Venetoclax and Romidepsin in Treating Patients With Recurrent or Refractory Mature T-Cell Lymphoma

Sponsor

City of Hope Medical Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03534180

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

52.3

Anticipated Duration (Months)

4.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects and best dose of venetoclax and romidepsin to see how well it works in treating patients with mature T-cell lymphoma that has come back (recurrent) or does not respond to treatment (refractory). Venetoclax and romidepsin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Anaplastic Large Cell Lymphoma Recurrent Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma	Other: Laboratory Biomarker Analysis Drug: Romidepsin Drug: Venetoclax	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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

EXPLORATORY OBJECTIVES:

To determine BCL2 protein expression in base line treatment tumor samples and correlatieon with response.
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.

Patients receive venetoclax orally (PO) once daily (QD) on days 1-28 and romidepsin intravenously (IV) on days 1, 8, and 15. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

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

Study Design

Study Type:

Interventional

Actual Enrollment :

9 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 2 Study of Venetoclax and Romidepsin With Safety Lead-In for Treatment of Relapsed/Refractory Mature T-Cell Lymphomas

Actual Study Start Date :

Aug 21, 2018

Anticipated Primary Completion Date :

Dec 30, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (venetoclax, romidepsin) Patients receive venetoclax PO QD on days 1-28 and romidepsin IV on days 1, 8, and 15. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis Correlative studies Drug: Romidepsin Given IV Other Names: Antibiotic FR 901228 Depsipeptide FK228 FR901228 Istodax N-[(3S,4E)-3-Hydroxy-7-mercapto-1-oxo-4-heptenyl]-D-valyl-D-cysteinyl-(2Z)-2-amino-2-butenoyl-L-valine, (4->1) Lactone, Cyclic Drug: Venetoclax Given PO Other Names: ABT-0199 ABT-199 ABT199 GDC-0199 RG7601 Venclexta Venclyxto

Arm

Intervention/Treatment

Experimental: Treatment (venetoclax, romidepsin)

Patients receive venetoclax PO QD on days 1-28 and romidepsin IV on days 1, 8, and 15. Treatment repeats every 28 days for up to 26 cycles in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis

Correlative studies

Drug: Romidepsin

Given IV

Other Names:

Antibiotic FR 901228

Depsipeptide

FK228

FR901228

Istodax

N-[(3S,4E)-3-Hydroxy-7-mercapto-1-oxo-4-heptenyl]-D-valyl-D-cysteinyl-(2Z)-2-amino-2-butenoyl-L-valine, (4->1) Lactone, Cyclic

Drug: Venetoclax

Given PO

Other Names:

ABT-0199

ABT-199

ABT199

GDC-0199

RG7601

Venclexta

Venclyxto

Outcome Measures

Primary Outcome Measures

Incidence of adverse events [Up to 30 days post-treatment]
Graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0. During the first 2 cycles, all grades of toxicity will be collected. After cycle 2, only the highest grade of any toxicity will be collected for each cycle during protocol treatment and for the period of safety follow-up after end of treatment.
Overall response rate (ORR) (Phase II) [Up to 24 months]
Assessed by Lugano Classification 2014. ORR includes the proportion of patients achieving completion response (CR) or partial response (PR). Rates and 95% Clopper-Pearson binomial confidence interval (CI) will be calculated for overall response rate. The response evaluation will be based on a Simon's Two-Stage Optimal design to distinguish a promising 30% response rate (alternative hypothesis) from a disappointing rate (null hypothesis) of 10%, at a one-sided type I error of 10% and a power of 80%.

Secondary Outcome Measures

Complete response rate (CR) [Up to 24 months]
Defined using by Lugano Classification 2014. Rates and 95% Clopper-Pearson binomial confidence interval (CI) will be calculated for overall response rate (patients that have confirmed CR or PR), as well as for CR rate. The response evaluation will be based on a Simon's Two-Stage Optimal design to distinguish a promising 30% response rate (alternative hypothesis) from a disappointing rate (null hypothesis) of 10%, at a one-sided type I error of 10% and a power of 80%.
Duration of response (DOR) [From the start of study treatment up to 24 months]
Assessed using Lugano Classification 2014. DOR will be estimated using the product-limit method of Kaplan- Meier with the Greenwood estimator of standard error.
Progression-free survival (PFS) [From the start of study treatment up to 24 months]
PFS to be estimated using the product-limit method of Kaplan- Meier with the Greenwood estimator of standard error. Median progression-free survival and overall survival and their corresponding 95% CIs will be estimated.
Overall survival (OS) [From the start of study treatment up to 24 months]
OS to be estimated using the product-limit method of Kaplan- Meier with the Greenwood estimator of standard error. Median progression-free survival and overall survival and their corresponding 95% CIs will be estimated.
Time to response (TTR) [From the start of study treatment up to 24 months]
Assessed by Lugano Classification 2014. TTR to be estimated using the product-limit method of Kaplan- Meier with the Greenwood estimator of standard error.

Other Outcome Measures

Change in Bcl-2 gene expression [At baseline and at the end of cycle 1 or 2 (each cycle is 28 days)]
Tumor tissue samples will be collected from participants for assessment. Summary statistics and plots will be used to describe the pre- and post-treatment gene expression levels and the associated change between the timepoints. Paired t-test or Wilcoxon signed rank test will be used to explore the difference in gene expression levels before and after treatment. Data transformation such as log transformation will be considered if appropriate. For the exploratory correlation of these gene expression level/change with response, analyses comparing groups of participants defined by response may be conducted by two-sample t-test or Wilcoxon rank sum test. For the exploratory correlation of these endpoints with survival outcomes, survival analysis techniques such as Log rank test will be used.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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. For anaplastic large cell lymphoma (ALCL) histologies this must include failure or intolerable side effects of brentuximab vedotin
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) and must be off immunosuppressive therapies
Absolute neutrophil count (ANC) >= 1,000/mm^3 (to be performed within 14 days prior to day 1 of protocol therapy)
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
Platelets >= 30,000/mm^3 (to be performed within 14 days prior to day 1 of protocol therapy)
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
Total bilirubin =< 1.5 x upper limit of normal (ULN) (=< 3 x 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 (to be performed within 14 days prior to day 1 of protocol therapy)
If hepatic involvement by lymphoma: AST =< 5 x ULN
Alanine aminotransferase (ALT) =< 3 x ULN (to be performed within 14 days prior to day 1 of protocol therapy)
If hepatic involvement by lymphoma: ALT =< 5 x ULN
Creatinine clearance of >= 50 mL/min per 24 hour urine or the Cockcroft-Gault formula (to be performed within 14 days prior to day 1 of protocol therapy)
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 7 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)
Congestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitions
Patients with known cardiac abnormalities such as:
Congenital long QT syndrome
QTc (corrected QT interval on electrocardiogram [ECG]) interval > 480 milliseconds
Any cardiac arrhythmia requiring anti-arrhythmic medication
Patients with a history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest, unless currently addressed with an automatic implantable cardioverter defibrillator (AICD)
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)