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

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ClinicalTrials.gov Identifier: NCT03969420
Recruitment Status : Not yet recruiting
First Posted : May 31, 2019
Last Update Posted : May 31, 2019
Sponsor:
Information provided by (Responsible Party):
Tolero Pharmaceuticals, Inc.

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

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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


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




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 ]


Information from the National Library of Medicine

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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.

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): NCT03969420


Contacts
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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
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Study Director: Stephen Anthony, DO Tolero Pharmaceuticals, Inc.

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

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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:
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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