A SELECTIVE, TYPE I , PAN-FLT3 TYROSINE 3 KINASE INHIBITOR

AML BACKGROUND

AML is a heterogeneous disorder of the hematopoietic progenitor cell, characterized by a block in differentiation and uncontrolled proliferation. AML is diagnosed in approximately 14,000 people in the US every year, and the annual death rate is greater than 10,000 people per year. Over the past 40 years there has been very little development in the standard of care for these patients. The majority of patients with AML who achieve a complete remission (CR) will relapse within three years after diagnosis. Patient prognosis after relapse is poor and treatment options are unsatisfactory.

In comparison to other cancers, AML contains very few mutations. This makes AML an ideal disease for the development of molecularly targeted therapies. Despite the simplicity of the AML genome, the complexity of leukemic clones and mutations that evolve during the course of the disease become even more complex after a patient has relapsed. Multiple mutations have been identified as putative driver mutations in AML and their role in AML is currently being evaluated. Mutational analysis of 502 patients in the ECOG E1900 trial reveals the frequency of such driver mutations with FLT3 mutations found in 37% of the patients1 (see Table 1).


Table 1 - Frequency of mutations from patient in the E1900 trial.1

Patients with a FLT3 mutation have a very poor prognosis. Many AML driver mutations such as IDH1, IDH2, and NPM1 can be successfully treated with standard chemotherapy; however, the presence of a FLT3 mutation worsens the outcome regardless of other mutations. Thus, inhibition of FLT3 signaling plays a critical role in the attempt to cure the disease.

FLT3 mutations can occur throughout the coding region. The common activating mutations which cause constitutive receptor activation include internal tandem duplications (ITD) or point mutations within the tyrosine kinase domain (TKD) or the juxtamembrane domain (JMD). In order to effectively block FLT3 activation, an agent must have the ability to block multiple activating mutations as well as both the inactive and active conformation of the FLT3 kinase. Agents, such as crenolanib, that can inhibit both the active and inactive conformation are considered type I inhibitors, whereas agents that only bind the inactive conformation are considered type II inhibitors. To completely block FLT3 signaling, a type I inhibitor is needed. 

 

A MUTATION SPECIFIC, TYPE 1 FLT3 INHIBITOR, SPARING C-KIT

 

 

 

CLINICAL TRIALS

  • ARO-004

    Phase II Study of Crenolanib in Subjects With Relapsed/Refractory AML With FLT3 Activating Mutation (NCT01522469)

    This is a Phase II open-label study of crenolanib besylate. This study will enroll subjects with relapsed or refractory AML with FLT3 activating mutations. Prior treatment with other FLT3 TKIs is allowed. Subjects will take crenolanib 200mg/m2/day divided in three doses daily (preferably every eight hours), taken orally at least 30 minutes pre or post meal until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Patients who are able to proceed to allogeneic stem cell transplant will be able to resume crenolanib therapy post-transplant in an attempt to maintain remission.

    For more information please see: clinicaltrials.gov

  • ARO-005

    A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations (NCT01657682)

    This is a Phase II open-label study of crenolanib besylate. This study will enroll subjects with relapsed acute myeloid leukemia (AML) with FLT3 activating mutations. Two cohorts of patients will be enrolled: those whose AML has recurred after prior chemotherapy (not including a FLT3 TKI), and those whose AML has progressed after prior therapy with a FLT3 TKI. Subjects will take crenolanib in three doses daily until disease progression, death, or the patient discontinues treatment for adverse events, investigator's judgment, or other reasons. Concurrent hydroxyurea is permitted during the first 28 days of study therapy.

    For more information please see: clinicaltrials.gov

  • ARO-006

    A Safety and Tolerability Study of Crenolanib in Combination With Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia Patients With FLT3 Mutations (NCT02283177)

    This is a double arm, Phase II study in newly diagnosed FLT-3 positive Acute Myeloid Leukemia (AML) patients scheduled to start at the University of Texas: Southwestern in the first quarter of 2015. Patients with FLT3-D835 mutations, FLT3-ITD (internal tandem duplications), or compound mutations will be eligible and receive daily doses of 100 mg crenolanib TID in combination with Ara-C + daunorubicin or Ara-C + idarubicin.

    For more information please see: clinicaltrials.gov

  • ARO-007

    Study of Crenolanib in Combination With Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia and Activating FLT3 Mutations (NCT02298166)

    The main trial is a double-blinded, placebo-controlled, randomized, Phase III, multi-center trial in adult patients with relapsed or refractory AML harboring an activating FLT3 mutation as defined in the inclusion/exclusion criteria.

    An initial safety run-in phase of the study will be performed in an open-label setting administering the study drug crenolanib with salvage chemotherapy consisting of mitoxantrone and cytarabine (MC) in 12 patients according to the experimental arm of the study. After completion of this safety run-in phase, toxicity and response data will be provided to the external Data and Safety Monitoring Board (DSMB) and the Trial Committee by the Coordinating Investigator. The Trial Committee will decide on the basis of these data and the recommendation of the DSMB on dose-modification and the further conduct of the study with regard to the double-blinded, placebo-controlled, randomized phase of the study. The double-blinded, placebo-controlled, randomized portion will start after the completion of the safety run-in phase and positive opinion of the Trial Committee.

    For more information please see: clinicaltrials.gov

  • ARO-008

    Crenolanib in Combination with Sorafenib in Patients with Refractory or Relapsed Hematologic Malignancies (NCT02270788)

    This is a pilot study to characterize the toxicity profile, to determine the maximum tolerated dose of the combination of crenolanib and sorafenib, and to determine the feasibility of administering these drugs in patients under the age of 25 with relapsed or refractory hematologic malignancies, including acute myeloid leukemia (AML), AML with prior myelodysplastic syndrome (MDS), and myeloperoxidase (MPO)-positive mixed phenotype acute leukemia with FLT3-internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations.

    The study will include two phases:

    • The dose-escalation phase will characterize the dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) or recommended Phase II dose (RP2D) of crenolanib when given in combination with sorafenib.
    • The dose-expansion cohort will further assess the safety and explore the efficacy of this combination.

     

    For more information please see: clinicaltrials.gov

  • ARO-009

    A Safety and Tolerability Study of Crenolanib Maintenance Following Allogeneic Stem Cell Transplantation in Patients with FLT3 positive Acute Myelogenous Leukemia

    This is a Phase II study of crenolanib given as a single agent post-allogeneic transplant to patients diagnosed with FLT3 mutant acute myelogenous leukemia (AML) to assess safety and tolerability. Patients will be separated into either haploidentical or non-haploidentical post-transplant cohorts and will be treated with 100 mg crenolanib TID for up to one year barring progression or unacceptable toxicity.

  • ARO-010

    Multi-agent Phase I/II Study of Crenolanib in Relapsed/Refractory AML patients

    This is a Phase I/II study of crenolanib combined with idarubicin and cytarabine, and crenolanib combined with 5-azacitadine in Acute Myeloid Leukemia (AML) patients with FLT3 activating mutations scheduled to open the first quarter of 2015 at the MD Anderson Cancer Center. Patients will either be given 100 mg Crenolanib TID in combination with HiDAC or 5-Azacitadine to determine DLT, MTD, and response rate of these combination therapies. Following remission, patients will continue on crenolanib for up to a year.


1Patel et al. N Engl J Med. 2012; 366(12):1079-1089
2Smith et al. Proc Natl Acad Sci USA 2014; 111(14):5319-5324
3Zimmerman, et al. Blood 2013; 122(22):3607-3615