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FLT3 Negative at Relapse

Leukemia Insights - Summer 2011

Therapeutic options for FLT3 negative patients are separated based on duration of initial CR and whether treatment is for first salvage or subsequent salvage.

A. 1st salvage & 1st CR duration > 12 months

  1. Ph III Vosaroxin + cytarabine vs. Placebo + Ara-C
  2. Ph I/II Sorafenib and 5-Azacitidine
  3. Ph I/II PKC412 and AZA
  4. Ph II MK-2206 (Age ≥ 60)
  5. Ph II AC220
  6. Ph I/II CIA vs. FAI
  7. Ph I MDX-1338/BMS936564

B. 1st salvage & 1st CR duration < 12 months

  1. Ph III Vosaroxin + Ara-C vs. Placebo + Ara-C
  2. Ph I/II Sorafenib and 5-Azacitidine
  3. Ph I/II PKC412 and AZA
  4. Ph II AC220
  5. Ph I MDX-1338/BMS936564

C. 2nd salvage

  1. Ph II MK-2206 (Age ≥ 60)
  2. Ph I/II Sorafenib and 5-Azacitidine
  3. Ph I/II PKC412 and AZA
  4. Ph I MDX-1338/BMS936564

Vosaroxin is mechanistically similar to the anthracyclines such as idarubicin and daunorubicin, and the anthracenedione, mitoxantrone. Vosaroxin in combination with cytarabine is being compared in this phase III trial to cytarabine alone as first salvage therapy for relapsed AML, an area of significant unmet need for therapeutic options (Lancet J, Leukemia 2011;Jul 15, 10.1038). 

The PI3K/AKT signaling pathway is essential for different physiological processes of cell growth, survival and suppression of apoptosis, and its constitutive activation has been implicated in the pathogenesis as well as the progression of a wide variety of neoplasias, including AML (Pal S, Expert Opin Investig Drugs, 2010, 19, 1355-66). MK-2206 is the first oral allosteric inhibitor of AKT to enter clinical development.

In a recent update of a phase II study of 63 patients treated with clofarabine, cytarabine and idarubicin (CIA), the overall response rate was 38% including 21% with complete remission (Faderl S, Blood, 2005, 105, 940). In view of this experience and in light of the possible usefulness of higher doses of anthracyclines (Fernandez H, N Engl J Med, 2009, 361, 1249-1259), and the synergistic activity of the combination of anthracyclines with nucleoside analogues, we are evaluating a randomized phase II Bayesian design the CIA combination at higher doses than established versus fludarabine, cytarabine and idarubicin (FAI) in patients with relapsed/refractory AML.

Based on preclinical studies, MDX-1338 (BMS-936564) a monoclonal antibody, is expected to achieve efficacy by potentiating the chemotherapeutic effect due to its ability to release malignant cells from a protective environment and by direct apoptosis (Fuchs E, Cell, 2004, 116, 769-778). The chemotherapy regimen consisting of mitoxantrone, etoposide, and cytarabine, was chosen to combine with MDX 1338 (BMS-936564), since this regimen is considered standard of care for relapsed, refractory AML.


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