Study to Assess the Safety, Tolerability and Pharmacokinetics of Fimepinostat (CUDC-907) in Patients With Lymphoma

Curis, Inc.106 enrolled

Overview

This is a phase 1, open-label, dose-escalation study of fimepinostat (CUDC-907) in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL), or high-grade B-cell lymphoma (HGBL) with or without MYC and BCL2 alterations. Fimepinostat (CUDC-907) is a multi-targeted agent designed to inhibit phosphoinositide 3-kinase (PI3K)and histone deacetylase (HDAC). The study is designed to assess the safety, the maximum tolerated dose, the recommended phase 2 dose (RP2D), pharmacokinetics and the anti-cancer activity of oral fimepinostat in combination with 1 or more anti-cancer regimens.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

106

Conditions

Lymphoma Relapsed Lymphoma Refractory Lymphoma Relapsed and/or Refractory Lymphoma

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients ≥ 18 years of age with any of the following: Histopathologically confirmed DLBCL or HGBL (i.e., HGBL with MYC, BCL2, and/or BCL6 rearrangements, HGBL, not otherwise specified \[NOS\], or DLBCL, NOS) that is refractory to, or has relapsed after, treatment with at least 1 prior regimen. Eligible sub-types include DHL, THL, or DEL, as well as DLBCL or HGBL without MYC and/or BCL2 alterations. Criteria for DHL are concurrent MYC translocation+ and BCL2 translocation+ by fluorescence in situ hybridization (FISH) (same criteria for THL, which also includes BCL6 translocation+ by FISH); criteria for DEL are concurrent overexpression of MYC (≥ 40%) and BCL2 (\> 50%) by immunohistochemistry (IHC). * Measurable disease by CT or PET/CT. MRI acceptable as per protocol. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. * Recovery to Grade 1 or baseline of any toxicity due to prior systemic treatments (excluding alopecia). * Absolute neutrophil count ≥ 1,000/µL; platelets ≥ 75,000/µL for patients with no bone marrow involvement by malignancy; platelets ≥ 50,000/µL for patients with bone marrow involvement by malignancy. * Creatinine ≤ 1.5x upper limit of normal (ULN); total bilirubin ≤ 1.5x ULN; AST/ALT ≤ 2.5x ULN. * Life expectancy of at least 3 months. Exclusion Criteria: * Intention to undergo stem cell transplant (SCT) or treatment with chimeric antigen receptor (CAR) T-cell therapy. * SCT therapy within 100 days prior to starting study treatment. * Systemic anti-cancer therapy or investigational agent within 3 weeks of study entry, except for nitrosoureas or mitomycin C (6 weeks). * Other non-cytotoxic anti-cancer therapy or investigational agent within 5 half-lives or 21 days prior to study treatment, whichever is shorter, as long as any drug related toxicities have resolved to Grade 1 or less. Dexamethasone up to 12 mg/d is allowed as supportive therapy and does not exclude participation. * Contraindication to venetoclax or rituximab. * Progressive disease during treatment or within 3 months of stopping prior treatment with a BCL2 inhibitor, histone deacetylase (HDAC) inhibitor, or phosphoinositide-3 kinase (PI3k) inhibitor, or prior discontinuation of any of these therapies due to clinically significant toxicity. * Graft vs. host disease following prior allogeneic transplant within 3 months prior to study treatment. * Ongoing treatment with chronic immunosuppressants. * Active CNS lymphoma. * Known gastrointestinal condition that would interfere with swallowing or the oral absorption or tolerance of fimepinostat. * Serious infection requiring systemic antibiotic therapy within 14 days prior to study treatment. * Uncontrolled or severe cardiovascular disease * Unstable or clinically significant concurrent medical condition. * Second primary malignancy within 2 years of study entry other than what is specified in the protocol. * Known HIV positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. * Active CMV infection, presence of CMV antigenemia, or evidence of any invasive CMV end organ disease (e.g., CMV colitis).

Locations (11)

USC/Norris Comprehensive Cancer Center

Los Angeles, California, United States

Florida Cancer Specialists

Sarasota, Florida, United States

Winship Cancer Institute, Emory University

Atlanta, Georgia, United States

University of Chicago Medicine

Chicago, Illinois, United States

University of Michigan

Ann Arbor, Michigan, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Stephenson Cancer Center, University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

MD Anderson Cancer Center

Houston, Texas, United States

...and 1 more locations

Outcomes

Primary Outcomes

To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral fimepinostat (CUDC-907) in combination with venetoclax and rituximab

To be evaluated in patients with relapsed and/or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). Within any given study arm, the highest dose level studied at which fewer than 2 out of 6 subjects (\< 33%) experience a dose limiting toxicity (DLT).

Time frame: At the end of cycle 1 or 2 (each cycle is 21 days)

To assess the safety and tolerability of fimepinostat in combination with anti-cancer regimens by evaluating the number of participants with adverse events assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, v4.0).

Number of participants with adverse events assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, v4.0).

Time frame: 18 months

To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating ORR

ORR assessments as measured using Lugano criteria.

Time frame: 24 months

To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating DOR

DOR assessments as measured using Lugano criteria.

Time frame: 24 months

Secondary Outcomes

To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by area under the concentration-time curve (AUC).

Pharmacokinetic parameters will include area under the concentration-time curve (AUC).