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)

The purpose of this study was 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 also evaluated 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 were also assessed.

This study was planned to have 2 phases:

Phase 1:

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

Phase 2:

The phase 2 portion of the study was to treat participants with gilteritinib and atezolizumab at the RP2D and was to be enrolled in two stages. The first stage was to evaluate the remission rate and if a minimum rate was to be achieved, a second stage of enrollment was to be continued.

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.