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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 : Completed
First Posted : December 6, 2012
Last Update Posted : May 6, 2021
Sponsor:
Collaborator:
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
Curis, Inc.

Tracking Information
First Submitted Date  ICMJE December 4, 2012
First Posted Date  ICMJE December 6, 2012
Last Update Posted Date May 6, 2021
Study Start Date  ICMJE December 2012
Actual Primary Completion Date October 9, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 3, 2020)
  • 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).
  • 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).
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: December 4, 2012)
To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral CUDC-907 in patients with relapsed or refractory lymphoma or multiple myeloma [ Time Frame: 21 days (1 cycle of study treatment) ]
The highest dose level studied at which fewer than 2 out of 6 subjects (< 33%) experience a dose limiting toxicity (DLT).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 28, 2019)
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 4, 2012)
  • To assess the safety and tolerability of CUDC-907 [ Time Frame: 18 months ]
    Number of participants with adverse events assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, v4.0).
  • To assess pharmacokinetics (PK) of oral CUDC-907 [ Time Frame: Pre-dose to 24 hours post-dose on the first and fifteenth day of study drug dosing ]
    Pharmacokinetic parameters will include area under the concentration-time curve (AUC), maximum plasma concentration (Cmax), half-life (T1/2), clearance (Cl) and volume of distribution (Vd).
  • To evaluate biomarkers of CUDC-907 activity [ Time Frame: Day 1, Day 8, and Day 15 of Cycle 1 dosing. ]
    Pre- and post-dose changes in acetylated histone H3 protein levels in peripheral blood mononuclear cells (PBMCs) on Day 1 and Day 15 of Cycle 1 dosing. Pre-dose values in acetylated histone H3 protein levels in PBMCs on Day 8 of Cycle 1 dosing.
  • To assess preliminary anti-cancer activity of CUDC-907 [ Time Frame: 18 months ]
    The Investigator will evaluate each subject for response to therapy according to standard response criteria for each individual subject's tumor type (e.g., Revised Response Criteria for Malignant Lymphoma and the International Uniform Response Criteria for Multiple Myeloma).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Assess the Safety, Tolerability and Pharmacokinetics of Fimepinostat (CUDC-907) in Patients With Lymphoma
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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)
Intervention  ICMJE
  • Drug: fimepinostat
    Other Name: CUDC-907
  • Drug: Rituximab
  • Drug: venetoclax
Study Arms  ICMJE
  • Experimental: Fimepinostat - Continuous Once Daily
    Fimepinostat 30-60 mg/day
    Intervention: Drug: fimepinostat
  • Experimental: Fimepinostat - 2x/week
    Fimepinostat 60-240 mg/day
    Intervention: Drug: fimepinostat
  • Experimental: Fimepinostat - 3x/week
    Fimepinostat 60-180 mg/day
    Intervention: Drug: fimepinostat
  • Experimental: Fimepinostat - 4x/week
    Fimepinosta 60-180 mg/day
    Intervention: Drug: fimepinostat
  • Experimental: Fimepinostat - 5x/week
    Fimepinostat 60-180 mg/day
    Intervention: Drug: fimepinostat
  • Experimental: Fimepinostat - Expansion 5x/week
    Fimepinostat 60 mg on the 5 days on/2 days off
    Intervention: Drug: fimepinostat
  • Experimental: Fimepinostat - Expansion 3x/week
    Fimepinostat 120 mg 3 days on/4 days off
    Intervention: Drug: fimepinostat
  • Experimental: Fimepinostat 60 mg - Combination w/ rituximab
    Fimepinostat 60 mg 5 days on.2 days off plus rituximab
    Interventions:
    • Drug: fimepinostat
    • Drug: Rituximab
  • Experimental: Fimepinostat 120 mg - Combination w/ rituximab
    Fimepinostat 120 mg 3x/week plus rituximab
    Interventions:
    • Drug: fimepinostat
    • Drug: Rituximab
  • Experimental: Fimepinostat - Biocomparability Arm
    Biocomparability Arm
    Intervention: Drug: fimepinostat
  • 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
    Interventions:
    • Drug: fimepinostat
    • 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
    Interventions:
    • Drug: fimepinostat
    • 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
    Interventions:
    • Drug: fimepinostat
    • Drug: Rituximab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 5, 2021)
106
Original Estimated Enrollment  ICMJE
 (submitted: December 4, 2012)
36
Actual Study Completion Date  ICMJE October 9, 2020
Actual Primary Completion Date October 9, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01742988
Other Study ID Numbers  ICMJE CUDC-907-101
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Curis, Inc.
Study Sponsor  ICMJE Curis, Inc.
Collaborators  ICMJE The Leukemia and Lymphoma Society
Investigators  ICMJE Not Provided
PRS Account Curis, Inc.
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP