Relapsed/Refractory Acute Myeloid Leukemia (AML) with MCL-1 dependence of =40% demonstrated by mitochondrial profiling. Newly diagnosed high-risk (NDHR) AML with MCL-1 dependence of = 40% demonstrated by mitochondrial profiling. Relapsed or primary refractory AML with varying levels of MCL 1 dependence demonstrated by mitochondrial profiling. MedDRA version: 20.0 Level: LLT Classification code 10060558 Term: Acute myeloid leukemia recurrent System Organ Class: 100000004864 MedDRA version: 2
Conditions
Interventions
Product Name: Alvocidib
Product Code: Alvocidib (Flavopiridol)
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: alvocidib hydrochloride
CAS Number: 131740-09-5
Current S
Sponsors
Tolero Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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 (no CR or CRi after 2 cycles of intensive anthracycline/cytarabine ± etoposide or cladribine induction) or have NDHR AML as defined in this protocol (see Section 4.4.4) 4.Demonstrate MCL-1 dependence of =40% by mitochondrial profiling in bone marrow, 30 - 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 209 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Stage 1: Primary Objective Primary Relapsed/Refractory AML Study Arm •To determine the CR rate in patients with relapsed or refractory AML with MCL-1 dependence of =40% Stage 2: Primary Objective •To compare CR rates between patients with relapsed or refractory AML with MCL-1 dependence of =40% receiving 1 cycle of ACM treatment and those receiving 1 cycle of CM. Exploratory Objective (Stage 2): •To determine if treatment with ACM can induce CR in patients with relapsed or refractory AML with MCL-1 dependence of =40% who failed to achieve CR following 1 cycle of CM. Exploratory Arms NDHR Exploratory Arm: To determine the CR rate in patients with newly diagnosed high-risk AML with MCL-1 dependence of =40% following 1 cycle of ACM treatment. MCL-1 Dependency Exploratory Arms: To model, by logistic regression (LR), the relationship between MCL-1 dependence and the CR rate in patients with relapsed or refractory AML after 1 cycle of ACM treatment ;Secondary Objective: "Not applicable";Primary end point(s): Rate of Complete Remission (CR) as defined by the International Working Group Criteria and 2010 European LeukemiaNet after Cycle 1 ;Timepoint(s) of evaluation of this end point: After every cycle at hematologic recovery or Day 45, whichever occurs fist. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Efficacy Endpoints • Overall Survival (OS) = Time from randomization (Day 1) until death from any cause • Combined CR Rate = Percentage of patients achieving a CR, CRi or CRp • Combined Response Rate = Percentage of patients achieving a CR, CRi, CRp, or PR • Rate of Stem Cell Transplantation = Percentage of patients proceeding directly to stem cell transplantation • 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 The CR rate in patients failing CM and crossing over to receive ACM will also be determined. The Complete Remission (CR) rate, defined as the percentage of patients achieving CR, will be determined separately for the Primary Relapsed/Refractory AML Study Arm and each of the four exploratory arms. Secondary endpoints described for Stage 1 will also be assessed separately for each Exploratory Arm. To address the newly added study objective, data from all relapsed or refractory AML patients who receive ACM (all cohorts named above except the NDHR Exploratory Arm) will be combined to estimate the parameters of a standard LR model. Complete details of the planned analysis will be documented in a full Statistical Analysis Plan, which will be finalized before locking the study database. ;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. | — |
Countries
Canada, Spain, United Kingdom, United States
Contacts
Public ContactMike Bernstein
Tolero Pharmaceuticals, Inc.
Outcome results
None listed