A Study Evaluating the Safety, Efficacy and Pharmacokinetics of Venetoclax Combined With Chemotherapy in Participants With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL

Study Overview
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Brief Summary
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This is a multicenter, open-label, dose-finding study of venetoclax administered orally in combination with rituximab (R) or obinutuzumab (G) and standard doses of cyclophosphamide, doxorubicin, vincristine and oral prednisone (CHOP) in participants with Non-Hodgkin's Lymphoma (NHL). The study consisted of 2 stages: a dose-finding Phase Ib stage and a Phase II expansion stage. In the Phase I portion of the study, participants were randomized to one of 2 treatment arms venetoclax in combination with R-CHOP (Arm A) and venetoclax in combination with G-CHOP (Arm B) and explored the doses of venetoclax in combination with R-CHOP and G-CHOP. The maximum tolerated dose (MTD) of venetoclax in combination with R-CHOP and G-CHOP was determined during the dose-finding stage. For the Phase II portion of the study, the venetoclax dose for venetoclax + R-CHOP was on a non-continuous dosing schedule as determined by the Phase Ib portion of the study based on safety and tolerability observed in participants treated in the dose escalation portion of the study. On 17 July 2016, Roche/Genentech as the sponsor of Study BO21005 (Goya study), a Phase III study that evaluated G CHOP versus R-CHOP in 1L DLBCL, informed through a press release that the primary endpoint of investigator-assessed PFS was not met. Given these results, Arm B (venetoclax + G-CHOP) was not expanded in Phase II in patients who are first-line with DLBCL.

Official Title
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A Phase Ib/II, Open-Label Study Evaluating the Safety, Efficacy and Pharmacokinetics of GDC-0199 (ABT-199) in Combination With Rituximab (R) or Obinutuzumab (G) Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Patients With B-Cell Non-Hodgkin's Lymphoma (NHL) and DLBCL

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Cyclophosphamide
* Drug: Obinutuzumab
* Drug: Rituximab
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General Inclusion Criteria: At least one bi-dimensionally measurable lymphoma lesion on CT scan defined as > 1.5 cm in its longest dimension, which is also FDG avid by screening PET scan. Confirmed availability of archival or freshly biopsied tumor tissue prior to study enrollment Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 Adequate hematologic function For female participants of childbearing potential, agreement to use highly effective forms of contraception Dose-Escalation Portion of the Study: Participants must have histologically confirmed B-cell NHL, except MCL or SLL Participants must have never received previous R-CHOP treatment Any relapsed/refractory participants that are enrolled during the dose escalation should have received only a single previous treatment regimen Expansion Portion of the Study: Participants must have previously untreated CD20-positive DLBCL and IPI score must be 2-5 Exclusion Criteria: General Exclusion Criteria: History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products Contraindication to receive any of the individual components of CHOP, rituximab or obinutuzumab Prior anthracycline therapy Participants with ongoing corticosteroid use >30 mg per day of prednisone or equivalent CNS lymphoma or primary mediastinal DLBCL Vaccination with live vaccines within 28 days prior to randomization Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1 History of other malignancy that could affect compliance with the protocol or interpretation of results Evidence of significant, uncontrolled concomitant disease Significant cardiovascular disease or significant pulmonary disease Left ventricular ejection fraction less than (<) 50% as defined by multiple-gated acquisition (MUGA) Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle 1 Day 1 Received the following agents within 7 days prior to the first dose of venetoclax: steroid therapy for anti-neoplastic intent; strong and moderate cytochrome P450 (CYP) 3A4 inhibitors or inducers; grapefruit/grapefruit products, seville oranges or star fruit within 3 days prior to the first dose of venetoclax Clinically significant history of liver disease, including viral or other hepatitis, current alcohol abuse, or cirrhosis Recent major surgery Women who are pregnant or lactating Dose-Escalation Portion of the Study: Participants with confirmed mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL) Expansion Portion of the Study: Participants with transformed lymphoma (participants with discordant bone marrow involvement (i.e., low grade histology in bone marrow) may be considered after discussion with the Medical Monitor) Prior therapy for NHL

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venetoclax + G-CHOP Arm<br>Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + obinutuzumab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + obinutuzumab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. | Drug: Venetoclax<br>* Venetoclax 200 to 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4-10 of Cycle 1 and Days 1-10 of Cycles 2-8 during Phase I and MTD will be administered according to the same schedule during Phase II.<br>* Other names: GDC-0199, ABT-199;Drug: Cyclophosphamide<br>* Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.<br>Drug: Obinutuzumab<br>* Obinutuzumab will be administered by IV infusion as an absolute dose of 1000 mg on Days 1, 8, 15 of Cycle 1 and Day 1 of Cycles 2-8 (cycle length = 21 days).<br>Drug: Doxorubicin<br>* Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.<br>Drug: Vincristine<br>* Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.<br>Drug: Prednisone<br>* Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.<br>|
| Experimental: Venetoclax + R-CHOP Arm<br>Phase I: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax + rituximab. Each cycle will consist of 21 days. Phase II: Participants will receive 6 cycles of CHOP and 8 cycles of venetoclax (at dose determined in Phase I) + rituximab. Each cycle will consist of 21 days. For both phase I and II, participants with ongoing response without excessive toxicity may receive up to eight cycles of CHOP following discussion between the investigator and the Medical Monitor. | Drug: Venetoclax<br>* Venetoclax 200 to 800 milligrams (mg) tablets will be administered orally once daily (QD) on Days 4-10 of Cycle 1 and Days 1-10 of Cycles 2-8 during Phase I and MTD will be administered according to the same schedule during Phase II.<br>* Other names: GDC-0199, ABT-199;Drug: Cyclophosphamide<br>* Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.<br>Drug: Rituximab<br>* Rituximab 375 mg/m^2 dose will be administered IV on Day 1 of every 21-day cycle.<br>* Other names: MabThera/Rituxan;Drug: Doxorubicin<br>* Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.<br>Drug: Vincristine<br>* Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.<br>Drug: Prednisone<br>* Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Number of Participants With Dose-Limiting Toxicities (DLTs) | DLTs were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (NCI CTCAE v4.0). Decrease in B cells, lymphopenia, and leukopenia caused by lymphopenia were not considered DLTs but instead were expected outcomes of study treatment. Any Grade >/= 3 adverse event, that was attributed to having a reasonable possibility of being related to the combined administration of venetoclax plus R-CHOP or G-CHOP, that could not be attributed by the investigator to an alternative, clearly identifiable cause such as tumor progression, concurrent illness or medical condition, or concomitant medication and that occurred during the DLT observation period (start of venetoclax treatment through end of Cycle 2) was considered a DLT for dose-escalation purposes. Grade 3 or 4 neutropenia or thrombocytopenia identified on Day 1 of Cycle 2 or 3, resulting in dose delay were considered DLTs. | Start of venetoclax administration (Cycle 1 Day 4 or 3 days after first CHOP dose) up to end of Cycle 2 (cycle length = 21 days) | 
| Percentage of Previously Untreated DLBCL Participants With Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Scan Using the Modified Lugano Classification Assessed by Independent Review Committee (IRC) | CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake </= mediastinum; 3) uptake < mediastinum but </= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy | Baseline up to end of treatment (up to approximately 6 months) | 
| Percentage of Participants With CR Defined by PET/CT Scan in Previously Untreated DLBCL Co-Expressing Both Bcl-2 and c-Myc Proteins (DE-DLBCL) Participants Assessed by IRC | CR was defined as follows according to modified Lugano classification for PET/CT-based response: Lymph nodes and extra-lymphatic sites with score 1, 2, or 3 with or without a residual mass on 5-point scale with 1) no uptake above background; 2) uptake </= mediastinum; 3) uptake < mediastinum but </= liver. No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. | Baseline up to end of treatment (up to approximately 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC) | AUC was calculated based on measurement of venetoclax concentration in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts. Data are reported as hour*micrograms per milliliter (hr*mcg/mL) | Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4 (cycle length = 21 days) | 
| Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax) | Tmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts. | Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days) | 
| Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax) | Cmax was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts. Data are reported as micrograms per milliliter | Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days) | 
| Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval | Cmin was determined based on measurement of venetoclax concentrations in plasma over time. Venetoclax exposure was pooled across Phase I and II for the R-CHOP 800 mg cohorts. | Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days) | 
| Prednisone Plasma PK: AUC | AUC was determined based on measurement of Predisone concentrations in plasma over time. | Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days) | 
| Prednisone Plasma PK: Tmax | Tmax was determined based on measurement of Predisone concentrations in plasma over time. | Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days) | 
| Prednisone Plasma PK: Cmax | Cmax was determined based on measurement of Predisone concentrations in plasma over time. | Predose (within 30 minutes) and 0.5, 1, 2, 4, 6 Hr after prednisone dose on Day 1 of Cycle 1 and 2 (cycle length = 21 days) | 
| Rituximab PK: Cmax | Cmax was determined using the post-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1. | End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) | 
| Rituximab PK: Cmin Within the Dosing Interval | Cmin was determined using the pre-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose on Day 1 of Cycle 2. | Pre-dose on Cycle 2 Day 1 (cycle length = 21 days) | 
| Obinutuzumab PK: Cmax | Cmax was determined using the post-dose obinutuzumab plasma concentrations at the 800 mg Venetoclax Dose using the end of infusion time point on Cycle 1 Day 1. | End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) | 
| Cyclophosphamide PK: Cmax | Cmax was determined using the post-dose Cyclophosphamide plasma concentrations on Cycle 1 Day 1. | End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) | 
| Doxorubicin PK: Cmax | Cmax was determined using the post-dose Doxorubicin plasma concentrations. | End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) | 
| Vincristine PK: Cmax | Cmax was determined using the post-dose Vincristine plasma concentrations. | End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) | 
| Percentage of Participants With Objective Response Defined as Partial Response (PR) or Complete Response (CR) Defined by Positron Emission Tomography-Computed Tomography (PET/CT) Using the Modified Lugano Classification Assessed by IRC | Objective Response defined as PR (partial response) or CR (complete response) at end of treatment. CR: Lymph nodes and extra-lymphatic sites with score 1, 2 or 3 on a 5-point scale (with a higher score being a worse outcome). No evidence of fluorodeoxyglucose (FDG)-uptake disease in marrow. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. PR: Lymph nodes and extralymphatic sites with score of 4 or 5 on the 5-point scale with reduced uptake compared with baseline and residual mass(es) of any size. CT-based response criteria for PR must also be met. No new lesions. In bone marrow residual uptake could be higher than in normal marrow but must be reduced compared with baseline; persistent focal changes in the marrow to be considered for further evaluation with magnetic resonance imaging (MRI) or biopsy or an interval scan. OR=PR+CR | Baseline to end of treatment (up to approximately 6 months) | 
| Percentage of Participants Who Are Alive and Without Disease Progression at Month 12 | Progressive disease (PD) was determined using the modified Lugano classification criteria. For PET-CT-based PD: Score 4 (uptake moderately > liver) or 5 (uptake markedly higher than liver and/or new lesions) with an increase in intensity of uptake from baseline in target nodes and nodal lesions, new FDG-uptake foci of extranodal lesions consistent with lymphoma at interim or end-of-treatment assessment, no non-measured lesions, new FDG-uptake foci consistent with lymphoma, new or recurrent FDG-uptake foci in bone marrow. For CT-based PD: >/= 50% decrease in SPD of up to 6 target measureable nodes and extranodal sites; non-measured lesion should be absent/normal, have regressed, but not increased; no new lesions. | Month 12 | 
| Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification | CR was defined as follows according to modified Lugano classification for CT-based response: Target nodes/nodal masses must have regressed to </= 1.5 cm in longest transverse diameter of a lesion (LDi), no extra-lymphatic sites of disease, absence of non-measured lesions, organ enlargement must have regressed to normal, no new lesions, and if the bone marrow was involved by lymphoma prior to treatment, the infiltrate must have cleared on repeat bone marrow biopsy. | Baseline up to end of treatment (approx. 6 months) | 
| Safety: Percentage of Participants With Adverse Events | An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. | Baseline up to approximately 36 months | 
| Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy | Maintenance of relative dose intensity was defined as a dose intensity of >/= 90%. | Baseline up to Cycle 6 (cycle length = 21 days) | 
| Relative Dose Intensity of Venetoclax | Dose intensity was categorized as < 80%, 80% to < 85%, 85% to < 90%, or >/= 90%. | Baseline up to Cycle 6 (cycle length = 21 days) |