ADMIRAL TRIAL

XOSPATA Was Evaluated in a Phase 3 Trial1,2

  • XOSPATA was evaluated in a Phase 3, open-label, multicenter, randomized clinical trial compared with a prespecified salvage chemotherapy in adult patients with relapsed or refractory FLT3m+ AML1,2
  • The efficacy of XOSPATA was based on an interim analysis and a final analysis1:
    • The first interim analysis evaluated the endpoints of CR/CRh, the duration of CR/CRh (DOR), and the rate of conversion from transfusion dependence to transfusion independence in 138 patients treated with XOSPATA
    • The final analysis evaluated the endpoint of OS and was measured from the date of randomization until death by any cause

ADMIRAL Study Design1,2

ADMIRAL Study Design ADMIRAL Study Design
  • Randomization was stratified by patient response to first-line AML treatment and prespecified chemotherapy1†
  • Prespecified chemotherapy regimens included1:
    • High-intensity combination regimens MEC and FLAG-IDA§
    • Low-intensity regimens LDAC and AZA

*XOSPATA was given orally at a starting dose of 120 mg daily until unacceptable toxicity or lack of clinical benefit.1

Prior AML chemotherapy regimens included standard-dose cytarabine + idarubicin (39%); high-dose cytarabine (27%); standard-dose cytarabine + daunorubicin (26%); azacitidine (7%); decitabine (5%); high-dose cytarabine + daunorubicin (4%); low-dose cytarabine (4%); high-dose cytarabine + idarubicin (3%); standard-dose cytarabine + mitoxantrone (3%); and standard-dose cytarabine + daunorubicin + cladribine (1%); as well as other regimens (44%).2

MEC: mitoxantrone 8 mg/m2, etoposide 100 mg/m2, and cytarabine 1000 mg/m2 once daily by IV infusion Days 1 to 5.1

§FLAG-IDA: granulocyte colony-stimulating factor 300 mcg/m2 once daily by SC injection Days 1 to 5, fludarabine 30 mg/m2 once daily by IV infusion Days 2 through 6, cytarabine 2000 mg/m2 once daily by IV infusion Days 2 through 6, idarubicin 10 mg/m2 once daily by IV infusion Days 2 through 4.1

llLDAC: cytarabine 20 mg twice daily by SC injection or IV infusion for 10 days.1

AZA: azacitidine 75 mg/m2 once daily by SC injection or IV infusion for 7 days.1

Eligibility Criteria3#

  • Adult patients with primary AML or AML secondary to MDS
  • No APL, BCR-ABL-positive leukemia, or AML secondary to chemotherapy for other neoplasms (except for MDS)
  • Positive for FLT3 mutations (FLT3-ITD, FLT3-TKD-D835, or FLT3-TKD-I836) as determined by the central lab
  • Refractory to, or relapsed after, first-line AML therapy (with or without HSCT)
  • Prior treatment with midostaurin or sorafenib was allowed
  • No clinically active central nervous system leukemia
  • Excluded patients with long QT syndrome at screening and patients with hypokalemia and hypomagnesemia at screening (defined as values below LLN)

#Does not include all patient inclusion and exclusion criteria for the ADMIRAL trial.3

ABL=Abelson murine leukemia viral oncogene homolog 1; AML=acute myeloid leukemia; APL=acute promyelocytic leukemia; BCR=breakpoint cluster region; CR=complete remission; CRh=complete remission with partial hematologic recovery; DOR=duration of remission; FLT3=FMS-like tyrosine kinase 3; HSCT=hematopoietic stem cell transplant; ITD=internal tandem duplication; IV=intravenous; LDAC=low-dose cytarabine; LLN=lower limit of normal; m+=mutation-positive; MDS=myelodysplastic syndrome; OS=overall survival; QT=cardiac ventricular repolarization; SC=subcutaneous; TKD=tyrosine kinase domain.

Select Safety Information

Prolonged QT Interval XOSPATA has been associated with prolonged cardiac ventricular repolarization (QT interval). 1% of the 317 patients with a post-baseline QTc measurement on treatment with XOSPATA in the clinical trial were found to have a QTc interval greater than 500 msec and 7% of patients had an increase from baseline QTc greater than 60 msec. Perform electrocardiogram (ECG) prior to initiation of treatment with XOSPATA, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles. Interrupt and reduce XOSPATA dosage in patients who have a QTcF >500 msec. Hypokalemia or hypomagnesemia may increase the QT prolongation risk. Correct hypokalemia or hypomagnesemia prior to and during XOSPATA administration.

ADMIRAL TRIAL

Characteristics of Patients Enrolled in the ADMIRAL Trial

Characteristics of Patients Enrolled in the ADMIRAL Trial Chart Characteristics of Patients Enrolled in the ADMIRAL Trial Chart Characteristics of Patients Enrolled in the ADMIRAL Trial Chart

**The remaining 5 patients were negative by the diagnostic test.2

††One patient in the comparator salvage chemotherapy arm had refractory relapse AML at baseline.1

‡‡The remaining 58 patients included those with cytogenetic risk status that cannot be categorized as intermediate, unfavorable, or favorable.2

§§Patients were defined as transfusion dependent at baseline if they were dosed and received any RBC or platelet transfusions within the 56-day baseline period.1

Patients could receive a transplant during the ADMIRAL trial2

  • Patients who achieved a response in either treatment arm that allowed them to undergo HSCT based on each institution's assessment—and who had a donor identified—went on to receive transplant during the study||||
    • 26% of patients in the XOSPATA arm (95% CI: 20.2, 31.4; n=63/247)
    • 15% of patients in the salvage chemotherapy arm (95% CI: 9.5, 22.9; n=19/124)

||||Treatment with XOSPATA was stopped prior to starting the conditioning regimen for HSCT. XOSPATA treatment could be resumed after transplant in patients who were between 30 and 90 days post-HSCT, had successful engraftment with ANC ≥500/mm3 and platelets ≥20,000/mm3 without transfusions, did not have Grade ≥2 acute GVHD, and were in CRc.2

ANC=absolute neutrophil count; CI=confidence interval; CRc=composite complete remission; ECOG PS=Eastern Cooperative Oncology Group performance status; GVHD=graft-vs-host disease; RBC=red blood cell.

Select Safety Information

Pancreatitis 4% of 319 patients treated with XOSPATA in the clinical trials experienced pancreatitis. Evaluate patients who develop signs and symptoms of pancreatitis. Interrupt and reduce the dose of XOSPATA in patients who develop pancreatitis.

ADMIRAL TRIAL: FINAL ANALYSIS

XOSPATA Delivered Superior Survival vs Salvage Chemotherapy in Relapsed or Refractory FLT3m+ AML1

Overall Survival: Intention-to-Treatment Set1,2

  • XOSPATA delivered superior survival with a median OS of 9.3 months (95% CI: 7.7, 10.7) vs 5.6 months with salvage chemotherapy (95% CI: 4.7, 7.3)1
  • XOSPATA improved median OS by 66% over salvage chemotherapy1
  • XOSPATA more than doubled the 1-year survival rate compared with salvage chemotherapy2¶¶
    • 37.1% with XOSPATA (95% CI: 30.7, 43.6)
    • 16.7% with salvage chemotherapy (95% CI: 9.9, 25.0)
  • In the exploratory subgroup analyses that evaluated survival according to whether patients were preselected for high-intensity chemotherapy or low-intensity chemotherapy1:
    • XOSPATA reduced the risk of death by 34% vs high-intensity salvage chemotherapy (HR=0.66; 95% CI: 0.47, 0.93)
    • XOSPATA reduced the risk of death by 44% vs low-intensity salvage chemotherapy (HR=0.56; 95% CI: 0.38, 0.84)

¶¶Survival rate and 95% CI were estimated using the Kaplan-Meier method and the Greenwood formula.2

HR=hazard ratio.

ADMIRAL TRIAL: INTERIM ANALYSIS

Interim Analysis Endpoints Included Rate of CR/CRh, DOR, and Rate of Conversion to Transfusion Independence1

Rate of CR/CRh1

  • Only responses prior to HSCT were included in the response rate
  • The median follow-up was 4.6 months (95% CI: 2.8, 15.8)
  • Among patients with FLT3-ITD or FLT3-ITD-TKD mutations, the rate of CR/CRh was 23% (n=29/126), and none of the 12 patients with FLT3-TKD only mutations achieved CR/CRh
  • In patients who achieved CR/CRh with XOSPATA (n=29/138), the median time to first response was 3.6 months (range: 0.9 to 9.6 months)
  • CR was defined as normal marrow differential with <5% blasts, ANC ≥1.0 x 109/L and platelets ≥100 x 109/L, no evidence of extramedullary leukemia, and must have been RBC and platelet transfusion independent
  • CRh was defined as marrow blasts <5%, partial hematologic recovery, ANC ≥0.5 x 109/L and platelets ≥50 x 109/L, no evidence of extramedullary leukemia, and could not have been classified as CR

Median Duration of Remission1

4.6 months

median duration of CR/CRh

(range: 0.1 to 15.8##; n=29/138)
8.6 months

median duration of CR

(range: 1.0 to 13.8; n=16/138)
2.9 months

median duration of CRh

(range: 0.1 to 15.8##; n=13/138)
  • 14 patients remained in remission at the time of the first interim DOR analysis
  • DOR was defined as the time from the date of either first CR or CRh until the date of a documented relapse of any type. Deaths were counted as events

##Response was ongoing.1

Transfusion Independence Conversion Rate1

  • Among patients in the XOSPATA arm who were transfusion dependent at baseline (n=106)
    • 31.1% became transfusion independent with XOSPATA during any 56-day post-baseline period (n=33/106)
  • Of the 32 patients in the XOSPATA arm who were transfusion independent at baseline, 53.1% remained transfusion independent during any 56-day post-baseline period (n=17/32)
  • Transfusion independence is defined as patients who were dependent on RBC and/or platelet transfusions at baseline and became independent of RBC and platelet transfusions during any 56-day post-baseline period
Select Safety Information

Embryo-Fetal Toxicity XOSPATA can cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 6 months after the last dose of XOSPATA. Advise males with female partners of reproductive potential to use effective contraception during treatment with XOSPATA and for at least 4 months after the last dose of XOSPATA. Pregnant women, patients becoming pregnant while receiving XOSPATA or male patients with pregnant female partners should be apprised of the potential risk to the fetus.

ADMIRAL TRIAL: FINAL ANALYSIS

OS Sensitivity Analysis of XOSPATA vs Salvage Chemotherapy Disregarding Outcomes Following HSCT2

OS Sensitivity Analysis: Patients Censored at HSCT2

  • A sensitivity analysis of OS was conducted to evaluate the efficacy of XOSPATA vs salvage chemotherapy by removing the effect of transplantation (censoring patients at the time of HSCT)2
  • In this sensitivity analysis, XOSPATA reduced the risk of death by 42% vs salvage chemotherapy (HR=0.58 [95% CI: 0.43, 0.76]; P<0.0001)2
  • In this sensitivity analysis, the median OS was 8.3 months with XOSPATA (95% CI: 6.7, 10.2) vs 5.3 months with salvage chemotherapy (95% CI: 4.3, 6.1)2
  • The 1-year survival rate was 30.5% with XOSPATA (95% CI: 23.2, 38.0) vs 8.7% with salvage chemotherapy (95% CI: 3.6, 16.5)2

The results of the OS sensitivity analysis in the ADMIRAL trial contributed to the clinical body of evidence for XOSPATA, but are not contained in the approved product labeling.

ADMIRAL TRIAL: FINAL ANALYSIS

Supportive Final Analysis Endpoints

CR Rate and Median DOR1

  • Only responses prior to HSCT were included in the response rate
  • DOR was defined as the time from the date of first remission until the date of a documented relapse
  • In the exploratory subgroup analyses that evaluated CR rates according to whether patients were preselected for high-intensity salvage chemotherapy or low-intensity salvage chemotherapy, the CR rate was:
    • 15.4% with XOSPATA (95% CI: 10.0, 22.3) vs 16.0% with high-intensity salvage chemotherapy (95% CI: 8.6, 26.3)
    • 12.2% with XOSPATA (95% CI: 6.5, 20.4) vs 2.0% with low-intensity salvage chemotherapy (95% CI: 0.1, 10.9)

CRc Rate and Median DOR in XOSPATA Arm2

The following results from the ADMIRAL trial contributed to the clinical body of evidence for XOSPATA, but are not contained in the approved product labeling.

  • The rate of CRc with XOSPATA was more than double the rate of CRc with salvage chemotherapy:
    • 54.3% with XOSPATA (95% CI: 47.8, 60.6; n=134/247)
    • 21.8% with salvage chemotherapy (95% CI: 14.9, 30.1; n=27/124)
  • The median duration of CRc was 4.6 months with XOSPATA (95% CI: 3.7, 7.7) and was not estimable with salvage chemotherapy (95% CI: 1.8, NE)
  • Rate of CRc was defined as the number of patients who achieved the best response of CRc (CR, CRp, or CRi) divided by the number of patients in the analysis population
  • The majority of patients who received salvage chemotherapy finished the study by Cycle 2 of treatment, resulting in a short duration of exposure, limited follow-up response, and high censoring of the duration of CRc

CR/CRh Rate and DOR in XOSPATA Arm1

  • The rate of CR/CRh in patients treated with XOSPATA was 22.6% (n=55/243) with a DOR of 7.4 months (range: <0.1+ to 23.1+ months)
  • Among patients treated with XOSPATA, the rate of CR/CRh was:
    • 22.8% in patients with FLT3-ITD only mutations (n=49/215)
    • 42.9% in patients with FLT3-ITD-TKD mutations (n=3/7)
    • 14.3% in patients with FLT3-TKD only mutations (n=3/21)
  • In patients who achieved CR/CRh with XOSPATA (n=55/243), the median time to first response was 2 months (range: 0.9 to 9.6 months)

Transfusion Independence Conversion Rate1

  • Among patients in the XOSPATA arm who were transfusion dependent at baseline (n=197)
    • 34.5% became transfusion independent with XOSPATA during any 56-day post-baseline period (n=68/197)
  • Of the 49 patients in the XOSPATA arm who were transfusion independent at baseline, 59.2% remained transfusion independent during any 56-day post-baseline period (n=29/49)
  • Transfusion independence is defined as patients who were dependent on RBC and/or platelet transfusions at baseline and became independent of RBC and platelet transfusions during any 56-day post-baseline period

XOSPATA is a FLT3 inhibitor that works differently than chemotherapy.
In the absence of disease progression or unacceptable toxicity, treatment for a minimum of 6 months is recommended to allow time for a clinical response.1

CRi=complete remission with incomplete hematologic recovery; CRp=complete remission with incomplete platelet recovery; NE=not estimable.

Select Safety Information

Adverse Reactions Fatal adverse reactions occurred in 2% of patients receiving XOSPATA. These were cardiac arrest (1%) and one case each of differentiation syndrome and pancreatitis. The most frequent (≥5%) nonhematological serious adverse reactions reported in patients were fever (13%), dyspnea (9%), renal impairment (8%), transaminase increased (6%) and noninfectious diarrhea (5%).

ADMIRAL TRIAL

Results Available in Publication

The complete ADMIRAL trial has been peer-reviewed and published in a medical journal. The efficacy and safety evaluated in the ADMIRAL trial contributed to the clinical body of evidence for XOSPATA.