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.
Participants are eligible to be included in the study if all of the following criteria
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
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
- 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.
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
4. History of severe allergic or anaphylactic reaction to humanized or murine monoclonal
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
- 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
12. Receipt of live-virus vaccines within 30 days prior to the initiation of study
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.