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

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ClinicalTrials.gov Identifier: NCT01742988
Recruitment Status : Recruiting
First Posted : December 6, 2012
Last Update Posted : September 12, 2019
Sponsor:
Collaborator:
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
Curis, Inc.

Study Description
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Brief Summary:
This is a phase 1/2, open-label, dose-escalation study of fimepinostat (CUDC-907) in patients with relapsed and/or refractory lymphoma, 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 Drug: Bendamustine Phase 1 Phase 2

Study Design
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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 1/2 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

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arms and Interventions
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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/ rituximab and bendamustine
Fimepinostat 60 mg 5 days on/2 days off plus rituximab aand bendamustine. Different combinations of dose levels for bendamustine will be explored
 Drug: fimepinostat
Other Name: CUDC-907

Drug: Rituximab
Drug: Bendamustine


Outcome Measures
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Primary Outcome Measures :
  1. In Ph1 Dose-Escalation period only: To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral fimepinostat (CUDC-907) in combination with 1 or more anti-cancer regimens [ 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) lymphoma or R/R diffuse large B-cell lymphoma (DLBCL), or high-grade B-cell lymphoma (HGBL). Combination anti-cancer regimens include: Venetoclax (patients with R/R DLBCL or HGBL); Rituximab + bendamustine (patients with R/R lymphoma); 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
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Information from the National Library of Medicine

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

Inclusion Criteria:

Subjects of ≥ 18 years of age with any of the following:

For Dose-Escalation cohorts:

  • Fimepinostat + venetoclax: Histopathologically confirmed DLBCL or HGBL that is refractory to, or has relapsed after, treatment with at least 1 prior regimen
  • Fimepinostat + rituximab + bendamustine: Histopathologically confirmed diagnosis of lymphoma (i.e., B-cell non-Hodgkin lymphoma [NHL], TCL, or HL) that is refractory to, or has relapsed after, treatment with at least 1 prior regimen.

For Dose-Expansion cohorts:

  • Fimepinostat + venetoclax: R/R DLBCL or HGBL with both MYC and BCL2 alterations and/or overexpression (DHL, THL, or DEL) that is refractory to, or has relapsed after, 1 or more prior lines of therapy.
  • Fimepinostat + rituximab + bendamustine: R/R DLBCL or HGBL that is refractory to, or has relapsed after, 1 or more prior lines of therapy
  • 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 or treatment with chimeric antigen receptor (CAR) T-cell therapy.
  • 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.
  • 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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01742988


Contacts
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Contact: Dena Grayson, MD, PhD clinicaltrials@curis.com

Locations
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United States, California
USC/Norris Comprehensive Cancer Center Active, not recruiting
Los Angeles, California, United States, 90033
United States, Florida
Florida Cancer Specialists Completed
Sarasota, Florida, United States, 34232
United States, Georgia
Winship Cancer Institute, Emory University Recruiting
Atlanta, Georgia, United States, 30322
Principal Investigator: Jonathon B Cohen, MD         
United States, Illinois
University of Chicago Medicine Recruiting
Chicago, Illinois, United States, 60637
Principal Investigator: Sonali Smith, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Principal Investigator: Tycel J Phillips, MD         
United States, New York
Memorial Sloan-Kettering Cancer Center Recruiting
New York, New York, United States, 10065
United States, Oklahoma
Stephenson Cancer Center, University of Oklahoma Health Sciences Center Completed
Oklahoma City, Oklahoma, United States, 73104
United States, Pennsylvania
Hospital of the University of Pennsylvania Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Principal Investigator: Stefan K Barta, MD         
United States, Tennessee
Sarah Cannon Research Institute Completed
Nashville, Tennessee, United States, 37203
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
United States, Washington
Swedish Cancer Institute Recruiting
Seattle, Washington, United States, 98104
Principal Investigator: Krish Patel, MD         
Sponsors and Collaborators
Curis, Inc.
The Leukemia and Lymphoma Society
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Curis, Inc.
ClinicalTrials.gov Identifier: NCT01742988    
Other Study ID Numbers: CUDC-907-101
First Posted: December 6, 2012    Key Record Dates
Last Update Posted: September 12, 2019
Last Verified: September 2019
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:
Layout table for 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
 Bendamustine Hydrochloride
Venetoclax
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action