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A Study of Crenolanib With Fludarabine and Cytarabine in Pediatric Patients With Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

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ClinicalTrials.gov Identifier: NCT03324243
Recruitment Status : Withdrawn (Withdrawn: Study halted prior to enrollment of first participant)
First Posted : October 27, 2017
Last Update Posted : January 10, 2019
Sponsor:
Information provided by (Responsible Party):
Arog Pharmaceuticals, Inc.

Brief Summary:
This is a phase II, multicenter, single-arm study to assess the safety and feasibility of combining crenolanib with fludarabine and cytarabine chemotherapy in pediatric patients with relapsed/refractory FLT3-mutated AML. Patients will receive up to two courses of salvage chemotherapy with fludarabine, cytarabine, and crenolanib. Response will be assessed between day 29-43 of each course.

Condition or disease Intervention/treatment Phase
Relapsed/Refractory FLT3-mutated AML Drug: Crenolanib Drug: Fludarabine Drug: Cytarabine Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Crenolanib With Fludarabine and Cytarabine in Pediatric Patients With Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia
Estimated Study Start Date : January 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: Crenolanib Drug: Crenolanib
66.7 mg/m2 three times a day (TID)
Other Name: Crenolanib besylate

Drug: Fludarabine
30 mg/m2/day, intravenous infusions over 30 mins.

Drug: Cytarabine
2000 mg/m2/day, intravenous infusions over 1-3 hours.




Primary Outcome Measures :
  1. Number of patients experiencing ≥ Grade 3 adverse events as assessed by CTCAE v4.0 [ Time Frame: From study entry to 30 days post-treatment ]
  2. Number of patients experiencing Grade 4 adverse events related to crenolanib as assessed by CTCAE v4.0 [ Time Frame: 60 days ]
  3. Rate of early mortality [ Time Frame: 60 days ]
    Number of patients who died within 60 days of start of therapy


Secondary Outcome Measures :
  1. Event-free survival (EFS) [ Time Frame: 4 years ]
    EFS is defined as the time from the date of start of treatment to the date of failure to achieve a remission, relapse, or death from any cause.

  2. Relapse-free survival (RFS) [ Time Frame: 4 years ]
    RFS is defined as the time from the date of remission to date of relapse or death.

  3. Overall survival (OS) [ Time Frame: 4 years ]
    OS is defined as the time from the date of start of treatment until death.



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Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 1 years and ≤ 21 years
  2. Confirmed diagnosis of AML according to World Health Organization (WHO) 2016 classification
  3. Definitive evidence of a FLT3-ITD and/or FLT3-TKD (D835/I836) mutation at the time of enrollment
  4. Patients must have histologically or molecularly confirmed relapsed or refractory AML
  5. Karnofsky or Lansky performance score ≥ 50. Use Karnofsky for patients > 16 years old and Lansky for patients ≤ 16 years of age.
  6. Adequate renal function, defined as:

    • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or
    • Normal serum creatinine based on age/gender
  7. Adequate liver function, defined as:

    • Serum total bilirubin ≤ 1.5x ULN for age,
    • Serum aspartate aminotransferase (AST) ≤ 3.0x ULN for age, and
    • Serum alanine aminotransferase (ALT) ≤ 3.0x ULN for age.

Exclusion Criteria:

  1. Patients with any of the following current or previous diagnoses:

    • Acute promyelocytic leukemia (APL)
    • Down syndrome
    • DNA fragility or bone marrow failure syndromes (such as Fanconi anemia, Bloom syndrome, Kostmann syndrome, or Shwachman syndrome)
    • AML secondary to prior MDS/MPN, including chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia
    • Blastic plasmacytoid dendritic cell neoplasm
    • Acute leukemia of ambiguous lineage
    • B-lymphoblastic leukemia/lymphoma
    • T-lymphoblastic leukemia/lymphoma, including early T-cell precursor lymphoblastic leukemia (ETP-ALL)
  2. Patients who are refractory to first line (induction and re-induction) and a second line (1st salvage) treatment for AML.
  3. Patients who have received more than 1 prior allogeneic HSCT
  4. Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection of which they exhibit ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment.
  5. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
  6. Known severe liver disease (e.g. cirrhosis, non-alcoholic steatohepatitis, sclerosing cholangitis or hyperbilirubinemia)
  7. Known, active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
  8. Currently receiving prophylactic treatment of hepatitis B with anti-viral therapy
  9. Known infection with human immunodeficiency virus (HIV)

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Responsible Party: Arog Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03324243     History of Changes
Other Study ID Numbers: ARO-014
First Posted: October 27, 2017    Key Record Dates
Last Update Posted: January 10, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia, Myeloid, Acute
Leukemia
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Vidarabine
Cytarabine
Fludarabine
Fludarabine phosphate
Crenolanib
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antiviral Agents
Anti-Infective Agents