Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Ibrutinib · 25 trials · 22 indications
ORR is defined as the percentage of participants who achieve complete response (CR) or partial response (PR) in the absence of new therapy for chronic graft versus host disease (cGVHD) and absence of progression of underlying disease or death based on the National Institutes of Health (NIH) Consensus Development Project Criteria (2014). 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; and chronic graft versus host disease (cGVHD) progression is defined as clinically meaningful worsening in 1 or more organs regardless of improvement in other organs.
PFS: time between date of randomization and date of disease progression, as assessed by IRC, or date of death due to any cause, whichever occurs first, regardless of use of subsequent anti-cancer therapy prior to PD or death using iWCLL2008 criteria : New enlarged lymph nodes \>15 mm, new hepatomegaly or splenomegaly, or other organ infiltrates, bone lesion, ascites or pleural effusion due to CLL; \>=50% increase in longest diameter (LDi) from nadir in existing lymph node (LDi \>15 mm) or \>=50% increase from nadir in sum of diameters of multiple nodes (and at least 1 node with LDi \>15 mm); \>=50% increase from nadir in enlargement of liver/spleen; \>=50% increase from baseline in lymphocyte count (ALC; to \>=5\*10\^9/L); or \>=50% increase from nadir in ALC in \>=2 serial assessments if ALC is \>=30000\*10\^9/L and lymphocyte doubling time is rapid unless considered treatment-related lymphocytosis; new cytopenia attributable to CLL; transformation to more aggressive histology.
Progression-free survival was defined as the interval between the date of randomization and the date of disease progression or death, whichever was first reported. International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for progressive disease (PD): New enlarged nodes greater than (\>)1.5 centimeter (cm), new hepatomegaly or splenomegaly, or other organ infiltrates; greater than or equal to (\>=)50 percent (%) increase from nadir in existing lymph node or \>=50% increase from nadir in sum of product of diameters of multiple nodes; \>=50% increase from nadir in enlargement of liver or spleen; \>=50% increase from baseline in lymphocyte count (and to \>=5\*10\^9/L) unless considered treatment-related lymphocytosis; New cytopenia (Hemoglobin b \[Hgb\] or platelets) attributable to chronic lymphocytic leukemia (CLL) and transformation to a more aggressive histology.
EFS: duration from randomization date to disease progression(PD) date, relapse from complete response(CR) assessed by investigator, initiation of subsequent systemic antilymphoma therapy for either positron emission tomography(PET)-positive/ biopsy-proven residual disease upon completion of \>=6 cycles of R-CHOP therapy/death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in sum of product of diameters(SPD) of \>1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
EFS: duration from randomization date to PD date, relapse from CR assessed by investigator, initiation of subsequent systemic antilymphoma therapy for either PET-positive/ biopsy-proven residual disease upon completion of \>=6 cycles of R-CHOP therapy/death, whichever occurred first. Responses were based on Revised Response Criteria for Malignant Lymphoma. PD: any new lesion or increase by 50% of previously involved sites from nadir; PD criteria: Appearance of new nodal lesion 1.5 cm in any axis, 50% increase in SPD of \>1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. CR: disappearance of all evidence of disease; CR criteria: nodal masses PET positive prior to therapy; mass of any size permitted if PET negative; regression to normal size on CT; spleen and liver: not palpable, nodules disappeared; bone marrow: infiltrate cleared on repeat biopsy.
Best ORR is defined as the percentage of participants who achieve complete remission (CR), complete remission with an incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria as assessed by investigator.
An adverse event (AE) was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs was defined as any new or worsening AE occurring at or after first dose of study treatment up to 30 days after last dose or prior to start of subsequent anticancer therapy, whichever occurred first. All TEAEs including serious and non-serious events were reported in this outcome measure.
An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs was defined as any new or worsening AE occurring at or after first dose of study treatment up to 30 days after last dose or prior to start of subsequent anticancer therapy, whichever occurred first. All TEAEs included serious and non-serious events were reported in this outcome measure.
An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs was defined as any new or worsening AE occurring at or after first dose of study treatment up to 30 days after last dose or prior to start of subsequent anticancer therapy, whichever occurred first. TEAEs were graded according to NCI-CTCAE v5.0 as Grade 1- Mild; Grade 2- Moderate; Grade 3- Severe or medically significant but not immediately life-threatening; Grade 4- Life-threatening consequences and Grade 5- Death related to AE. Number of participants with grade 3 or higher TEAEs (including serious and non-serious events) were reported in this outcome measure.
An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. TEAEs was defined as any new or worsening AE occurring at or after first dose of study treatment up to 30 days after last dose or prior to start of subsequent anticancer therapy, whichever occurred first. TEAEs were graded according to NCI-CTCAE v5.0 as Grade 1- Mild; Grade 2- Moderate; Grade 3- Severe or medically significant but not immediately life-threatening; Grade 4- Life-threatening consequences and Grade 5- Death related to AE. Number of participants with grade 3 or higher TEAEs (including serious and non-serious events) were reported in this outcome measure.
An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. A serious AE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a suspected transmission of any infectious agent via a medicinal product, or was medically important. TESAEs was defined as SAEs occurring at or after first dose of study treatment up to 30 days after last dose or prior to start of subsequent anticancer therapy, whichever occurred first.
An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. A serious AE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a suspected transmission of any infectious agent via a medicinal product, or was medically important. TESAEs was defined as SAEs occurring at or after first dose of study treatment up to 30 days after last dose or prior to start of subsequent anticancer therapy, whichever occurred first.
Number of participants with clinical abnormalities in hematology laboratory parameters were reported. Hematology parameters included: Activated partial thromboplastin time (aPTT), hemoglobin, neutrophil count, white blood cell (WBC) count, lymphocyte count, platelet count and prothrombin international normalized ratio (INR). Abnormality criteria was assessed as per NCI CTCAE v5.0 grading, where Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening. Grade 0 was assigned when the laboratory value was not assigned a Grade 1 or higher. Only those categories in which at least 1 participant had data were reported.
Number of participants with clinical abnormalities in hematology laboratory parameters were reported. Hematology parameters included: Activated partial thromboplastin time (aPTT), hemoglobin, neutrophil count, white blood cell (WBC) count, lymphocyte count, platelet count and prothrombin international normalized ratio (INR). Abnormality criteria was assessed as per NCI CTCAE v5.0 grading, where Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening. Grade 0 was assigned when the laboratory value was not assigned a Grade 1 or higher. Only those categories in which at least 1 participant had data were reported.
Number of participants with clinical abnormalities in chemistry laboratory parameters were reported. Chemistry parameters included: sodium, aspartate aminotransferase (AST), potassium, alanine aminotransferase (ALT), creatinine, total bilirubin (BL), alkaline phosphatase, albumin, and calcium. Abnormality criteria was assessed as per NCI CTCAE v5.0 grading, where Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening. Grade 0 was assigned when the laboratory value was not assigned a Grade 1 or higher. Only those categories in which at least 1 participant had data were reported.
Number of participants with clinical abnormalities in chemistry laboratory parameters were reported. Chemistry parameters included: sodium, aspartate aminotransferase (AST), potassium, alanine aminotransferase (ALT), creatinine, total bilirubin, alkaline phosphatase, albumin, and calcium. Abnormality criteria was assessed as per NCI CTCAE v5.0 grading, where Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening. Grade 0 was assigned when the laboratory value was not assigned a Grade 1 or higher. Only those categories in which at least 1 participant had data were reported.
PFS of the high/high-intermediate risk patients from date of enrolment
PFS of the high/high-intermediate risk patients from date of enrolment
PFS of the high/high-intermediate risk patients from date of enrolment
PFS will be measured from start of treatment to time of progression. Evidence of clinical progression will be documented by imaging (CT scan) for patients who have measurable disease. Progression is defined using the LUGANO Criteria, as a Deauville score of 4 or 5 (increased uptake compared to baseline) or the appearance of new lesions
Overall response is defined as achievement of complete response (CR) or partial response (PR), as assessed by the Independent Review Committee (IRC), based on the Revised Response Criteria for Malignant Lymphoma. CR is: a) disappearance of all detectable disease symptoms and signs; b) lymph nodes and nodal masses must have regressed on computed tomography (CT) to normal size; c) negative positron emission tomography (PET) scan; d) normal sized spleen or liver if enlarged before therapy; d) bone marrow infiltrate must be cleared if would have been involved before treatment; e) no new sites of disease. PR is: a) greater than 50 percent decrease in the sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, splenic and hepatic nodules; b) no increase in the size of other nodes, liver, or spleen, c) no measurable disease in other organs; d) no new sites of disease; e) 1 PET-positive site of disease (required for the CT+PET assessment of PR).
The Cmax is the maximum observed plasma concentration.
The Cmax is the maximum observed plasma concentration.
The Cmax is the maximum observed plasma concentration.
The Cmax is the maximum observed plasma concentration.
The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
The AUC(0-t) is the area under the plasma concentration-time curve from time zero to any time 't'.
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Area under the concentration-time curve (AUC) from time 0 to the time of the last measurable (non-below quantification limit \[non-BQL\]) concentration, calculated by linear-linear trapezoidal summation.
The AUC (0-infinity) is the area under the plasma concentration time curve from time zero to infinite time, calculated as the sum of AUC (0-last) and C (0-last)/lambda(z); wherein AUC (0-last) is area under the plasma concentration time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda (z) is elimination rate constant.
Maximum observed analyte concentration will be assessed.
Tmax is defined as actual sampling time to reach maximum observed analyte concentration will be assessed.
The elimination halflife (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration time curve and calculated as 0.693/apparent terminal elimination rate constant (λz).
Apparent terminal elimination rate constant, estimated by linear regression using the terminal loglinear phase of the log transformed concentration versus time data.
The Cmax is the maximum observed plasma concentration.
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time.
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Lambda(z) is first-order elimination rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve.
The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).
The Cmax is the maximum observed plasma concentration.
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
The AUC (0-last) is the area under the plasma concentration-time curve from time zero to last quantifiable time.
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Lambda(z) is first-order elimination rate constant associated with the terminal portion of the curve, determined as the negative slope of the terminal log-linear phase of the drug concentration-time curve.
The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).
The Tmax is the time to reach the maximum observed plasma concentration of Ibrutinib.
The AUC (0-48hrs) is the area under the plasma Ibrutinib concentration-time curve from 0 to 48 hours post dosing.
The AUC (0-last) is the area under the plasma Ibrutinib concentration-time curve from time 0 to time of the last observed quantifiable concentration (C\[last\]).
Ratio of ibrutinib metabolite concentration to parent compound (ibrutinib) concentration will be assessed.
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Intensity of Adverse Events will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE).
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Incidence was defined as the number of participants who experienced an adverse event within their period of participation in this study. Incidence of adverse events will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE).
The Cmax is the maximum observed plasma concentration.
The Cmin is the minimum observed plasma concentration.
The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.
The AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours.
ORR is percentage of participants achieving a complete response (CR), CR with incomplete marrow recovery (CRi), nodular partial response (nPR) or PR. IWCLL 2008 criteria: CR- No lymphadenopathy and hepatosplenomegaly, no constitutional symptoms, neutrophils \>1.5\*10\^9/L, platelets \>100\*10\^9/L, Hgb \>11 g/dL and absolute lymphocyte count \<4000/mcL; CRi- CR with incomplete recovery of bone marrow; nPR- participants meet criteria for CR, but the bone marrow biopsy shows B-lymphoid nodules, may represent a clonal infiltrate; PR- \>=50% drop in lymphocyte count from baseline or \<=4.0\*10\^9/L with following: \>=50% decrease in sum products of up to 6 lymph nodes, no new enlarged lymph nodes, When abnormal, \>=50% decrease in enlargement of spleen from baseline or normalization and a response in 1 of following: Neutrophils \>1.5\*10\^9/L, Platelets\>100000/mcL and Hgb\>11 g/dL or \>=50% improvement over baseline in all. This outcome measure was planned to be analyzed for specified arm only.
ORR defined as percentage of participants achieving a CR, CRi, nPR or PR. As per Non-Hodgkin Lymphoma, Cheson 2014, CR is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. PR is \>= 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. Progressive disease (PD) \>= 50% increase from nadir in the sum of the products of at least two lymph nodes, or appearance of a new lesion greater than 1.5 cm in any axis even if other lesions are decreasing in size. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. This outcome measure was planned to be analyzed for specified arms only.
An AE is any untoward medical occurrence in a participant participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. TEAEs for the treatment phase included events with an onset date/time on or after the start of study intervention through end of study were considered as treatment-emergent.
The AUC (0-24hrs) is the area under the plasma Ibrutinib concentration-time curve from 0 to 24 hours post dosing.
The AUC (0-infinity) is the area under the plasma Ibrutinib concentration-time curve from time 0 to infinite time, calculated as the sum of AUC (0-last) and C(last)/lambda(z), in which AUC(0-last) is area under the plasma Ibrutinib concentration-time curve from time zero to time of the last quantifiable concentration, C(last) is the last observed quantifiable concentration and lambda(z) is elimination rate constant.
The %AUC(infinity,ex) is calculated by dividing the difference of AUC(0-infinity) and AUC(0-last) by AUC(0-infinity) and then multiplying by 100, (AUC\[0-infinity\] - AUC\[0-last\])\*100/AUC\[0-infinity\].
The Lambda (z) determined by linear regression of the terminal points of the ln-linear plasma concentration-time curve.
The r\^2 \[adjusted\] for the number of points used in the estimation of lambda\[z\].
The Frel will be calculated as individual Cmax and AUC treatment ratios (for the comparison of food effect). Calculated as: \[(AUC\[0-infinity\]\[test\]/AUC\[0-infinity\]\[ref\])\*(Dose\[ref\]/Dose\[test\])\]\*100.
Metabolite to parent drug ratio for maximum observed plasma concentration of Ibrutinib.
The QTc interval, as measured by electrocardiograms will evaluate the potential effect of ibrutinib on QTc interval duration.
Pharmacokinetic parameter Cmax of ibrutinib will be determined.
Pharmacokinetic parameter tmax of ibrutinib will be determined.
Pharmacokinetic parameter AUC of ibrutinib will be determined.
Pharmacokinetic parameter Ae of ibrutinib will be determined by multiplying the urinary volume with the urinary concentration.
| Arm | Type | Description |
|---|---|---|
| Ibrutinib | EXPERIMENTAL | Participants will receive 420 milligram (mg) oral ibrutinib once daily starting on Week 1 Day 1, unless they have intervening unacceptable toxicity or meet other criteria for participants discontinuation. |
| Treatment Arm A: Ibrutinib and Venetoclax (I+VEN) | EXPERIMENTAL | Participants will initially receive ibrutinib (420 mg \[milligrams\]/day) for 3 cycles. Venetoclax dose ramp up (from 20 to 400 mg over 5 weeks) will begin at Cycle 4 and the combination of ibrutinib and venetoclax will be given for 12 cycles (each cycle is equivalent to 28 days). Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity. |
| Treatment Arm B: Chlorambucil and Obinutuzumab (G-Clb) | ACTIVE_COMPARATOR | Participants will receive chlorambucil and obinutuzumab (G-Clb) for 6 cycles. Participants will receive obinutuzumab, 1000 mg intravenously (IV) on Days 1, 8 and 15 of Cycle 1, and on Day 1 of Cycles 2 to 6 and chlorambucil 0.5 milligrams per kilogram (mg/kg) body weight, on Days 1 and 15 of Cycles 1 to 6. Participants who subsequently develop progressive disease may enter to Subsequent Therapy Phase to receive single-agent ibrutinib until disease progression or unacceptable toxicity. |
| Treatment Arm A | EXPERIMENTAL | - |
| Treatment Arm B | EXPERIMENTAL | - |
| Treatment Arm A: placebo + R-CHOP | PLACEBO_COMPARATOR | Treatment Arm A = placebo + R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) |
| Treatment Arm B: ibrutinib + R-CHOP | EXPERIMENTAL | Treatment Arm B = ibrutinib + R-CHOP |
| Temsirolimus | EXPERIMENTAL | - |
| Ibrutinib + BR | EXPERIMENTAL | Ibrutinib 420 mg will be administered orally once daily on a continuous schedule. All subjects will receive background therapy with bendamustine and rituximab (BR) for a maximum of 6 cycles (a cycle is defined as 28 days, with the exception of Cycle 1, which will be 29 days to allow for rituximab dosing prior to bendamustine and study medication). |
| Placebo + BR | PLACEBO_COMPARATOR | Matching placebo will be administered orally once daily on a continuous schedule. All subjects will receive background therapy with BR for a maximum of 6 cycles (a cycle is defined as 28 days, with the exception of Cycle 1, which will be 29 days to allow for rituximab dosing prior to bendamustine and study medication). |
| Cohort 1a: Ibrutinib Lead-in+Fixed Duration Ibrutinib+Venetoclax | EXPERIMENTAL | Participants will receive ibrutinib 420 milligrams (mg) capsule every day (QD) for a lead-in of 3 cycles (1 cycle = 28 days). From Cycle 4, venetoclax 400 mg tablet dose ramp-up (from 20 to 400 mg over 5 weeks) will begin, and venetoclax 400 mg QD will be administered with ibrutinib 420 mg QD, orally for 12 cycles through Cycle 15. |
| Cohort 1b: Ibrutinib Lead-in+Fixed Duration Ibrutinib+Venetoclax | EXPERIMENTAL | Participants will receive ibrutinib 420 mg capsule QD for a lead-in of 3 cycles (1 cycle = 28 days). From Cycle 4, venetoclax 400 mg tablet dose ramp-up (from 20 to 400 mg over 5 weeks) will begin and ibrutinib dose will be reduced to 280 mg and will be administered QD, venetoclax 400 mg tablets QD will be administered with ibrutinib 280 mg for 12 cycles through Cycle 15. |
| Cohort 2a: Continuous Ibrutinib Monotherapy | EXPERIMENTAL | Participants will receive ibrutinib 420 mg QD (or last tolerated dose) until disease progression (PD) or unacceptable toxicity. |
| Cohort 2b: Continuous Ibrutinib Monotherapy | EXPERIMENTAL | Participants will receive ibrutinib 420 mg QD for 1 cycle (1 cycle = 28 days) followed by Ibrutinib 280 mg QD (or last tolerated dose) and continue until disease progression or unacceptable toxicity. |
| Phase 2: Treatment Arm A1 (Rituximab plus Ibrutinib) | EXPERIMENTAL | Participants will receive rituximab 375 milligrams per meter square (mg/m\^2) intravenously (IV) on Day 1 of Cycles 1 to 6 with ibrutinib 560 milligrams (mg) orally, once daily starting on Day 1 of Cycle 1 until disease progression or unacceptable toxicity (each cycle length is 28 days). |
| Phase 2: Treatment Arm A2 (Rituximab plus Ibrutinib) | EXPERIMENTAL | Participants will receive rituximab 375 mg/m\^2 IV on Day 1 of Cycles 1 to 6 with ibrutinib 420 mg orally, once daily starting on Day 1 of Cycle 1 until disease progression or unacceptable toxicity (each cycle length is 28 days). |
| Phase 2: Treatment Arm A3 (Rituximab plus Ibrutinib) | EXPERIMENTAL | Participants will receive rituximab 375 mg/m\^2 IV on Day 1 of Cycles 1 to 6 with ibrutinib 140 mg orally, twice daily starting on Day 1 of Cycle 1 until disease progression or unacceptable toxicity (each cycle length is 28 days). |
| Phase 2: Treatment Arm B (Rituximab plus Lenalidomide or Bortezomib) | EXPERIMENTAL | Participants will receive rituximab 375 mg/m\^2 IV on Day 1 of Cycles 1 to 6 (each cycle length is 21 or 28 days) with physician's choice of either lenalidomide 20 mg orally, once daily from Day 1 through Day 21 of 28-day cycle or bortezomib 1.3 mg/m\^2 IV or subcutaneously (SC) on Days 1, 4, 8 and 11 of a 21-day cycle until disease progression or unacceptable toxicity. |
| Ibrutinib+R-CHOP | EXPERIMENTAL | Screening phase for selection of Activated-B-Cell (ABC)-DLBCL Induction phase: R-CHOP21 x 5 cycles in combination with ibrutinib Maintenance phase: maintenance with Ibrutinib for 18 months for patients responding to the induction phase (CR or PR) |
| Treatment (ibrutinib) | EXPERIMENTAL | Patients receive ibrutinib orally PO QD on days 1-28. Courses repeat every 28 days for up to 4 years in the absence of disease progression, unacceptable toxicity, or patient preference. |
| Ibrutinib + Oral Contraceptives + Probe Drugs (CYP) | EXPERIMENTAL | Pre-treatment Phase: Participants will receive a single dose of oral contraceptive (OC) consisting of ethinylestradiol (EE) 30 microgram (mcg) and levonorgestrel (LN) 150 mcg on Study Day 1, and probe drugs (CYP) consisting of bupropion 75 milligram (mg) and midazolam 2 mg on Study Day 3, followed by a washout period from Study Days 4 to 7. Treatment Phase: Participants will receive ibrutinib 560 mg (4\*140 mg capsules) once daily (QD) on Days 8 to 26 along with midazolam 2 mg once orally on Study Day 8 (Cycle 1 Day 1), OC once orally on Study Day 22 (Cycle 1 Day 15; EE and LN), and bupropion 75 mg and midazolam 2 mg once orally on Study Day 24 (Cycle 1 Day 17). From Study Day 27 (Cycle 1 Day 20) and onwards participants will continue oral treatment with ibrutinib 420 mg (3\*140 mg capsules) or 560 mg QD (depending on the subtype of B-cell malignancy) up to the end of Cycle 6 (each cycle will consist of 28 days). |
| Treatment Sequence 1 : ABAB | EXPERIMENTAL | Participants will receive 140 milligram (mg) of ibrutinib administered as one IMBRUVICA 140-mg oral capsule (Treatment A) in Period 1, 140 mg of ibrutinib administered as one ibrutinib 140-mg oral tablet (Treatment B) in Period 2, then Treatment A in period 3 and then followed by Treatment B in Period 4. Each intervention Period will be separated by a washout period of 7-9 days. |
| Treatment Sequence 2 : BABA | EXPERIMENTAL | Participants will receive (Treatment B) Period 1, then Treatment A in Period 2, then Treatment B in Period 3 and then followed by Treatment A in Period 4. Each intervention Period will be separated by a washout period of 7-9 days. |
| Treatment Sequence 1 | EXPERIMENTAL | Participants will receive treatment A, on Day 1 of Intervention Period 1 followed by treatment B , on Day 1 of Intervention Period 2 followed by treatment A, Day 1 of Intervention Period 3 and then followed by treatment B, on Day 1 of Intervention Period 4. Each intervention Period will be separated by a washout period of 7-9 days. |
| Treatment Sequence 2 | EXPERIMENTAL | Participants will receive treatment B, on Day 1 of Intervention Period 1 followed by treatment A, on Day 1 of Intervention Period 2 followed by treatment B, Day 1 of Intervention Period 3 and then followed by treatment A, on Day 1 of Intervention Period 4. Each intervention Period will be separated by a washout period of 7-9 days. |
| Ibrutinib + Omeprazole | EXPERIMENTAL | Participants will receive a dose of Ibrutinib 560 milligram (mg) orally (4 x 140 mg capsules) on Day 1 and Day 7 and Omeprazole at a dose of 40 mg tablets orally once on Days 3 through 7. |
| Part 1: Ibrutinib+Erythromycin+Voriconazole | EXPERIMENTAL | Participants will receive oral treatment in six, 28-days cycles. In Cycle 1, participants will take ibrutinib 560 milligram (mg) (4\*140 mg capsules) once daily (QD) from Days 1- 4; on Days 5-11 ibrutinib 140 mg capsule QD in combination with erythromycin 500 mg tablet 3 times daily (TID); on Days 12-13 ibrutinib 140 mg capsule QD; on Days 14-18 ibrutinib 560 mg (4\*140 mg capsules) QD; on Days 19-25 ibrutinib 140 mg capsule QD in combination with voriconazole 200 mg tablet twice daily (BD); on Days 26-27 ibrutinib 140 mg capsule orally QD; and on Day 28 and in subsequent treatment Cycles (2-6) participants will continue oral treatment with ibrutinib 420 mg or 560 mg QD (depending on the subtype of B-cell malignancy). |
| Part 2: Ibrutinib+ Erythromycin+Voriconazole | EXPERIMENTAL | Participants will receive oral treatment in six, 28-days cycles. In Cycle 1, participants will take ibrutinib 560 mg (4\*140 mg capsules) QD from Days 1- 4; on Days 5-18 ibrutinib 560 mg (4\*140 mg capsules) QD in combination with either erythromycin 500 mg tablet TID (Group 1) or voriconazole 200 mg tablet BD (Group 2); on Day 19 and in subsequent treatment Cycles (2-6) participants will continue oral treatment with ibrutinib 420 mg or 560 mg QD (depending on the subtype of B-cell malignancy). |
| Cohort A1 | EXPERIMENTAL | Participants will receive ibrutinib 420 milligram (mg) capsule orally once daily and nivolumab intravenously as 3 milligram/kilogram (mg/kg) every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. |
| Cohort A2 | EXPERIMENTAL | Participants will receive ibrutinib 560 mg capsule orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. |
| Cohort B1 | EXPERIMENTAL | Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. |
| Cohort B2 | EXPERIMENTAL | Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. |
| Cohort B3 | EXPERIMENTAL | Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. |
| Cohort B4 | EXPERIMENTAL | Participants will receive ibrutinib recommended Phase 2 dose (RP2D) orally once daily and nivolumab intravenously as 3 mg/kg every 2 weeks for 14-daily dosing cycles and will be continued until disease progression or unacceptable toxicity. |
| Group 1: Sequence 1 (ABC) | EXPERIMENTAL | Participants will receive Treatment A (Ibrutinib 560 milligram \[mg\] capsules \[reference\] under fasted conditions) in Period 1; followed by Treatment B (Ibrutinib 560 mg suspension under fasted conditions) in Period 2; followed by Treatment C (Ibrutinib 560 mg suspension under fed conditions) in Period 3. A washout period of 7 (plus \[+\] / minus \[-\] 2) days will be maintained between each treatment period. |
| Group 1: Sequence 2 (BCA) | EXPERIMENTAL | Participants will receive Treatment B (Ibrutinib 560 mg suspension under fasted conditions) in Period 1; followed by Treatment C (Ibrutinib 560 mg suspension under fed conditions) in Period 2; followed by Treatment A (Ibrutinib 560 mg capsules \[reference\] under fasted conditions) in Period 3. A washout period of 7 (+/- 2) days will be maintained between each treatment period. |
| Group 1: Sequence 3 (CAB) | EXPERIMENTAL | Participants will receive Treatment C (Ibrutinib 560 mg suspension under fed conditions) in Period 1; followed by Treatment A (Ibrutinib 560 mg capsules \[reference\] under fasted conditions) in Period 2; followed by Treatment B (Ibrutinib 560 mg suspension under fasted conditions) in Period 3. A washout period of 7 (+/- 2) days will be maintained between each treatment period. |
| Group 1: Sequence 4 (ACB) | EXPERIMENTAL | Participants will receive Treatment A (Ibrutinib 560 mg capsules \[reference\] under fasted conditions) in Period 1; followed by Treatment C (Ibrutinib 560 mg suspension under fed conditions) in Period 2; followed by Treatment B (Ibrutinib 560 mg suspension under fasted conditions) in Period 3. A washout period of 7 (+/- 2) days will be maintained between each treatment period. |
| Group 1: Sequence 5 (BAC) | EXPERIMENTAL | Participants will receive Treatment B (Ibrutinib 560 mg suspension under fasted conditions) in Period 1; followed by Treatment A (Ibrutinib 560 mg capsules \[reference\] under fasted conditions) in Period 2; followed by Treatment C (Ibrutinib 560 mg suspension under fed conditions) in Period 3. A washout period of 7 (+/- 2) days will be maintained between each treatment period. |
| Group 1: Sequence 6 (CBA) | EXPERIMENTAL | Participants will receive Treatment C (Ibrutinib 560 mg suspension under fed conditions) in Period 1; followed by Treatment B (Ibrutinib 560 mg suspension under fasted conditions) in Period 2; followed by Treatment A (Ibrutinib 560 mg capsules \[reference\] under fasted conditions) in Period 3. A washout period of 7 (+/- 2) days will be maintained between each treatment period. |
| Group 2: Sequence 1 (AFDE) | EXPERIMENTAL | Participants will receive Treatment A (Ibrutinib 560 mg capsules \[reference\] under fasted conditions) in Period 1; followed by Treatment F (Ibrutinib 560 mg sprinkle capsule granules suspended in water under fasted conditions) in Period 2; followed by Treatment D (Ibrutinib 560 mg sprinkle capsule granules under fasted conditions) in Period 3; followed by Treatment E (Ibrutinib 560 mg sprinkle capsule granules under fed conditions) in Period 4. A washout period of 7 (+/- 2) days will be maintained between each treatment period. |
| Group 2: Sequence 2 (DAEF) | EXPERIMENTAL | Participants will receive Treatment D (Ibrutinib 560 mg sprinkle capsule granules under fasted conditions) in Period 1; followed by Treatment A (Ibrutinib 560 mg capsules \[reference\] under fasted conditions) in Period 2; followed by Treatment E (Ibrutinib 560 mg sprinkle capsule granules under fed conditions) in Period 3; followed by Treatment F (Ibrutinib 560 mg sprinkle capsule granules suspended in water under fasted conditions) in Period 4. A washout period of 7 (+/- 2) days will be maintained between each treatment period. |
| Group 2: Sequence 3 (EDFA) | EXPERIMENTAL | Participants will receive Treatment E (Ibrutinib 560 mg sprinkle capsule granules under fed conditions) in Period 1; followed by Treatment D (Ibrutinib 560 mg sprinkle capsule granules under fasted conditions) in Period 2; followed by Treatment F (Ibrutinib 560 mg sprinkle capsule granules suspended in water under fasted conditions) in Period 3; followed by Treatment A (Ibrutinib 560 mg capsules \[reference\] under fasted conditions) in Period 4. A washout period of 7 (+/- 2) days will be maintained between each treatment period. |
| Group 2: Sequence 4 (FEAD) | EXPERIMENTAL | Participants will receive Treatment F (Ibrutinib 560 mg sprinkle capsule granules suspended in water under fasted conditions) in Period 1; followed by Treatment E (Ibrutinib 560 mg sprinkle capsule granules under fed conditions) in Period 2; followed by Treatment A (Ibrutinib 560 mg capsules \[reference\] under fasted conditions) in Period 3; followed by Treatment D (Ibrutinib 560 mg sprinkle capsule granules under fasted conditions) in Period 4. A washout period of 7 (+/- 2) days will be maintained between each treatment period. |
| Part 1: Ibrutinib 840 milligram (mg) | EXPERIMENTAL | Participants will receive ibrutinib 840 mg (6\*140 mg capsules) + 6 placebo capsules on Day 1 of Part 1, Period 1. |
| Part 1: Ibrutinib 1680 mg | EXPERIMENTAL | Participants will receive ibrutinib 1680 mg (12\*140 mg capsules) on Day 1 of Part 1, Period 2. |
| Part 2: Treatment A | EXPERIMENTAL | Participants will receive ibrutinib, 1680 mg (12\*140 mg capsules) + 1 moxifloxacin-matching placebo capsule Day 1of Part 2. |
| Part 2: Treatment B | EXPERIMENTAL | Participants will receive ibrutinib, 840 mg (6\*140 mg capsules) + 6 ibrutinib-matching placebo capsules + 1 moxifloxacin-matching placebo capsule. |
| Part 2: Treatment C | EXPERIMENTAL | Participants will receive placebo (12 ibrutinib-matching placebo capsules + 1 moxifloxacin-matching placebo capsule) Day 1 of Part 2. |
| Part 2: Treatment D | EXPERIMENTAL | Participants will receive moxifloxacin 400 mg (1 capsule) + 12 ibrutinib-matching placebo capsules Day 1 of Part 2. |
| Ibrutinib and Ketoconazole | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| Ibrutinib | DRUG | Participants will receive 420 mg (3 \* 140 mg capsules) oral ibrutinib once daily starting on Week 1 Day 1, unless they have intervening unacceptable toxicity or meet other criteria for participants discontinuation. |
| Venetoclax | DRUG | Participants will receive venetoclax in combination with ibrutinib for a total of 12 cycles, beginning at Cycle 4. For the first 5 weeks of venetoclax treatment, the treatment dose will be ramped up from 20 to 400 mg. |
| Chlorambucil | DRUG | Participants will receive chlorambucil at a dose of 0.5 mg/kg body weight on Days 1 and 15 of Cycles 1 to 6. |
| Obinutuzumab | DRUG | Participant will receive obinutuzumab 1000 mg intravenously on Days 1, 8, and 15 of Cycle 1, and Day 1 of Cycles 2 to 6. |
| Ibrutinib (as Subsequent Therapy) | DRUG | Participants will receive ibrutinib 420 mg orally once daily until disease progression or unacceptable toxicity during the subsequent therapy phase. |
| Rituximab | DRUG | Up to 6 cycles (total of 8 doses administered by intravenous infusion): 375 mg/m2 on Day 1 of Cycle 1, 500 mg/m2 on Day 15 of Cycle 1 (Weeks 1-4); 500 mg/m2 on Day 1 and Day 15 of Cycle 2 (Weeks 5-8); and 500 mg/m2 on Day 1 of Cycles 3-6 (Weeks 9-24). |
| Placebo | DRUG | 4 matched capsules administered by mouth once daily (21-day cycles) |
| Cyclophosphamide | DRUG | 750 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles) |
| Doxorubicin | DRUG | 50 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles) |
| Vincristine | DRUG | 1.4 mg/m2 administered intravenously once on Day 1 of each cycle (21-day cycles) |
| Prednisone (or equivalent) | DRUG | 100 mg capsules administered by mouth once daily on Day 1 to Day 5 of each cycle |
| Bendamustine | DRUG | 90 mg/m2 administered intravenously on Days 1-2, Cycles 1-6 |
| Temsirolimus | DRUG | 175 mg once daily intravenous infusion on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each 21-day cycle |
| Bendamustine hydrochloride | DRUG | Type=exact number, unit=mg, number=70 mg/m2, route=intravenous use. Administered intravenously on Cycle 1, Days 2-3 and Cycles 2-6, Days 1-2. |
| Lenalidomide | DRUG | Lenalidomide capsules will be administered orally. |
| Bortezomib | DRUG | Bortezomib will be administered either intravenously or subcutaneously. |
| laboratory biomarker analysis | OTHER | Correlative studies |
| OC: Ethinylestradiol (EE) 30 mcg and Levonorgestrel (LN) 150 mcg | DRUG | Single dose of oral contraceptives (OC) (1 tablet containing 30 mcg EE and 150 mcg LN) will be taken orally on Study Days 1 and 22. |
| Bupropion | DRUG | Bupropion 75 mg tablet as a part of CYP cocktail will be taken on Study Days 3 and 24. |
| Midazolam | DRUG | Midazolam 2 mg (1 milliliter \[mL\]) oral solution will be taken on Study Days 3 and 24 (as a part of CYP cocktail) and on Study Day 8 (alone). |
| IMBRUVICA | DRUG | IMBRUVICA (reference treatment), 140-mg capsule |
| IMBRUVICA (Treatment A) | DRUG | IMBRUVICA (reference treatment), 4\*140 milligram (mg), capsules. |
| Ibrutinib (Treatment B) | DRUG | Ibrutinib (test treatment), 1\*560 mg, tablet. |
| Omeprazole | DRUG | Omeprazole will be administered at dose of 40 mg tablets orally once daily from Day 3 to Day 7. |
| Erythromycin | DRUG | Erythromycin 500 mg tablet will be taken orally TID (Part1 Cycle 1: on Days 5-10 and morning dose on Day 11; Part2 Cycle 1: on Days 5-17 and morning dose on Day 18). |
| Voriconazole | DRUG | Voriconazole 200 mg tablet will be taken orally BD (Part1 Cycle 1: on Days 19-25; Part2 Cycle 1: on Days 5-17). |
| Nivolumab | DRUG | Participants will receive nivolumab intravenously as 3 mg/kg on Day 1 every cycle of 14 days. |
| Ibrutinib (Treatment A) [Reference] | DRUG | Participants will receive Ibrutinib 560 milligram (mg) (4\*140 mg) capsule as Treatment A under fasted conditions in one of the treatment periods. |
| Ibrutinib (Treatment C) | DRUG | Participants will receive Ibrutinib 560 mg suspension as Treatment C under fed (high-fat) conditions in one of the treatment periods. |
| Ibrutinib (Treatment D) | DRUG | Participants will receive Ibrutinib 560 mg sprinkle capsule granules as Treatment D under fasted conditions in one of the treatment periods. |
| Ibrutinib (Treatment E) | DRUG | Participants will receive Ibrutinib 560 mg sprinkle capsule granules as Treatment E under fed (high-fat) conditions in one of the treatment periods. |
| Ibrutinib (Treatment F) | DRUG | Participants will receive Ibrutinib 560 mg sprinkle capsule granules suspended in water as Treatment F under fasted conditions in one of the treatment periods. |
| Moxifloxacin | DRUG | Participants will receive a single oral dose of 1 moxifloxacin capsule (400 mg) in Treatment D. |
| Ibrutinib-matching placebo | DRUG | Participants will receive a single oral dose of 12 ibrutinib-matching placebo capsules in Treatment B and 6 ibrutinib-matching placebo capsules in Treatment C and D. |
| Moxifloxacin-matching placebo | DRUG | Participants will receive a single oral dose of 1 moxifloxacin-matching placebo capsule in Treatment A, B, and C. |
| Ketoconazole | DRUG | Ketoconazole (400 mg \[2 x 200 mg\] once daily) will be orally administered on Days 4, 5, 6, 7, 8 and 9. |
Inclusion Criteria: * Steroid dependent/refractory chronic graft versus host disease (cGVHD) defined as modified National Institutes of Health (NIH) criteria (2014) below at any time post-hematopoietic cell transplant (post-HCT): a) Dependent disease, defined as, when glucocorticoid (prednisolone d...
| Company | Ticker | Trials | Lead Phase | Drugs |
|---|---|---|---|---|
| Incyte Corporation | INCY | 10 | PHASE3 | INCA034176 |
| Sanofi SA Sponsored ADR | SNY | 2 | PHASE3 | Belumosudil, Prednisone, Prednisolone |
| Johnson & Johnson | JNJ | 1 | PHASE3 | Ibrutinib |
| Syndax Pharmaceuticals Inc | SNDX | 1 | PHASE2 | Axatilimab |
| Theriva Biologics, Inc. | TOVX | 1 | PHASE1 | Undisclosed |