Venetoclax in Treating Participants With Recurrent or Refractory Mature T-Cell Lymphoma

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of venetoclax, including the dose ramp-up, in adults
with relapsed or refractory mature T-cell lymphoma. (Safety Lead-in) II. To estimate the
overall response rate (ORR) of venetoclax in patients with relapsed or refractory mature
T-cell lymphoma. (Phase 2)

SECONDARY OBJECTIVES:

I. To evaluate the complete response rate, duration of response, time to response, overall
survival and progression free survival of venetoclax in relapsed/refractory mature T-cell
lymphoma. (Phase 2) II. To further characterize the safety and toxicities of venetoclax in
relapsed/refractory mature T-cell lymphoma. (Phase 2)

EXPLORATORY OBJECTIVES:

I. To determine changes in Bcl-2 gene expression in pre- and post-treatment tumor samples of
mature T- cell lymphoma.

OUTLINE: This is a safety lead-in dose-escalation study, followed by a phase II study.

Participants receive venetoclax orally (PO) once daily (QD) on days 1-28. Treatment repeats
every 28 days for up to 26 courses in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, participants are followed up periodically for up to 24
months.

Inclusion Criteria:

- Documented informed consent of the participant and/or the legally authorized
representative

- Be willing to provide tissue

- Eastern Cooperative Oncology Group (ECOG) =< 2

- Resolution of all acute toxic effects of prior therapy or surgical procedures to
Common Terminology Criteria for Adverse Events (CTCAE) grade =< 1 (except alopecia)

- Failed at least 2 prior systemic therapies

- Histologically confirmed peripheral T-cell lymphoma (PTCL) as defined by the World
Health Organization (WHO) criteria 2016, excluding cutaneous T-cell lymphoma (CTCL);
transformed mycosis fungoides is allowed

- Measurable disease defined as:

- Computed tomography (CT)/magnetic resonance imaging (MRI)/ or positron emission
tomography (PET) scan, with at least one nodal site of disease which is 1.5 cm in
longest dimension, and/or spleen > 13 cm in vertical length, and/or diffuse
enlargement of liver with or without focal nodules (Lugano 2014); extra nodal
sites with biopsy proven abnormal lesions are allowed including skin

- Patients with only bone marrow involvement will be acceptable

- Prior stem cell transplant allowed

- If allogeneic hematopoietic cell transplantation (HCT) must have recovered from
acute toxicity

- Cannot have active acute or chronic graft versus host disease (GvHD)

- To be performed within 14 days prior to day 1 of protocol therapy: absolute neutrophil
count (ANC) >= 1,000/mm^3

- NOTE: Growth factor is not permitted within 7 days of ANC assessment unless
cytopenia is secondary to disease involvement

- Exception: Unless documented bone marrow involvement by lymphoma

- To be performed within 14 days prior to day 1 of protocol therapy: platelets >=
30,000/mm^3 * NOTE: Platelet transfusions are not permitted within 7 days of platelet
assessment unless cytopenia is secondary to disease involvement

* Exception: Unless documented bone marrow involvement by lymphoma

- To be performed within 14 days prior to day 1 of protocol therapy: total bilirubin =<
1.5 x upper limit of normal (ULN) (=< for Gilbert's syndrome or documented hepatic
involvement by lymphoma)

- To be performed within 14 days prior to day 1 of protocol therapy: aspartate
aminotransferase (AST) =< 3 x ULN * If hepatic involvement by lymphoma: AST =< 5 x ULN

- To be performed within 14 days prior to day 1 of protocol therapy: alanine
aminotransferase (ALT) =< 3 x ULN

* If hepatic involvement by lymphoma: ALT =< 5 x ULN

- To be performed within 14 days prior to day 1 of protocol therapy: creatinine
clearance of >= 50 mL/min per 24 hour urine or the Cockcroft-Gault formula

- Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

* If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required

- Agreement by WOCBP and males of childbearing potential* to use an adequate method of
birth control (hormonal contraception is inadequate) or abstain from heterosexual
activity for the course of the study through 90 days after the last dose of protocol
therapy * Childbearing potential defined as not being surgically sterilized (men and
women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

- Bcl2 inhibitors

- Any systemic anti-lymphoma therapy, including monoclonal antibody within 28 days or 5
half-lives (whichever is shorter) of initiating protocol therapy

- Radiation and/or surgery (except lymph node or other diagnostic biopsies) within 14
days prior to day 1 of protocol therapy

- Short course systemic corticosteroids for disease control, improvement of performance
status or non-cancer indication within 7 days prior to day 1 of protocol therapy;
stable ongoing corticosteroid use (i.e. at least 30 days) up to an equivalent dose of
20 mg of prednisone is permissible

- Strong or moderate CYP3A inhibitors within 3 days prior to day 1 of protocol therapy

- Strong or moderate CYP3A inducers within 7 days prior to day 1 of protocol therapy

- P-gp inhibitors within 7 days prior to day 1 of protocol therapy

- Narrow therapeutic index P-gp substrates within 7 days prior to day 1 of protocol
therapy

- Any other investigational agent or used an investigational device within 21 days prior
to day 1 of protocol therapy

- Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g.,
gastric bypass surgery, gastrectomy)

- Active human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or hepatitis B
virus (HBV); subjects who have an undetectable HIV viral load with CD4 > 200 and are
on highly active antiretroviral therapy (HAART) medication are allowed; subjects who
are positive for hepatitis B core antibody or hepatitis B surface antigen must have a
negative polymerase chain reaction (PCR) result before enrollment; those who are PCR
positive will be excluded; patients who have had hepatitis C but have finished
treatment and are PCR negative will be allowed (testing to be done only in patients
suspected of having infections or exposures)

- Concurrent malignancy requiring active therapy

- Known central nervous system or meningeal involvement (in the absence of symptoms,
investigation into central nervous system involvement is not required)

- A history of prior significant toxicity, other than thrombocytopenia, from another
Bcl-2 family protein inhibitor

- Congestive heart failure (CHF) that meets New York Heart Association (NYHA) class II
to IV definitions

- Active infection requiring systemic therapy

- Unable to swallow capsules, has a partial or small bowel obstruction, or has a
gastrointestinal condition resulting in a malabsorptive syndrome (e.g. small bowel
resection with malabsorption)

- WOCBP: Pregnant or breastfeeding

- Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns with clinical
study procedures

- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)