Acute Myeloid LeukemiaPhase 1/2NCT03760666
A Study of Brequinar in Subjects With Relapsed/Refractory Acute Myeloid Leukemia
A Phase 1/2 study testing Brequinar/Brequinar + Ribavirin in people with Acute Myeloid Leukemia, run by Clear Creek Bio, Inc. at 6 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Acute Myeloid Leukemia
- What is being tested?
- Brequinar/Brequinar + Ribavirin
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 17 participants
- Where
- 6 sitesUnited States
- Study dates
- 20 Dec 2018to 9 Feb 2021
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 1. 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.
- 12-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
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- 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.
Who cannot join
- 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:
- Intrathecal chemotherapy for prophylactic use or maintenance of controlled CNS leukemia.
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- 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.
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114
Beth-Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Cleveland Clinic Lerner College of Medicine
Cleveland, Ohio, 44195
City of Hope
Duarte, California, 91010
The University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
About this study
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
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.
Read the 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). Active Cohort 2 subjects on brequinar alone twice weekly may roll over into brequinar twice weekly + ribavirin BID. Cohort 3 subjects will begin treatment with brequinar alone twice weekly then move to brequinar twice weekly + ribavirin BID as tolerated. Both the brequinar and ribavirin doses may be adjusted based on safety, tolerability, and enzyme inhibition levels.
- Conditions
- Acute Myeloid Leukemia
- Being tested
- Brequinar/Brequinar + Ribavirin
- Keywords
- DHODH, Brequinar, Differentiation, IMPDH Inhibition
- Medical subject headings
- Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Brequinar/Brequinar + RibavirinDrug
The first 14 participants had brequinar monotherapy; the final 3 subjects were also exposed to a combination of brequinar + ribavirin.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Brequinar/Brequinar + Ribavirin |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 months
Secondary outcomes (9)
Overall Response Rate (ORR)
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. No participant met the efficacy endpoint to be included in this analysis
Measured: 12 months
Complete Remission (CR) Rate
The proportion of subjects in the Efficacy Analysis Set with best overall response of CR. No participant met this efficacy endpoint to be included in this analysis.
Measured: Up to approximately 12 months
Complete Remission With Incomplete Hematologic Recovery (CRi) Rate
The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRi. No participant met this efficacy endpoint to be included in this analysis.
Measured: Up to approximately 12 months
Complete Remission With Partial Hematological Recovery (CRh) Rate
The proportion of subjects in the Efficacy Analysis Set with a best overall response of CRh. No participant met this efficacy endpoint to be included in this analysis.
Measured: Up to approximately 12 months
Morphologic Leukemia Free State (MLFS) Rate
The proportion of subjects in the Efficacy Analysis Set with a best overall response of MLFS. No participant met this efficacy endpoint to be included in this analysis.
Measured: Up to approximately 12 months
Partial Remission (PR) Rate
The proportion of subjects in the Efficacy Analysis Set with a best overall response of PR. No participant met this efficacy endpoint to be included in this analysis.
Measured: Up to approximately 12 months
Event Free Survival (EFS) Rate
Interval between first dose and relapse (>=5% bone marrow blasts, reappearance of blasts in blood, or development of extramedullary disease), disease progression, or both. No participant met this efficacy endpoint to be included in this analysis.
Measured: Up to approximately 12 months
Duration of Response
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. No participant met this efficacy endpoint to be included in this analysis.
Measured: Up to approximately 12 months
Brequinar Pharmacokinetics - Area Under the Curve (AUC)
The plot of drug concentration in blood plasma vs. time.
Measured: First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Nov 2018
- Study start20 Dec 2018
- Primary completion31 Dec 2020
- Study completion9 Feb 2021
Why it stopped: No efficacy observed, COVID-19 caused sites to shut down
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Acute Myeloid LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Clear Creek Bio, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03760666
- Sponsor's protocol ID
- CCB-01
- Status last verified
- Aug 2022
- First submitted
- 27 Nov 2018
- Last updated
- 8 Aug 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Study at a glance
From the registry record, last updated by the sponsor on 8 Aug 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03760666
- Acronym / sponsor ID
- CCB-01
- Conditions
- Acute Myeloid Leukemia
- Keywords
- DHODH, Brequinar, Differentiation, IMPDH Inhibition
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: No efficacy observed, COVID-19 caused sites to shut down
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Clear Creek Bio, Inc.Industry (pharma, biotech, devices)
- Study start
- 20 Dec 2018 (actual)
- Primary completion
- 31 Dec 2020 (actual)
- Study completion
- 9 Feb 2021 (actual)
- First posted
- 30 Nov 2018 (actual)
- Results
- Posted 8 Aug 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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). Active Cohort 2 subjects on brequinar alone twice weekly may roll over into brequinar twice weekly + ribavirin BID. Cohort 3 subjects will begin treatment with brequinar alone twice weekly then move to brequinar twice weekly + ribavirin BID as tolerated. Both the brequinar and ribavirin doses may be adjusted based on safety, tolerability, and enzyme inhibition levels.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Brequinar/Brequinar + Ribavirin | Experimental | Drug: Brequinar/Brequinar + RibavirinBrequinar 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 1. 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.
- 12-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).
Key exclusion criteria (14 listed)
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Brequinar/Brequinar + RibavirinThe first 14 participants had brequinar monotherapy; the final 3 subjects were also exposed to a combination of brequinar + ribavirin. | Drug | Brequinar/Brequinar + Ribavirin |
Primary outcome
Number of Participants With Treatment-Related Adverse Events
Time frame: 12 months
The number of participants with grade 3 or greater treatment-related adverse events as assessed by CTCAE v. 4.03.
9 secondary outcomes
Overall Response Rate (ORR)
Time frame: 12 months
Complete Remission (CR) Rate
Time frame: Up to approximately 12 months
Complete Remission With Incomplete Hematologic Recovery (CRi) Rate
Time frame: Up to approximately 12 months
Complete Remission With Partial Hematological Recovery (CRh) Rate
Time frame: Up to approximately 12 months
Morphologic Leukemia Free State (MLFS) Rate
Time frame: Up to approximately 12 months
Partial Remission (PR) Rate
Time frame: Up to approximately 12 months
Event Free Survival (EFS) Rate
Time frame: Up to approximately 12 months
Duration of Response
Time frame: Up to approximately 12 months
Brequinar Pharmacokinetics - Area Under the Curve (AUC)
Time frame: First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Aug 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Brequinar/Brequinar + Ribavirin in people with Acute Myeloid Leukemia, run by Clear Creek Bio, Inc. at 6 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 8 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Aug 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Treatment-Related Adverse Events (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Aug 2022.