Study to Investigate Idelalisib in Combination With Chemotherapeutic Agents, Immunomodulatory Agents and Anti-CD20 Monoclonal Antibody (mAb) in Participants With Relapsed or Refractory Indolent B-cell Non-Hodgkin's Lymphoma, Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the safety of idelalisib in combination with an anti-CD20 monoclonal antibody (mAb), a chemotherapeutic agent, a mammalian target of rapamycin (mTOR) inhibitor, a protease inhibitor, an antiangiogenic agent, and/or an immunomodulatory agent in participants with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (NHL), mantle cell lymphoma (MCL), or chronic lymphocytic leukemia (CLL).

Official Title
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A Phase I Study to Investigate the Safety and Clinical Activity of Idelalisib in Combination With Chemotherapeutic Agents, Immunomodulatory Agents and Anti-CD20 mAb in Subjects With Relapsed or Refractory Indolent B-cell Non-Hodgkin Lymphoma, Mantle Cell Lymphoma or Chronic Lymphocytic Leukemia

Conditions
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Indolent Non-Hodgkin's Lymphoma, Chronic Lymphocytic Leukemia, Mantle Cell Lymphoma

Intervention / Treatment
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* Drug: Idelalisib
* Drug: Rituximab
* Drug: Bendamustine
* Drug: Ofatumumab
* Drug: Fludarabine
* Drug: Everolimus
* Drug: Bortezomib
* Drug: Chlorambucil
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Age ≥ 18 Previously treated with relapsed or refractory disease (refractory defined as not responding to a standard regimen or progressing within 6 months of the last course of a standard regimen) Disease status requirement: For CLL patients, symptomatic disease that mandates treatment as defined by the International Workshop on Chronic Lymphocytic Lymphoma (IWCLL) 2008 criteria For indolent NHL and MCL patients, measurable disease by CT scan defined as at least 1 lesion that measures > 2 cm in a single dimension WHO performance status of ≤ 2 For men and women of child-bearing potential, willing to use adequate contraception (ie, latex condom, cervical cap, diaphragm, abstinence, etc.) for the entire duration of the study. For Cohort 7 only: Women of child bearing potential must have 2 negative pregnancy tests prior to starting lenalidomide. Able to provide written informed consent Key Exclusion Criteria: Is not a good candidate to receive any of the drugs administered in the study for a given disease (idelalisib, bendamustine, rituximab, ofatumumab, fludarabine, everolimus, bortezomib, or chlorambucil), according to the clinical judgment of the investigator Patients with atypical immunophenotype with t(11:14) translocation or cyclin D1 over-expression (CLL patients only) Had radiotherapy, radioimmunotherapy, biological therapy, chemotherapy, or treatment with an investigational product within 4-weeks prior to the baseline disease status tests Had treatment with a short course of corticosteroids for symptom relief within 1-week prior to the baseline disease status tests Has had an allogeneic hematopoietic stem cell transplant Has known active central nervous system involvement of the malignancy Is pregnant or nursing Has active, serious infection requiring systemic therapy. Patients may receive prophylactic antibiotics and antiviral therapy at the discretion of the investigator Has absolute neutrophil count (ANC) < 1000/µL, unless it is related to underlying CLL, MCL or indolent NHL, the latter documented by > 50% infiltration of bone marrow by tumor cells Has platelet count < 75000/µL, unless it is related to underlying CLL, MCL, or iNHL, the latter documented by > 50% infiltration of bone marrow by tumor cells Has serum creatinine ≥ 2.0 mg/dL For Cohort 7 only: Has creatinine clearance < 60 mL/min Has serum bilirubin ≥ 2 mg/dL (unless due to Gilbert's syndrome) for patients with iNHL or CLL; for patients with MCL, serum bilirubin ≥ 1.5 x upper limit of normal Has serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≥ 2 x upper limit of normal Has Child-Pugh Class B or C hepatic impairment Has a positive test for HIV antibodies Has active hepatitis B or C (confirmed by RNA test). Patients with serologic evidence of prior exposure are eligible. Prior treatment with idelalisib Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Idelalisib + Rituximab<br>Participants with chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) will receive treatments as follows: Cohort 1a: Idelalisib (IDELA) 100 mg orally twice daily (BID) on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 intravenously (IV) on Days 1, 8, 15 & 22, Cycles 1 & 2 Cohort 2a: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Days 1, 8, 15, & 22, Cycles 1 & 2 Cohort 3e: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Days 1, 8, 15, & 22, Cycles 1 & 2 Cohort 4a: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle, starting Cycle 2 Day 1 with the 5th dose of rituximab + rituximab 375 mg/m^2 IV on Days 1, 8, 15, & 22, Cycles 1 & 2 | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: Zydelig®;Drug: Rituximab<br>* Rituximab administered intravenously<br>* Other names: Rituxan;|
| Experimental: Idelalisib + Rituximab + Bendamustine<br>Participants with CLL, iNHL and mantle cell lymphoma (MCL) will receive treatments as follows: Cohort 3a: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Day 1 of each 28-day cycle, Cycles 1 - 6 + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6 Cohort 3b: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Day 1 of each 28-day cycle, Cycles 1 - 6 + bendamustine 70 mg/m^2 IV on Days 1 & 2 of each 28-day cycle from Cycles 1 - 6 Cohort 5c: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Day 1 of each 28-day cycle, Cycles 1 - 6 + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6 | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: Zydelig®;Drug: Rituximab<br>* Rituximab administered intravenously<br>* Other names: Rituxan;Drug: Bendamustine<br>* Bendamustine administered intravenously<br>* Other names: Treanda;|
| Experimental: Idelalisib + Bendamustine<br>Participants with CLL and iNHL will receive treatments as follows: Cohort 1b: IDELA 100 mg orally BID on Days 1 - 28 of each 28-day cycle + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6 Cohort 2b: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6 Cohort 3f: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6 Cohort 3g: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + bendamustine 70 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6 Cohort 4b: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle starting Cycle 2, Day 3 (after the Cycle 2 bendamustine dosing) + bendamustine 90 mg/m^2 IV on Days 1 & 2 of each 28-day cycle, Cycles 1 - 6 | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: Zydelig®;Drug: Bendamustine<br>* Bendamustine administered intravenously<br>* Other names: Treanda;|
| Experimental: Idelalisib + Ofatumumab<br>Participants with CLL will receive treatments as follows: Cohort 3c: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + ofatumumab 12 doses (300 mg (Day 1 or Day 2, Dose 1), followed 1 week later by 1,000 mg weekly for 7 doses (Doses 2 - 8), followed 5 weeks later by 1,000 mg every 4 weeks for 4 doses (Doses 9 - 12)) | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: Zydelig®;Drug: Ofatumumab<br>* Ofatumumab administered intravenously<br>* Other names: Arzerra;|
| Experimental: Idelalisib + Fludarabine<br>Participants with CLL will receive treatments as follows: Cohort 3d: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + fludarabine 40 mg/m^2 orally on Days 1 - 5 of each 28-day cycle, Cycles 1 - 6 | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: Zydelig®;Drug: Fludarabine<br>* Fludarabine administered orally<br>* Other names: Fludara;|
| Experimental: Idelalisib + Everolimus<br>Participants with MCL will receive treatments as follows: Cohort 5a: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + everolimus 10 mg orally once daily on Days 1 - 28 of each 28-day cycle | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: Zydelig®;Drug: Everolimus<br>* Everolimus administered orally twice daily until disease progression<br>* Other names: RAD-001;|
| Experimental: Idelalisib + Bortezomib<br>Participants with MCL will receive treatments as follows: Cohort 5b: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + bortezomib 1.3 mg/m^2 subcutaneously on Days 1, 8 & 15 of each 28-day cycle | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: Zydelig®;Drug: Bortezomib<br>* Bortezomib administered as a subcutaneous injection<br>* Other names: codenamed PS-341;|
| Experimental: Idelalisib + Chlorambucil<br>Participants with CLL will receive treatments as follows: Cohort 6a: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + chlorambucil 10 mg/m^2 orally once daily for 7 days every 28 days, Cycles 1 - 12 | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: Zydelig®;Drug: Chlorambucil<br>* Chlorambucil administered on Days 1-7 every 28 days to allow appropriate therapy for participants with CLL and to coordinate into a cycle period equivalent to other study treatment regimens.<br>* Other names: Leukeran;|
| Experimental: Idelalisib + Rituximab + Chlorambucil<br>Participants with CLL will receive treatments as follows: Cohort 6b: IDELA 150 mg orally BID on Days 1 - 28 of each 28-day cycle + rituximab 375 mg/m^2 IV on Day 1 of each 28-day cycle, Cycles 1 - 6 + chlorambucil 10 mg/m^2 orally once daily for 7 days every 28 days, Cycles 1 - 12 | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: Zydelig®;Drug: Rituximab<br>* Rituximab administered intravenously<br>* Other names: Rituxan;Drug: Chlorambucil<br>* Chlorambucil administered on Days 1-7 every 28 days to allow appropriate therapy for participants with CLL and to coordinate into a cycle period equivalent to other study treatment regimens.<br>* Other names: Leukeran;|
| Experimental: Idelalisib + Rituximab + Lenalidomide<br>Participants with CLL and iNHL will receive treatments as follows: Cohort 7a: IDELA 150 mg orally BID on Days 1 - 35 of Cycle 1 (35 days) & Days 1 - 28 of all subsequent 28-day cycles + rituximab 375 mg/m^2 IV on Days 1 & 8 of Cycle 1 & Day 1 of Cycles 2 - 6 + lenalidomide 5 mg orally once daily on Days 8 - 28 of Cycle 1 (35 days) & Days 1 - 21 of next five 28-day cycles Cohort 7b: IDELA 150 mg orally BID on Days 1 - 35 of Cycle 1 (35 days) & Days 1 - 28 of all subsequent 28-day cycles + rituximab 375 mg/m^2 IV on Days 1 & 8 of Cycle 1 & Day 1 of Cycles 2 - 6 + lenalidomide 10 mg orally once daily on Days 8 - 28 of Cycle 1 (35 days) & Days 1 - 21 of next five 28-day cycles Cohort 7c: IDELA 150 mg orally BID on Days 1 - 35 of Cycle 1 (35 days) & Days 1 - 28 of all subsequent 28-day cycles + rituximab 375 mg/m^2 IV on Days 1 & 8 of Cycle 1 & Day 1 of Cycles 2 - 6 + lenalidomide 20 mg orally once daily on Days 8 - 28 of Cycle 1 (35 days) & Days 1 - 21 of next five 28-day cycles | Drug: Idelalisib<br>* Idelalisib tablet administered orally<br>* Other names: Zydelig®;Drug: Rituximab<br>* Rituximab administered intravenously<br>* Other names: Rituxan;Drug: Lenalidomide<br>* Lenalidomide administered orally<br>* Other names: Revlimid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Exposure to IDELA | Duration of exposure to IDELA was summarized using descriptive statistics. | First dose date up to 12 months | 
| Toxicity of Administration of IDELA | Percentage of participants experiencing toxicities of administration of IDELA were measured according to the Common Terminology Criteria for Adverse Events v4.02 | First dose date up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall Response Rate (ORR) was defined as the percentage of participants achieving a complete response (CR) or partial response (PR). The response definitions were based on the following standard criteria established for each indication: CLL: International Workshop on chronic lymphocytic leukemia (IWCLL),2008 iNHL & MCL: Cheson, 2007 | Up to 5 years | 
| Duration of Response | Duration of response (DOR) was defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of disease progression or death from any cause. | Up to 5 years | 
| Time to Response | Time to response (TTR) was defined as the interval from the start of study drug to the first documentation of CR or PR. | Up to 5 years | 
| Progression-free Survival | Progression free survival (PFS) was defined as the interval from the start of study drug to the earlier of the first documentation of disease progression or death from any cause. The response definitions were based on the following standard criteria established for each indication: CLL: International Workshop on chronic lymphocytic leukemia (IWCLL), 2008 iNHL & MCL: Cheson, 2007 | Up to 5 years | 
| Overall Survival | Overall Survival (OS) was defined as the interval from the start of study drug to death from any cause. | Up to 5 years | 
| Plasma Concentration of IDELA (Cohort 1, Cohorts 2 and 3, Cohort 5) |  | Predose, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0 hours postdose at Week 0; predose, 1.5 hours postdose at Weeks 4, 12, and 24 | 
| Plasma Concentration of IDELA (Cohort 4) |  | Predose at Week 0; predose, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0 hours postdose at Week 4; predose, 1.5 hours postdose at Week 12; and predose, 1.5 hours postdose at Week 24 | 
| Plasma Concentration of IDELA (Cohort 6) |  | Predose, 1.5 hours postdose at Weeks 0, 4, 12 and 24 | 
| Plasma Concentration of IDELA (Cohort 7) |  | Predose, 1.5 hours postdose at Weeks 0, 5 and 13 | 
| Sub-study: Plasma Concentration of IDELA (Cohorts 1-4) |  | pre dose and 0.5, 1, 1.5, 2.0, 3.0, 4.0, and 6.0 hours post dose | 
| Plasma Concentration of Bendamustine |  | Predose, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 3.0, 4.0, 5.0, 6.0 hours postdose at Week 0 | 
| Plasma Concentration of Everolimus |  | Predose, 1.5 hours postdose at Weeks 0 and 4 | 
| Plasma Concentration of Lenalidomide |  | Predose, 1.5 hours postdose at Week 1 and predose at Week 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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phosphatidylinositol 3-kinase, Ofatumumab, indolent non-Hodgkin lymphoma (iNHL)