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)

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase 1/2 Study of ASP2215 (Gilteritinib) Combined With Atezolizumab in Patients With Relapsed or Treatment Refractory FLT3 Mutated Acute Myeloid Leukemia (AML)

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

Intervention / Treatment
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* Drug: gilteritinib
* Drug: atezolizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gilteritinib 120 mg + Atezolizumab 420 mg<br>Participants received 120 milligrams (mg) giltertinib (3 tablets of 40 mg) orally, once a day in continuous 28-day cycles in combination with atezolizumab 420 mg adminstered by intravenous infusion (over 60 minutes) once every 2 weeks of 28-day cycle until the participant no longer received clinical benefit from therapy, unacceptable toxicity occurred or the participant met a treatment discontinuation criterion (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab). | Drug: gilteritinib<br>* Oral tablet<br>* Other names: ASP2215;Drug: atezolizumab<br>* Intravenous infusion<br>|
| Experimental: Gilteritinib 120 mg + Atezolizumab 840 mg<br>Participants received 120 mg giltertinib (3 tablets of 40 mg) orally, once a day in continuous 28-day cycles in combination with atezolizumab 840 mg administered by intravenous infusion (over 60 minutes) once every 2 weeks of 28-day cycle until the participant no longer received clinical benefit from therapy, unacceptable toxicity occurred or the participant met a treatment discontinuation criterion (Maximum treatment duration was 126 days for gilteritinib and 70 days for atezolizumab). | Drug: gilteritinib<br>* Oral tablet<br>* Other names: ASP2215;Drug: atezolizumab<br>* Intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLT) | DLTs were defined as: Confirmed Hy's Law case Any Grade ≥ 3 non-hematologic or extramedullary toxicity with the following exceptions: Anorexia or fatigue Grade 3 nausea and/or vomiting if participant did not require tube feeding or total parenteral nutrition, or diarrhea if the events did not require or prolong hospitalization that could be managed to grade ≤ 2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset. Grade 3 mucositis that resolved to Grade ≤ 2 within 7 days of onset Grade 3 fever with neutropenia, with or without infection Grade 3 infection Grade 3 infusion-related toxicity, if successfully managed and resolved within 72 hours. | Day 1 up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Complete Remission (CRc) Rate | CRc was defined as rate of all complete and incomplete remissions i.e. CR + CR with incomplete platelet recovery (CRp) + CR with incomplete hematological recover (CRi). Participants were classified as: CR if they achieved morphologic leukemia-free state & their bone marrow was regenerating normal hematopoietic cells. If they had absolute neutrophil count (ANC) > 1 × 10^9/L, platelet count ≥ 100 × 10^9/L, normal marrow differential < 5% blasts, & were red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and platelet transfusion prior to disease assessment). There was also no evidence of extramedullary leukemia. CRp if they achieved CR with incomplete platelet recovery (< 100 × 10^9/L). CRi if they achieved CR with incomplete hematological recovery with residual neutropenia < 1 × 10^9/L, with or without complete platelet recovery. RBC and platelet transfusion independence was not required. Percentage of participants with CRc was reported. | From the date of first dose up to end of treatment (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab) | 
| Plasma Ctrough Concentration of Gilteritinib | Plasma Ctrough concentrations of gilteritinib was reported. One cycle = 28 days. C= cycle, D=day | Pre-dose on C1D1, C1D8, C1D15, C2D1,C2D15, C3D1, C3D15, C4D1, C4D15, C5D1, C5D15, C6D1, C6D15 | 
| Complete Remission (CR) Rate | Participants were classified as CR if they achieved a morphologic leukemia-free state and their bone marrow was regenerating normal hematopoietic cells. In addition, these participants had ANC > 1 × 10^9/L, platelet count ≥ 100 × 10^9/L, normal marrow differential with < 5% blasts, and were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion prior to disease assessment). There was also no evidence of extramedullary leukemia. CR rate was defined as the number of participants with CR divided by the number of participants in the analysis population. Percentage of participants with CR was reported. | From the date of first dose up to end of treatment (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab) | 
| Complete Remission With Partial Hematologic Recovery (CRh) Rate | Participants were classified as CRh if they achieved CR with ANC level of > 0.5 × 10^9/L and platelet count of > 50 × 10^9/L. CRh rate was defined as the number of participants with CRh divided by the number of participants in the analysis population. Participants were classified as CR if they achieved a morphologic leukemia-free state and their bone marrow was regenerating normal hematopoietic cells. In addition, these participants had ANC > 1 × 10^9/L, platelet count ≥ 100 × 10^9/L, normal marrow differential with < 5% blasts, and were RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion prior to disease assessment). There was also no evidence of extramedullary leukemia. Percentage of participants with CRh was reported. | From the date of first dose up to end of treatment (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab) | 
| Best Response Rate | Best response was defined as the best-measured response (CR, CRp, CRi or PR) post-treatment. Best response rate was defined as the number of participants with CR or CRp or CRi or PR divided by the number of participants in the analysis population (i.e., CR+ CRp + CRi + PR). Participants with unknown or missing response, or who provide no information on response at the end of study will be treated as non-responders and will be included in the denominator when calculating rates. CR, CRp and CRi were described in outcome measure 2#. Participants were classified as PR if their bone marrow was regenerating normal hematopoietic cells with evidence of peripheral recovery with no (or only a few regenerating) circulating blasts and a decrease of at least 50% in the percentage of blasts in the bone marrow aspirate/biopsy, with the total marrow blasts between 5% and 25%. Percentage of participants with best response was reported. | From the date of first dose up to end of treatment (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab) | 
| Duration of Remission (DoR) | DoR: duration of CRc, CR, CRi, CRp & response (CRc + PR). Duration of CRc/CR/CRi/CRp: time from date of first CRc/CR/CRi/CRp until date of documented relapse for participants who achieved CRc/CR/CRi/CRp. Duration of response: time from date of either first CRc or PR until date of documented relapse of any type for participants who achieved CRc or PR. CRc, CR, CRi, CRp were described in outcome measure #2 & PR was described in outcome measure #6. Relapse after CR, CRp or CRi: reappearance of leukemic blasts in peripheral blood or ≥ 5% blasts in bone marrow aspirate/biopsy not attributable to any other cause or reappearance or new appearance of extramedullary leukemia. Relapse after PR: reappearance of significant numbers of peripheral blasts & an increase in the percentage of blasts in the bone marrow aspirate/biopsy to > 25% not attributable to any other cause or reappearance or new appearance of extramedullary leukemia. Analysis was performed using Kaplan-Meier estimates. | From date of first response until the date of documented relapse (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab) | 
| Event Free Survival (EFS) | EFS was defined as time from date of first dose until date of documented relapse from CR, CRp or CRi, treatment failure or death from any cause, whichever occurred first. CRc, CR, CRi, CRp were described in Outcome measure #2. For a participant with none of these events, EFS was censored at date of last disease assessment. Relapse after CR, CRp or CRi was defined as reappearance of leukemic blasts in peripheral blood or ≥ 5% blasts in bone marrow aspirate/biopsy not attributable to any other cause or reappearance or new appearance of extramedullary leukemia. Relapse after PR was defined with reappearance of significant numbers of peripheral blasts & an increase in the percentage of blasts in the bone marrow aspirate/biopsy to > 25% not attributable to any other cause or reappearance or new appearance of extramedullary leukemia. Treatment failure was defined as lack of CR, CRp or CRi, & was determined at the end of treatment (EoT). Analysis was performed using Kaplan-Meier estimates. | From the date of first dose until the date of documented relapse from CR, CRp or CRi, treatment failure or death from any cause, whichever occurred first (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab) | 
| Overall Survival (OS) | OS was defined as the time from the date of first dose until the date of death from any cause. For a participant who was not known to have died by the end of study follow-up, overall survival was censored at the date of last contact. Analysis was performed using Kaplan-Meier estimates. | From the date of first dose until the date of death from any cause (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab) | 
| Number of Participants With Treatment-Emergent Adverse Events | An AE was any untoward medical occurrence in a participant administered study drug, & which did not necessarily have to have a causal relationship with this treatment. Abnormalities was defined as AE only if met 1 of the criteria:Induced clinical signs/symptoms, required active intervention, required interruption or discontinuation of ST, abnormality or investigational value was clinically significant. Serious AE:resulted in death, was life threatening, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital anomaly/birth defect, required hospitalization or prolongation of hospitalization, other medically important events. Any AE recorded on treatment including within 30 days from last study treatment was classified as treatment-emergent AE (TEAE). Grades(Gr) based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) (Gr 1=mild, Gr 2=moderate, Gr 3 =severe, Gr 4 =life threatening, Gr 5 =death). | Baseline to 30 days after last study treatment (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab) | 
| Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Score | ECOG performance status was measured on an 6 point scale. 0-Fully active, able to carry on all pre-disease performance without restriction. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Dead. | Baseline and end of treatment (EoT) (Maximum treatment duration was 535 days for gilteritinib and 112 days for atezolizumab) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, gilteritinib, ASP2215, Acute Myeloid Leukemia, FLT3