitaxel to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.) Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with paclitaxel. |
| Cohort 3: Gastric Adenocarcinoma (GA or GC) | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of docetaxel to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.) Phase 2: Participants receive docetaxel at the RP2D determined in Phase 1b in combination with docetaxel. |
| Cohort 4: Colorectal Adenocarcinoma (CRC) | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of cetuximab to determine RP2D of ibrutinib. (The RP2D was determined for each cohort separately.) Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with cetuximab. |
| Cohort 5: Urothelial Carcinoma (UC) Ibrutinib | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels to determine the RP2D of ibrutinib.(The RP2D was determined for each cohort separately.) Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b. |
| Cohort 6: Urothelial Carcinoma (UC) With Pembrolizumab | EXPERIMENTAL | Phase 1b: Participants receive ibrutinib at various dose levels in combination with a fixed dose of pembrolizumab to determine the RP2D of ibrutinib. (The RP2D was determined for each cohort separately.) Phase 2: Participants receive ibrutinib at the RP2D determined in Phase 1b in combination with pembrolizumab. |
| Phase 1b/ 2: Follicular lymphoma expansion cohort | EXPERIMENTAL | In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 explored in cohort 1 and followed a 6+3 dose de-escalation design. Phase 2 used the phase 1b starting dose. |
| Phase 1b/ 2: Diffuse large B-cell lymphoma expansion cohort | EXPERIMENTAL | In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 explored in cohort 1 and followed a 6+3 dose de-escalation design. Phase 2 used the phase 1b starting dose. |
| Phase 1b | EXPERIMENTAL | In the Phase 1b (safety portion) of the study, a starting dose of 560 mg of ibrutinib and 10 mg/kg of MEDI4736 will be explored and will follow a 6+3 dose de-escalation design and will include a sentinel participant which will have a 3-day observation period prior to dosing of subsequent participants. Participants with one of the following three tumor types will be eligible for enrollment: NSCLC (adenocarcinoma and squamous-cell carcinoma), Breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma). |
| Phase 2 | EXPERIMENTAL | Participants with one of three solid tumor types (Stage III/IV) will be enrolled in the Phase 2 portion of this protocol: NSCLC (adenocarcinoma and squamous-cell carcinoma), Breast cancer (triple-negative and HER2-positive cancer), and Pancreatic cancer (adenocarcinoma) and treated at the R2PD of ibrutinib and durvalumab determined in Phase 1b. An interim analysis will be performed to evaluate the response and the safety profile, and the study may be discontinued based on the interim efficacy and/or safety results. |
| Phase 1b: Dose Level 1 | EXPERIMENTAL | Subjects receive daily dose of 420 mg of Ibrutinib capsules |
| Phase 1b: Dose Level 2 | EXPERIMENTAL | Subjects receive daily dose of 280 mg of Ibrutinib capsules |
| Phase 1b: Dose Level 3 | EXPERIMENTAL | Subjects receive daily dose of 140 mg of Ibrutinib capsules |
| Part 1: Dose Level 1 | EXPERIMENTAL | Ibrutinib 560 mg PO + DA-EPOCH-R |
| Part 1: Dose Level 2 | EXPERIMENTAL | Ibrutinib 560 mg (PO) +lenalidomide 15 mg (PO) + DA-EPOCH-R |
| Part 1: Dose Level 3 | EXPERIMENTAL | Ibrutinib 560 mg (PO) +lenalidomide 20 mg (PO) + DA-EPOCH-R |
| Part 1: Dose Level 4 | EXPERIMENTAL | Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R |
| Part 2: RP2D | EXPERIMENTAL | Recommended Phase 2 Dose(RP2D): Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R |
| Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1) | EXPERIMENTAL | Ibrutinib 560 mg administered orally (PO) once daily (QD) beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered intravenously (IV) on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 1b: Enrolled at Lenalidomide Dose 10 mg (Dose Level -1) | EXPERIMENTAL | De-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 10 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 1b: Enrolled at Lenalidomide Dose 15 mg (Dose Level 1+) | EXPERIMENTAL | Re-escalation cohort: Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 15 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 1b: Enrolled at Lenalidomide Dose 20 mg (Dose Level 2) | EXPERIMENTAL | Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 1b: Enrolled at Lenalidomide Dose 25 mg (Dose Level 3) | EXPERIMENTAL | Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 2: Enrolled at Lenalidomide Dose 20 mg | EXPERIMENTAL | Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 20 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 2: Enrolled at Lenalidomide Dose 25 mg | EXPERIMENTAL | Ibrutinib 560 mg administered PO QD beginning Cycle 1 Day 1 until disease progression or unacceptable toxicity. Lenalidomide 25 mg administered PO QD on Days 1-21 of each 28-day cycle until disease progression or unacceptable toxicity. Rituximab 375 mg/m\^2 administered IV on Day 1 of each 28-day cycle for 6 cycles. |
| Phase 1 - Dose Finding | EXPERIMENTAL | Ibrutinib PO 560mg + Carfilzomib IV 20/27mg/m2 + Dexamethasone PO 20mg |
| Phase 2b - Main Study | EXPERIMENTAL | Ibrutinib PO 560mg + Carfilzomib IV 20/36mg/m2 + Dexamethasone PO 20mg |
| Phase 2b - Sub-study | EXPERIMENTAL | Ibrutinib PO 840 mg + Carfilzomib IV 20/36 mg/m2 + Dexamethasone PO 20 mg |
| Name | Type | Description |
|---|---|---|
| Ibrutinib | BIOLOGICAL | Cycles 1 - X: 420 mg daily, d1-28 p.o. |
| Venetoclax | BIOLOGICAL | Arm VG Cycle 1: 20 mg (2 tabl. at 10 mg), d22-28 p.o. Cycle 2: 50 mg (1 tabl. at 50 mg), d1-7; 100 mg (1 tabl. at 100 mg), d8-14; 200 mg (2 tabl. at 100 mg), d15-21; 400 mg (4 tabl. at 100 mg), d22-28 p.o. Cycles 3-12: 400 mg (4 tabl. at 100 mg), d1-28 p.o. Arm VI Cycle 4: 20 mg (2 tabl. at 10 mg), d1-7; 50 mg (1 tabl. at 50 mg), d8-14; 100 mg (1 tabl. at 100 mg), d15-21; 200 mg (2 tabl. at 100 mg), d22-28 p.o. Cycles 5-15: 400 mg (4 tabl. at 100 mg), d1-28 p.o. |
| Obinutuzumab | BIOLOGICAL | Cycle 1: (100 mg, d1 + 900 mg, d2) or 1000 mg, d1; 1000 mg, d8 + d15 i.v. Cycle 2 - 6: 1000 mg, d1 i.v. |
| Rituximab | DRUG | Will receive rituximab: 375 mg/m\^2 on days 1, 8, 15 and 22 of cycle 1 |
| Placebo | OTHER | Placebo capsules will be similarly dosed at 4 capsules daily. |
| Placebo Oral tablet to match Venetoclax | DRUG | Administered orally once daily |
| Prednisone | DRUG | Prednisone administered daily |
| Ibrutinib Oral Capsule | DRUG | Ibrutinib 560mg administered orally daily |
| Gemcitabine | DRUG | - |
| Nab-paclitaxel | DRUG | - |
| Chlorambucil | DRUG | Chlorambucil will be supplied as 2 mg film-coated tablets for oral (PO) administration |
| Next-line ibrutinib | DRUG | Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily |
| Bortezomib | DRUG | Cycles 1-8: (21-day cycle): Bortezomib 1.3 mg/m\^2 sub-cutaneously on days 1, 4, 8, and 11 of each Cycle Cycles 9-12: (42-day cycle): Bortezomib 1.3 mg/m\^2 sub-cutaneously on days 1, 8, 22 and 29 of each Cycle |
| Dexamethasone | DRUG | Cycles 1-8: (21-day cycle): Dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11 and 12 of each cycle Cycles 9-12: (42-day cycle): Dexamethasone 20 mg orally on days 1, 2, 8, 9, 22, 23, 29 and 30 of each cycle Cycles 13+ (28-day cycle): Dexamethasone 40 mg orally once weekly Dose adjustment of dexamethasone to 10 mg on days specified during cycles 1-12 and 20 mg weekly during cycles 13+ is recommended for subjects \>75 years of age. Following implementation of Protocol Amendment 4, dexamethasone administration was reduced to Days 1, 4, 8 and 11 during each 21-day cycle (Cycles 1-8) and on Days 1, 8, 22, 29 on each 42-day cycle (Cycles 9-12) and unchanged thereafter. |
| Fludarabine | DRUG | IV purine analogue chemotherapy agent |
| Cyclophosphamide | DRUG | IV alkylator chemotherapy agent |
| Trastuzumab | DRUG | 8 mg/kg loading dose (first dose), followed by 6 mg/kg every 3 weeks, administered intravenously (IV) |
| Ibrutinib 560 mg | DRUG | 560 mg by mouth daily |
| Ibrutinib 840 mg | DRUG | 840 mg by mouth daily |
| Ibrutinib 420 mg | DRUG | 420 mg by mouth daily |
| everolimus | DRUG | Everolimus 10 mg tablets should be taken orally once daily at the same time every day, either consistently with food or consistently without food. Four (4) x 2.5 mg tablets or two (2) x 5.0 mg tablets may be substituted if 10 mg tablet strength is not available. |
| paclitaxel | DRUG | Paclitaxel should be administered as a 60-minute (±10 minutes) infusion. Paclitaxel should be given at a dose level of 80 mg/m\^2, once weekly, in continual 3 weekly cycles. |
| docetaxel | DRUG | Docetaxel administered as a 60 minute infusion (±10 minutes) at a dose level of 60 - 75 mg/m\^2 (according to local institutional standard of care), given continually in 21-day cycles. |
| cetuximab | DRUG | Cetuximab 400 mg/m\^2 administered as a 120-minute IV infusion. The recommended subsequent weekly dose (all other infusions) is 250 mg/m\^2 infused over 60 minutes. |
| pembrolizumab | DRUG | Pembrolizumab 200 mg intravenous (IV) every 3 weeks. |
| MEDI4736 | DRUG | - |
| Durvalumab | DRUG | Anti PDL-1 |
| DA-EPOCH-R | DRUG | Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim |
| Lenalidomide | DRUG | Lenalidomide |
| Carfilzomib | DRUG | - |
Inclusion Criteria: 1. Documented CLL requiring treatment according to iwCLL criteria. 2. Age at least 18 years. 3. Life expectancy ≥ 6 months. 4. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements. 5. Adequate bone ...
Ibrutinib is an investigational small molecule BTK inhibitor in clinical development for oncology indications including breast neoplasms, chronic lymphoid leukemia, metastatic renal cell carcinoma, chronic lymphocytic leukemia, mantle-cell lymphoma, and leukemia. It is being developed by AbbVie Inc. (ABBV) and is currently in Phase 2 clinical development.
Ibrutinib targets BTK, or Bruton's tyrosine kinase, and acts as an inhibitor of this enzyme. BTK is a key signaling molecule in B-cell development and function, and its inhibition is being studied as a therapeutic approach in various hematologic malignancies and other cancers.
Ibrutinib is being developed by AbbVie Inc., a biopharmaceutical company traded on the New York Stock Exchange under the ticker symbol ABBV. The drug is a small molecule BTK inhibitor currently in Phase 2 clinical trials for multiple oncology indications.
Ibrutinib is currently in Phase 2 clinical development. It is an investigational drug and has not been approved by the FDA. The development program includes completed trials in Phase 1, Phase 2, and Phase 3, with one active Phase 2 trial ongoing.
Ibrutinib has been studied in four clinical trials, including NCT02195869 in chronic graft versus host disease, NCT02401048 in relapsed or refractory lymphomas, NCT02910583 in treatment-naive chronic lymphocytic leukemia, and NCT03112174 in mantle cell lymphoma. Three trials are completed and one is active.
Yes, Ibrutinib is also known as Ibrutinib 560 mg. This alternative name refers to the 560 mg dose strength of the drug. Readers searching for either name will find information about the same BTK inhibitor being developed by AbbVie Inc.