Alvocidib Biomarker-driven Phase 2 AML Study

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ClinicalTrials.gov Identifier: NCT02520011

Recruitment Status : Recruiting

First Posted : August 11, 2015

Last Update Posted : December 20, 2018

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Sponsor:

Information provided by (Responsible Party):

Tolero Pharmaceuticals, Inc.

Study Description

Brief Summary:

The purpose of this two-stage Phase 2 study is to assess the clinical response (Complete Remission) of ACM (Alvocidib/Cytarabine/Mitoxantrone) compared to CM (Cytarabine/Mitoxantrone) treatment in refractory or relapsed AML patients with demonstrated MCL-1 dependence of ≥ 40% by mitochondrial profiling in bone marrow.

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia	Drug: Alvocidib Drug: Cytarabine Drug: Mitoxantrone	Phase 2

Detailed Description:

In Stage 1 of the study, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 40% by mitochondrial profiling in bone marrow will receive treatment with ACM.

In Stage 2, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 40% by mitochondrial profiling in bone marrow will be randomized 1:1 to receive either treatment with ACM or CM.

In the NDHR exploratory arm, all eligible patients with newly diagnosed high-risk (NDHR) AML with MCL-1 dependence of ≥40% by mitochondrial profiling in bone marrow will receive treatment with ACM.

In the MCL-1 dependency exploratory arms, all eligible AML patients with demonstrated MCL-1 dependence of ≥ 30 - <40% (Arm A), 15% - <30% (Arm B), or 0 - <15% (Arm C) by mitochondrial profiling in bone marrow who are either in first relapse (within 24 months of CR) or have primary refractory AML (ie, no CR or CRi after 2 cycles of intensive anthracycline/cytarabine ± etoposide or cladribine induction) will receive treatment with ACM.

Study Design


Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	209 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase 2, Randomized, Biomarker-driven Study in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With an Exploratory Arm in Patients With Newly Diagnosed High-Risk AML and Exploratory Arms With Varying Levels of MCL-1 Dependence
Actual Study Start Date :	March 14, 2016
Estimated Primary Completion Date :	March 2019
Estimated Study Completion Date :	December 2019

Resource links provided by the National Library of Medicine

Genetics Home Reference related topics: Core binding factor acute myeloid leukemia Cytogenetically normal acute myeloid leukemia Familial acute myeloid leukemia with mutated CEBPA

MedlinePlus related topics: Acute Myeloid Leukemia Leukemia

Drug Information available for: Cytarabine Mitoxantrone Mitoxantrone hydrochloride

Genetic and Rare Diseases Information Center resources: Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: ACM (Stage 1 / Stage 2) A: alvocidib, 30 mg/m2 as a 30 minute intravenous (IV) bolus followed by 60 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3; C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 6-8; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine	Drug: Alvocidib Drug: Cytarabine Other Name: ara-c Drug: Mitoxantrone Other Name: mitoxantrone hydrochloride
Active Comparator: CM (Stage 2) C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 1-3; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine	Drug: Cytarabine Other Name: ara-c Drug: Mitoxantrone Other Name: mitoxantrone hydrochloride
Experimental: Exploratory Arm - NDHR A: alvocidib, 30 mg/m2 as a 30 minute intravenous (IV) bolus followed by 60 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3; C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 6-8; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine	Drug: Alvocidib Drug: Cytarabine Other Name: ara-c Drug: Mitoxantrone Other Name: mitoxantrone hydrochloride
Experimental: Exploratory Arm A - MCL-1 Dependence 30-<40% A: alvocidib, 30 mg/m2 as a 30 minute intravenous (IV) bolus followed by 60 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3; C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 6-8; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine	Drug: Alvocidib Drug: Cytarabine Other Name: ara-c Drug: Mitoxantrone Other Name: mitoxantrone hydrochloride
Experimental: Exploratory Arm B - MCL-1 Dependence 15-<30% A: alvocidib, 30 mg/m2 as a 30 minute intravenous (IV) bolus followed by 60 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3; C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 6-8; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine	Drug: Alvocidib Drug: Cytarabine Other Name: ara-c Drug: Mitoxantrone Other Name: mitoxantrone hydrochloride
Experimental: Exploratory Arm C - MCL-1 Dependence 0-<15% A: alvocidib, 30 mg/m2 as a 30 minute intravenous (IV) bolus followed by 60 mg/m2 over 4 hours as an IV infusion administered daily on Days 1-3; C: cytarabine (ara-c), 2 gm/m2 by continuous IV infusion over 72 hours on Days 6-8; M: mitoxantrone (mitoxantrone hydrochloride), 40 mg/m2 by IV infusion over 1-2 hours starting 12 hours after completing cytarabine	Drug: Alvocidib Drug: Cytarabine Other Name: ara-c Drug: Mitoxantrone Other Name: mitoxantrone hydrochloride

Outcome Measures

Primary Outcome Measures :

Complete Remission (CR) rate = Percentage of patients achieving CR after Cycle 1 as defined in Stage 1 by the International Working Group Criteria and 2010 European LeukemiaNet (ELN) criteria and in Stage 2 by the 2017 ELN criteria. [ Time Frame: 3 months ]

Secondary Outcome Measures :

Overall Survival (OS) Rate [ Time Frame: 2 years ]
Day 1 until death from any cause
Combined CR Rate = Percentage of patients achieving CR, CRi, CRp (CRp is kept in definitions for Combined CR Rate / Combined Remission Rate as Stage-1 patients were assessed by IWG criteria. CRp won't be used for assessing Stage-2 patients.) [ Time Frame: 3 months ]
Combined Response Rate = Percentage of patients achieving CR, CRi, CRp, PR [ Time Frame: 3 months ]
Rate of Stem Cell Transplantation [ Time Frame: 6 months ]
Event-Free Survival [ Time Frame: 2 years ]

Other Outcome Measures:

Mortality [ Time Frame: 30 and 60 days ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 65 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Be between the ages of ≥18 and ≤65 years
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
Be in first relapse (within 24 months of CR) or have failed induction therapy* (no CR or CRi after treatment with an intensive regimen (eg, anthracycline/cytarabine ± etoposide, gemtuzumab ozogamicin, or cladribine) or have newly diagnosed high-risk AML as defined in this protocol.

*Induction therapy may involve 1 or 2 cycles of the same regimen. Efficacy assessment of induction therapy must be >21 days from the start of the previous induction cycle.
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)
Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2
Have a serum creatinine level ≤1.8 mg/dL
Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN)
Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia)
Have a left ventricular ejection fraction (LVEF) >45% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan
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.
Be able to comply with the requirements of the entire study.
Provide written informed consent prior to any study related procedure.

Exclusion Criteria:

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).
Received any previous treatment with alvocidib or any other CDK inhibitor
Received a hematopoietic stem cell transplant within the previous 2 months
Have clinically significant graft versus host disease (GVHD), or GVHD requiring initiation or escalation of treatment within the last 21 days
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.
Received >360 mg/m2 equivalents of daunorubicin
Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #5 above)
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.
Diagnosed with acute promyelocytic leukemia (APL, M3)
Have active central nervous system (CNS) leukemia
Have evidence of uncontrolled disseminated intravascular coagulation
Have an active, uncontrolled infection
Have other life-threatening illness
Have other active malignancies or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia
Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol.
Are pregnant and/or nursing
Have received any live vaccine within 14 days prior to first study drug administration.

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02520011

Contacts


Contact: Judy Costas, BSN	361-649-9176	jcostas@toleropharma.com

Show 30 Study Locations

Sponsors and Collaborators

Tolero Pharmaceuticals, Inc.

Investigators


Study Director:	Stephen Anthony, DO	Tolero Pharmaceuticals

More Information


Responsible Party:	Tolero Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT02520011 History of Changes
Other Study ID Numbers:	TPI-ALV-201
First Posted:	August 11, 2015 Key Record Dates
Last Update Posted:	December 20, 2018
Last Verified:	December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No


Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Tolero Pharmaceuticals, Inc.:


Refractory AML Relapsed AML AML Newly diagnosed high-risk AML

Additional relevant MeSH terms:


Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Neoplasms by Histologic Type Neoplasms Cytarabine Alvocidib Mitoxantrone Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Antiviral Agents	Anti-Infective Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Analgesics Sensory System Agents Peripheral Nervous System Agents Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Growth Inhibitors Growth Substances Protein Kinase Inhibitors

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