Acute Myeloid Leukemia
Conditions
Keywords
DHODH, Brequinar, Differentiation, IMPDH Inhibition
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.
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.
Interventions
DRUGBrequinar/Brequinar + Ribavirin
The first 14 participants had brequinar monotherapy; the final 3 subjects were also exposed to a combination of brequinar + ribavirin.
Sponsors
Clear Creek Bio, Inc.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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, T-cell leukemia (T-ALL), bi-lineal leukemia (BLL), or mixed phenotypic acute leukemia (MPAL) and 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 ≥ 50 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. Use of supportive care measures per institution's standard of care is permitted at any time. 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. 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). 7. Active cerebrospinal involvement of AML, T-cell leukemia (T-ALL), bi-lineal leukemia (BLL), or mixed phenotypic acute leukemia (MPAL). 8. Diagnosis of acute promyelocytic leukemia (APL) 9. Clinically active hepatitis B (HBV) or hepatitis C (HCV) infection. 10. Severe gastrointestinal or metabolic condition that could interfere with the absorption of oral study medication. 11. 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. 12. Nursing women or women of childbearing potential (WOCBP) with a positive pregnancy test. 13. Documented hemoglobinopathy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Related Adverse Events | 12 months | The number of participants with grade 3 or greater treatment-related adverse events as assessed by CTCAE v. 4.03. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission (CR) Rate | Up to approximately 12 months | 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. |
| Complete Remission With Incomplete Hematologic Recovery (CRi) Rate | Up to approximately 12 months | 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. |
| Complete Remission With Partial Hematological Recovery (CRh) Rate | Up to approximately 12 months | 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. |
| Morphologic Leukemia Free State (MLFS) Rate | Up to approximately 12 months | 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. |
| Overall Response Rate (ORR) | 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. No participant met the efficacy endpoint to be included in this analysis |
| Event Free Survival (EFS) Rate | 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. No participant met this efficacy endpoint to be included in this analysis. |
| Duration of Response | 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. No participant met this efficacy endpoint to be included in this analysis. |
| Brequinar Pharmacokinetics - Area Under the Curve (AUC) | First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours. | The plot of drug concentration in blood plasma vs. time. |
| Partial Remission (PR) Rate | Up to approximately 12 months | 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. |
Countries
United States
Participant flow
Recruitment details
Cohort 1 (N = 5) 12/20/2018 - 04/01/2019. Cohort 2 (N = 11) 10/25/2019 - 11/20/2020. Cohort 3 (N = 1) 01/12/21 - 02/03/2021. Participants were enrolled at hematology oncology units at major hospitals. Only 17 of the 27 planned participants were enrolled due to lack of efficacy with either brequinar monotherapy or the brequinar + ribavirin combination. Participants were to be treated in the study for up to one year.
Pre-assignment details
All subjects had relapsed/refractory AML and had no other viable treatment options. Data were reported and analyzed by cohort.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 5 subjects were enrolled in this cohort and started dosing at 500 mg/m2 twice weekly. | 5 |
| Cohort 2 Six (6) Cohort 2 subjects started dosing with brequinar monotherapy at 500 mg/m2 on a once-weekly basis and five (5) Cohort 2 subjects started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. | 11 |
| Cohort 3 One subject was enrolled into this cohort and started dosing with brequinar monotherapy at 350 mg/m2 on a once-weekly basis. Ribavirin was added at 1000 mg p.o. BID. | 1 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 | 1 |
| Overall Study | AML Disease Progression | 3 | 3 | 0 |
| Overall Study | Physician Decision | 0 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 2 | Total | Cohort 3 | Cohort 1 |
|---|---|---|---|---|
| Age, Continuous | 72.5 years STANDARD_DEVIATION 7.13 | 68.8 years STANDARD_DEVIATION 13.15 | 66.0 years STANDARD_DEVIATION 0 | 60.4 years STANDARD_DEVIATION 20.89 |
| Body Surface Area | 1.82 meters squared STANDARD_DEVIATION 0.306 | 1.86 meters squared STANDARD_DEVIATION 0.259 | 2.0 meters squared STANDARD_DEVIATION 0 | 1.94 meters squared STANDARD_DEVIATION 0.126 |
| ECOG (European Cooperative Oncology Group ECOG Score of 0 | 1 Participants | 3 Participants | 0 Participants | 2 Participants |
| ECOG (European Cooperative Oncology Group ECOG Score of 1 | 9 Participants | 11 Participants | 0 Participants | 2 Participants |
| ECOG (European Cooperative Oncology Group ECOG Score of 2 | 1 Participants | 3 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 13 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 11 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 11 participants | 17 participants | 1 participants | 5 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 14 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 5 | 3 / 11 | 0 / 1 |
| other Total, other adverse events | 5 / 5 | 11 / 11 | 1 / 1 |
| serious Total, serious adverse events | 3 / 5 | 6 / 11 | 1 / 1 |
Outcome results
Primary
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.
Time frame: 12 months
Population: The Safety Population was used for this analysis. The Safety Population consisted of all subjects who were enrolled in the study and received at least one dose of brequinar. Data were reported and analyzed by cohort.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Number of Participants With Treatment-Related Adverse Events | 2 Participants |
| Cohort 2 | Number of Participants With Treatment-Related Adverse Events | 3 Participants |
| Cohort 3 | Number of Participants With Treatment-Related Adverse Events | 1 Participants |
Secondary
Brequinar Pharmacokinetics - Area Under the Curve (AUC)
The plot of drug concentration in blood plasma vs. time.
Time frame: First day of dosing: baseline (pre-dose), 1 hour, 2 hours, 4 hours, 6 hours.
Population: This population included subjects who completed at least Week 1 of the study. Results are based on Week 1 samples obtained on the first day of dosing at baseline (pre-dose) then at Hour 1, 2, 4, and 6. Data were reported and analyzed by cohort.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Brequinar Pharmacokinetics - Area Under the Curve (AUC) | 501.0 micrograms.hr/mL | Standard Deviation 354.5 |
| Cohort 2 | Brequinar Pharmacokinetics - Area Under the Curve (AUC) | 546.5 micrograms.hr/mL | Standard Deviation 564.1 |
| Cohort 3 | Brequinar Pharmacokinetics - Area Under the Curve (AUC) | 130.5 micrograms.hr/mL | Standard Deviation 0 |
Secondary
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.
Time frame: Up to approximately 12 months
Population: The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.
Secondary
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.
Time frame: Up to approximately 12 months
Population: The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.
Secondary
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.
Time frame: Up to approximately 12 months
Population: The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.
Secondary
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.
Time frame: Up to approximately 12 months
Population: Subjects with a response. No subjects achieved this status. Data were reported and analyzed by cohort.
Secondary
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.
Time frame: Up to approximately 12 months
Population: The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.
Secondary
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.
Time frame: Up to approximately 12 months
Population: The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.
Secondary
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
Time frame: 12 months
Population: The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.
Secondary
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.
Time frame: Up to approximately 12 months
Population: The Efficacy Analysis Set was a subset of the Safety population with measurable AML disease at baseline and at least one post-baseline disease response assessment. No subjects achieved this status. Data were reported and analyzed by cohort.