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

Phase 1 Open Label, Multi-center, Dose-Escalation Study to Assess the Safety, Tolerability and Pharmacokinetics of Orally Administered Fimepinostat (CUDC-907), a PI3K and HDAC Inhibitor, in Subjects With Refractory or Relapsed Lymphoma

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 Overview

• Status: Completed
• Conditions: Lymphoma; Refractory Lymphoma; Relapsed Lymphoma; Relapsed and/or Refractory Lymphoma; Relapsed Ddiffuse Large B-Cell Lymphoma (DLBCL); Refractory Diffuse Large B-Cell Lymphoma (DLBCL); Relapsed and/or Refractory Diffuse Large B-Cell Lymphoma (DLBCL); Double-hit Lymphoma (DHL); Triple-hit Lymphoma (THL); Double-expressor Lymphoma (DEL); High-grade B-cell Lymphoma (HGBL)
• Intervention / Treatment: Drug: Rituximab; Drug: venetoclax; Drug: fimepinostat

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • USC/Norris Comprehensive Cancer Center
  • Florida
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute, Emory University
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medicine
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Stephenson Cancer Center, University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Washington
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Fimepinostat - Continuous Once Daily; Fimepinostat 30-60 mg/day	Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat - 2x/week; Fimepinostat 60-240 mg/day	Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat - 3x/week; Fimepinostat 60-180 mg/day	Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat - 4x/week; Fimepinosta 60-180 mg/day	Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat - 5x/week; Fimepinostat 60-180 mg/day	Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat - Expansion 5x/week; Fimepinostat 60 mg on the 5 days on/2 days off	Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat - Expansion 3x/week; Fimepinostat 120 mg 3 days on/4 days off	Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat 60 mg - Combination w/ rituximab; Fimepinostat 60 mg 5 days on.2 days off plus rituximab	Drug: Rituximab; Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat 120 mg - Combination w/ rituximab; Fimepinostat 120 mg 3x/week plus rituximab	Drug: Rituximab; Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat - Biocomparability Arm; Biocomparability Arm	Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat 30 mg - Combination w/ venetoclax; Fimepinostat 30 mg 5 days on/2 days off plus venetoclax. Different combinations of dose levels for venetoclax will be explored	Drug: venetoclax; Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat 60 mg - Combination w/ venetoclax; Fimepinostat 60 mg 5 days on/2 days off plus venetoclax. Different combinations of dose levels for venetoclax will be explored	Drug: venetoclax; Drug: fimepinostat; Other Names: CUDC-907
EXPERIMENTAL: Fimepinostat - Combination w/ venetoclax and rituximab; Fimepinostat and venetoclax dosed at dose levels determined for that combination. Rituximab dosed at 375 mg/m2 IV on Day 1 of each 21 day cycle	Drug: Rituximab; Drug: fimepinostat; Other Names: CUDC-907

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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).	18 months
To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating ORR	ORR assessments as measured using Lugano criteria.	24 months
To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating DOR	DOR assessments as measured using Lugano criteria.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Pre-dose to 21 - 28 days post dose
To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by maximum plasma concentration (Cmax).	Pharmacokinetic parameters will include maximum plasma concentration (Cmax).	Pre-dose to 21 - 28 days post dose
To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by half-life (T1/2).	Pharmacokinetic parameters will include half-life (T1/2).	Pre-dose to 21 - 28 days post dose
To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by clearance (Cl).	Pharmacokinetic parameters will include clearance (Cl).	Pre-dose to 21 - 28 days post dose
To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by volume of distribution (Vd).	Pharmacokinetic parameters will include volume of distribution (Vd).	Pre-dose to 21 - 28 days post dose
To assess PK of venetoclax when administered in combination with fimepinostat as measured by area under the concentration-time curve (AUC).	Pharmacokinetic parameters will include area under the concentration-time curve (AUC).	Pre-dose to 21 - 28 days post dose
To assess PK of venetoclax when administered in combination with fimepinostat as measured by maximum plasma concentration (Cmax).	Pharmacokinetic parameters will include maximum plasma concentration (Cmax).	Pre-dose to 21 - 28 days post dose
To assess PK of venetoclax when administered in combination with fimepinostat as measured by half-life (T1/2).	Pharmacokinetic parameters will include half-life (T1/2).	Pre-dose to 21 - 28 days post dose
To assess PK of venetoclax when administered in combination with fimepinostat as measured by clearance (Cl).	Pharmacokinetic parameters will include clearance (Cl).	Pre-dose to 21 - 28 days post dose
To assess PK of venetoclax when administered in combination with fimepinostat as measured by volume of distribution (Vd).	Pharmacokinetic parameters will include volume of distribution (Vd).	Pre-dose to 21 - 28 days post dose
To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by OS.	OS measured using RECIL 2017 criteria and revised RECIST 1.1.	24 months
To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by PFS.	PFS measured using RECIL 2017 criteria and revised RECIST 1.1.	24 months
To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by ORR.	ORR measured using RECIL 2017 criteria and revised RECIST 1.1.	24 months
To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by DOR.	DOR measured using RECIL 2017 criteria and revised RECIST 1.1.	24 months
To evaluate biomarkers of fimepinostat activity	Exploratory biological markers of fimepinostat activity will be assessed in PBMCs, plasma, and tumor and samples to explore biomarkers that correlate with safety and/or efficacy, such as CREBBP/EP300.	24 months

Collaborators and Investigators

• Sponsor: Curis, Inc.
• Collaborators: The Leukemia and Lymphoma Society

Publications and helpful links

General Publications

• Oki Y, Kelly KR, Flinn I, Patel MR, Gharavi R, Ma A, Parker J, Hafeez A, Tuck D, Younes A. CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial. Haematologica. 2017 Nov;102(11):1923-1930. doi: 10.3324/haematol.2017.172882. Epub 2017 Aug 31.
• Younes A, Berdeja JG, Patel MR, Flinn I, Gerecitano JF, Neelapu SS, Kelly KR, Copeland AR, Akins A, Clancy MS, Gong L, Wang J, Ma A, Viner JL, Oki Y. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2016 May;17(5):622-31. doi: 10.1016/S1470-2045(15)00584-7. Epub 2016 Mar 31.

Study record dates

Study Major Dates

• Study Start: December 1, 2012
• Primary Completion (ACTUAL): October 9, 2020
• Study Completion (ACTUAL): October 9, 2020

Study Registration Dates

• First Submitted: December 4, 2012
• First Submitted That Met QC Criteria: December 4, 2012
• First Posted (ESTIMATE): December 6, 2012

Study Record Updates

• Last Update Posted (ACTUAL): May 6, 2021
• Last Update Submitted That Met QC Criteria: May 5, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: DLBCL; Lymphoma; Diffuse Large B-Cell Lymphoma; Open-Label; HDAC; MYC; HGBL; High-grade B-Cell Lymphoma; Double-hit Lymphoma (DHL); Triple-hit Lymphoma (THL); Double-expressor Lymphoma (DEL); P13K
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Venetoclax; Rituximab
• Other Study ID Numbers: CUDC-907-101