A Dose-Finding and Efficacy Study of Venetoclax, CC-486, and Obinutuzumab in Follicular Lymphoma

Phase 1

Terminated

Conditions: Follicular Lymphoma

Interventions: Drug: Venetoclax
Drug: Obinutuzumab
Drug: CC-486

Registration Number: NCT04722601

Lead Sponsor: University of Chicago

Brief Summary: This study focuses on finding a safe and tolerable dose for a three-drug regimen that combines venetoclax (Venclexta Ⓡ), CC-486 (also known as oral azacitidine) and obinutuzumab (Gazyva Ⓡ) to treat cancer participants who have minimally pretreated follicular lymphoma and have experienced disease progression despite trying previous cancer therapies. If a safe and tolerable drug dose can be found in the first phase of the study, doctors leading the study will launch a second phase of the study within an expansion cohort. Participants in this expansion cohort will receive the dose established in the first phase of the study to determine the efficacy of the regimen/ established dose. Participants in the expansion cohort will also receive the same study drugs from the first phase of the study, but in a different order/combination (first pairing the two oral drugs, CC-486 and venetoclax, then adding the third drug, obinutuzumab to treatment). The end goal of this research is to establish a new chemotherapy-sparing treatment option for patients with follicular lymphoma that is just as effective (or better) than current standard of care options.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 2

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1(Dose-Finding Arm): Group 2 - Dose Level 2 /Second Dose	Venetoclax	Participants in group 2 will receive a three-drug regimen of venetoclax, CC-486, and obinutuzumab at the second highest dose (dose level 2) set by doctors leading the study. Participants in this group will receive: * Venetoclax: 600 mg on days 1-28 * CC-486: 200 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle. Treatment using these three study drugs (venetoclax, CC-486, and obinutuzumab) will be given in 12 consecutive cycles that run for 28 days during each cycle (336 days).
Phase 1(Dose-Finding Arm): Group 2 - Dose Level 2 /Second Dose	CC-486	Participants in group 2 will receive a three-drug regimen of venetoclax, CC-486, and obinutuzumab at the second highest dose (dose level 2) set by doctors leading the study. Participants in this group will receive: * Venetoclax: 600 mg on days 1-28 * CC-486: 200 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle. Treatment using these three study drugs (venetoclax, CC-486, and obinutuzumab) will be given in 12 consecutive cycles that run for 28 days during each cycle (336 days).
Phase 1 (Dose-Finding Arm) - Group 4 - Lower Dose Level 1	CC-486	Participants in this group will received a lower dose of the three-drug regimen using venetoclax, CC-486 and obinutuzumab set by doctors leading the study. Inclusion in this group is optional and based on whether the participant reports serious adverse events/side effects in response to a higher dose of the regimen. If participants are included in this group, they will receive: * Venetoclax: 400 mg on days 1-28 * CC-486: 150 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle.
Phase 1(Dose-Finding Arm): Group 1 - Dose Level 1 / Starting Dose	CC-486	Phase 1/the dose-finding arm of this study will use three dose levels (a starting dose, second dose and highest dose) of the venetoclax, CC-486 and obinutuzumab regimen. If participants in group 1 don't experience severe negative side effects to the starting dose of the regimen, then more participants will be assigned to groups 2 and 3 to take higher doses until the safest/ most tolerable dose is found. Group 1/ Dose Level 1: Participants in group 1 will receive a three-drug regimen of venetoclax, CC-486, and obinutuzumab at a starting dose used in previous human studies. Participants in this group will receive: * Venetoclax: 400 mg on days 1-28 * CC-486: 200 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle. Treatment using these three study drugs (venetoclax, CC-486, and obinutuzumab) will be given in 12 consecutive cycles that run for 28 days during each cycle (336 days).
Phase 2 (Efficacy Arm/ Expansion Cohort)	CC-486	Participants in this arm will help test the efficacy of the three-drug regimen and dose established in the phase 1 of the study. Participants will take two drugs (venetoclax and CC-48) used in the same three-drug regimen during the first phase of this study. These two drugs will be paired together by themselves and given to participants in the expansion cohort before obinutuzumab (a third drug) is added during cycle 4 of treatment.
Phase 1 (Dose-Finding Arm) - Group 3 - Dose Level 3/ Highest Dose	CC-486	Participants in group 3 will receive a three-drug regimen of venetoclax, CC-486, and obinutuzumab at the highest dose (dose level 3) set by doctors leading the study. Participants in this group will receive: * Venetoclax: 800 mg on days 1-28 * CC-486: 200 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle. Treatment using these three study drugs (venetoclax, CC-486, and obinutuzumab) will be given in 12 consecutive cycles that run for 28 days during each cycle (336 days).
Phase 1 (Dose-Finding Arm) - Group 5 - Lower Dose Level 2	CC-486	Participants in this group will received the second lowest dose of the three-drug regimen using venetoclax, CC-486 and obinutuzumab set by doctors leading the study. Inclusion in this group is optional and based on whether the participant reports serious adverse events/side effects in response to a higher dose of the regimen. If participants are included in this group, they will receive: * Venetoclax: 400 mg on days 1-10 only * CC-486: 150 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle.
Phase 1(Dose-Finding Arm): Group 1 - Dose Level 1 / Starting Dose	Venetoclax	Phase 1/the dose-finding arm of this study will use three dose levels (a starting dose, second dose and highest dose) of the venetoclax, CC-486 and obinutuzumab regimen. If participants in group 1 don't experience severe negative side effects to the starting dose of the regimen, then more participants will be assigned to groups 2 and 3 to take higher doses until the safest/ most tolerable dose is found. Group 1/ Dose Level 1: Participants in group 1 will receive a three-drug regimen of venetoclax, CC-486, and obinutuzumab at a starting dose used in previous human studies. Participants in this group will receive: * Venetoclax: 400 mg on days 1-28 * CC-486: 200 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle. Treatment using these three study drugs (venetoclax, CC-486, and obinutuzumab) will be given in 12 consecutive cycles that run for 28 days during each cycle (336 days).
Phase 1(Dose-Finding Arm): Group 1 - Dose Level 1 / Starting Dose	Obinutuzumab	Phase 1/the dose-finding arm of this study will use three dose levels (a starting dose, second dose and highest dose) of the venetoclax, CC-486 and obinutuzumab regimen. If participants in group 1 don't experience severe negative side effects to the starting dose of the regimen, then more participants will be assigned to groups 2 and 3 to take higher doses until the safest/ most tolerable dose is found. Group 1/ Dose Level 1: Participants in group 1 will receive a three-drug regimen of venetoclax, CC-486, and obinutuzumab at a starting dose used in previous human studies. Participants in this group will receive: * Venetoclax: 400 mg on days 1-28 * CC-486: 200 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle. Treatment using these three study drugs (venetoclax, CC-486, and obinutuzumab) will be given in 12 consecutive cycles that run for 28 days during each cycle (336 days).
Phase 2 (Efficacy Arm/ Expansion Cohort)	Venetoclax	Participants in this arm will help test the efficacy of the three-drug regimen and dose established in the phase 1 of the study. Participants will take two drugs (venetoclax and CC-48) used in the same three-drug regimen during the first phase of this study. These two drugs will be paired together by themselves and given to participants in the expansion cohort before obinutuzumab (a third drug) is added during cycle 4 of treatment.
Phase 2 (Efficacy Arm/ Expansion Cohort)	Obinutuzumab	Participants in this arm will help test the efficacy of the three-drug regimen and dose established in the phase 1 of the study. Participants will take two drugs (venetoclax and CC-48) used in the same three-drug regimen during the first phase of this study. These two drugs will be paired together by themselves and given to participants in the expansion cohort before obinutuzumab (a third drug) is added during cycle 4 of treatment.
Phase 1(Dose-Finding Arm): Group 2 - Dose Level 2 /Second Dose	Obinutuzumab	Participants in group 2 will receive a three-drug regimen of venetoclax, CC-486, and obinutuzumab at the second highest dose (dose level 2) set by doctors leading the study. Participants in this group will receive: * Venetoclax: 600 mg on days 1-28 * CC-486: 200 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle. Treatment using these three study drugs (venetoclax, CC-486, and obinutuzumab) will be given in 12 consecutive cycles that run for 28 days during each cycle (336 days).
Phase 1 (Dose-Finding Arm) - Group 3 - Dose Level 3/ Highest Dose	Venetoclax	Participants in group 3 will receive a three-drug regimen of venetoclax, CC-486, and obinutuzumab at the highest dose (dose level 3) set by doctors leading the study. Participants in this group will receive: * Venetoclax: 800 mg on days 1-28 * CC-486: 200 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle. Treatment using these three study drugs (venetoclax, CC-486, and obinutuzumab) will be given in 12 consecutive cycles that run for 28 days during each cycle (336 days).
Phase 1 (Dose-Finding Arm) - Group 3 - Dose Level 3/ Highest Dose	Obinutuzumab	Participants in group 3 will receive a three-drug regimen of venetoclax, CC-486, and obinutuzumab at the highest dose (dose level 3) set by doctors leading the study. Participants in this group will receive: * Venetoclax: 800 mg on days 1-28 * CC-486: 200 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle. Treatment using these three study drugs (venetoclax, CC-486, and obinutuzumab) will be given in 12 consecutive cycles that run for 28 days during each cycle (336 days).
Phase 1 (Dose-Finding Arm) - Group 4 - Lower Dose Level 1	Venetoclax	Participants in this group will received a lower dose of the three-drug regimen using venetoclax, CC-486 and obinutuzumab set by doctors leading the study. Inclusion in this group is optional and based on whether the participant reports serious adverse events/side effects in response to a higher dose of the regimen. If participants are included in this group, they will receive: * Venetoclax: 400 mg on days 1-28 * CC-486: 150 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle.
Phase 1 (Dose-Finding Arm) - Group 4 - Lower Dose Level 1	Obinutuzumab	Participants in this group will received a lower dose of the three-drug regimen using venetoclax, CC-486 and obinutuzumab set by doctors leading the study. Inclusion in this group is optional and based on whether the participant reports serious adverse events/side effects in response to a higher dose of the regimen. If participants are included in this group, they will receive: * Venetoclax: 400 mg on days 1-28 * CC-486: 150 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle.
Phase 1 (Dose-Finding Arm) - Group 5 - Lower Dose Level 2	Venetoclax	Participants in this group will received the second lowest dose of the three-drug regimen using venetoclax, CC-486 and obinutuzumab set by doctors leading the study. Inclusion in this group is optional and based on whether the participant reports serious adverse events/side effects in response to a higher dose of the regimen. If participants are included in this group, they will receive: * Venetoclax: 400 mg on days 1-10 only * CC-486: 150 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle.
Phase 1 (Dose-Finding Arm) - Group 5 - Lower Dose Level 2	Obinutuzumab	Participants in this group will received the second lowest dose of the three-drug regimen using venetoclax, CC-486 and obinutuzumab set by doctors leading the study. Inclusion in this group is optional and based on whether the participant reports serious adverse events/side effects in response to a higher dose of the regimen. If participants are included in this group, they will receive: * Venetoclax: 400 mg on days 1-10 only * CC-486: 150 mg on days 1-14 * Obinutuzumab: 1000 mg on days 1, 8 and 15 of cycle 1, and on day 1 of each following cycle.

Primary Outcome Measures

Name	Time	Method
Phase I Objective: Maximum Tolerated Dose of Venetoclax and CC-486 As Assessed by Rate of Reported Dose Limiting Toxicities (Side Effects) According to CTCAE Criteria Version 5	336 days (the duration of phase 1 treatment)	The maximum tolerated dose of venetoclax and CC-486 in patients with minimally pre-treated follicular lymphoma. Doctors leading the study will find the maximum tolerated dose by assessing the rate of serious side effects (known as "dose limiting toxicities") according to the NCI Common Terminology Criteria (CTCAE) for Adverse Events Version 5.
Phase I Objective: Number of Participants Who Discontinue Venetoclax, CC-486 and Obinutuzumab Regimen Due to Reported Side Effects as Assessed by CTCAE Criteria Version 5	336 days (duration of phase 1 treatment)	The number of participants who discontinue the three-drug regimen of venetoclax, CC-486, and obinutuzumab during phase 1 of the study due to serious side effects (grade 3/4) as assessed by the NCI Common Terminology Criteria (CTCAE) for Adverse Events Version 5.
Phase I Objective: Number of Participants Taking Venetoclax, CC-486 and Obinutuzumab Who Report Serious Side Effects As Assessed by CTCAE Version 5	336 days (duration of phase 1 treatment)].	The number of participants who report serious side effects in response to the three-drug regimen of venetoclax, CC-486 and obinutuzumab during phase 1 treatment. Serious side effects will be defined as grade 3/ 4 according to criteria set by the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.
4. Phase II Objective: Number of Participants Who Do Not Show Signs of Cancer After Taking CC-486 and Obinutuzumab (Oral Therapies) As Assessed by PET/CT Whole Body Scan (Based on Lugano Criteria)	336 days (duration of phase 1 treatment)	The number of participants who do not show detectable signs of cancer (also known as "complete response") after taking combined CC-486 and obinutuzumab as assessed by positron emission tomography (PET scan) based on Lugano criteria.

Secondary Outcome Measures

Name	Time	Method
Phase II Objective: The Length of Time That Half of Participants in the Expansion Group Are Alive After Receiving Phase 1 Dose of Treatment As Assessed at End of Study and 5 Years After Study is Complete	55 months (at study conclusion) and 5 years after end of study	The length of time that half of the participants in the expansion/phase II study group are alive after taking the maximum tolerated dose established in the first phase of the study. This time, also known as "median overall survival," will be documented at the end of the study and five years after study completion.
Phase II Objective: Number of Participants Who Do Not Show Signs of Follicular Lymphoma After Venetoclax and CC-486 As Assessed by PET Scan (Based on Lugano Criteria)	84 days (three cycles of combined oral therapies venetoclax and CC-486 oral	Number of participants in phase II group who do not show signs of follicular lymphoma after receiving three cycles of venetoclax + CC-486 (combined oral therapy). This will be assessed by positron emission tomography (PET scan) based on Lugano criteria.
Phase II Objective: Number of Participants Who Do Not Show Signs of Follicular Lymphoma 30 Months After Treatment As Assessed by PET Scan (Based on Lugano Criteria	30 months and 336 days (treatment period); approximately 3.4 years	Number of participants who do not show signs of follicular lymphoma (also known as "complete response rate") 30 months after starting treatment. This will be assessed by positron emission tomography (PET scan) based on Lugano criteria.
Phase II Objective: The Average Length of Time Participants Treated at Phase 1 Dose Live With Follicular Lymphoma Without Symptoms of Cancer Worsening As Assessed at End of Study and 5 Years After Study is Complete	55 months (at study conclusion) and 5 years after end of study	The average length of time study participants in the expansion/phase II group of the study live with follicular lymphoma, but it does not get worse (also known as "median progression-free survival" of participants). This time will be assessed at the conclusion of study and five years after study completion.