Duvelisib and Nivolumab in Treating Patients With Richter Syndrome or Transformed Follicular Lymphoma

Sponsor

David Bond, MD (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03892044

Collaborator

(none)

Enrollment

Location

Arm

37.8

Anticipated Duration (Months)

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I trial studies the side effects and best dose of duvelisib when given together with nivolumab in treating patients with Richter syndrome or transformed follicular lymphoma. Duvelisib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving duvelisib and nivolumab may work better in treating patients with Richter syndrome or transformed follicular lymphoma compared to giving duvelisib or nivolumab alone.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia Recurrent Diffuse Large B-Cell Lymphoma Refractory Diffuse Large B-Cell Lymphoma Richter Syndrome Small Lymphocytic Lymphoma Transformed Chronic Lymphocytic Leukemia to Diffuse Large B-Cell Lymphoma Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma Transformed Small Lymphocytic Lymphoma to Diffuse Large B-Cell Lymphoma	Drug: Duvelisib Biological: Nivolumab	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To determine the maximum-tolerated dose (MTD) of duvelisib in combination with nivolumab for patients with Richter?s syndrome or transformed follicular lymphoma.

SECONDARY OBJECTIVES:

To assess preliminary efficacy of duvelisib in combination with nivolumab in Richter?s syndrome and transformed follicular lymphoma (overall response rate, progression free survival, overall survival).
To determine the toxicity profile of duvelisib in combination with nivolumab.

EXPLORATORY OBJECTIVES:

To correlate response to duvelisib in combination with nivolumab with cytogenetic/fluorescence in-situ hybridization (FISH) abnormalities of the chronic lymphocytic leukemia (CLL) and lymphoma compartments (for patients with Richter?s syndrome) at baseline.
To correlate response to duvelisib in combination with nivolumab with baseline deoxyribonucleic acid (DNA) mutation of CLL and lymphoma as assessed in tumor samples and cell free DNA.
To determine changes in T, B, and natural killer (NK) cell number and function during duvelisib plus nivolumab therapy.

OUTLINE: This is a dose-escalation study of duvelisib.

Patients receive duvelisib orally (PO) twice daily (BID) on days 1-28 and nivolumab intravenously (IV) over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months thereafter.

Study Design

Study Type:

Interventional

Actual Enrollment :

7 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Study of Duvelisib in Combination With Nivolumab for Patients With Richter's Syndrome and Transformed Follicular Lymphoma

Actual Study Start Date :

Nov 5, 2019

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (duvelisib, nivolumab) Patients receive duvelisib PO BID on days 1-28 and nivolumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Duvelisib Given PO Other Names: 8-Chloro-2-phenyl-3-((1S)-1-(7H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one INK-1197 IPI-145 Biological: Nivolumab Given IV Other Names: BMS-936558 MDX-1106 NIVO ONO-4538 Opdivo

Arm

Intervention/Treatment

Experimental: Treatment (duvelisib, nivolumab)

Patients receive duvelisib PO BID on days 1-28 and nivolumab IV over 60 minutes on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Duvelisib

Given PO

Other Names:

8-Chloro-2-phenyl-3-((1S)-1-(7H-purin-6-ylamino)ethyl)isoquinolin-1(2H)-one

INK-1197

IPI-145

Biological: Nivolumab

Given IV

Other Names:

BMS-936558

MDX-1106

NIVO

ONO-4538

Opdivo

Outcome Measures

Primary Outcome Measures

Maximum-tolerated dose (MTD) of duvelisib [Up to 28 days]
The MTD is defined as the highest dose level where at most one patient out of six experiences dose-limiting toxicities.

Secondary Outcome Measures

Overall response rate [Up to 3 years]
Will be defined as the proportion of patients achieving a complete or partial response; any eligible patient who begins treatment with the combination regimen will be included in the denominator. Will be calculated with a 95% binomial confidence interval.
Progression-free survival (PFS) [From cycle 1, day 1 to date of progression or death, assessed up to 3 years]
The method of Kaplan Meier will be used to estimate PFS.
Overall survival (OS) [From cycle 1, day 1 to date of progression or death, assessed up to 3 years]
The method of Kaplan Meier will be used to estimate OS.

Other Outcome Measures

Response to duvelisib in combination with nivolumab [Baseline]
Will be correlated with cytogenetic/fluorescence in-situ hybridization abnormalities of the chronic lymphocytic leukemia (CLL) and lymphoma compartments (for patients with Richter syndrome). The chi-squared test and logistic regression will be utilized to evaluate the association.
Response to duvelisib in combination with nivolumab [Baseline]
Will be correlated with deoxyribonucleic acid (DNA) mutation of CLL and lymphoma and assessed in tumor samples and cell free DNA. The chi-squared test and logistic regression will be utilized to evaluate the association.
Changes in T, B, and NK cell number and function [Up to 3 years]
Will be summarized using graphical method in a descriptive manner and tested using nonparametric Wilcoxon signed-rank test due to small sample size.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Diagnosis of CLL or small lymphocytic lymphoma (SLL) meeting International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria AND biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), clinically consistent with Richter?s syndrome (RS) OR histologically diagnosed relapsed or refractory DLBCL including transformed follicular lymphoma (tFL) ineligible for or refractory to platinum containing salvage therapy for the dose escalation portion of the study. For the dose expansion phase only patients with CLL with transformation to DLBCL or tFL will be eligible
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Absolute neutrophil count (ANC) >= 500/uL
Platelet count >= 30,000/uL (unless due to bone marrow involvement)
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 ULN
Total bilirubin =< 1.5 ULN (unless due to liver involvement, hemolysis, or Gilbert?s disease)
Creatinine clearance >= 40 mL/min (Cockcroft-Gault estimated)
Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug
Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) or urine pregnancy test at screening. Women who are pregnant or breastfeeding are ineligible for this study
Patients must sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study

Exclusion Criteria:

Documented infection with human immunodeficiency virus (HIV) or chronic, active hepatitis B or C infection
Any chemotherapy or monoclonal antibodies within 14 days or kinase inhibitors (except BTKi) within 5 half-lives before cycle 1, day 1 (C1D1). BTK inhibitors may be continued until 2 days prior to C1D1. Steroids are allowed for palliation of symptoms due to lymphoma
Toxicity from previous therapy which has not resolved to grade 1 (or patient?s previous baseline)
Other active malignancies except those treated with curative intent with no active disease at the time of study entry or those felt to be at low risk of progression or recurrence over the next 2 years (such as low risk prostate cancer on active surveillance)
New York Heart Association (NYHA) class III/IV heart disease or other significant medical condition or organ system dysfunction which could compromise the subject?s safety or put the study outcomes at undue risk
Uncontrolled systemic infection
Unable to swallow capsules or significant malabsorption syndrome, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction at the time of screening
Patients who are pregnant or breastfeeding
Patients with known central nervous system (CNS) involvement by CLL or lymphoma
Patients who have underwent autologous or allogeneic stem cell transplant =< 4 weeks prior to C1D1 or have active graft-versus-host disease are excluded