Clinical trial NCT01742988: Study to Assess the Safety, Tolerability and Pharmacokinetics of Fimepinostat (CUDC-907) in Patients With Lymphoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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)
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
Lead sponsor: Curis, Inc.
Sponsor class: INDUSTRY
Collaborators: name: The Leukemia and Lymphoma Society
First posted: 2012-12-06
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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).

Primary outcomes:
measure: To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral fimepinostat (CUDC-907) in combination with venetoclax and rituximab
timeFrame: At the end of cycle 1 or 2 (each cycle is 21 days)
measure: 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).
timeFrame: 18 months
measure: To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating ORR
timeFrame: 24 months
measure: To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating DOR
timeFrame: 24 months
Secondary outcomes:
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).
timeFrame: Pre-dose to 21 - 28 days post dose
measure: To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by maximum plasma concentration (Cmax).
timeFrame: Pre-dose to 21 - 28 days post dose
measure: To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by half-life (T1/2).
timeFrame: Pre-dose to 21 - 28 days post dose
measure: To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by clearance (Cl).
timeFrame: Pre-dose to 21 - 28 days post dose
measure: To assess pharmacokinetics (PK) of fimepinostat when administered in combination with anti-cancer regimens as measured by volume of distribution (Vd).
timeFrame: Pre-dose to 21 - 28 days post dose
measure: To assess PK of venetoclax when administered in combination with fimepinostat as measured by area under the concentration-time curve (AUC).
timeFrame: Pre-dose to 21 - 28 days post dose
measure: To assess PK of venetoclax when administered in combination with fimepinostat as measured by maximum plasma concentration (Cmax).
timeFrame: Pre-dose to 21 - 28 days post dose
measure: To assess PK of venetoclax when administered in combination with fimepinostat as measured by half-life (T1/2).
timeFrame: Pre-dose to 21 - 28 days post dose
measure: To assess PK of venetoclax when administered in combination with fimepinostat as measured by clearance (Cl).
timeFrame: Pre-dose to 21 - 28 days post dose
measure: To assess PK of venetoclax when administered in combination with fimepinostat as measured by volume of distribution (Vd).
timeFrame: Pre-dose to 21 - 28 days post dose
measure: To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by OS.
timeFrame: 24 months
measure: To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by PFS.
timeFrame: 24 months
measure: To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by ORR.
timeFrame: 24 months
measure: To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by DOR.
timeFrame: 24 months
measure: To evaluate biomarkers of fimepinostat activity
timeFrame: 24 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center
state: California
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Atlanta
country: United States
facility: Winship Cancer Institute, Emory University
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Medicine
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center, University of Oklahoma Health Sciences Center
state: Oklahoma
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
Study officials:
References:
citation: Oki Y, Kelly KR, Flinn I, Patel MR, Gharavi R, Ma A, Parker J, Hafeez A, Tuck D, Younes A. CUDC-907 in relapsed/refractory diffuse large B-cell lymphoma, including patients with MYC-alterations: results from an expanded phase I trial. Haematologica. 2017 Nov;102(11):1923-1930. doi: 10.3324/haematol.2017.172882. Epub 2017 Aug 31.
citation: Younes A, Berdeja JG, Patel MR, Flinn I, Gerecitano JF, Neelapu SS, Kelly KR, Copeland AR, Akins A, Clancy MS, Gong L, Wang J, Ma A, Viner JL, Oki Y. Safety, tolerability, and preliminary activity of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K, in patients with relapsed or refractory lymphoma or multiple myeloma: an open-label, dose-escalation, phase 1 trial. Lancet Oncol. 2016 May;17(5):622-31. doi: 10.1016/S1470-2045(15)00584-7. Epub 2016 Mar 31.