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

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01742988
• Other study ID #: CUDC-907-101
• Status: Completed
• Phase: Phase 1
• Start date: December 2012
• Est. completion date: October 9, 2020

Study information

• Verified date: May 2021
• Source: Curis, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: October 9, 2020
• Est. primary completion date: October 9, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Double-expressor Lymphoma (DEL)
• Double-hit Lymphoma (DHL)
• High-grade B-cell Lymphoma (HGBL)
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
• Refractory Lymphoma
• Relapsed and/or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
• Relapsed and/or Refractory Lymphoma
• Relapsed Ddiffuse Large B-Cell Lymphoma (DLBCL)
• Relapsed Lymphoma
• Triple-hit Lymphoma (THL)

Intervention

Drug:
• fimepinostat

• Rituximab

• venetoclax

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Winship Cancer Institute, Emory University	Atlanta	Georgia
United States	University of Chicago Medicine	Chicago	Illinois
United States	MD Anderson Cancer Center	Houston	Texas
United States	USC/Norris Comprehensive Cancer Center	Los Angeles	California
United States	Sarah Cannon Research Institute	Nashville	Tennessee
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Stephenson Cancer Center, University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Florida Cancer Specialists	Sarasota	Florida
United States	Swedish Cancer Institute	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Curis, Inc.	The Leukemia and Lymphoma Society

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral fimepinostat (CUDC-907) in combination with venetoclax and rituximab	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).	At the end of cycle 1 or 2 (each cycle is 21 days)
Primary	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).	Number of participants with adverse events assessed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, v4.0).	18 months
Primary	To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating ORR	ORR assessments as measured using Lugano criteria.	24 months
Primary	To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating DOR	DOR assessments as measured using Lugano criteria.	24 months
Secondary	To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by area under the concentration-time curve (AUC).	Pharmacokinetic parameters will include area under the concentration-time curve (AUC).	Pre-dose to 21 - 28 days post dose
Secondary	To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by maximum plasma concentration (Cmax).	Pharmacokinetic parameters will include maximum plasma concentration (Cmax).	Pre-dose to 21 - 28 days post dose
Secondary	To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by half-life (T1/2).	Pharmacokinetic parameters will include half-life (T1/2).	Pre-dose to 21 - 28 days post dose
Secondary	To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by clearance (Cl).	Pharmacokinetic parameters will include clearance (Cl).	Pre-dose to 21 - 28 days post dose
Secondary	To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by volume of distribution (Vd).	Pharmacokinetic parameters will include volume of distribution (Vd).	Pre-dose to 21 - 28 days post dose
Secondary	To assess PK of venetoclax when administered in combination with fimepinostat as measured by area under the concentration-time curve (AUC).	Pharmacokinetic parameters will include area under the concentration-time curve (AUC).	Pre-dose to 21 - 28 days post dose
Secondary	To assess PK of venetoclax when administered in combination with fimepinostat as measured by maximum plasma concentration (Cmax).	Pharmacokinetic parameters will include maximum plasma concentration (Cmax).	Pre-dose to 21 - 28 days post dose
Secondary	To assess PK of venetoclax when administered in combination with fimepinostat as measured by half-life (T1/2).	Pharmacokinetic parameters will include half-life (T1/2).	Pre-dose to 21 - 28 days post dose
Secondary	To assess PK of venetoclax when administered in combination with fimepinostat as measured by clearance (Cl).	Pharmacokinetic parameters will include clearance (Cl).	Pre-dose to 21 - 28 days post dose
Secondary	To assess PK of venetoclax when administered in combination with fimepinostat as measured by volume of distribution (Vd).	Pharmacokinetic parameters will include volume of distribution (Vd).	Pre-dose to 21 - 28 days post dose
Secondary	To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by OS.	OS measured using RECIL 2017 criteria and revised RECIST 1.1.	24 months
Secondary	To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by PFS.	PFS measured using RECIL 2017 criteria and revised RECIST 1.1.	24 months
Secondary	To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by ORR.	ORR measured using RECIL 2017 criteria and revised RECIST 1.1.	24 months
Secondary	To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by DOR.	DOR measured using RECIL 2017 criteria and revised RECIST 1.1.	24 months
Secondary	To evaluate biomarkers of fimepinostat activity	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.	24 months