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

• ClinicalTrials.gov Identifier: NCT02055820
• Recruitment Status: Completed
• First Posted: February 5, 2014
• Results First Posted: December 20, 2018
• Last Update Posted: June 11, 2020
• Sponsor: Hoffmann-La Roche
• Collaborator: AbbVie
• Information provided by (Responsible Party): Hoffmann-La Roche

Tracking Information

• First Submitted Date: February 4, 2014
• First Posted Date: February 5, 2014
• Results First Submitted Date: June 26, 2018
• Results First Posted Date: December 20, 2018
• Last Update Posted Date: June 11, 2020
• Actual Study Start Date: November 17, 2013
• Actual Primary Completion Date: June 28, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 26, 2020)

• Safety: Number of Participants With Dose-Limiting Toxicities (DLTs) [ Time Frame: 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) ]
  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.
• 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) [ Time Frame: Baseline up to end of treatment (up to approximately 6 months) ]
  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
• 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 [ Time Frame: Baseline up to end of treatment (up to approximately 6 months) ]
  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.

Original Primary Outcome Measures (submitted: February 4, 2014)

• Safety: Incidence of dose-limiting toxicities [ Time Frame: Approximately 9 months ]
• Complete response (CR) defined by PET/CT scan and bone marrow examination [ Time Frame: Approximately 9 months ]

Current Secondary Outcome Measures (submitted: May 26, 2020)

• Venetoclax Plasma PK: Area Under the Plasma Concentration-Time Curve (AUC) [ Time Frame: Predose (within 30 minutes) & 2, 4, 6, 8 hours (Hr) postdose on Cycle 1 Day 4 (cycle length = 21 days) ]
  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)
• Venetoclax Plasma PK: Time to Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days) ]
  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.
• Venetoclax Plasma PK: Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days) ]
  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
• Venetoclax Plasma PK: Minimum Plasma Concentration (Cmin) Within the Dosing Interval [ Time Frame: Predose (within 30 minutes) & 2, 4, 6, 8 Hr postdose on Cycle 1 Day 4 (cycle length = 21 days) ]
  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.
• Prednisone Plasma PK: AUC [ Time Frame: 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) ]
  AUC was determined based on measurement of Predisone concentrations in plasma over time.
• Prednisone Plasma PK: Tmax [ Time Frame: 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) ]
  Tmax was determined based on measurement of Predisone concentrations in plasma over time.
• Prednisone Plasma PK: Cmax [ Time Frame: 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) ]
  Cmax was determined based on measurement of Predisone concentrations in plasma over time.
• Rituximab PK: Cmax [ Time Frame: End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) ]
  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.
• Rituximab PK: Cmin Within the Dosing Interval [ Time Frame: Pre-dose on Cycle 2 Day 1 (cycle length = 21 days) ]
  Cmin was determined using the pre-dose rituximab plasma concentrations at the 800 mg Venetoclax Dose on Day 1 of Cycle 2.
• Obinutuzumab PK: Cmax [ Time Frame: End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) ]
  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.
• Cyclophosphamide PK: Cmax [ Time Frame: End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) ]
  Cmax was determined using the post-dose Cyclophosphamide plasma concentrations on Cycle 1 Day 1.
• Doxorubicin PK: Cmax [ Time Frame: End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) ]
  Cmax was determined using the post-dose Doxorubicin plasma concentrations.
• Vincristine PK: Cmax [ Time Frame: End of Infusion on Cycle 1 Day 1 (cycle length = 21 days) ]
  Cmax was determined using the post-dose Vincristine plasma concentrations.
• 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 [ Time Frame: Baseline to end of treatment (up to approximately 6 months) ]
  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
• Percentage of Participants Who Are Alive and Without Disease Progression at Month 12 [ Time Frame: 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.
• Percentage of Participants With CR Defined by Computed Tomography (CT) Scan Using the Modified Lugano Classification [ Time Frame: Baseline up to end of treatment (approx. 6 months) ]
  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.
• Safety: Percentage of Participants With Adverse Events [ Time Frame: Baseline up to approximately 36 months ]
  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.
• Safety: Percentage of Participants Maintaining Relative Dose Intensity of CHOP Chemotherapy [ Time Frame: Baseline up to Cycle 6 (cycle length = 21 days) ]
  Maintenance of relative dose intensity was defined as a dose intensity of >/= 90%.
• Relative Dose Intensity of Venetoclax [ Time Frame: Baseline up to Cycle 6 (cycle length = 21 days) ]
  Dose intensity was categorized as < 80%, 80% to < 85%, 85% to < 90%, or >/= 90%.

Original Secondary Outcome Measures (submitted: February 4, 2014)

• Relative dose intensity [ Time Frame: Approximately 9 months ]
• Objective response (partial or complete response) rate [ Time Frame: Approximately 9 months ]
• Response duration, defined as time from first documented response until relapse or death. [ Time Frame: Approximately 2 years ]
• Safety: Incidence of adverse events [ Time Frame: Approximately 1 year ]
• Progression-free survival [ Time Frame: Approximately 2 years ]
• Overall survival [ Time Frame: Approximately 2 years ]
• CR defined by CT scan and bone marrow examination [ Time Frame: Approximately 9 months ]
• Pharmacokinetics: plasma concentration-time profile of GDC-0199 [ Time Frame: Approximately 9 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Lymphoma, Non-Hodgkin

Intervention

• Drug: Venetoclax
  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.
  Other Name: GDC-0199, ABT-199
• Drug: Cyclophosphamide
  Cyclophosphamide 750 milligrams per square meter (mg/m^2) administered intravenously (IV) on Day 1 of each 21-day cycle up to Cycle 6.
• Drug: Obinutuzumab
  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).
• Drug: Rituximab
  Rituximab 375 mg/m^2 dose will be administered IV on Day 1 of every 21-day cycle.
  Other Name: MabThera/Rituxan
• Drug: Doxorubicin
  Doxorubicin 50 mg/m^2 administered IV on Day 1 of each 21-day cycle up to Cycle 6.
• Drug: Vincristine
  Vincristine 1.4 mg/m^2 (maximum 2 mg) administered IV on Day 1 of each 21-day cycle up to Cycle 6.
• Drug: Prednisone
  Prednisone 100 mg per day orally on Days 1-5 of each 21-day cycle up to Cycle 6.

Study Arms

• Experimental: Venetoclax + G-CHOP Arm
  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.
  Interventions:

  • Drug: Venetoclax
  • Drug: Cyclophosphamide
  • Drug: Obinutuzumab
  • Drug: Doxorubicin
  • Drug: Vincristine
  • Drug: Prednisone
• Experimental: Venetoclax + R-CHOP Arm
  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.
  Interventions:

  • Drug: Venetoclax
  • Drug: Cyclophosphamide
  • Drug: Rituximab
  • Drug: Doxorubicin
  • Drug: Vincristine
  • Drug: Prednisone

Publications *

• Zelenetz AD, Salles G, Mason KD, Casulo C, Le Gouill S, Sehn LH, Tilly H, Cartron G, Chamuleau MED, Goy A, Tam CS, Lugtenburg PJ, Petrich AM, Sinha A, Samineni D, Herter S, Ingalla E, Szafer-Glusman E, Klein C, Sampath D, Kornacker M, Mobasher M, Morschhauser F. Venetoclax plus R- or G-CHOP in non-Hodgkin lymphoma: results from the CAVALLI phase 1b trial. Blood. 2019 May 2;133(18):1964-1976. doi: 10.1182/blood-2018-11-880526. Epub 2019 Mar 8.
• Samineni D, Huang W, Gibiansky L, Ding H, Zhang R, Li C, Sinha A, Rajwanshi R, Humphrey K, Bazeos A, Salem AH, Miles D. Population Pharmacokinetics and Exposure-Response Analyses for Venetoclax in Combination with R-CHOP in Relapsed/Refractory and Previously Untreated Patients with Diffuse Large B Cell Lymphoma. Adv Ther. 2022 Jan;39(1):598-618. doi: 10.1007/s12325-021-01919-z. Epub 2021 Nov 25.
• Morschhauser F, Feugier P, Flinn IW, Gasiorowski R, Greil R, Illes A, Johnson NA, Larouche JF, Lugtenburg PJ, Patti C, Salles GA, Trneny M, de Vos S, Mir F, Samineni D, Kim SY, Jiang Y, Punnoose E, Sinha A, Clark E, Spielewoy N, Humphrey K, Bazeos A, Zelenetz AD. A phase 2 study of venetoclax plus R-CHOP as first-line treatment for patients with diffuse large B-cell lymphoma. Blood. 2021 Feb 4;137(5):600-609. doi: 10.1182/blood.2020006578. Erratum In: Blood. 2021 Apr 1;137(13):1844.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 29, 2017): 267
• Original Estimated Enrollment (submitted: February 4, 2014): 248
• Actual Study Completion Date: June 28, 2019
• Actual Primary Completion Date: June 28, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Canada, Czechia, France, Hungary, Italy, Netherlands, Spain, United States
• Removed Location Countries: Czech Republic, Germany

Administrative Information

• NCT Number: NCT02055820
• Other Study ID Numbers: GO27878; 2013-003749-40 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Same as current
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Same as current
• Collaborators: AbbVie

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Hoffmann-La Roche
• Verification Date: May 2020