Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication IMBRUVICA is a kinase inhibitor indicated for the treatment of: Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) ( 1.1 ). Adult patients with chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion ( 1.2 ). Adult patients with Waldenström’s macroglobulinemia (WM) ( 1.3 ). FDA label
Also known as PCI-32765 (Ibrutinib), Ibrutinib, JNJ-54179060, Imbruvica, Bruton's tyrosine kinase inhibitor PCI-32765, BTK inhibitor PCI-32765, CRA-032765
PCI-32765 · 29 trials · 28 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.
PFS was defined as the time from randomization to CLL progression or death, whichever occurred first. Progression is characterized by any of the following: * ≥ 50% increase from nadir since start of treatment (tx) in the sum of the products of at least 2 lymph nodes on 2 consecutive examinations 2 weeks apart * ≥ 50% increase from nadir since start of tx in the size of liver and/or spleen * ≥ 50% increase in the absolute number of circulating lymphocytes not due to tumor flare reaction. The absolute lymphocyte count must be ≥ 5x10\^9/L to qualify as disease progression. * Transformation to a more aggressive histology (e.g. Richter's syndrome or prolymphocytic leukemia with \> 55% prolymphocytes). For patients who achieve a complete response or nodular partial response, progression is defined as recurrence of circulating leukemia cell clone in the peripheral blood and an absolute lymphocyte count \> 5x10\^9/L and/or recurrence of palpable lymphadenopathy \> 1.5 cm by physical exam.
PFS was defined as duration (in months) from the date of randomization to the date of disease progression or relapse from complete response (CR) or death, whichever was first reported. PFS was assessed by the investigator based on the 2007 Revised Response Criteria for Malignant Lymphoma. Disease progression was defined as any new lesion or increase by greater than or equal to (\>=) 50 percent (%) of previously involved sites from nadir disease progression criteria: Appearance of new nodal lesion 1.5 centimeters (cm) in any axis, 50% increase in sum of product of diameters (SPD) of greater than (\>) 1 node or 50% increase in longest diameter of previously identified node 1 cm in short axis. Participants who were progression-free and alive or had unknown status were censored at the last tumor assessment. Kaplan-Meier method was used for the analysis. Stratification factors were used for the analysis.
PFS in MZL participants was defined as duration (in months) from the date of randomization to the date of disease progression or relapse from CR or death, whichever was first reported. PFS was assessed by the investigator based on the 2007 Revised Response Criteria for Malignant Lymphoma. Disease progression was defined as any new lesion or increase by \>=50% of previously involved sites from nadir disease progression 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. Participants who were progression-free and alive or had unknown status were censored at the last tumor assessment. Kaplan-Meier method was used for the analysis. For this outcome measure, unstratified analysis was performed on participants with MZL.
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.
Rate of participants achieving complete remission (CR) with undetectable minimal residual disease (uMRD) in bone marrow, assessed according to 2018 iwCLL response criteria.
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.
ORR is defined as the percentage of participants achieving a best overall response of confirmed complete response (CR), very good partial response (VGPR) or partial response (PR) according to the modified sixth IWWM criteria (National Comprehensive Cancer Network \[NCCN\] version 2, 2019), as assessed by the Independent Review Committee (IRC). CR: Immunoglobulin M (IgM) in normal range, disappearance of monoclonal protein by immunofixation, no histologic evidence of bone marrow involvement, resolution of any adenopathy/organomegaly (if present at baseline) along with no signs or symptoms attributable to Waldenstrom's Macroglobulinemia (WM); VGPR and PR: greater than or equal to (\>=) 90 percent (%) (for VGPR) and \>=50% (for PR) reduction of serum IgM, decrease in adenopathy/organomegaly (if present at baseline) on physical examination or computerized tomography (CT) scan, no new symptoms or signs of active disease.
The primary endpoint is the rate of 1 year progression free survival (1YPFS).
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).
To determine the pediatric recommended phase 2 dose (RP2D) of ibrutinib, when combined with indoximod-based chemo-immunotherapy (Regimen A)
Defined as the proportion of patients with a best objective response of either complete response (CR) or partial response (PR), using "immunotherapy Response Assessment for Neuro-Oncology" (iRANO) criteria
To determine the pediatric recommended phase 2 dose (RP2D) of ibrutinib, when combined with indoximod-based chemo-immunotherapy (Regimen B)
Defined as the proportion of patients with a best objective response of either complete response (CR) or partial response (PR), using "immunotherapy Response Assessment for Neuro-Oncology" (iRANO) criteria
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.
4 weeks after initiation of treatment.
No unacceptable toxicity has been observed during step A, thefore the second step (step B) was initiated
The third step started, because no unacceptable toxicity has been observed during the second step
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.
Ratio of ibrutinib metabolite concentration to parent compound (ibrutinib) concentration will be assessed.
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.
| 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. |
| Arm A (ibrutinib, rituximab) | EXPERIMENTAL | Patients receive ibrutinib PO QD on days 1-28. Beginning cycle 2, patients also receive rituximab IV over 4 hours on days 1 and 2 of cycle 2, and day 1 of cycles 3-7. Treatment repeats every 28 days for 7 cycles in the absence of unacceptable toxicity. In the absence of disease progression, patients may continue ibrutinib PO QD for a maximum of 10 years. |
| Arm B (rituximab, fludarabine phosphate, cyclophosphamide) | ACTIVE_COMPARATOR | Patients receive rituximab IV over 4 hours on days 1 and 2 of cycle 1, and day 1 of cycles 2-6. Patients also receive fludarabine phosphate IV over 30 minutes and cyclophosphamide IV over 30 minutes on days 1-3. Treatment repeats every 28 days for 6 cycles in the absence of unacceptable toxicity. |
| Treatment Arm A | PLACEBO_COMPARATOR | Treatment Arm A = background immune-chemotherapy (bendamustine and rituximab \[BR\] or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone \[R-CHOP\]) for 6 cycles + placebo. |
| Treatment Arm B | EXPERIMENTAL | Treatment Arm B = background immune-chemotherapy (BR or R-CHOP) for 6 cycles + PCI-32765 (Ibrutinib). |
| 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). |
| EVI combination | EXPERIMENTAL | Participants receive sequential treatment with ibrutinib, followed by ibrutinib plus venetoclax, and subsequently the triple combination of ibrutinib, venetoclax, and epcoritamab as a fixed-duration treatment regimen. |
| 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. |
| Methotrexate, Ibrutinib +/- Rituximab | EXPERIMENTAL | Cycles 1-6, q14 days Day 1: Methotrexate + Rituximab Days 6-14: Ibrutinib daily orally |
| 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 + Rituximab | EXPERIMENTAL | Participants will receive ibrutinib 420 milligram (mg) orally, once daily, from Day 1 of Week 1 until disease progression or unacceptable toxicity in combination with rituximab 375 milligram per square meter (mg/m\^2) intravenously (IV) on Day 1 of Weeks 1 to 4 and Weeks 17 to 20. |
| Bortezomib-Rituximab-Ibrutinib | EXPERIMENTAL | Cycle 1: Rituximab: 375 mg/m2 intravenously (i.v) day 1; Bortezomib:1.6 mg/ m2 subcutanously (SC) day 1,8,15; Ibrutinib: 420 mg orally (p.o.) day 1-28; Cycle 2-6 Rituximab: 1400 mg absolute SC day 1; Bortezomib:1.6 mg/ m2 SC day 1,8,15; Ibrutinib: 420 mg p.o. day 1-28; Maintenance I (1 cycle = 56 days): Ibrutinib 420 mg p.o. daily, until evidence of progressive disease or no longer tolerated by the subject (for a maximum of 10 years); Rituximab 1400 mg absolute SC day 1, every second month for 24 months (month 7-30); Maintenance II (1 cycle = 84 days): Ibrutinib 420 mg p.o. daily, until evidence of progressive disease or no longer tolerated by the subject (for a maximum of 10 years); |
| 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. |
| PCI-32765 (Ibrutinib) | EXPERIMENTAL | - |
| Regimen A | EXPERIMENTAL | Patients will be treated with ibrutinib plus indoximod, cyclophosphamide, and etoposide. Cycles are a minimum of 28 days. |
| Regimen B | EXPERIMENTAL | Patients will be treated with ibrutinib plus indoximod and temozolomide. Cycles are a minimum of 28 days. |
| 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). |
| Ibrutinib - GA101 - GDC_0199 | EXPERIMENTAL | STEP A:C1:Ibrutinib 560mg D2-28;GA101 1000mg day 1/2,8,15;C2-6:Ibrutinib 560mg D 1-28;GA101 1000mg D1 / C7 (Maintenance phase)-C24:Ibrutinib 560mg D1-28 (until progression);GA101 1000mg D1 every 2cycles (from C8) STEP B:C1:Ibrutinib 560mg D2-28;GA101 1000mg D1/2,8,15 / C1bis : Ibrutinib 560mg day 1-28 ; GA101 1000mg D 1 ; GDC-0199 20mg/d at W1, 50mg/d at W2, 100mg at W3, 200 mg/d at W4 / C2-6:Ibrutinib 560mg D1-28;GA101 1000mg D1;GDC-0199:400mg/d W1 and 400, 600 or 800mg/d W2-3-4 + 400, 600 or 800 mg/d C3-C6 (patients 1-12).Patients 13-24:GDC-199 400mg/d / C7(Maintenance phase)-C23:Ibrutinib 560mg D1-28 (until progression);GA101 1000mg D1 every 2 cycles (from C8);GDC:400, 600 or 800 mg D1-28 (patient 1-12).Patients 13-24 : 400mg/d STEP C:C1-C1bis=Step B; C2-6:Ibrutinib 560mg D1-28;GA101 1000mg D1;GDC:400mg/d C7 (Maintenance phase)-C23 : Ibrutinib 560mg D1-28 (--\>progression);GA101 1000mg D1/2 cycles (from C8);GDC-0199 400mg/d |
| 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. |
| Patients with mild hepatic function | EXPERIMENTAL | Patients will receive PCI-32765 140 mg, orally, as a single dose, on Day 1. |
| Patients with moderate hepatic function | EXPERIMENTAL | Patients will receive PCI-32765 140 mg, orally, as a single dose, on Day 1. |
| Patients with severe hepatic function | EXPERIMENTAL | Patients will receive PCI-32765 140 mg, orally, as a single dose, on Day 1. |
| Patients with normal hepatic function | EXPERIMENTAL | Patients will receive PCI-32765 140 mg, orally, as a single dose, on Day 1. |
| PCI-32765 | EXPERIMENTAL | Patients will receive oral doses of PCI-32765 in Cohort 1, Cohort 2 and CLL/SLL Cohort. In Cohort 1, single oral dose of PCI-32765 140 mg and 280 mg will be given before administration of daily oral doses of 420 mg per day for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter. In Cohort 2 and CLL/SLL Cohort, PCI-32765 560 mg and 420 mg per day, respectively will be administered daily for 35 days in Cycle 1 and for 28 days in Cycle 2 and thereafter. |
| 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. |
| Cyclophosphamide | DRUG | Given IV |
| Fludarabine Phosphate | DRUG | Given IV |
| Laboratory Biomarker Analysis | OTHER | Correlative studies |
| Pharmacogenomic Study | OTHER | Correlative studies |
| Quality-of-Life Assessment | OTHER | Ancillary studies |
| Rituximab | BIOLOGICAL | Given IV |
| Bendamustine | DRUG | 90 milligram per meter square (mg/m\^2) administered intravenously on Days 1 to 2 of Cycles 1 to 6. |
| Doxorubicin | DRUG | 50 mg/m\^2 administered intravenously on Day 1 of Cycles 1 to 6. |
| Vincristine | DRUG | 1.4 mg/m\^2 (maximum total 2 mg) administered intravenously on Day 1 of Cycles 1 to 6. |
| Prednisone | DRUG | 100 mg administered orally on Days 1 to 5 of Cycles 1 to 6. |
| PCI-32765 (Ibrutinib) | DRUG | 560 mg (4\*140 mg) capsules administered orally once daily, continuously starting on Cycle 1, Day 1. |
| Placebo | DRUG | Placebo (4 capsules) matched to ibrutinib administered orally once daily, continuously starting on Cycle 1, Day 1. |
| Prednisone (or equivalent) | DRUG | 100 mg capsules administered by mouth once daily on Day 1 to Day 5 of each cycle |
| 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. |
| Ibrutinib Oral Tablet | DRUG | Orally once daily, administered alone during the initial treatment phase and continued in combination with venetoclax and epcoritamab according to the study treatment schedule. |
| Venetoclax Oral Tablet | DRUG | Oral administration as part of the study treatment regimen, in combination with ibrutinib and subsequently with epcoritamab according to the study treatment schedule. |
| Epcoritamab | DRUG | Subcutaneous administration as part of the study treatment regimen in combination with ibrutinib and venetoclax according to the study treatment schedule |
| Methotrexate | DRUG | 3.5mg/m2 IV |
| Rituximab (where available) | DRUG | 375mg/m2 / 1400mg IV or SC |
| Lenalidomide | DRUG | Lenalidomide capsules will be administered orally. |
| Bortezomib | DRUG | Bortezomib will be administered either intravenously or subcutaneously. |
| Ibrutinib / Bortezomib / Rituximab | DRUG | Induction (Rituximab / Bortezomib / Ibrutinib), Maintenance I (Ibrutinib / Rituximab), Maintenance II (Ibrutinib) |
| Indoximod | DRUG | Indoximod will be taken by mouth twice daily, throughout each treatment cycle. |
| Etoposide | DRUG | Etoposide will be taken by mouth once daily, on days 1-21 of each treatment cycle. |
| Temozolomide | DRUG | Temozolomide will be taken by mouth once daily, on days 1-5 of each treatment cycle. |
| 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). |
| Ibrutinib + GA101 +GDC-0199 | DRUG | Step A : 9 patients receive the combination of Ibrutinib + GA101 Step B : 24 patients receive the combination of Ibrutinib + GA101 + GDC-0199 Step C : 15 untreated patients receive the combination of Ibrutinib + GA101 + GDC-0199 |
| 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. |
| PCI-32765 | DRUG | PCI-32765 140 mg will be administered as a single dose, orally, on Day 1. |
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...
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PCI-32765 is an investigational small molecule developed by Johnson & Johnson (ticker JNJ). It has been studied in hepatic impairment, lymphoma, and recurrent mature B-cell neoplasms. The drug is also known as ibrutinib, and it appears in trial records under both names, including PCI-32765 (Ibrutinib) and PCI-32765 (Treatment A).
PCI-32765 has been studied in lymphoma, including previously treated indolent non-Hodgkin lymphoma and refractory follicular lymphoma. It has also been evaluated in recurrent mature B-cell neoplasms and in participants with varying degrees of hepatic impairment. These are investigational uses studied in clinical trials, not approved indications.
Johnson & Johnson, which trades under the ticker JNJ, is the developer of PCI-32765. The company sponsored the clinical trials evaluating the drug in lymphoma, recurrent mature B-cell neoplasms, and hepatic impairment.
PCI-32765 has been studied across Phase 1, Phase 2, and Phase 3 clinical trials. The Phase 1 studies evaluated pharmacokinetics in hepatic impairment and activity in recurrent mature B-cell neoplasms, while later-phase studies evaluated it in lymphoma. It is an investigational agent and is not an approved product.
PCI-32765 has been evaluated in four completed trials: NCT01974440, a Phase 3 study in previously treated indolent non-Hodgkin lymphoma; NCT01779791, a Phase 2 study in refractory follicular lymphoma; NCT01767948, a Phase 1 pharmacokinetic study in hepatic impairment; and NCT01704963, a Phase 1 study in recurrent mature B-cell neoplasms.
Yes, PCI-32765 is also known as ibrutinib. Trial records list the drug under both names, including PCI-32765 (Ibrutinib) and PCI-32765 (Treatment A), so searches for either name refer to the same investigational small molecule developed by Johnson & Johnson.