Clinical Trials /

Crenolanib in Combination With Sorafenib in Patients With Refractory or Relapsed Hematologic Malignancies

NCT02270788

Description:

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. 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 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.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Crenolanib in Combination With Sorafenib in Patients With Refractory or Relapsed Hematologic Malignancies
  • Official Title: A Phase I Pharmacokinetic, Pharmacodynamic and Feasibility Study of Crenolanib in Combination With Sorafenib in Patients With Refractory or Relapsed Hematologic Malignancies (ARO-008)

Clinical Trial IDs

  • ORG STUDY ID: RELHEM2
  • SECONDARY ID: NCI-2014-01784
  • NCT ID: NCT02270788

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
CrenolanibCP-868,596, IND 112201Study Participants
SorafenibSorafenib tosylate, BAY-43-9006, Nexavar®Study Participants
methotrexate, hydrocortisone and cytarabine with leucovorinTriple IT chemotherapyStudy Participants

Purpose

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. 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 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.

Detailed Description

      Each course of therapy will be 28 days (±5 days), unless disease progression is seen while on
      the combination of crenolanib with sorafenib. Patients may receive subsequent courses (up to
      a total of 365 days) if there is no disease progression or unacceptable toxicity.

      In Day 1 of Course 1, crenolanib is given once in the morning followed by characterization of
      the pharmacokinetic profile over the following 24-hour period. Starting with day 2 of Course
      1, crenolanib will be given 3 times per day through day 28. On Days 8 to 28 of Course 1,
      sorafenib will be given once per day. Inter-patient dose escalation or de-escalation of
      crenolanib will be performed based on tolerability and toxicity.

      Response will be assessed on days 8 and at end of course. If disease progresses prior to day
      8, then sorafenib can be given before day 8.

      In subsequent courses (up to 365 days), crenolanib and sorafenib are given on days 1 through
      28. The treating physician may increase or decrease the sorafenib dose and frequency of
      administration per the trial's dosing table on the basis of effects and tolerability. If
      necessary, the crenolanib dose can be decreased per protocol.

      Maintenance therapy must start no sooner than 30 days and no later than 120 days after
      hematopoietic stem cell therapy (HSCT). Single agent crenolanib will start at the last dose
      tolerated prior to HSCT. Crenolanib maintenance can be given for up to 365 days and
      additional therapy can be provided after discussion after discussion with the PI, in patients
      who continue to benefit after 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Study ParticipantsExperimentalAll participants who consent and are enrolled on the study. Interventions: Crenolanib, sorafenib, triple intrathecal chemotherapy (methotrexate, hydrocortisone and cytarabine with leucovorin).
  • Crenolanib
  • Sorafenib
  • methotrexate, hydrocortisone and cytarabine with leucovorin

Eligibility Criteria

        Inclusion Criteria - Initial Enrollment:

          -  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 (St. Jude participants must be aged 1 to
             25 years, inclusive).

          -  Karnofsky or Lansky performance score is > 60%. The Lansky performance score should be
             used for participants < 16 years and the 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 - Initial Enrollment:

          -  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, in the
             opinion of the investigator, 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.

        Inclusion Criteria - Maintenance Therapy After HSCT:

          -  Patient must have received crenolanib on this protocol prior to HSCT to continue on to
             maintenance.

          -  Patient must be within 30 - 120 days after hematopoietic stem cell transplant (HSCT).

          -  Response to previous treatment on this protocol: at least resistant disease with
             clinical benefit or better response.

          -  Patient is off or on a stable dose of immunosuppressive drugs for management or
             prophylaxis of graft-versus-host-disease (GVHD) (defined as no escalation of therapy
             for GVHD) within 14 days prior to starting crenolanib.

          -  Patient must have recovered from acute side effects of HSCT, defined as having <Grade
             2 non-hematological toxicity related to the transplant (exceptions are alopecia and
             other non-acute toxicities).

          -  Adequate hematopoietic recovery (ANC >500/mm^3 and platelet count >50,000/mm^3)

          -  Research participant or legal guardian/representative is able and willing to give
             written informed consent.
      
Maximum Eligible Age:39 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicity (DLT)
Time Frame:Through Day 28 of Course 1
Safety Issue:
Description:Any participant who experiences DLT at any time during cycle 1 of protocol therapy is considered evaluable for toxicity. Participants without DLT and can be followed for 28 days are also considered evaluable for toxicity. Participants who are not evaluable for toxicity (such as those removed early from therapy to start alternate therapy) at a given dose level will be replaced.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:St. Jude Children's Research Hospital

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