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

NCT01742988

Description:

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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: CUDC-907-101
  • NCT ID: NCT01742988

Conditions

  • 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)

Interventions

DrugSynonymsArms
fimepinostatCUDC-907Fimepinostat - 2x/week
RituximabFimepinostat - Combination w/ rituximab and bendamustine
venetoclaxFimepinostat 30 mg - Combination w/ venetoclax
BendamustineFimepinostat - Combination w/ rituximab and bendamustine

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Fimepinostat - Continuous Once DailyExperimentalFimepinostat 30-60 mg/day
  • fimepinostat
Fimepinostat - 2x/weekExperimentalFimepinostat 60-240 mg/day
  • fimepinostat
Fimepinostat - 3x/weekExperimentalFimepinostat 60-180 mg/day
  • fimepinostat
Fimepinostat - 4x/weekExperimentalFimepinosta 60-180 mg/day
  • fimepinostat
Fimepinostat - 5x/weekExperimentalFimepinostat 60-180 mg/day
  • fimepinostat
Fimepinostat - Expansion 5x/weekExperimentalFimepinostat 60 mg on the 5 days on/2 days off
  • fimepinostat
Fimepinostat - Expansion 3x/weekExperimentalFimepinostat 120 mg 3 days on/4 days off
  • fimepinostat
Fimepinostat 60 mg - Combination w/ rituximabExperimentalFimepinostat 60 mg 5 days on.2 days off plus rituximab
  • fimepinostat
  • Rituximab
Fimepinostat 120 mg - Combination w/ rituximabExperimentalFimepinostat 120 mg 3x/week plus rituximab
  • fimepinostat
  • Rituximab
Fimepinostat - Biocomparability ArmExperimentalBiocomparability Arm
  • fimepinostat
Fimepinostat 30 mg - Combination w/ venetoclaxExperimentalFimepinostat 30 mg 5 days on/2 days off plus venetoclax. Different combinations of dose levels for venetoclax will be explored
  • fimepinostat
  • venetoclax
Fimepinostat 60 mg - Combination w/ venetoclaxExperimentalFimepinostat 60 mg 5 days on/2 days off plus venetoclax. Different combinations of dose levels for venetoclax will be explored
  • fimepinostat
  • venetoclax
Fimepinostat - Combination w/ rituximab and bendamustineExperimentalFimepinostat 60 mg 5 days on/2 days off plus rituximab aand bendamustine. Different combinations of dose levels for bendamustine will be explored
  • fimepinostat
  • Rituximab
  • Bendamustine

Eligibility 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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)
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Pharmacokinetic parameters will include area under the concentration-time curve (AUC).
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters will include maximum plasma concentration (Cmax).
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters will include half-life (T1/2).
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters will include clearance (Cl).
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters will include volume of distribution (Vd).
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters will include area under the concentration-time curve (AUC).
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters will include maximum plasma concentration (Cmax).
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters will include half-life (T1/2).
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters will include clearance (Cl).
Measure: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
Safety Issue:
Description:Pharmacokinetic parameters will include volume of distribution (Vd).
Measure:To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by OS.
Time Frame:24 months
Safety Issue:
Description:OS measured using RECIL 2017 criteria and revised RECIST 1.1.
Measure:To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by PFS.
Time Frame:24 months
Safety Issue:
Description:PFS measured using RECIL 2017 criteria and revised RECIST 1.1.
Measure:To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by ORR.
Time Frame:24 months
Safety Issue:
Description:ORR measured using RECIL 2017 criteria and revised RECIST 1.1.
Measure:To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by DOR.
Time Frame:24 months
Safety Issue:
Description:DOR measured using RECIL 2017 criteria and revised RECIST 1.1.
Measure:To evaluate biomarkers of fimepinostat activity
Time Frame:24 months
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Curis, Inc.

Trial Keywords

  • 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

Last Updated

September 11, 2019