E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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. |
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E.1.1.1 | Medical condition in easily understood language |
Cancer of the blood and bone marrow cells |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060558 |
E.1.2 | Term | Acute myeloid leukemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000887 |
E.1.2 | Term | Acute myeloid leukemia in remission |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054294 |
E.1.2 | Term | Acute myeloid leukemia (in remission) |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 - <40% for MCL-1 Dependency Exploratory Arm A, 15% - <30% (MCL 1 Dependency Exploratory Arm B), or 0 - <15% (MCL-1 Dependency Exploratory Arm C).
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.) |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Rate of Complete Remission (CR) as defined by the International Working Group Criteria and 2010 European LeukemiaNet after Cycle 1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After every cycle at hematologic recovery or Day 45, whichever occurs fist. |
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E.5.2 | 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.
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E.5.2.1 | 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
cytarabine (Ara-c) and mitoxantrone (mitoxantrone hydrochloride) |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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After maximum of 4 cycles of CM/ACM, patients will have an-off study visit (in clinic) and then be followed by telephone contact every month for first 12 months after date of randomization (month 1 to month 13) and then every two months from month 14 to month 24 after date of randomization. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |