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

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

Status
Completed
Phases
Phase 1
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT01742988
Enrollment
106
Registered
2012-12-06
Start date
2012-12-31
Completion date
2020-10-09
Last updated
2021-05-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Double-expressor Lymphoma (DEL), Double-hit Lymphoma (DHL), High-grade B-cell Lymphoma (HGBL), Lymphoma, 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)

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

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.

Interventions

DRUGfimepinostat
DRUGRituximab
DRUGvenetoclax

Sponsors

The Leukemia and Lymphoma Society
CollaboratorOTHER
Curis, Inc.
Lead SponsorINDUSTRY

Study design

Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

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).

Design outcomes

Primary

MeasureTime frameDescription
To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of oral fimepinostat (CUDC-907) in combination with venetoclax and rituximabAt 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 monthsNumber 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 ORR24 monthsORR assessments as measured using Lugano criteria.
To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens by evaluating DOR24 monthsDOR assessments as measured using Lugano criteria.

Secondary

MeasureTime frameDescription
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 dosePharmacokinetic 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 dosePharmacokinetic 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 dosePharmacokinetic 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 dosePharmacokinetic parameters will include maximum plasma concentration (Cmax).
To assess PK of venetoclax when administered in combination with fimepinostat as measured by clearance (Cl).Pre-dose to 21 - 28 days post dosePharmacokinetic parameters will include clearance (Cl).
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 dosePharmacokinetic parameters will include half-life (T1/2).
To evaluate the efficacy of fimepinostat in combination with anti-cancer regimens as measured by OS.24 monthsOS 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 monthsPFS 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 monthsORR 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 monthsDOR measured using RECIL 2017 criteria and revised RECIST 1.1.
To evaluate biomarkers of fimepinostat activity24 monthsExploratory 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.
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 dosePharmacokinetic parameters will include volume of distribution (Vd).
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 dosePharmacokinetic 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 dosePharmacokinetic 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 dosePharmacokinetic parameters will include half-life (T1/2).

Countries

United States

Outcome results

None listed

Source: ClinicalTrials.gov · Data processed: Mar 13, 2026