Study of Alvocidib in Patients With Relapsed/Refractory AML Following Treatment With Venetoclax Combination Therapy

• ClinicalTrials.gov Identifier: NCT03969420
• Recruitment Status: Active, not recruiting
• First Posted: May 31, 2019
• Last Update Posted: November 25, 2020
• Sponsor: Sumitomo Dainippon Pharma Oncology, Inc
• Information provided by (Responsible Party): Sumitomo Dainippon Pharma Oncology, Inc

Study Description

Brief Summary:

This study will evaluate the safety and efficacy of alvocidib in patients with AML who have either relapsed from or are refractory to venetoclax in combination with azacytidine or decitabine.

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia (AML)	Drug: Alvocidib (flavopiridol) and cytarabine (Ara-C); Drug: Alvocidib (flavopiridol)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 134 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, Two-stage
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Open-label, Randomized, Two-stage Clinical Study of Alvocidib in Patients With Relapsed/Refractory Acute Myeloid Leukemia Following Treatment With Venetoclax Combination Therapy
• Actual Study Start Date: January 15, 2020
• Estimated Primary Completion Date: March 2022
• Estimated Study Completion Date: March 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Stage 1: Arm 1; Refractory (i.e., failed to achieve a CR/CRi or achieved a CR/CRi with duration <90 days)	Drug: Alvocidib (flavopiridol) and cytarabine (Ara-C); Alvocidib (flavopiridol), administered intravenously, + cytarabine (Ara-C), administered by subcutaneous injection
Experimental: Stage 1: Arm 2; Relapsed (i.e., reoccurrence of disease following a CR/CRi with duration ≥90 days).	Drug: Alvocidib (flavopiridol); Administered intravenously

Outcome Measures

Primary Outcome Measures :

1. Rate of combined complete remission (complete remission (CR) + CR with incomplete hematological recovery (CRi)), as defined by the International Working Group Criteria and 2017 European LeukemiaNet) [ Time Frame: 18 months ]

Secondary Outcome Measures :

1. Median overall survival. [ Time Frame: 42 months ]
2. CR rate [ Time Frame: 18 months ]
3. Composite CR rate - Combined CR + CRi + CRh (CR + partial recovery of both blood cell types) [ Time Frame: 18 months ]
4. Combined Response Rate - CR + CRi + CRh + MLFS (Morphologic leukemia-free state) + PR (partial response) [ Time Frame: 18 months ]
5. EFS (Event-free survival) defined as the time from first treatment (Day 1) until (a) treatment failure, (b) relapse after CR, /CRi, or CRh or (c) death from any cause, whichever occurs first, censored at 2 years [ Time Frame: 42 months ]
6. Duration of composite CR, defined as the time from first documented response of CR, CRi or CRhi to relapse or death from any cause [ Time Frame: 18 months ]
7. Rates of 28- and 56-day Transfusion Independence (TI) = Percentages of patients who do not receive red blood cell (RBC) transfusions, platelet (PLT) transfusions, and neither RBC nor PLT transfusions for 28 and 56 days; comprised of 6 secondary endpoints [ Time Frame: 44 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Be ≥18 years of age.
2. Have an established, pathologically confirmed diagnosis 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. Have received initial induction therapy with venetoclax in combination with azacytidine or decitabine (with or without other investigational agents as part of a clinical trial; requires Medical Monitor review) and were either refractory (failed to achieve a CR/CRi or achieved a CR/CRi with duration <90 days) or have relapsed (reoccurrence of disease following a CR/CRi with duration ≥90 days).
4. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2.
5. Have a glomerular filtration rate (GFR) ≥30 mL/min using the Cockcroft-Gault equation.
6. Have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) level ≤5 times upper limit of normal (ULN).
7. Have a total bilirubin level ≤2.0 mg/dL (unless secondary to Gilbert syndrome, hemolysis, or leukemia).
8. Be infertile 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 prior to study entry, for the duration of study participation, and for at least 3 months (males) and 6 months (females) after the last dose of study drug.
9. Be able to comply with the requirements of the entire study.
10. 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.

Exclusion Criteria:

1. Received any previous treatment with alvocidib or any other CDK inhibitor or received prior anti-leukemic therapy other than first-line venetoclax in combination with azacytidine or decitabine.
2. 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.
3. Received an allogeneic stem cell transplant within 60 days of the start of study treatment. Patients who received an allogeneic stem cell transplant must be off all immunosuppressants at the time of study treatment
4. Are receiving or have received systemic therapy for graft-versus-host disease.
5. Have a peripheral blast count of >30,000/mm3 (may use hydroxyurea as in #2 above).
6. Received antileukemic therapy within the last 2 weeks or 3-5 half lives of the prior therapy (with the exception of hydroxyurea or if the patient has definite refractory disease), whichever is less. Refractory patients who received therapy within the last 2 weeks may be eligible with prior approval of the Medical Monitor.
7. Diagnosed with acute promyelocytic leukemia (APL-M3).
8. Have active central nervous system (CNS) leukemia.
9. Have evidence of uncontrolled disseminated intravascular coagulation.
10. Have an active, uncontrolled infection.
11. Have other life-threatening illness.
12. Have other active malignancies requiring treatment or diagnosed with other malignancies within the last 6 months, except nonmelanoma skin cancer or cervical intraepithelial neoplasia.
13. Have mental deficits and/or psychiatric history that may compromise the ability to give written informed consent or to comply with the study protocol.
14. Are pregnant and/or nursing.
15. Have received any live vaccine within 14 days prior to first study drug administration.

Contacts and Locations

Locations

United States, California

Community Medical Providers

Clovis, California, United States, 93611

City of Hope National Medical Center, City of Hope Medical Center

Duarte, California, United States, 91010

Ronald Reagan UCLA Medical Center

Los Angeles, California, United States, 90095

University of California, San Francisco Medical Center

San Francisco, California, United States, 94143

United States, Florida

Advent Health Medical Group Blood & Marrow Transplant at Orlando

Orlando, Florida, United States, 32804

Orlando Health, Inc, Univ of Florida Health Cancer Center

Orlando, Florida, United States, 32806

United States, Indiana

Indiana Blood and Marrow Translplantation - Clinic

Indianapolis, Indiana, United States, 46237

United States, Kansas

University of Kansas Medical Center

Westwood, Kansas, United States, 66205

United States, Louisiana

Ochsner Medical Center

New Orleans, Louisiana, United States, 70121

United States, New Mexico

University of New Mexico

Albuquerque, New Mexico, United States, 87106

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

Columbia University Medical Center

New York, New York, United States, 10027

United States, North Carolina

University of North Carolina (UNC)

Chapel Hill, North Carolina, United States, 27599

United States, Ohio

Ohio State University

Columbus, Ohio, United States, 43210

United States, Oregon

Oregon Health & Sciences University - Knight Cancer Institute - Center for Hematologic Malignancies

Portland, Oregon, United States, 97239

United States, Pennsylvania

Allegheny Health Network

Pittsburgh, Pennsylvania, United States, 15212

United States, Texas

Baylor University Center

Dallas, Texas, United States, 75211

United States, Washington

University of Washington

Seattle, Washington, United States, 98195

Sponsors and Collaborators

Sumitomo Dainippon Pharma Oncology, Inc

Investigators

• Study Director: Stephen Anthony, DO; Sumitomo Dainippon Pharma Oncology, Inc

More Information

• Responsible Party: Sumitomo Dainippon Pharma Oncology, Inc
• ClinicalTrials.gov Identifier: NCT03969420
• Other Study ID Numbers: TPI-ALV-202
• First Posted: May 31, 2019
• Last Update Posted: November 25, 2020
• Last Verified: November 2020

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

Keywords provided by Sumitomo Dainippon Pharma Oncology, Inc:

Tolero, Phase 2, AML, Relapsed, Refractory, Alvocidib, Venetoclax

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type; Neoplasms; Cytarabine; Alvocidib; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Growth Inhibitors; Growth Substances; Protein Kinase Inhibitors; Enzyme Inhibitors