A Phase 2 Clinical Trial in Patients with Acute Myeloid Leukemia (AML).

Phase 1

Conditions: Relapsed/Refractory Acute Myeloid Leukemia (AML)
MedDRA version: 20.0Level: LLTClassification code 10060558Term: Acute myeloid leukemia recurrentSystem Organ Class: 100000012987
MedDRA version: 20.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000012984
MedDRA version: 20.0Level: LLTClassification code 10000887Term: Acute myeloid leukemia in remissionSystem Organ Class: 100000012977
MedDRA version: 20.0Level: LLTClassification code 10054294Term: Acute myeloid leukemia (in remission)System Organ Class: 100000012977
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2017-001178-41-ES

Lead Sponsor: Tolero Pharmaceuticals, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 104

Inclusion Criteria

During Prescreening:
1. Be between the ages of =18 and =65 years
2. Have an established, pathologically confirmed diagnoses of AML by World Health Organization (WHO) criteria excluding acute promyelocytic leukemia (APL-M3) with a bone marrow of >5% blasts based on histology or flow cytometry
3. Be in first relapse (within 24 months of CR) or have primary refractory AML (refractory to initial induction therapy using 1 or 2 cycles of intensive anthracycline/cytarabine ± etoposide or cladribine induction) or have newly diagnosed high-risk AML as defined in this protocol
4. Demonstrate NOXA BH3 priming of =40% by mitochondrial profiling in bone marrow or 30-39% for NOXA Exploratory Arm.
During Screening:
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) =2
6. Have a serum creatinine level =1.8 mg/dL
7. Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level =5 times upper limit of normal (ULN)
8. Have a total bilirubin level =2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia)
9. Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
10. Be nonfertile or agree to use an adequate method of contraception. Sexually active patients and their partners must use an effective method of contraception associated with a low failure rate during and for 6 months after completion of study therapy.
11. Be able to comply with the requirements of the entire study.
12. Provide written informed consent prior to any study related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.)
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 119
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. Received more than 2 cycles of induction therapy for AML. Investigational agents as part of front-line therapy for AML may by acceptable following discussion with the Medical Monitor. Hydroxyurea is permitted (see #5 below).
2. Received any previous treatment with alvocidib or any other CDK inhibitor
3. Received a hematopoietic stem cell transplant within the previous 2 months
4. Have clinically significant graft versus host disease (GVHD), or GVHD requiring initiation or escalation of treatment within the last 21 days
5. Require concomitant chemotherapy, radiation therapy, or immunotherapy. Hydroxyurea is allowed up to the evening before starting (but not within 12 hours) of starting treatment on either arm.
6. Received >360 mg/m2 equivalents of daunorubicin
7. Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #5 above)
8. Received antileukemic therapy within the last 3 weeks (with the exception of hydroxyurea or if the patient has definite refractory disease). Refractory patients who received therapy within the last 3 weeks may be eligible with prior approval of the Medical Monitor.
9. Diagnosed with acute promyelocytic leukemia (APL, M3)
10. Have active central nervous system (CNS) leukemia
11. Have evidence of uncontrolled disseminated intravascular coagulation
12. Have an active, uncontrolled infection
13. Have other life-threatening illness
14. Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia
15. Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol.
16. Are pregnant and/or nursing.
17. Have received any live vaccine within 14 days prior to first study drug administration.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Stage 1: To determine the CR rate in patients with relapsed or refractory AML with NOXA BH3 priming =40%.<br>Stage 2: To compare CR rates between patients with relapsed or refractory AML with NOXA BH3 priming =40% receiving 1-2 cycles of ACM treatment and those receiving 1-2 cycles of CM.<br>Exploratory Objective (Stage 2): To determine if treatment with ACM can induce CR in patients with relapsed or refractory AML with NOXA BH3 priming =40% who failed to achieve CR following 1-2 cycles of CM.;Secondary Objective: Not applicable;Primary end point(s): Complete Remission (CR) rate = Percentage of patients achieving CR;Timepoint(s) of evaluation of this end point: After every cycle at hematologic recovery or Day 45, whichever occurs fist.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Secondary Efficacy Endpoints<br>• Overall Survival (OS) = Time from randomization (Day 1) until death from any cause<br>• Combined CR Rate = Percentage of patients achieving a CR, CRi or CRp<br>• Combined Response Rate = Percentage of patients achieving a CR, CRi, CRp, or PR<br>• Rate of Stem Cell Transplantation = Percentage of patients proceeding directly to stem cell transplantation<br>• Event-free Survival (EFS) = Time from randomization (Day 1) until (a) treatment failure, (b) relapse after CR, or (c) death from any cause, whichever occurs first, censored at 2 years<br>The CR rate in patients failing CM and crossing over to receive ACM will also be determined.;Timepoint(s) of evaluation of this end point: Follow-up by telephone every month during 12 months from month 1 to month 13 from randomization and then every 2 months from month 14 to 24 from randomization. This follow-up is made after receiving 4 cycles and off-study visit.