RELHEM2: Crenolanib and Sorafenib Tosylate in Treating Patients with Refractory or Relapsed Hematologic Malignancies

A Phase I Pharmacokinetic, Pharmacodynamic and Feasibility Study of Crenolanib in Combination with Sorafenib in Patients with Refractory or Relapsed Hematologic Malignancies (ARO-008)


Leukemia / Lymphoma

Phase I/II

Diseases Treated:

Refractory or relapsed hematologic malignancies (leukemia)

Eligibility Overview:

  • Between the ages of 1 and 25 years
  • FLT3-mutated AML that has returned or did not respond to previous chemotherapy
  • No history of HIV infection, hepatitis B, or hepatitis C
  1. Primary Objective

    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 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.

    Trial Outline

    The study will include 2 phases:

    • The dose-escalation phase will characterize the dose-limiting toxicities (DLTs) and determine the maximum tolerated dose (MTD) or recommended phase 2 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

    Study Arms

    Experimental: Study Participants

    All participants who consent and are enrolled on the study.


    Drug: Crenolanib

    Day 1 of Course 1: once followed by pharmacokinetic analysis. Days 2-28 of cycle 1: 3 times per day. Crenolanib dose will not be adjusted unless the participant experiences side effects. All subsequent courses: 3 times per day on Days 1-28.

    Drug: Sorafenib

    Days 8-28 of course 1: given orally once each day. All subsequent courses: given orally on Days 1-28 once per day. This is a dose-finding study for the use of sorafenib in combination with crenolanib. Different doses will be given to several participants, with the first participants receiving a lower dose than typically used in children as a single agent. If the drug does not cause serious side effects, it will be given to other study participants at a higher dose. If side effects occur, the dose will be lowered.

    Drugs: Methotrexate, hydrocortisone and cytarabine with leucovorin

    Triple IT therapy includes methotrexate, hydrocortisone and cytarabine with leucovorin rescue given on day 8. All participants will receive one IT chemotherapy on Day 8 of the first cycle. If they do not have leukemia cells in their spinal fluid, they will receive only one IT chemotherapy per cycle. If leukemia cells are present in their spinal fluid, they will receive IT chemotherapy weekly during the course.

    Eligibility Criteria

    Inclusion Criteria:

    • Participant has a relapsed or refractory hematologic malignancy (with any measurable disease) with FLT3-ITD or TKD mutations and one of the following diagnoses:
      • Acute myeloid leukemia (AML)
      • AML with prior myelodysplastic syndrome (MDS)
      • Myeloperoxidase (MPO)-positive mixed phenotype acute leukemia
    • Participant's disease has relapsed after, is refractory to induction and/or salvage therapy, or has relapsed after hematopoietic stem cell transplant (HSCT)
    • Participant disease tested positive for FLT3-ITD or -TKD within 60-day screening period
    • Participant's age is 1 to 25 years, inclusive
    • Karnofsky or Lansky performance score is >60
      • Lansky performance score for participants <16 years
      • Karnofsky performance score for participants ≥16 years.
    • Adequate organ function defined as:
      • Bilirubin ≤ 1.5 x upper limit of normal (ULN)
      • ALT ≤ 3 x ULN and AST ≤ 3 x ULN
      • Serum creatinine ≤ 1.5 x ULN
    • Participant must have recovered from the acute side effects of all prior anti-cancer therapy, and:
      • At least 2 weeks have elapsed since prior systemic cytotoxic chemotherapy (except intrathecal chemotherapy, hydroxyurea, low-dose cytarabine, and / or low dose maintenance therapy such as vincristine, mercaptopurine, methotrexate or glucocorticoids), and
      • If the participant received a prior allogeneic HSCT, at least 30 days have elapsed and there is no evidence of clinically significant graft versus host disease requiring treatment and / or have > grade 2 persistent non-hematologic toxicity related to a transplant

    Exclusion Criteria:

    • Concurrent chemotherapy, or targeted anti-cancer agents, other than hydroxyurea, low-dose cytarabine, intrathecal therapy and / or low dose maintenance therapy such as vincristine, mercaptopurine, methotrexate or glucocorticoids
    • Patient with concurrent severe and / or uncontrolled medical conditions that may impair participation in the study or the evaluation of safety and / or efficacy
    • Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive)
    • Prior crenolanib treatment for a non-leukemic indication
    • Major surgical procedures within 14 days of Day 1 administration of crenolanib
    • Pregnant or lactating (female participant of childbearing potential must have negative serum or urine pregnancy test required within 7 days prior to start of treatment)
    • Male or female participant of reproductive potential must agree to use appropriate methods of contraception for the duration of study treatment and for at least 30 days after last dose of protocol treatment
    • Inability or unwillingness or research participant or legal guardian / representative to give written informed consent

    Study Design

    • Endpoint Classification: Safety / Efficacy Study
    • Intervention Model: Single Group Assignment
    • Masking: Open Label
    • Primary Purpose: Treatment
  2. About this clinical trial

    RELHEM2 is a Phase I clinical trial for patients with FLT3-mutated acute myeloid leukemia (AML) whose cancer has come back or did not respond to previous chemotherapy. The gene called FMS-like tyrosine kinase-3, or FLT3 for short, plays an important role in the normal production of blood cells. In FLT3-mutated AML, the FLT3 gene has mutated, which means it has permanent changes, which allow the leukemia cells to grow.

    Patients with AML, but who do NOT have the FLT3 gene mutation, are typically treated with high-dose chemotherapy and bone marrow transplantation. Since high-dose chemotherapy may not be effective in treating patients with FLT3-mutated AML that has returned or did not respond to chemotherapy, St. Jude researchers are determined to find new treatments for these patients.

    Purpose of this clinical trial

    In this clinical trial, St. Jude researchers want to find out if combining crenolanib and sorafenib, which are two cancer medications, is a safe option for treating patients with FLT3-mutated AML. Crenolanib and sorafenib, when given alone, have been shown to be well-tolerated and effective for the treatment of FLT3-mutated AML that has returned or did not respond to previous treatment in adult patients.

    In a prior study at St. Jude, sorafenib has been shown to be safe and effective in treating children with AML, especially in those with FLT3-mutated AML. Sorafenib is approved by the US Food and Drug Administration (FDA) to treat kidney, liver, and thyroid cancers in adults. Several studies have shown that sorafenib is also safe and effective in treating leukemias in children and adults, but it has not yet been approved by the FDA for treating leukemia, and its use AML is considered experimental. The study drug crenolanib has not been approved the FDA and its use in treating AML is also experimental.

    It is hoped this two-drug combination therapy will prove to be a safe and potentially effective treatment for children with FLT-3 mutated AML.


    • Treatment (up to 1 year) – All participants will receive combination therapy of sorafenib and crenolanib. Treatment will be completed early when participants receive bone marrow transplantation.
    • Post-treatment (minimum of 4 weeks) – After the treatment phase is completed, participants will be watched for side effects.

    Eligibility overview

    • Between the ages of 1 and 25 years
    • FLT3-mutated AML that has returned or did not respond to previous chemotherapy
    • No history of HIV infection, hepatitis B, or hepatitis C
  3. RELHEM2  Quick View
    Sponsor St. Jude Children’s Research Hospital identifier NCT02270788
    Trial start date October 2014
    Estimated enrollment 24
    Study type Interventional
    Study phase Phase 1
    Condition Acute Myeloid Leukemia 
    Ages 1 year to 25 years
    Principal investigator Hiroto Inaba, MD, PhD
    Study site St. Jude Children's Research Hospital
    For a consultation or to discuss RELHEM2 St. Jude Physician/Patient Referral Office


Hiroto Inaba, MD, PhD

St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis, TN 38105  USA
Voice: 1-888-226-4343 or 901-595-4055
24-Hour Emergency Access Pager: 1-800-349-4334

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