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

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ClinicalTrials.gov Identifier: NCT03534180
Recruitment Status : Recruiting
First Posted : May 23, 2018
Last Update Posted : April 12, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Tracking Information
First Submitted Date  ICMJE May 9, 2018
First Posted Date  ICMJE May 23, 2018
Last Update Posted Date April 12, 2021
Actual Study Start Date  ICMJE August 21, 2018
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 7, 2021)
  • Incidence of adverse events [ Time Frame: 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) [ Time Frame: 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%.
Original Primary Outcome Measures  ICMJE
 (submitted: May 21, 2018)
  • Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0 [ Time Frame: Up to 30 days post-treatment ]
    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) assessed by Lugano Classification 2014 (Phase II) [ Time Frame: Up to 24 months ]
    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%.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 7, 2021)
  • Complete response rate (CR) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 21, 2018)
  • Complete response rate (CR) defined using by Lugano Classification 2014 [ Time Frame: Up to 24 months ]
    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) assessed using Lugano Classification 2014 [ Time Frame: From the start of study treatment up to 24 months ]
    DOR will be estimated using the product-limit method of Kaplan- Meier with the Greenwood estimator of standard error.
  • Progression-free survival (PFS) [ Time Frame: 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) [ Time Frame: 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) assessed by Lugano Classification 2014 [ Time Frame: From the start of study treatment up to 24 months ]
    TTR to be estimated using the product-limit method of Kaplan- Meier with the Greenwood estimator of standard error.
Current Other Pre-specified Outcome Measures
 (submitted: April 7, 2021)
Change in Bcl-2 gene expression [ Time Frame: 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.
Original Other Pre-specified Outcome Measures
 (submitted: May 21, 2018)
Change in Bcl-2 gene expression [ Time Frame: At baseline and during course 1 or 2 (each course 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.
 
Descriptive Information
Brief Title  ICMJE Venetoclax and Romidepsin in Treating Patients With Recurrent or Refractory Mature T-Cell Lymphoma
Official Title  ICMJE A Phase 2 Study of Venetoclax and Romidepsin With Safety Lead-In for Treatment of Relapsed/Refractory Mature T-Cell Lymphomas
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.
Detailed Description

PRIMARY OBJECTIVES:

I. 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:

I. 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:

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

II. 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Anaplastic Large Cell Lymphoma
  • Recurrent Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
  • Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Drug: Romidepsin
  • Drug: Venetoclax
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 7, 2021)
26
Original Estimated Enrollment  ICMJE
 (submitted: May 21, 2018)
20
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03534180
Other Study ID Numbers  ICMJE 18119
NCI-2018-00810 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
18119 ( Other Identifier: City of Hope Comprehensive Cancer Center )
P30CA033572 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party City of Hope Medical Center
Study Sponsor  ICMJE City of Hope Medical Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Jasmine M Zain City of Hope Medical Center
PRS Account City of Hope Medical Center
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP