A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations

Study Overview
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Brief Summary
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This pilot Phase II study is designed to evaluate the efficacy and tolerability of crenolanib in two cohorts of AML patients with FLT3 activation mutations (patients whose leukemia has recurred after prior chemotherapy not including a FLT3 TKI and patients whose leukemia has progressed after prior therapy with a FLT3 TKI).

Detailed Description
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This is a Phase II open label study of crenolanib besylate. This study will enroll subjects with relapsed acute myeloid leukemia (AML) with FLT3 activating mutations. Two cohorts of patients will be enrolled: those whose AML has recurred after prior chemotherapy without a FLT3 TKI, and those whose AML has progressed after prior therapy with FLT3 TKIs. Subjects will take Crenolanib besylate at 100 mg TID until disease progression, death, or unacceptable toxicities. Concurrent hydroxyurea is permitted during the first 28 days of study therapy.

Official Title
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A Phase II Study of Crenolanib in Relapsed/Refractory Acute Myeloid Leukemia Patients With FLT3 Activating Mutations

Conditions
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Acute Myeloid Leukemia With FLT3 Activating Mutations That Has Relapsed or Been Refractory After One or More Prior Therapies

Intervention / Treatment
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* Drug: Crenolanib besylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed primary AML relapsed or refractory after prior therapy, AML secondary to antecedent chemotherapy or radiation therapy, or AML due to prior myelodysplastic syndrome (MDS)/ myeloproliferative neoplasm (MPN) as defined by WHO criteria with presence of either FLT3 ITD and/or other FLT3 activating mutations Patients with secondary AML should have failed no more than two (2) prior regimens Patients with antecedent MDS/MPN, defined by WHO criteria, without any prior therapy for AML, regardless of the number of therapies for MDS/ MPN Patients with primary AML should have received no more than two (2) prior cytotoxic containing salvage regimens. Reinduction with the same regimen or stem cell transplant will not be considered a separate salvage regimen. Change of drugs will be considered a salvage regimen. Unlimited FLT3 TKI therapy (even in combination with cytotoxics/hypomethylating agents) is allowed for patients enrolled in cohort B Patients must have tested positive for FLT3-ITD and /or other FLT3 activating mutations within 30 day screening period Males and females age ≥18 years ECOG PS 0-2 Adequate liver function, defined as bilirubin ≤1.5x ULN, ALT ≤3.0x ULN, and AST ≤3.0x ULN Adequate renal function, defined as serum creatinine ≤1.5x ULN Recovery from non-hematological toxicities of prior therapy (including HSCT) to no more than grade 1 (except alopecia) Subjects should have received no anti-leukemic therapy (except hydroxyurea) prior to the first dose of crenolanib as follows: for 14 days for classical cytotoxic agents and for five times the t1/2 (half-life) for FLT3 inhibitors and antineoplastic agents that are neither cytotoxic nor FLT3 inhibitors (e.g. hypomethylating agent or MEK inhibitor) Negative pregnancy test for WOCBP Able and willing to provide written informed consent. Exclusion Criteria: Absence of a FLT3 activating mutation <5% blasts in blood or marrow at screening Concurrent chemotherapy, or targeted anti-cancer agents, other than hydroxyurea Patient with concurrent severe and/or uncontrolled medical conditions that in the opinion of the investigator may impair the participation in the study or the evaluation of safety and/or efficacy HIV infection or active hepatitis B (defined as hepatitis B surface antigen positive) or C (defined as hepatitis C antibody positive) Known clinically active central nervous system (CNS) leukemia Patients less than 30 days post HSCT Subjects who have clinically significant graft versus host disease requiring treatment and /or have >grade 2 persistent non hematological toxicity related to transplant Prior crenolanib treatment for a non-leukemic indication Major surgical procedures within 14 days of Day 1 administration of crenolanib. Unwillingness or inability to comply with protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A - No prior FLT3 TKI exposure<br>Will enroll relapsed/refractory AML patients with FLT3 activating mutations who progressed on one or more prior chemotherapy regimens excluding any FLT3 TKI. | Drug: Crenolanib besylate<br>* Crenolanib besylate, 100 mg TID, taken orally at least 30 minutes pre- or post- meal. Patients will complete a daily diary to record the date, time and amount (number of tablets) of crenolanib taken and eating schedule. Concurrent hydroxyurea (maximum 5g total daily dose x 14 days) is permitted during the first 28 days of study therapy.<br>|
| Experimental: Cohort B - Prior therapy with FLT3 TKI<br>Will enroll relapsed/refractory AML patients with FLT3 activating mutations whose leukemia has progressed and have history of prior therapy with one or more FLT3 TKIs. | Drug: Crenolanib besylate<br>* Crenolanib besylate, 100 mg TID, taken orally at least 30 minutes pre- or post- meal. Patients will complete a daily diary to record the date, time and amount (number of tablets) of crenolanib taken and eating schedule. Concurrent hydroxyurea (maximum 5g total daily dose x 14 days) is permitted during the first 28 days of study therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate of Patients Receiving Crenolanib Therapy | To determine the response rate to crenolanib. CR Complete remission (CR) response criteria include a post-baseline bone marrow (BM) biopsy or aspiration % blasts <5%, absolute neutrophil count (ANC) >1×10^9/L and platelet count >100×10^9/L. CRi response included all CR criteria met, except participant did not experience either platelet recovery or ANC recovery. Partial Response (PR) response included a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline to a post-baseline result between 5% to 25% in the bone marrow aspirate or biopsy. Blast reduction (BR) response included a decrease of ≥50% in % blasts. Resistant Disease (RD) was defined as the absence of CR, CRi, CRp, PR or MLFS. | From the date of first dose to the end of protocol treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Overall Survival | To determine the overall survival of AML patients with activating FLT3 mutations treated with crenolanib | From the date of first dose up to end of treatment, up to 24 months. | 
| Study Drug Exposure | To determine the study drug exposure of relapse/refractory AML patients receiving 100 mg crenolanib besylate tablets three times daily. | Defined as the duration from first day to the last dose, up to 24 months, interruptions in study drug administration were not counted. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FLT3, Crenolanib, Acute, Myeloid, AML