Study to Assess the Safety, Tolerability and Pharmacokinetics of Fimepinostat (CUDC-907) in Patients With Lymphoma
Study Details
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Fimepinostat - Continuous Once Daily Fimepinostat 30-60 mg/day |
Drug: fimepinostat
Other Names:
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Experimental: Fimepinostat - 2x/week Fimepinostat 60-240 mg/day |
Drug: fimepinostat
Other Names:
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Experimental: Fimepinostat - 3x/week Fimepinostat 60-180 mg/day |
Drug: fimepinostat
Other Names:
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Experimental: Fimepinostat - 4x/week Fimepinosta 60-180 mg/day |
Drug: fimepinostat
Other Names:
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Experimental: Fimepinostat - 5x/week Fimepinostat 60-180 mg/day |
Drug: fimepinostat
Other Names:
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Experimental: Fimepinostat - Expansion 5x/week Fimepinostat 60 mg on the 5 days on/2 days off |
Drug: fimepinostat
Other Names:
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Experimental: Fimepinostat - Expansion 3x/week Fimepinostat 120 mg 3 days on/4 days off |
Drug: fimepinostat
Other Names:
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Experimental: Fimepinostat 60 mg - Combination w/ rituximab Fimepinostat 60 mg 5 days on.2 days off plus rituximab |
Drug: fimepinostat
Other Names:
Drug: Rituximab
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Experimental: Fimepinostat 120 mg - Combination w/ rituximab Fimepinostat 120 mg 3x/week plus rituximab |
Drug: fimepinostat
Other Names:
Drug: Rituximab
|
Experimental: Fimepinostat - Biocomparability Arm Biocomparability Arm |
Drug: fimepinostat
Other Names:
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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 Names:
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 Names:
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 Names:
Drug: Rituximab
|
Outcome Measures
Primary Outcome Measures
- To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral fimepinostat (CUDC-907) in combination with venetoclax and rituximab [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). [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 [24 months]
ORR assessments as measured using Lugano criteria.
- To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating DOR [24 months]
DOR assessments as measured using Lugano criteria.
Secondary Outcome Measures
- To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by area under the concentration-time curve (AUC). [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). [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). [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). [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). [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). [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). [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). [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). [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). [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. [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. [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. [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. [24 months]
DOR measured using RECIL 2017 criteria and revised RECIST 1.1.
- To evaluate biomarkers of fimepinostat activity [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
Criteria
Inclusion Criteria:
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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).
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Measurable disease by CT or PET/CT. MRI acceptable as per protocol.
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Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
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Recovery to Grade 1 or baseline of any toxicity due to prior systemic treatments (excluding alopecia).
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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.
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Creatinine ≤ 1.5x upper limit of normal (ULN); total bilirubin ≤ 1.5x ULN; AST/ALT ≤ 2.5x ULN.
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Life expectancy of at least 3 months.
Exclusion Criteria:
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Intention to undergo stem cell transplant (SCT) or treatment with chimeric antigen receptor (CAR) T-cell therapy.
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SCT therapy within 100 days prior to starting study treatment.
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Systemic anti-cancer therapy or investigational agent within 3 weeks of study entry, except for nitrosoureas or mitomycin C (6 weeks).
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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.
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Contraindication to venetoclax or rituximab.
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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.
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Graft vs. host disease following prior allogeneic transplant within 3 months prior to study treatment.
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Ongoing treatment with chronic immunosuppressants.
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Active CNS lymphoma.
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Known gastrointestinal condition that would interfere with swallowing or the oral absorption or tolerance of fimepinostat.
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Serious infection requiring systemic antibiotic therapy within 14 days prior to study treatment.
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Uncontrolled or severe cardiovascular disease
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Unstable or clinically significant concurrent medical condition.
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Second primary malignancy within 2 years of study entry other than what is specified in the protocol.
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Known HIV positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.
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Active CMV infection, presence of CMV antigenemia, or evidence of any invasive CMV end organ disease (e.g., CMV colitis).
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | USC/Norris Comprehensive Cancer Center | Los Angeles | California | United States | 90033 |
2 | Florida Cancer Specialists | Sarasota | Florida | United States | 34232 |
3 | Winship Cancer Institute, Emory University | Atlanta | Georgia | United States | 30322 |
4 | University of Chicago Medicine | Chicago | Illinois | United States | 60637 |
5 | University of Michigan | Ann Arbor | Michigan | United States | 48109 |
6 | Memorial Sloan-Kettering Cancer Center | New York | New York | United States | 10065 |
7 | Stephenson Cancer Center, University of Oklahoma Health Sciences Center | Oklahoma City | Oklahoma | United States | 73104 |
8 | Hospital of the University of Pennsylvania | Philadelphia | Pennsylvania | United States | 19104 |
9 | Sarah Cannon Research Institute | Nashville | Tennessee | United States | 37203 |
10 | MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
11 | Swedish Cancer Institute | Seattle | Washington | United States | 98104 |
Sponsors and Collaborators
- Curis, Inc.
- The Leukemia and Lymphoma Society
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CUDC-907-101