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

Phase 2

Withdrawn

• Conditions: Relapsed/Refractory FLT3-mutated AML
• Interventions: Drug: Crenolanib; Drug: Fludarabine; Drug: Cytarabine

• Registration Number: NCT03324243
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-10-18
• Study First Submitted QC: 2017-10-24
• Study First Posted: 2017-10-27
• Study Start: 2018-01
• Status Verified: 2019-01
• Last Update Submitted: 2019-01-08
• Last Update Posted: 2019-01-10
• Primary Completion: 2020-12
• Study Completion: 2020-12

Recruitment & Eligibility

• Status: WITHDRAWN
• Sex: All
• Target Recruitment: Not specified

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.

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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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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Crenolanib	Crenolanib	-
Crenolanib	Fludarabine	-
Crenolanib	Cytarabine	-

Primary Outcome Measures

Name	Time	Method
Number of patients experiencing ≥ Grade 3 adverse events as assessed by CTCAE v4.0	From study entry to 30 days post-treatment
Number of patients experiencing Grade 4 adverse events related to crenolanib as assessed by CTCAE v4.0	60 days
Rate of early mortality	60 days	Number of patients who died within 60 days of start of therapy

Secondary Outcome Measures

Name	Time	Method
Event-free survival (EFS)	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.
Relapse-free survival (RFS)	4 years	RFS is defined as the time from the date of remission to date of relapse or death.
Overall survival (OS)	4 years	OS is defined as the time from the date of start of treatment until death.