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

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Relapsed/Refractory FLT3-mutated AML
• Intervention / Treatment: Drug: Crenolanib; Drug: Fludarabine; Drug: Cytarabine

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Crenolanib	Drug: Crenolanib; 66.7 mg/m2 three times a day (TID); Other Names: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Number of patients who died within 60 days of start of therapy	60 days

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Arog Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): January 1, 2018
• Primary Completion (ANTICIPATED): December 1, 2020
• Study Completion (ANTICIPATED): December 1, 2020

Study Registration Dates

• First Submitted: October 18, 2017
• First Submitted That Met QC Criteria: October 24, 2017
• First Posted (ACTUAL): October 27, 2017

Study Record Updates

• Last Update Posted (ACTUAL): January 10, 2019
• Last Update Submitted That Met QC Criteria: January 8, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fludarabine; Cytarabine; Crenolanib
• Other Study ID Numbers: ARO-014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No