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

• ClinicalTrials.gov Identifier: NCT01742988
• Recruitment Status: Active, not recruiting
• First Posted: December 6, 2012
• Last Update Posted: March 23, 2020
• Sponsor: Curis, Inc.
• Collaborator: The Leukemia and Lymphoma Society
• Information provided by (Responsible Party): Curis, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Lymphoma; Relapsed Lymphoma; Refractory 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)	Drug: fimepinostat; Drug: Rituximab; Drug: venetoclax	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 180 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: December 2012
• Estimated Primary Completion Date: December 2020
• Estimated Study Completion Date: December 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Fimepinostat - Continuous Once Daily; Fimepinostat 30-60 mg/day	Drug: fimepinostat; Other Name: CUDC-907
Experimental: Fimepinostat - 2x/week; Fimepinostat 60-240 mg/day	Drug: fimepinostat; Other Name: CUDC-907
Experimental: Fimepinostat - 3x/week; Fimepinostat 60-180 mg/day	Drug: fimepinostat; Other Name: CUDC-907
Experimental: Fimepinostat - 4x/week; Fimepinosta 60-180 mg/day	Drug: fimepinostat; Other Name: CUDC-907
Experimental: Fimepinostat - 5x/week; Fimepinostat 60-180 mg/day	Drug: fimepinostat; Other Name: CUDC-907
Experimental: Fimepinostat - Expansion 5x/week; Fimepinostat 60 mg on the 5 days on/2 days off	Drug: fimepinostat; Other Name: CUDC-907
Experimental: Fimepinostat - Expansion 3x/week; Fimepinostat 120 mg 3 days on/4 days off	Drug: fimepinostat; Other Name: CUDC-907
Experimental: Fimepinostat 60 mg - Combination w/ rituximab; Fimepinostat 60 mg 5 days on.2 days off plus rituximab	Drug: fimepinostat; Other Name: CUDC-907; Drug: Rituximab
Experimental: Fimepinostat 120 mg - Combination w/ rituximab; Fimepinostat 120 mg 3x/week plus rituximab	Drug: fimepinostat; Other Name: CUDC-907; Drug: Rituximab
Experimental: Fimepinostat - Biocomparability Arm; Biocomparability Arm	Drug: fimepinostat; Other Name: 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: fimepinostat; Other Name: CUDC-907; Drug: venetoclax
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: fimepinostat; Other Name: CUDC-907; Drug: venetoclax
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: fimepinostat; Other Name: CUDC-907; Drug: Rituximab

Outcome Measures

Primary Outcome Measures :

1. To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral fimepinostat (CUDC-907) in combination with venetoclax and rituximab [ Time Frame: At the end of cycle 1 or 2 (each cycle is 21 days) ]
   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).
2. 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). [ Time Frame: 18 months ]
   Number of participants with adverse events assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, v4.0).
3. To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating ORR [ Time Frame: 24 months ]
   ORR assessments as measured using Lugano criteria.
4. To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating DOR [ Time Frame: 24 months ]
   DOR assessments as measured using Lugano criteria.

Secondary Outcome Measures :

1. To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by area under the concentration-time curve (AUC). [ Time Frame: Pre-dose to 21 - 28 days post dose ]
   Pharmacokinetic parameters will include area under the concentration-time curve (AUC).
2. To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by maximum plasma concentration (Cmax). [ Time Frame: Pre-dose to 21 - 28 days post dose ]
   Pharmacokinetic parameters will include maximum plasma concentration (Cmax).
3. To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by half-life (T1/2). [ Time Frame: Pre-dose to 21 - 28 days post dose ]
   Pharmacokinetic parameters will include half-life (T1/2).
4. To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by clearance (Cl). [ Time Frame: Pre-dose to 21 - 28 days post dose ]
   Pharmacokinetic parameters will include clearance (Cl).
5. To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by volume of distribution (Vd). [ Time Frame: Pre-dose to 21 - 28 days post dose ]
   Pharmacokinetic parameters will include volume of distribution (Vd).
6. To assess PK of venetoclax when administered in combination with fimepinostat as measured by area under the concentration-time curve (AUC). [ Time Frame: Pre-dose to 21 - 28 days post dose ]
   Pharmacokinetic parameters will include area under the concentration-time curve (AUC).
7. To assess PK of venetoclax when administered in combination with fimepinostat as measured by maximum plasma concentration (Cmax). [ Time Frame: Pre-dose to 21 - 28 days post dose ]
   Pharmacokinetic parameters will include maximum plasma concentration (Cmax).
8. To assess PK of venetoclax when administered in combination with fimepinostat as measured by half-life (T1/2). [ Time Frame: Pre-dose to 21 - 28 days post dose ]
   Pharmacokinetic parameters will include half-life (T1/2).
9. To assess PK of venetoclax when administered in combination with fimepinostat as measured by clearance (Cl). [ Time Frame: Pre-dose to 21 - 28 days post dose ]
   Pharmacokinetic parameters will include clearance (Cl).
10. To assess PK of venetoclax when administered in combination with fimepinostat as measured by volume of distribution (Vd). [ Time Frame: Pre-dose to 21 - 28 days post dose ]
    Pharmacokinetic parameters will include volume of distribution (Vd).
11. To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by OS. [ Time Frame: 24 months ]
    OS measured using RECIL 2017 criteria and revised RECIST 1.1.
12. To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by PFS. [ Time Frame: 24 months ]
    PFS measured using RECIL 2017 criteria and revised RECIST 1.1.
13. To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by ORR. [ Time Frame: 24 months ]
    ORR measured using RECIL 2017 criteria and revised RECIST 1.1.
14. To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by DOR. [ Time Frame: 24 months ]
    DOR measured using RECIL 2017 criteria and revised RECIST 1.1.
15. To evaluate biomarkers of fimepinostat activity [ Time Frame: 24 months ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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).

Contacts and Locations

Locations

United States, California

USC/Norris Comprehensive Cancer Center

Los Angeles, California, United States, 90033

United States, Florida

Florida Cancer Specialists

Sarasota, Florida, United States, 34232

United States, Georgia

Winship Cancer Institute, Emory University

Atlanta, Georgia, United States, 30322

United States, Illinois

University of Chicago Medicine

Chicago, Illinois, United States, 60637

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, New York

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10065

United States, Oklahoma

Stephenson Cancer Center, University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States, 73104

United States, Pennsylvania

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

Sarah Cannon Research Institute

Nashville, Tennessee, United States, 37203

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Washington

Swedish Cancer Institute

Seattle, Washington, United States, 98104

Sponsors and Collaborators

Curis, Inc.

The Leukemia and Lymphoma Society

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Curis, Inc.
• ClinicalTrials.gov Identifier: NCT01742988
• Other Study ID Numbers: CUDC-907-101
• First Posted: December 6, 2012
• Last Update Posted: March 23, 2020
• Last Verified: March 2020

Keywords provided by Curis, Inc.:

Lymphoma; DLBCL; MYC; Diffuse Large B-Cell Lymphoma; HGBL; High-grade B-Cell Lymphoma; Double-hit Lymphoma (DHL); Triple-hit Lymphoma (THL); Double-expressor Lymphoma (DEL); P13K; HDAC; Open-Label

Additional relevant MeSH terms:

Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Rituximab; Venetoclax; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents