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)

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.

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.

Plasma Ctrough concentrations of gilteritinib was reported. One cycle = 28 days.

C= cycle, D=day

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.

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.

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.

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.

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.

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.

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).

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.