A Study to Assess Safety and Efficacy of Venetoclax in Combination With Gilteritinib in Participants With Relapsed/Refractory Acute Myeloid Leukemia

• ClinicalTrials.gov Identifier: NCT03625505
• Recruitment Status: Completed
• First Posted: August 10, 2018
• Last Update Posted: September 14, 2021
• Sponsor: AbbVie
• Collaborators: Astellas Pharma Inc; Genentech, Inc.
• Information provided by (Responsible Party): AbbVie

Tracking Information

• First Submitted Date: August 8, 2018
• First Posted Date: August 10, 2018
• Last Update Posted Date: September 14, 2021
• Actual Study Start Date: October 18, 2018
• Actual Primary Completion Date: August 31, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 14, 2020)

• Recommended Phase 2 Dose (RPTD) of Co-administered Study Drugs [ Time Frame: Up to approximately 6 months after the last participant is enrolled ]
  The RPTD of co-administered venetoclax and gilteritinib will be determined during the dose escalation phase of the study. RPTD will be determined using available safety and pharmacokinetics data.
• Modified Composite Complete Remission (CRc) [ Time Frame: Up to approximately 6 months after the last participant is enrolled ]
  Modified CRc rate is defined as the proportion of participants with documented complete response (CR) + CR with partial blood count recovery (CRp) + CR with incomplete blood count recovery (CRi) plus Morphologic Leukemia-Free State (MLFS) based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML).

Original Primary Outcome Measures (submitted: August 8, 2018)

• Recommended Phase 2 Dose (RPTD) of co-administered Study Drugs [ Time Frame: Up to approximately 6 months after the last subject is enrolled ]
  The RPTD of co-administered venetoclax and gilteritinib will be determined during the dose escalation phase of the study. RPTD will be determined using available safety and pharmacokinetics data.
• Composite Complete Remission (CRc) Rate [ Time Frame: Up to approximately 6 months after the last subject is enrolled ]
  CRc rate is defined as the proportion of participants with documented complete response (CR) + CR with incomplete platelet recovery (CRp) + CR with incomplete blood count recovery (CRi) based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML).

Current Secondary Outcome Measures (submitted: August 14, 2020)

• Pharmacokinetics - Cmax of Venetoclax [ Time Frame: Approximately 16 days after first dose of study drug ]
  Maximum observed plasma concentration (Cmax) of study drug.
• Pharmacokinetics - Cmax of Gilteritinib [ Time Frame: Approximately 16 days after first dose of study drug ]
  Maximum observed plasma concentration (Cmax) of study drug.
• Pharmacokinetics - Tmax of Venetoclax [ Time Frame: Approximately 16 days after first dose of study drug ]
  Time to maximum plasma concentration (Tmax) of study drug.
• Pharmacokinetics - Tmax of Gilteritinib [ Time Frame: Approximately 16 days after first dose of study drug ]
  Time to maximum plasma concentration (Tmax) of study drug.
• Pharmacokinetics - AUCt of Venetoclax [ Time Frame: Approximately 16 days after first dose of study drug ]
  Area Under the Plasma Concentration-time Curve (AUC) from Time 0 to Time of the Last Measurable Concentration (AUCt) of study drug.
• Pharmacokinetics - AUCt of Gilteritinib [ Time Frame: Approximately 16 days after first dose of study drug ]
  Area Under the Plasma Concentration-time Curve (AUC) from Time 0 to Time of the Last Measurable Concentration (AUCt) of study drug.
• Pharmacokinetics - AUC0-24 Post-dose of Study Drug of Venetoclax [ Time Frame: Approximately 16 days after first dose of study drug ]
  Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of study drug.
• Pharmacokinetics - AUC0-24 Post-dose of Study Drug of Gilteritinib [ Time Frame: Approximately 16 days after first dose of study drug ]
  Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of study drug.
• Composite Complete Remission (CRc) Rate [ Time Frame: Up to approximately 6 months after the last participant is enrolled ]
  CRc is defined as the proportion of participants with documented CR + CRp + CRi based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML).
• Duration of Response (DOR) of Modified Composite Complete Remission (CRc) [ Time Frame: Up to approximately 6 months after the last participant is enrolled ]
  DOR of modified CRc will be defined as time from the first date achieving modified CRc to disease progression (including morphologic relapse) or death from any cause whichever is earlier.
• Complete Remission (CR) + with Partial Hematologic Recovery (CRh) [ Time Frame: Up to approximately 6 months after the last participant is enrolled ]
  It is defined as the proportion of participants achieving CR or CRh based on guidelines adapted from the International Working Group (IWG) for Acute Myeloid Leukemia (AML).
• Duration of Response (DOR) of Complete Remission (CR) + Complete Remission with Partial Hematologic Recovery (CRh) [ Time Frame: Up to approximately 6 months after the last participant is enrolled ]
  DOR of CR + CRh will be defined as time from the first date achieving CR and/or CRh to disease progression (including morphologic relapse) or death from any cause whichever is earlier.
• Number of Participants With Adverse Events [ Time Frame: From first dose of study drug until 30 days or 5 half-lives after discontinuation of study drug administration will be collected (up to approximately 4 years) ]
  An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

Original Secondary Outcome Measures (submitted: August 8, 2018)

• Pharmacokinetics - Cmax [ Time Frame: Approximately 16 days after first dose of study drug ]
  Maximum observed plasma concentration (Cmax) of study drug.
• Pharmacokinetics - Tmax [ Time Frame: Approximately 16 days after first dose of study drug ]
  Time to maximum plasma concentration (Tmax) of study drug.
• Pharmacokinetics - AUCt [ Time Frame: Approximately 16 days after first dose of study drug ]
  Area Under the Plasma Concentration-time Curve (AUC) from Time 0 to Time of the Last Measurable Concentration (AUCt) of study drug.
• Pharmacokinetics - AUC0-24 Post-dose of study drug [ Time Frame: Approximately 16 days after first dose of study drug ]
  Area under the plasma concentration-time curve from 0 to 24 hours (AUC24) post-dose of study drug.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Assess Safety and Efficacy of Venetoclax in Combination With Gilteritinib in Participants With Relapsed/Refractory Acute Myeloid Leukemia
• Official Title: A Multicenter, Open-Label Phase 1b Study to Assess Safety and Efficacy of Venetoclax in Combination With Gilteritinib in Subjects With Relapsed/Refractory Acute Myeloid Leukemia
• Brief Summary: A dose-escalation study evaluating the safety, tolerability, pharmacokinetics (PK) and efficacy of venetoclax, in combination with gilteritinib, in participants with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have failed to respond to, and/or have relapsed or progressed after at least 1 prior therapy.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Acute Myeloid Leukemia (AML)

Intervention

• Drug: Venetoclax
  tablet, oral
  Other Names:

  • ABT-199
  • GDC-0199
• Drug: Gilteritinib
  tablet, oral
  Other Name: ASP-2215

Study Arms

• Experimental: Dose Escalation Venetoclax + Gilteritinib
  Different combinations of dose levels for venetoclax in combination with gilteritinib will be administered to determine the recommended phase 2 dose (RPTD).
  Interventions:

  • Drug: Venetoclax
  • Drug: Gilteritinib
• Experimental: Dose Expansion Venetoclax + Gilteritinib
  Participants will receive venetoclax in combination with gilteritinib at the dose determined in dose escalation portion.
  Interventions:

  • Drug: Venetoclax
  • Drug: Gilteritinib

• Publications *: Daver N, Perl AE, Maly J, Levis M, Ritchie E, Litzow M, McCloskey J, Smith CC, Schiller G, Bradley T, Tiu RV, Naqvi K, Dail M, Brackman D, Siddani S, Wang J, Chyla B, Lee P, Altman JK. Venetoclax Plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia. J Clin Oncol. 2022 Dec 10;40(35):4048-4059. doi: 10.1200/JCO.22.00602. Epub 2022 Jul 18.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 24, 2021): 61
• Original Estimated Enrollment (submitted: August 8, 2018): 52
• Actual Study Completion Date: August 31, 2021
• Actual Primary Completion Date: August 31, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Should have an established, confirmed diagnosis of Acute Myeloid Leukemia (AML) by World Health Organization (2016).
• Should have failed at least 1 line of prior therapy (defined as failure to respond to therapy, and/or progression during or after therapy).
• Should have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Should have adequate hematologic, kidney and liver function as described in the protocol.
• For participants enrolling into the Expansion Cohort only: a documented FMS-like Tyrosine Kinase (FLT3) mutation in bone marrow or peripheral blood, as described in the protocol.

Exclusion Criteria:

• Has a diagnosis of acute promyelocytic leukemia (APL) or BCR-ABL-positive leukemia.
• Has a history of other malignancies within 2 years prior to study entry, with exceptions as described in the protocol.
• Has active central nervous system leukemia.
• Has a history of chronic New York Heart Association (NYHA) class IV heart failure.
• Has a corrected QT interval of > 450 ms.
• Has a chronic respiratory disease that requires continuous oxygen use.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03625505
• Other Study ID Numbers: M16-802
• 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
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: AbbVie
• Original Responsible Party: Same as current
• Current Study Sponsor: AbbVie
• Original Study Sponsor: Same as current

Collaborators

• Astellas Pharma Inc
• Genentech, Inc.

Investigators

• Study Director: ABBVIE INC.; AbbVie

• PRS Account: AbbVie
• Verification Date: September 2021