CPI-613 in Combination With Bendamustine in Patients With Relapsed/Refractory T-Cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to determine if it is possible to give CPI-613 with the drug Bendamustine for 2 days every 28 days without causing severe side effects. In addition, this study will also test the safety of CPI-613 when given in combination with Bendamustine.

Detailed Description
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Primary Objectives: A pilot Study to evaluate the feasibility, safety and tolerability of a two day course per cycle of Bendamustine plus CPI-613 in patients with relapsed and refractory T cell non-hodgkin lymphoma. Exploratory Objectives To evaluate: Overall response rate (ORR) and disease control rate (DCR) derived from the Lugano classification. Duration of response (DOR) derived from the Lugano classification. Progression-Free-Survival (PFS) derived from Lugano classification. Overall Survival (OS). Single cell transcriptomics from PMBCs pre- and post-treatment; for correlative analyses of blood PBMC (and possibly excess pre-treatment tumor biopsy) cell population diversity and functional states to reveal potential mechanisms of drug treatment with regard to patient response status.

Official Title
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Pilot Study of CPI-613, in Combination With Bendamustine, in Patients With Relapsed or Refractory T-Cell Non-Hodgkin Lymphoma

Conditions
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Relapsed T-Cell Lymphoma, Refractory T-Cell Lymphoma, Non Hodgkin Lymphoma

Intervention / Treatment
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* Drug: CPI 613
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet all of the following inclusion criteria before enrollment: Histologically or cytologically confirmed PTCL (all subtypes) or CTCL (mycosis fungoides/Sezary syndrome) as defined by 2016 World Health Organization (WHO) classification. For patients with PTCL: Patients must have relapsed/refractory disease to one or more systemic therapies. Patients with CD30-positive lymphoma must have received, be ineligible for, or intolerant to brentuximab vedotin. Patients with limited prior exposure to Bendamustine (less than 2 full cycles or ≤ 480 mg/m2) may be included, based on PI discretion. Patients must have measurable disease (e.g., a tumor mass >1 cm or evidence of bone marrow involvement). For patients with CTCL, Stage IB-IVB mycosis fungoides or Sezary syndrome are eligible Patients must have relapsed/refractory disease to at least one previous systemic therapy. Psoralen plus ultraviolet light therapy (PUVA) is not considered to be a systemic therapy. Male and female patients 18 years of age and older Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Expected survival greater than 3 months. Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must use accepted contraceptive methods (abstinence, intrauterine device [IUD], oral contraceptive or double barrier device) during the study, and must have a negative serum or urine pregnancy test within 1 week prior to treatment initiation. Fertile men must practice effective contraceptive methods during the study, unless documentation of infertility exists. At least 2 weeks must have elapsed from prior chemotherapy drugs (other than steroids) or radiation At least 6 weeks must have elapsed from prior autologous stem cell transplant and 12 weeks must have elapsed from prior allogeneic stem cell transplant. Laboratory values ≤2 weeks must be: Adequate hematological function (absolute neutrophil count [ANC] ≥1,500/mm3, platelets ≥100,000/mm3). In subjects with known bone marrow involvement, ANC must be ≥ 1000/mm3 and platelets ≥75,000/mm3; Adequate hepatic function (aspartate aminotransferase [AST/SGOT] less than or equal to 3x upper normal limit [UNL], alanine aminotransferase [ALT/SGPT] less than or equal to 3x UNL (≤5x UNL if liver metastases present), bilirubin less than or equal to 1.5x UNL); Adequate renal function (serum creatinine less than or equal to 1.5 mg/dL or 133 µmol/L). No evidence of current infection. Mentally competent, ability to understand and willingness to sign the informed consent form. Exclusion Criteria: Patients with the following characteristics are excluded: Known cerebral metastases, central nervous system (CNS) or epidural tumor. History of prior malignancy and considered to be at greater than 30% risk of relapse Patients receiving any other standard or investigational treatment for their cancer, or any other investigational agent for any indication, within the past 2 weeks prior to initiation of treatment with study drugs (steroids are allowed) Patients with a history of allogeneic transplant must not have ≥ grade 3 graft-versus-host disease (GVHD) or any clinically significant GVHD requiring systemic immunosuppression. Serious medical illness that would potentially increase patients' risk for toxicity. Pregnant women, or women of child-bearing potential not using reliable means of contraception (because the teratogenic potential of CPI-613 is unknown). Lactating females. Fertile men unwilling to practice contraceptive methods during the study period. Any condition or abnormality which may, in the opinion of the investigator, compromise the safety of patients. Unwilling or unable to follow protocol requirements. Active heart disease including but not limited to symptomatic congestive heart failure, symptomatic coronary artery disease, symptomatic angina pectoris, symptomatic myocardial infarction or symptomatic congestive heart failure. Evidence of current infection.. Patients with known HIV infection, hepatitis B, or hepatitis C with positive viral load. Patients who have received cancer immunotherapy of any type within the past 2 weeks prior to initiation of CPI-613 treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CPI-613 in Combination with Bendamustine<br>CPI-613 at 2500 mg/m2 is infused intravenously (IV) via a central catheter over 2 hrs on Days 1and 2. Bendamustine at 90 mg/m2 is infused IV over 10 minutes on Days 1 and 2 of each treatment cycle, given immediately after CPI-613 administration. | Drug: CPI 613<br>* CPI-613 is to be given as 2-hr IV infusion via a central venous catheter. The starting dose of CPI-613 will be 2500 mg/m2 which was determined to be the MTD in the previous phase I clinical trial.<br>* Other names: devimistat;Drug: Bendamustine<br>* Bendamustine at 90 mg/m2 is infused by IV over 10 minutes on Days 1 and 2 of each treatment cycle. Bendamustine is given immediately after CPI-613 administration.<br>* Other names: Bendamustine Hydrochloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants To Successfully Complete Therapy Regimen | Feasibility will be defined as 75% of patients being successfully able to complete 80% of their therapy regimens. Toxicity data will be collected on all patients who receive at least one dose of treatment on the study | 8 weeks after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall response rate is defined as the proportion of patients who achieve a best overall response complete response or partial response during or following study treatment according to the Lugano Classification (Stage I - involvement in a single lymph node region to Stage IV diffuse or disseminated involvement of one or more extranodal organs or tissue). | Up to 12 weeks post treatment | 
| Disease Control Rate | Disease control rate defined as the proportion of patients who achieve a best overall response of complete response, partial response, or stable disease (SD). Best overall response of stable disease must have met the response stable disease criteria at least once ≥12 weeks after start of study treatment. | Up to 12 weeks post treatment | 
| Duration of Response | Duration of Response will be defined for responders (patients with a best overall response of complete response or partial response). It is the time from the date of the first documented complete response or partial response until the date of the first date of progressive disease, or death due to any cause, whichever occurs first. If a patient has not progressed or died by the analysis cutoff date, duration of response will be censored at the time of the last adequate tumor assessment on or before the cutoff date. | Up to 12 weeks post treatment | 
| Progression Free Survival | Progression free survival defined as the time from the start of study treatment until the first date of progressive disease, or death due to any cause, whichever occurs first. If a patient has not progressed or died by the analysis cutoff date, progression free survival will be censored at the time of the last adequate tumor assessment on or before the cutoff date. | Up to 12 weeks post treatment | 
| Overall Survival | Overall survival is measured from the start of study treatment until death due to any cause. If a patient is not known to have died at the date of the analysis cut-off, overall survival will be censored at the last date that: Patient is documented to be alive. At the time of single cell sequencing. | Up to 5 years post treatment |