Clinical Trials /

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

NCT04722601

Description:

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.

Related Conditions:
  • Follicular Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Dose-Finding and Efficacy Study of Venetoclax, CC-486, and Obinutuzumab in Follicular Lymphoma
  • Official Title: A Multicenter, Single-Arm, Phase I/II Dose Finding and Efficacy Study of Venetoclax, CC-486, and Obinutuzumab in Minimally-Pretreated Follicular Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: IRB20-0986
  • NCT ID: NCT04722601

Conditions

  • Follicular Lymphoma

Interventions

DrugSynonymsArms
VenetoclaxVenclexta, VenclyxtoPhase 1 (Dose-Finding Arm) - Group 3 - Dose Level 3/ Highest Dose
ObinutuzumabGazyvaPhase 1 (Dose-Finding Arm) - Group 3 - Dose Level 3/ Highest Dose
CC-486azacitidinePhase 1 (Dose-Finding Arm) - Group 3 - Dose Level 3/ Highest Dose

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Phase 1(Dose-Finding Arm): Group 1 - Dose Level 1 / Starting DoseExperimentalPhase 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).
  • Venetoclax
  • Obinutuzumab
  • CC-486
Phase 2 (Efficacy Arm/ Expansion Cohort)ExperimentalParticipants 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.
  • Venetoclax
  • Obinutuzumab
  • CC-486
Phase 1(Dose-Finding Arm): Group 2 - Dose Level 2 /Second DoseExperimentalParticipants 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).
  • Venetoclax
  • Obinutuzumab
  • CC-486
Phase 1 (Dose-Finding Arm) - Group 3 - Dose Level 3/ Highest DoseExperimentalParticipants 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).
  • Venetoclax
  • Obinutuzumab
  • CC-486
Phase 1 (Dose-Finding Arm) - Group 4 - Lower Dose Level 1ExperimentalParticipants 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.
  • Venetoclax
  • Obinutuzumab
  • CC-486
Phase 1 (Dose-Finding Arm) - Group 5 - Lower Dose Level 2ExperimentalParticipants 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.
  • Venetoclax
  • Obinutuzumab
  • CC-486

Eligibility Criteria

        INCLUSION CRITERIA

        Participants are eligible to be included in the study if all of the following criteria
        apply:

          1. Male and female participants who are at least 18 years old with a medically confirmed
             diagnosis of grade 1-3a follicular lymphoma by 2017 World Health Organization
             criteria. A prior tissue or bone marrow biopsy may be used to confirm diagnosis if
             collected within 90 days of initiating therapy.

          2. Treatment-naive (you have never had treatment for your cancer) or if you have received
             treatment, you have received fewer than two prior lines of anti-CD20 monotherapy
             consisting of a total of 16 or fewer doses.

          3. Must have Stage II-IV disease on screening PET imaging with measurable disease,
             according to Lugano Classification. Measurable disease will be defined as at least one
             lesion that can be accurately measured in at least two dimensions and quantifiable
             avidity ( a tumor containing antibodies that have a higher rate/stability of binding
             with an antigen) to F-fluorodeoxyglucose (also known as "FDG" - a glucose analogue
             that can be high in cancerous tumors) . Minimum measurement must be >15 mm in the
             longest diameter by >10 mm in the short axis.

          4. Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less as defined
             in Appendix B. Performance status must be evaluated within 28 days prior to treatment
             initiation.

          5. There must be a clear way to indicate that you need treatment, either by meeting one
             or more of the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria for
             treatment (Brice et al. 1997), the existence of cancer-related pain or other
             uncontrollable symptoms. Study participant whose need for treatment can be supported
             by the judgment of a primary oncologist based on the pace of their disease
             progression/other clinical criteria are also eligible for the study. Study
             participants must have documented progression of disease.

          6. Not be a candidate for standard-of-care chemoimmunotherapy in the judgment of the
             primary oncologist OR standard chemoimmunotherapy was discussed with the primary
             oncologist and declined by the participant.

          7. A male participant must agree to use contraception during the treatment period of this
             study, and for at least 90 days after the last dose of venetoclax or 18 months after
             the last dose of obinutuzumab, whichever is longer, and refrain from donating sperm
             during this period. With pregnant female partners, men must remain abstinent or use a
             condom during the treatment period and for at least 6 months after the last dose of
             obinutuzumab to avoid exposing the embryo.

          8. A female participant is eligible to participate if she is not pregnant, breastfeeding,
             and at least one of the following conditions applies:

               -  She is not a woman of childbearing potential

               -  She is a woman of childbearing potential who agrees to follow the contraceptive
                  guidance during the treatment period and for at least 30 days after the last dose
                  of venetoclax or 18 months after the last dose of obinutuzumab, whichever is
                  longer.

               -  Participants must have a negative pregnancy test within 72 hours of beginning
                  treatment if they are women of childbearing potential.

          9. The participant (or legally acceptable representative if applicable) provides written
             informed consent for the trial.

         10. Have adequate organ function that can be confirmed by clinical laboratory values
             within 28 days prior to treatment initiation.

        EXCLUSION CRITERIA

        Participants are excluded from the study if any of the following criteria apply:

          1. A a woman of childbearing potential who has a positive urine pregnancy test within 72
             hours prior to treatment allocation. If the urine test is positive or cannot be
             confirmed as negative, a serum pregnancy test will be required. Note: In the event
             that 72 hours have elapsed between the screening pregnancy test and the first dose of
             study treatment, another pregnancy test (urine or serum) must be performed and must be
             negative in order for the subject to start receiving study medication.

          2. Has received any prior systemic therapy other than anti-CD20 monoclonal antibody or
             radiotherapy prior to the first dose of study medication. Subjects must not have had a
             prior dose of anti-CD20 monoclonal antibody therapy within 28 days prior to the first
             dose of study medication.

          3. Known hypersensitivity or allergy to any of the study drugs, xanthine oxidase
             inhibitors and/or rasburicase, mannitol, murine products, or any components of the
             drug formulations.

          4. History of severe allergic or anaphylactic reaction to humanized or murine monoclonal
             antibodies.

          5. History of other malignancy that could affect compliance with the study or
             interpretation of results such as:

               -  Participants with a history of basal or squamous cell carcinoma or stage 1
                  melanoma of the skin or in situ carcinoma of the cervix are eligible.

               -  Participants with a malignancy that has been treated with surgery alone with the
                  intent to cure the participant will also be excluded. Individuals in documented
                  remission without treatment for 2 years prior to enrollment may be included at
                  the discretion of the doctor leading the study.

          6. Has medical/clinical evidence of transformation to an aggressive lymphoma subtype
             including grade 3b Follicular Lymphoma.

          7. Has received the following agents within 7 days prior to the first dose of venetoclax:

               -  Steroid therapy for anti-neoplastic intent

               -  A strong or moderate Cytochrome P450 3A (abbreviated as "CYP3A" inhibitor).

               -  CYP3A inducers

               -  Consumed grapefruit, grapefruit products, Seville oranges (including marmalade
                  containing Seville oranges), or star fruit within 3 days prior to the first dose
                  of venetoclax

               -  P-glycoprotein (P-gp) inhibitors or narrow therapeutic index P-gp substrates

          8. Evidence of significant, uncontrolled diseases that could affect the participant's
             ability to fulfill their role in the study/ protocol or interpretation of results or
             that could increase risk to the participant, including renal disease that would
             preclude chemotherapy administration or pulmonary disease (including obstructive
             pulmonary disease and history of bronchospasm).

          9. 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.
             Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing
             signs/symptoms related to the infection without improvement despite appropriate
             antibiotics, antiviral therapy and/or other treatment) will result in study exclusion.
             Caution should be exercised when considering the use of any of the study medication in
             participants with a history of recurring or chronic infections.

         10. Clinically significant history of liver disease, including viral or other hepatitis,
             current alcohol abuse, or cirrhosis.

         11. Presence of positive test results for hepatitis B virus (HBV), hepatitis B surface
             antigen (HBsAg), or hepatitis C (HCV) antibody. Participants who are positive for HCV
             antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible
             for study participation. Participants with occult or prior HBV infection (defined as
             positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included
             if HBV DNA is undetectable. These participants must be willing to undergo monthly HBV
             DNA testing.

         12. Receipt of live-virus vaccines within 30 days prior to the initiation of study
             treatment

         13. Malabsorption syndrome, inability to swallow a large number of pills, or other
             condition that precludes enteral route of administration.

         14. A history of progressive multifocal leukoencephalopathy (PML) or known prior infection
             with the John Cunningham (JC) virus.

         15. Significant active cardiac disease within the previous 6 months including New York
             Heart Association class 4 heart failure, unstable angina, or myocardial infarction.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Time Frame:336 days (the duration of phase 1 treatment)
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Time Frame:55 months (at study conclusion) and 5 years after end of study
Safety Issue:
Description: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.
Measure: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
Time Frame:55 months (at study conclusion) and 5 years after end of study
Safety Issue:
Description: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.
Measure: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)
Time Frame:84 days (three cycles of combined oral therapies venetoclax and CC-486 oral
Safety Issue:
Description: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.
Measure: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
Time Frame:30 months and 336 days (treatment period); approximately 3.4 years
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Chicago

Trial Keywords

  • follicular lymphoma, FL

Last Updated

January 25, 2021