INDOXIMOD IN COMBINATION WITH IDARUBICIN AND CYTARABINE FOR UPFRONT TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (AML): PHASE 1 REPORT
Author(s): ,
Ashkan Emadi
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States;Medicine,University of Maryland,Baltimore,United States;Pharmacology,University of Maryland,Baltimore,United States
,
Noa G. Holtzman
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States;Medicine,University of Maryland,Baltimore,United States
,
Mohammad Imran
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States
,
Firas El Chaer
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States
,
Madhurima Koka
Affiliations:
Pathology,University of Maryland,Baltimore,United States
,
Zeba Singh
Affiliations:
Pathology,University of Maryland,Baltimore,United States
,
Amir Shahlaee
Affiliations:
Institute for Asthma and Allergy,Chevy Chase,United States
,
Edward A. Sausville
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States;Medicine,University of Maryland,Baltimore,United States;Pharmacology,University of Maryland,Baltimore,United States
,
Jennie Law
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States;Medicine,University of Maryland,Baltimore,United States
,
Seung Tae Lee
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States;Medicine,University of Maryland,Baltimore,United States
,
Arnob Banerjee
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States;Medicine,University of Maryland,Baltimore,United States
,
Aaron Rapoport
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States;Medicine,University of Maryland,Baltimore,United States
,
Maria R. Baer
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States;Medicine,University of Maryland,Baltimore,United States
,
Vu H. Duong
Affiliations:
University of Maryland Greenebaum Comprehensive Cancer Center,Baltimore,United States;Medicine,University of Maryland,Baltimore,United States
,
David H. Munn
Affiliations:
Georgia Cancer Center and Departments of Pediatrics,Medical College of Georgia,Augusta,United States
,
Michael Loken
Affiliations:
Hematologics Inc.,Seattle,United States
,
Eugene Kennedy
Affiliations:
NewLink Genetics Co.,Ames,United States
,
Nicholas Vahanian
Affiliations:
NewLink Genetics Co.,Ames,United States
Charles Link
Affiliations:
NewLink Genetics Co.,Ames,United States
EHA Learning Center. Emadi A. May 18, 2017; 180688
Dr. Ashkan Emadi
Dr. Ashkan Emadi

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Abstract
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Abstract: E912

Type: Eposter Presentation

Background
AML cells can acquire immune evasion and tolerance through overexpression of indoleamine 2,3-dioxygenase (IDO), which exerts immunomodulatory effects through tryptophan (Trp) catabolism and kynurenine production. By degrading Trp, IDO shifts the balance from a Trp-rich environment, which encourages T-cell proliferation and activation, to a Trp-poor environment leading to immune system suppression. We hypothesized that incorporation of indoximod, an inhibitor of the IDO pathway, into conventional remission induction and consolidation would be well tolerated without adding significant toxicity and may improve clinical outcomes of patients (pts) with newly diagnosed AML.

Aims
The primary objective of the phase 1 portion of the trial is to characterize the regimen limiting toxicities (RLT) as well as the recommended phase 2 dose (RP2D) of indoximod in combination with standard of care (SOC) chemotherapy for frontline AML treatment. A key secondary objective is to determine the minimal (or measurable) residual disease (MRD) status, as measured by multi-color flow cytometry, in pts with AML who receive indoximod in combination with SOC at the end of induction, after completion of the 1st cycle of consolidation, and before maintenance or proceeding to allogeneic stem cell transplantation (allo-HSCT).

Methods
This is a phase 1b / randomized phase 2a trial of indoximod in combination with 7+3 remission induction consisting of cytarabine (100 mg/m2/day continuous infusion for 7 days) and idarubicin (12 mg/m2/day for 3 days) and high dose cytarabine (HiDAC) consolidation, as SOC, in pts with newly diagnosed AML (NCT02835729), with a 3+3 design for the phase 1 portion. Indoximod is given orally every 8 hours starting on day 8 of induction onward. Indoximod is held on days that pts receive HiDAC consolidation, and it is discontinued 4 weeks prior to allo-HSCT. The phase 1 consists of 4 dose levels [400 mg (-1), 600 mg (0, starting dose), 1000 mg (1), 1200 mg (2)] in combination with SOC.

Results
Twelve pts have been enrolled, as of March 1, 2017. Median age is 53 (range 18-69) years, and 4 pts are female. According to 2017 European Leukemia Net risk stratification, 9 had favorable risk (3 with DNMT3A and 2 with low allelic ratio (<0.5) of FLT3-ITD) and 3 had adverse risk. No RLT was observed with the 1st and 2nd dose levels. The most frequently reported adverse events (regardless of attribution), were febrile neutropenia, diarrhea, nausea and vomiting, dyspnea, hypotension, and hypoxia. Three pts are no longer on study: 1 (dose level 0) due to inability to swallow indoximod after hypoxic respiratory failure during induction, 1 (dose level 1) withdrew consent for personal reasons after only 2 doses of indoximod, and 1 (dose level 2) was taken off due to eligibility. The remaining 9 pts are still on study; 3 pts in dose level 2 are currently receiving induction and are not evaluable. Five of 6 (83%) evaluable pts in dose levels 0 and 1 achieved complete remission (CR) after induction. All 5 pts demonstrated no evidence of MRD at levels <0.02% (MRD-neg) post-induction and remained MRD-neg post cycle 1 of HiDAC. One pt in dose level 1 with favorable risk (normal karyotype, mutations in DNMT3A/NPM1/NRAS) had primary refractory disease. The pt who was unable to swallow indoximod had favorable risk (normal karyotype, mutations in DNMT3A/NPM1) and achieved morphologic CR but had MRD at the end of induction, and ultimately relapsed after 2 cycles of HiDAC consolidation.

Conclusion
Indoximod does not appear to add significant toxicity to standard remission induction and consolidation in pts with newly diagnosed AML. Initial data suggest a high rate of MRD-neg after one cycle of induction chemotherapy.

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): AML, Immune therapy

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