A Study of ASP2215 (Gilteritinib) Combined With Atezolizumab in Patients With Relapsed or Treatment Refractory FMS-like Tyrosine Kinase (FLT3) Mutated Acute Myeloid Leukemia (AML)

• ClinicalTrials.gov Identifier: NCT03730012
• Recruitment Status: Active, not recruiting
• First Posted: November 5, 2018
• Last Update Posted: April 9, 2021
• Sponsor: Astellas Pharma Global Development, Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Tracking Information

• First Submitted Date: November 1, 2018
• First Posted Date: November 5, 2018
• Last Update Posted Date: April 9, 2021
• Actual Study Start Date: June 19, 2019
• Estimated Primary Completion Date: July 31, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 1, 2018)

• Dose Limiting Toxicities (DLT) - (phase 1) [ Time Frame: Up to 28 days ]
  Incidence of dose limiting toxicities
• Composite complete remission (CRc) rate (phase 1 and phase 2) [ Time Frame: Up to 56 days (2 cycles of treatment) ]
  Number of participants with CRc. CRc is defined as a complete remission (CR), complete remission without platelet recovery (CRp) or complete remission with incomplete hematologic recovery (CRi). CRc rate is defined as the rate of all complete and incomplete remission (i.e., CR + CRp + CRi).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 4, 2019)

• PK of Gilteritinib in plasma: (Ctrough) [ Time Frame: Up to 6 months ]
  Ctrough will be derived from pharmacokinetic (PK) plasma samples collected.
• Complete Remission (CR) rate [ Time Frame: Up to 3 years ]
  Number of participants with complete remission (CR)
• Best Response rate (CRc + partial remission [PR]) [ Time Frame: Up to 3 years ]
  Best response is defined as the best-measured response (CR, CRp, CRi or PR) post-treatment.
• Duration of remission [ Time Frame: Up to 3 years ]
  Duration of remission is defined as time from date of first CRc, CR, CRi, CRp, and response (CRc + PR) until the date of documented relapse. Duration of remission includes duration of CRc, CR, CRi, CRp and response (CRc + PR).
• Event Free Survival (EFS) [ Time Frame: Up to 3 years ]
  EFS is defined as the time from the date of enrollment until the date of documented relapse from CR, CRp or CRi, treatment failure or death from any cause, whichever occurs first.
• Overall Survival (OS) [ Time Frame: Up to 3 years ]
  OS is defined as the time from the date of enrollment until the date of death from any cause. For a subject who is not known to have died by the end-of-study follow-up, OS is censored at the date of last contact.
• Complete Remission (CR) rate with partial hematologic recovery (CRh) [ Time Frame: Up to 3 years ]
  Number of participants with complete remission (CR) with partial hematologic recovery (CRh)
• Safety assessed by Adverse Events [ Time Frame: Up to 3 years ]
  An AE is any untoward medical occurrence in a participant administered a study drug, and which does not necessarily have to have a causal relationship with this treatment.
• Number of participants with laboratory value abnormalities and/or adverse events (AEs) [ Time Frame: Up to 3 years ]
  Number of participants with potentially clinically significant laboratory values
• Number of participants with vital sign abnormalities and/or adverse events (AEs) [ Time Frame: Up to 3 years ]
  Number of participants with potentially clinically significant vital sign values.
• Safety assessed by 12-lead electrocardiogram (ECG) [ Time Frame: Up to 3 years ]
  12-lead ECGs will be recorded in triplicate (3 separate ECGs, 10 minutes resting prior to first ECG and at least 5 minutes apart per time point) and transmitted electronically for central reading. The mean of the triplicate ECG from central read will be used for all final treatment decisions and adverse event reporting.
• Safety assessed by Eastern Cooperative Oncology Group (ECOG) performance score [ Time Frame: Up to 3 years ]
  ECOG performance status measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2= Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; 5=Dead. 0=Best status; 5=Worst status.

Original Secondary Outcome Measures (submitted: November 1, 2018)

• PK of Gilteritinib in plasma: (Ctrough) [ Time Frame: Up to 6 months ]
  Ctrough will be derived from pharmacokinetic (PK) plasma samples collected.
• Complete Remission (CR) rate [ Time Frame: Up to 3 years ]
  Number of participants with complete remission (CR)
• Best Response rate (CRc + partial remission [PR]) [ Time Frame: Up to 3 years ]
  Best response is defined as the best-measured response (CR, CRp, CRi or PR) post-treatment.
• Duration of remission [ Time Frame: Up to 3 years ]
  Duration of remission is defined as time from date of first CRc, CR, CRi, CRp, and response (CRc + PR) until the date of documented relapse. Duration of remission includes duration of CRc, CR, CRi, CRp and response (CRc + PR).
• Event Free Survival (EFS) [ Time Frame: Up to 3 years ]
  EFS is defined as the time from the date of enrollment until the date of documented relapse from CR, CRp or CRi, treatment failure or death from any cause, whichever occurs first.
• Overall Survival (OS) [ Time Frame: Up to 3 years ]
  OS is defined as the time from the date of enrollment until the date of death from any cause. For a subject who is not known to have died by the end-of-study follow-up, OS is censored at the date of last contact.
• Safety assessed by Adverse Events [ Time Frame: Up to 3 years ]
  An AE is any untoward medical occurrence in a participant administered a study drug, and which does not necessarily have to have a causal relationship with this treatment.
• Number of participants with laboratory value abnormalities and/or adverse events (AEs) [ Time Frame: Up to 3 years ]
  Number of participants with potentially clinically significant laboratory values
• Number of participants with vital sign abnormalities and/or adverse events (AEs) [ Time Frame: Up to 3 years ]
  Number of participants with potentially clinically significant vital sign values.
• Safety assessed by 12-lead electrocardiogram (ECG) [ Time Frame: Up to 3 years ]
  12-lead ECGs will be recorded in triplicate (3 separate ECGs, 10 minutes resting prior to first ECG and at least 5 minutes apart per time point) and transmitted electronically for central reading. The mean of the triplicate ECG from central read will be used for all final treatment decisions and adverse event reporting.
• Safety assessed by Eastern Cooperative Oncology Group (ECOG) performance score [ Time Frame: Up to 3 years ]
  ECOG performance status measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2= Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; 5=Dead. 0=Best status; 5=Worst status.

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

Descriptive Information

• Brief Title: A Study of ASP2215 (Gilteritinib) Combined With Atezolizumab in Patients With Relapsed or Treatment Refractory FMS-like Tyrosine Kinase (FLT3) Mutated Acute Myeloid Leukemia (AML)
• Official Title: Phase 1/2 Study of ASP2215 (Gilteritinib) Combined With Atezolizumab in Patients With Relapsed or Treatment Refractory FLT3 Mutated Acute Myeloid Leukemia (AML)

Brief Summary

The purpose of this study is to determine the safety and tolerability of gilteritinib given in combination with atezolizumab in participants with relapsed or treatment refractory FMS-like tyrosine kinase 3 (FLT3) mutated AML and to determine the composite complete remission (CRc) rate for participants who either discontinued the study or completed 2 cycles of gilteritinib given in combination with atezolizumab.

This study will also evaluate pharmacokinetics (PK), response to treatment, remission and survival. Adverse events (AEs), clinical laboratory results, vital signs, electrocardiograms (ECGs), and Eastern Cooperative Oncology Group (ECOG) performance status scores will also be assessed.

Detailed Description

This study will have 2 phases.

Phase 1:

The phase 1 portion of this study is to establish the recommended phase 2 dose (RP2D) of gilteritinib given in combination with atezolizumab.

Phase 2:

The phase 2 portion of the study will treat patients with gilteritinib and atezolizumab at the RP2D and will enroll in two stages. The first stage will evaluate the remission rate and if a minimum rate is achieved, a second stage of enrollment will continue.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Acute Myeloid Leukemia (AML)
• Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) Mutation

Intervention

• Drug: gilteritinib
  Gilteritinib is administered orally
  Other Name: ASP2215
• Drug: atezolizumab
  Atezolizumab is administered by intravenous infusion

Study Arms

Experimental: Gilteritinib plus Atezolizumab

Participants will be treated with gilteritinib once daily for the phase 1 portion of the study to establish the recommended dose for the phase 2 portion. In the phase 2 portion, the participants will be treated with gilteritinib once daily at dose determined by the phase 1 portion of the study. Atezolizumab will be administered once every 2 weeks for the phase 1 and 2 portions of the study. Participants will be treated on continuous cycles until they no longer derive clinical benefit in the judgment of the treating physician, have unacceptable toxicity, undergo hematopoietic stem cell transplantation (HSCT), or meet 1 of the discontinuation criteria; whichever occurs first.

Interventions:

• Drug: gilteritinib
• Drug: atezolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 8, 2021): 12
• Original Estimated Enrollment (submitted: November 1, 2018): 61
• Estimated Study Completion Date: June 30, 2025
• Estimated Primary Completion Date: July 31, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Subject is considered an adult according to local regulation at the time of signing informed consent form (ICF).

• Subject has defined AML by the World Health Organization (WHO) criteria (2017) and fulfills one of the following:

  • Refractory to at least 1 cycle of induction chemotherapy
  • Relapsed after achieving remission with a prior therapy
• Subject is positive for FLT3 mutation in bone marrow or blood after completion of the subject's last interventional treatment.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening.

• Subject must meet the following criteria as indicated on the clinical laboratory tests:

  • Serum Aspartate aminotransferase (AST) and Alanine Aminotransferease (ALT) ≤ 2.5 x upper limit of normal (ULN)
  • Serum total bilirubin (TBL) ≤ 1.5 x ULN
  • Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of > 50 mL/min as calculated by the Modification of Diet in Renal Disease equation.
• Subject is suitable for oral administration of study drug.

• A female subject is eligible to participate if she is not pregnant and at least one of the following conditions applies:

  • Not a woman of childbearing potential (WOCBP) OR
  • WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 180 days after the final study drug administration.
• Female subject must agree not to breastfeed starting at screening and throughout the study period, and for at least 180 days after the final study drug administration.
• Female subject must not donate ova starting at screening and throughout the study period, and for at least 180 days after the final study drug administration.
• A male subject must not donate sperm starting at screening and throughout the treatment period, and for at least 120 days after the final study drug administration.
• A male subject with female partner(s) of child-bearing potential must agree to use contraception during the treatment period, and for at least 120 days after the final study drug administration.
• Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the treatment period, and for 120 days after the final study drug administration.
• Subject agrees not to participate in another investigational study while on treatment.

Exclusion Criteria:

• Subject was diagnosed as acute promyelocytic leukemia.
• Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
• Subject has AML secondary to prior chemotherapy for other neoplasms (except for myelodysplastic syndrome).
• Subject has clinically active central nervous system leukemia.

• Subject has uncontrolled or significant cardiovascular disease, including:

  • A myocardial infarction within 12 months
  • Uncontrolled angina within 6 months
  • History of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, torsades de pointes) or any history of arrhythmia
  • Uncontrolled hypertension
• Subject has baseline left ventricular ejection fraction that is ≥ 45%.
• Subject has mean triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at Screening based on central reading.
• Subject has congenital or acquired Long QT Syndrome at screening.
• Subject has hypokalemia and/or hypomagnesemia at screening.
• Subject has been diagnosed with another malignancy that requires concurrent treatment or hepatic malignancy regardless of the need for treatment.
• Subject has clinically significant coagulation abnormality unless secondary to AML.
• Subject is receiving or plans to receive concomitant chemotherapy or immunotherapy.
• Subject has had major surgery within 4 weeks prior to the first study dose.
• Subject has radiation therapy within 4 weeks prior to the first study dose.
• Subject requires treatment with concomitant drugs that are strong inducers of Cytochrome P450 (CYP3A).
• Subject has known pulmonary disease with diffusion capacity of lung for carbon monoxide ≤ 65%, forced expiratory volume in the first second (FEV1) ≤ 65%, dyspnea at rest or requiring oxygen or any pleural neoplasm.
• Subject with systemic fungal, bacterial, viral or other uncontrolled infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. Subject needs to be off pressors and have negative blood cultures for 48 hours.
• Subject has not recovered from any prior therapy related toxicities.
• Subject is known to have human immunodeficiency virus infection.
• Subject has active hepatitis B or C or other active hepatic disorder.
• Subject has previously been treated with gilteritinib, quizartinib or crenolanib (will only apply to subjects enrolled in the phase 2 portion of the study).
• Subject has active clinically significant graft-versus-host disease (GVHD) or is on treatment with systemic corticosteroids for GVHD.
• Subject has relapsed after allogeneic hematopoietic stem cell transplant (HCST).
• Subject has an active autoimmune disorder that makes the subject unsuitable for study treatment or participation.
• Subject has any condition that makes the subject unsuitable for study participation.

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: NCT03730012
• Other Study ID Numbers: 2215-CL-1101
• 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

• Plan to Share IPD: Undecided
• Plan Description: Studies conducted with product indications or formulations that remain in development are assessed after study completion to determine if Individual Participant Data can be shared. The plan to share Individual Participant Data is based on the status of product approval or termination of the compound, in addition to other study-specific criteria described on www.clinicalstudydatarequest.com under "Sponsor Specific Details for Astellas."

• Responsible Party: Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
• Study Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Executive Medical Director; Astellas Pharma Global Development

• PRS Account: Astellas Pharma Inc
• Verification Date: April 2021