A Study of Brequinar in Subjects With Relapsed/Refractory Acute Myeloid Leukemia

NCT03760666 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: CCB-01
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 6

Brief Summary

A Phase 1b/2a multi-center, open-label, non-randomized study to assess the safety, tolerability and efficacy of dose-adjusted brequinar in adult subjects with acute myeloid leukemia (AML). Ribavirin BID may be added to brequinar twice weekly in eligible subjects.

Conditions

Acute Myeloid Leukemia

Keywords

DHODH; Brequinar; Differentiation; IMPDH Inhibition

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Treatment-Related Adverse Events

  The number of participants with grade 3 or greater treatment-related adverse events as assessed by CTCAE v. 4.03.

  12 months

Secondary Outcomes (9)

• Overall Response Rate (ORR)

  12 months

• Complete Remission (CR) Rate

  Up to approximately 12 months

• Complete Remission With Incomplete Hematologic Recovery (CRi) Rate

  Up to approximately 12 months

• Complete Remission With Partial Hematological Recovery (CRh) Rate

  Up to approximately 12 months

• Morphologic Leukemia Free State (MLFS) Rate

  Up to approximately 12 months

Study Arms (1)

Brequinar/Brequinar + Ribavirin

EXPERIMENTAL

Brequinar and ribavirin were dosed orally; brequinar starting doses ranged from 200 mg/m2 to 500 mg/m2. Brequinar doses were adjusted by cohort for starting dose and regimen (either twice-weekly or once-weekly). In addition, the dose for each participant was also adjusted (either escalated or decreased) based on safety, brequinar PK and levels of dihydroorotate (DHO). Ribavirin 1000 mg twice a day (bid) was added in combination with brequinar for the final 3 study participants.

Drug: Brequinar/Brequinar + Ribavirin

Interventions

Brequinar/Brequinar + Ribavirin DRUG

The first 14 participants had brequinar monotherapy; the final 3 subjects were also exposed to a combination of brequinar + ribavirin.

Brequinar/Brequinar + Ribavirin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Willing and able to provide written informed consent for the trial.
• Patients 18 years of age or older, with relapsed/refractory AML by World Health Organization classification, T-cell leukemia (T-ALL), bi-lineal leukemia (BLL), or mixed phenotypic acute leukemia (MPAL) and who have exhausted available therapy.
• ECOG Performance Status 0 to 2.
• lead ECG with no clinically unacceptable findings; adequate cardiac function/NYHA Class 0 to 2.
• Adequate hepatic function (unless deemed to be related to underlying leukemia).
• Direct bilirubin ≤ 2 x ULN
• ALT ≤ 3 x ULN
• AST ≤ 3 x ULN
• Adequate renal function as documented by creatinine clearance ≥ 50 mL/min based on the Cockcroft-Gault equation.
• In the absence of rapidly proliferative disease, the interval from prior leukemia-directed therapy to first dose of study drug will be at least 7 days for cytotoxic or non-cytotoxic (immunotherapy) agents. Use of supportive care measures per institution's standard of care is permitted at any time.
• The effects of brequinar on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and for 90 days after completion of brequinar administration.
• Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug.

You may not qualify if:

• Patients in need of immediate leukapheresis.
• Any concurrent uncontrolled clinically significant medical condition, laboratory abnormality, or psychiatric illness that could place the participant at unacceptable risk of study treatment.
• QTc interval using Fridericia's formula (QTcF) ≥ 470 msec. Participants with a bundle branch block and prolonged QTc interval may be eligible after discussion with the medical monitor.
• Pre-existing liver disease.
• The use of other chemotherapeutic agents or anti-leukemic agents is not permitted during study with the following exceptions:
• a. Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS leukemia.
• Presence of graft versus host disease (GVHD) which requires an equivalent dose of ≥ 0.5 mg/kg/day of prednisone or therapy beyond systemic corticosteroids (e.g. cyclosporine or other calcineurin inhibitors or other immunosuppressive agents used for GVHD).
• Active cerebrospinal involvement of AML, T-cell leukemia (T-ALL), bi-lineal leukemia (BLL), or mixed phenotypic acute leukemia (MPAL).
• Diagnosis of acute promyelocytic leukemia (APL)
• Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
• Severe gastrointestinal or metabolic condition that could interfere with the absorption of oral study medication.
• Prior malignancy, unless it has not been active or has remained stable for at least 2 years. Participants with treated non-melanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible if definitive treatment for the condition has been completed. Participants with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if at the active surveillance stage, hormonal therapy has been initiated, or the malignancy has been surgically removed or treated with definitive radiotherapy.
• Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test.
• Documented hemoglobinopathy.

Sponsors & Collaborators

• Clear Creek Bio, Inc.: lead

Study Sites (6)

City of Hope

Duarte, California, 91010, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Beth-Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Cleveland Clinic Lerner College of Medicine

Cleveland, Ohio, 44195, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

brequinar; Ribavirin

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Ribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Limitations and Caveats

CCB-01 was a small, open-label study in patients who had exhausted all other therapy options for their relapsed/refractory acute myeloid leukemia (AML). The study was stopped early due to lack of efficacy and inability to recruit new patients during the COVID-19 pandemic.

Results Point of Contact

• Title: Vice President, Clinical Operations
• Organization: Clear Creek Bio, Inc.

clinical@clearcreekbio.com

(617) 765-2252

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Subjects start dosing with brequinar alone; Cohort 2 subjects may roll over into ribavirin dosing; Cohort 3 subjects started with brequinar monotherapy then added ribavirin dosing.

Study Record Dates

• First Submitted: November 27, 2018
• First Posted: November 30, 2018
• Study Start: December 20, 2018
• Primary Completion: December 31, 2020
• Study Completion: February 9, 2021
• Last Updated: August 8, 2022
• Results First Posted: August 8, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR, ANALYTIC CODE
• Time Frame: Requests for data can be submitted at any time and if the below conditions are met data will be accessible for 12 months, with possible extensions considered.
• Access Criteria: Requests for data may be made by qualified researchers who plan to engage in rigorous, independent scientific research. Data will be provided following review and approval of a research proposal including a formal statistical analysis plan and execution of a Data Sharing Agreement.

Locations

US (6)