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

• ClinicalTrials.gov Identifier: NCT03969420
• Recruitment Status: Not yet recruiting
• First Posted: May 31, 2019
• Last Update Posted: May 31, 2019
• Sponsor: Tolero Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Tolero Pharmaceuticals, 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: 128 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
• Estimated Study Start Date: September 2019
• Estimated Primary Completion Date: September 2023
• Estimated Study Completion Date: September 2023

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: 48 months ]

Secondary Outcome Measures :

1. Stage 2 regimen to be selected based on Stage 1 performance. [ Time Frame: 12 months ]
2. Median overall survival. [ Time Frame: 48 months ]
3. CR rate [ Time Frame: 48 months ]
4. Composite CR rate - Combined CR + CRi + CRh (CR + partial recovery of both blood cell types) [ Time Frame: 48 months ]
5. Combined Response Rate - CR + CRi + CRh + MLFS (Morphologic leukemia-free state) + PR (partial response) [ Time Frame: 48 months ]
6. 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: 24 months ]
7. 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: 48 months ]
8. Safety and tolerability of the regimen, as determined by analyzing the incidence rates of treatment-emergent adverse events (TEAEs) [ Time Frame: 48 months ]
9. Mortality (all causes) at 30 and 60 days following last treatment [ Time Frame: 48 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. Are refractory (i.e., 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 duration ≥90 days) after initial induction therapy with venetoclax in combination with azacytidine or decitabine.
4. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2.
5. Have a glomerular filtration rate (GFR) ≥30 mL/min.
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 a previous treatment with alvocidib or any other CDK inhibitor.
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 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.
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 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

Contacts

Contact: Reyna Bishop, MS, RD; 512-363-8755; rbishop@toleropharma.com

Contact: Susan Smith, MSN; 210-414-7702; su.smith@toleropharma.com

Sponsors and Collaborators

Tolero Pharmaceuticals, Inc.

Investigators

• Study Director: Stephen Anthony, DO; Tolero Pharmaceuticals, Inc.

More Information

• Responsible Party: Tolero Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03969420 History of Changes
• Other Study ID Numbers: TPI-ALV-202
• First Posted: May 31, 2019
• Last Update Posted: May 31, 2019
• Last Verified: May 2019

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

Keywords provided by Tolero Pharmaceuticals, 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; Venetoclax; 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