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出境医 / 临床实验 / Study of Alvocidib in Patients With Relapsed/Refractory AML Following Treatment With Venetoclax Combination Therapy

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

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
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 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 : May 2021
Estimated Study Completion Date : November 2021
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
Layout table for eligibility information
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
Show Show 18 study locations
Sponsors and Collaborators
Sumitomo Dainippon Pharma Oncology, Inc
Investigators
Layout table for investigator information
Study Director: Stephen Anthony, DO Sumitomo Dainippon Pharma Oncology, Inc
Tracking Information
First Submitted Date  ICMJE May 29, 2019
First Posted Date  ICMJE May 31, 2019
Last Update Posted Date April 29, 2021
Actual Study Start Date  ICMJE January 15, 2020
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 22, 2020) 		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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: May 29, 2019) 		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 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 22, 2020)
  • Median overall survival. [ Time Frame: 42 months ]
  • CR rate [ Time Frame: 18 months ]
  • Composite CR rate - Combined CR + CRi + CRh (CR + partial recovery of both blood cell types) [ Time Frame: 18 months ]
  • Combined Response Rate - CR + CRi + CRh + MLFS (Morphologic leukemia-free state) + PR (partial response) [ Time Frame: 18 months ]
  • 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 ]
  • 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 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2019)
  • Stage 2 regimen to be selected based on Stage 1 performance. [ Time Frame: 12 months ]
  • Median overall survival. [ Time Frame: 48 months ]
  • CR rate [ Time Frame: 48 months ]
  • Composite CR rate - Combined CR + CRi + CRh (CR + partial recovery of both blood cell types) [ Time Frame: 48 months ]
  • Combined Response Rate - CR + CRi + CRh + MLFS (Morphologic leukemia-free state) + PR (partial response) [ Time Frame: 48 months ]
  • 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 ]
  • 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 ]
  • Safety and tolerability of the regimen, as determined by analyzing the incidence rates of treatment-emergent adverse events (TEAEs) [ Time Frame: 48 months ]
  • Mortality (all causes) at 30 and 60 days following last treatment [ Time Frame: 48 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Alvocidib in Patients With Relapsed/Refractory AML Following Treatment With Venetoclax Combination Therapy
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomized, Two-stage
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia (AML)
Intervention  ICMJE
  • Drug: Alvocidib (flavopiridol) and cytarabine (Ara-C)
    Alvocidib (flavopiridol), administered intravenously, + cytarabine (Ara-C), administered by subcutaneous injection
  • Drug: Alvocidib (flavopiridol)
    Administered intravenously
Study Arms  ICMJE
  • Experimental: Stage 1: Arm 1
    Refractory (i.e., failed to achieve a CR/CRi or achieved a CR/CRi with duration <90 days)
    Intervention: Drug: Alvocidib (flavopiridol) and cytarabine (Ara-C)
  • Experimental: Stage 1: Arm 2
    Relapsed (i.e., reoccurrence of disease following a CR/CRi with duration ≥90 days).
    Intervention: Drug: Alvocidib (flavopiridol)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: April 28, 2021) 		11
Original Estimated Enrollment  ICMJE
 (submitted: May 29, 2019) 		128
Estimated Study Completion Date  ICMJE November 2021
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03969420
Other Study ID Numbers  ICMJE TPI-ALV-202
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Sumitomo Dainippon Pharma Oncology, Inc
Study Sponsor  ICMJE Sumitomo Dainippon Pharma Oncology, Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Stephen Anthony, DO Sumitomo Dainippon Pharma Oncology, Inc
PRS Account Sumitomo Dainippon Pharma Oncology, Inc
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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