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

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ClinicalTrials.gov Identifier: NCT03760666
Recruitment Status : Recruiting
First Posted : November 30, 2018
Last Update Posted : March 8, 2019
Sponsor:
Information provided by (Responsible Party):
Clear Creek Bio, Inc.

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).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Brequinar Phase 1 Phase 2

Detailed Description:
Up to 27 subjects will be entered in this 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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2a Open-label, Multi-center Study to Assess the Safety, Efficacy and Pharmacokinetics of Intrapatient Dose-adjusted Brequinar and Inhibition of Dihydroorotate Dehydrogenase (DHODH) in Adult Subjects With AML
Actual Study Start Date : November 26, 2018
Estimated Primary Completion Date : December 31, 2019
Estimated Study Completion Date : June 30, 2020


Arm Intervention/treatment
Experimental: Brequinar
Brequinar dosed orally. Multiple doses.
Drug: Brequinar
Oral brequinar will be administered twice-weekly. After the first cohort of 6 subjects, dose adjustments can occur every 14-day cycle both at the intra-subject and the inter-cohort level depending on safety, efficacy, and biomarker levels.




Primary Outcome Measures :
  1. Number of Participants with Treatment-Related Adverse Events [ Time Frame: 12 months ]
    The number of subjects with treatment-related adverse events as assessed by CTCAE v. 4.03.


Secondary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: 12 months ]
    The number of participants in the Efficacy Analysis Set with best overall response of one of the responses of CR, CRi, CRh, PR, of MLFS.

  2. Complete Remission (CR) rate [ Time Frame: Up to approximately 12 months ]
    The proportion of subjects in the Efficacy Analysis Set with best overall response of CR

  3. Complete Remission with Incomplete Hematologic Recovery (CRi) rate [ Time Frame: Up to approximately 12 months ]
    The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRi

  4. Complete Remission with Partial Hematological Recovery (CRh) rate [ Time Frame: Up to approximately 12 months ]
    The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRh

  5. Morphologic Leukemia Free State (MLFS) rate [ Time Frame: Up to approximately 12 months ]
    The proportion of subjects in the Efficacy Analysis Set with a best overall response of MLFS

  6. Partial Remission (PR) rate [ Time Frame: Up to approximately 12 months ]
    The proportion of subjects in the Efficacy Analysis Set with a best overall response of PR

  7. Event free survival (EFS) rate [ Time Frame: Up to approximately 12 months ]
    Interval between first dose and relapse (>=5% bone marrow blasts, reappearance of blasts in blood, or development of extramedullary disease), disease progression, or both

  8. Duration of response [ Time Frame: Up to approximately 12 months ]
    The duration of response is defined as the number of days from the time response criteria are initially met for CR, CRi, CRh, PR, or MLFS (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, or death due to any cause. Participants without events reported are censored at the last disease evaluation.

  9. Brequinar Pharmacokinetics - Elimination Half-Life (T 1/2) [ Time Frame: Up to 14 days after first dose. ]
    The period of time required for the concentration of drug in plasma to be reduced by one-half.

  10. Brequinar Pharmacokinetics - AUC [ Time Frame: Up to 14 days after first dose. ]
    The plot of drug concentration in blood plasma vs. time.

  11. DHO Plasma Level [ Time Frame: Up to 14 days after first dose. Pre-dose at the beginning of each cycle (every 2 weeks for 3 months then every 4 weeks). ]
    Plasma level of DHO



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Willing and able to provide written informed consent for the trial.
  2. Patients 18 years of age or older, with relapsed/refractory AML by World Health Organization classification who have exhausted available therapy.
  3. ECOG Performance Status 0 to 2.
  4. 12-lead ECG with no clinically unacceptable findings; adequate cardiac function/NYHA Class 0 to 2.
  5. Adequate hepatic function (unless deemed to be related to underlying leukemia).

    1. Direct bilirubin ≤ 2 x ULN
    2. ALT ≤ 3 x ULN
    3. AST ≤ 3 x ULN
  6. Adequate renal function as documented by creatinine clearance ≥ 30 mL/min based on the Cockcroft-Gault equation.
  7. 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. Hydrea is allowed up to 48 hours prior to the first dose for patients with rapidly proliferative disease.
  8. 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.
  9. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug.

Exclusion Criteria:

  1. Patients in need of immediate leukapheresis.
  2. Any concurrent uncontrolled clinically significant medical condition, laboratory abnormality, or psychiatric illness that could place the participant at unacceptable risk of study treatment.
  3. 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.
  4. Pre-existing liver disease.
  5. 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.

  6. Use of hydroxyurea for the purpose of leukemic cytoreduction may be allowed during the first 2 weeks of therapy if in the best interest of the participant and is approved by the medical monitor. Hydroxyurea can be used to treat leukocytosis if concurrent with and thought to be associated with presumed differentiation syndrome.
  7. 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).
  8. Active cerebrospinal involvement of AML.
  9. Diagnosis of acute promyelocytic leukemia (APL)
  10. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection.
  11. Severe gastrointestinal or metabolic condition that could interfere with the absorption of oral study medication.
  12. 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.
  13. Nursing women or women of childbearing potential (WOCBP) with a positive urine pregnancy test.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03760666


Contacts
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Contact: Barbara L Powers, MSN, PhD (617) 765-2252 clinical@clearcreekbio.com

Locations
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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Amandeep Salhotra, MD    626-256-4673    asalhotra@coh.org   
Principal Investigator: Amandeep Salhotra, MD         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Amir T Fathi, MD    617-724-1124    afathi@partners.org   
Principal Investigator: Amir Fathi, MD         
Beth-Israel Deaconess Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Lourdes M Mendez, MD    617-667-7000    lmendez@bidmc.harvard.edu   
Principal Investigator: Lourdes M Mendez, MD         
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Eric S Winder, MD    617-632-1906    erics_winer@dfci.harvard.edu   
Principal Investigator: Eric S Winer, MD         
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Courtney DiNardo, MD    713-794-1141    cdinardo@mdanderson.org   
Principal Investigator: Courtney DiNardo, MD         
Sponsors and Collaborators
Clear Creek Bio, Inc.

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Responsible Party: Clear Creek Bio, Inc.
ClinicalTrials.gov Identifier: NCT03760666     History of Changes
Other Study ID Numbers: CCB-01
First Posted: November 30, 2018    Key Record Dates
Last Update Posted: March 8, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Clear Creek Bio is committed to responsible data sharing regarding the clinical trials we sponsor. Data that may be shared include access to anonymized participant and trial level data (analysis data sets), as well as other information (e.g., protocol) as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Clear Creek Bio, Inc.:
DHODH
Brequinar
Differentiation
Additional relevant MeSH terms:
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Brequinar
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs