Abstract 3610

The activated FMS-like tyrosine kinase 3 (FLT3) receptor promotes proliferation, survival and differentiation of primitive hematopoietic progenitor cells, with downstream targets including the Raf/MEK/ERK pathway. Methylation-associated silencing inactivates certain tumor suppressor genes as effectively as some mutations potentially acting as one of the cancer predisposing hits of the two-hit = leukemogenesis hypothesis.

Methods:

We present data from a phase I, single-center study designed to determine the MTD and recommended Phase II dose of midostaurin (PKC412), a FLT3 inhibitor, combined either sequentially (days 8–21) or concurrently (days 1–28) with decitabine 20 mg/m2 days 1–5 in AML patients. Additional endpoints: tolerability; exploratory activity assessments. Adult AML patients with relapsed or refractory (R/R) disease or elderly (≥ 60 years) patients unable to receive standard induction chemotherapy, with ECOG PS ≤2, were eligible and received treatment for 3 cycles or until disease progression. Previous hypomethylating agents were allowed.

Results:

Enrollment is complete with 16 patients (Table 1) with 15 evaluable for safety (1 pt withdrew prior to receiving any midostaurin). One patient in cohort 1 remains on study in cycle 14. Median number of cycles completed was 2 with 5 patients receiving 3 or more cycles. Median age was 68 years (range 48–81) with 9 males. The number of newly diagnosed and R/R patients was evenly split at 8 each. Of note, 3 of 8 patients (38%) with R/R disease had relapsed subsequent to allogeneic hematopoietic stem cell transplant (HSCT). Only 2 of 16 patients (13%) had FLT3 ITD mutations and no patient had KIT mutations. Additionally, 44% of patients had received prior therapy with either azacitidine or decitabine.

Table 1.
Age and GenderCohortAML StatusMutation StatusMidostaurin DoseDecitabine DoseNumber of Cycles completedPrior hypomethylating therapyBest Response (CR, PR, SD, PD)Reason for Study Withdrawal
81/M New FLT3 WT; KIT-   No CR Voluntary 
74/F R/R FLT3 WT; KIT- 25 mg bid (d 8–21)  Yes SD Poor QOL 
71/M R/R FLT3 WT; KIT-   14 No PR Still on study 
66/F R/R FLT3 WT; KIT-   — Yes PD Progression 
63/F New FLT3 MUT; KIT-   — No Not evaluable DLT (QTc > 500) 
70/F New FLT3 WT; KIT-   — No Not evaluable Voluntary 
48/M R/R FLT3 MUT; KIT-   No CR HSCT 
64/M New FLT3 WT; KIT- 50 mg bid (d 8–21) 20mg/m2 IV (d 1–5) Yes CRi HSCT 
74/M R/R FLT3 WT; KIT-   Yes SD Progression 
68/M New FLT3 WT; KIT-   No PR Fungal Pneumonia 
65/F R/R (HSCT) FLT3 WT; KIT-   No SD Viral Pneumonia 
54/F R/R (HSCT) FLT3 WT; KIT-   No SD Fungal Pneumonia 
66/M New FLT3 WT; KIT-   No SD Progression 
68/F R/R (HSCT) FLT3 WT; KIT-   Yes PD Progression 
76/M New FLT3 WT; KIT- 50 mg bid (d 1–28)  — Yes Not evaluable DLT (Pulmonary) 
80/M New FLT3 WT; KIT-   — Yes Not evaluable DLT (Pulmonary) 
Age and GenderCohortAML StatusMutation StatusMidostaurin DoseDecitabine DoseNumber of Cycles completedPrior hypomethylating therapyBest Response (CR, PR, SD, PD)Reason for Study Withdrawal
81/M New FLT3 WT; KIT-   No CR Voluntary 
74/F R/R FLT3 WT; KIT- 25 mg bid (d 8–21)  Yes SD Poor QOL 
71/M R/R FLT3 WT; KIT-   14 No PR Still on study 
66/F R/R FLT3 WT; KIT-   — Yes PD Progression 
63/F New FLT3 MUT; KIT-   — No Not evaluable DLT (QTc > 500) 
70/F New FLT3 WT; KIT-   — No Not evaluable Voluntary 
48/M R/R FLT3 MUT; KIT-   No CR HSCT 
64/M New FLT3 WT; KIT- 50 mg bid (d 8–21) 20mg/m2 IV (d 1–5) Yes CRi HSCT 
74/M R/R FLT3 WT; KIT-   Yes SD Progression 
68/M New FLT3 WT; KIT-   No PR Fungal Pneumonia 
65/F R/R (HSCT) FLT3 WT; KIT-   No SD Viral Pneumonia 
54/F R/R (HSCT) FLT3 WT; KIT-   No SD Fungal Pneumonia 
66/M New FLT3 WT; KIT-   No SD Progression 
68/F R/R (HSCT) FLT3 WT; KIT-   Yes PD Progression 
76/M New FLT3 WT; KIT- 50 mg bid (d 1–28)  — Yes Not evaluable DLT (Pulmonary) 
80/M New FLT3 WT; KIT-   — Yes Not evaluable DLT (Pulmonary) 
Safety profile:

All patients whom received treatment (15) experienced adverse events (AE), the majority of which were Grade 1/2 in severity and included fatigue, nausea, mouth sores, and insomnia. Most AEs were hematologic, including anemia, thrombocytopenia, and neutropenia as expected in this population. Three patients developed dose limiting toxicities: 2 patients in cohort 3 developed pulmonary edema requiring mechanical ventilation and 1 patient in cohort 2 developed a prolonged QTc > 500 msec. All but two of 15 patients required admission for neutropenic fever. Three patients developed fungal (2) or viral pneumonia (1) and expired. However, most study treatments were given in the clinic allowing patients to spend a majority of the time as an outpatient.

Response:

Of twelve patients evaluable for response, 10 (83%) achieved stable disease (SD) or better while on trial. Three of the 12 patients (25%) had a complete response (CR or CRi) after 1 cycle (28 days) and 2 of these patients were able to undergo allogeneic HSCT. Of the two patients with FLT3 ITD mutations, one patient was evaluable for response and achieved a CR (cohort 2). Pharmacokinetic analysis is ongoing.

Conclusion:

These data indicate that the combination of decitabine with sequential midostaurin is possible without significant unexpected toxicity. The MTD for this combination was determined to be decitabine 20mg/m2 IV daily × 5 days (days 1–5) followed by midostaurin 50mg po bid days 8–21 given every 4 weeks. In addition, the combination shows promising clinical activity in R/R and untreated AML in elderly patients.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.