Pilot Study of Crenolanib Combined With Standard Salvage Chemotherapy in Subjects With R/R AML

Study Overview
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Brief Summary
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The proposed study is designed to combine crenolanib with standard salvage chemotherapy to treat patients with R/R AML irrespective the FLT3 status.

Detailed Description
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Open label, dose de-escalation, pilot trial of crenolanib with standard salvage chemotherapy. Subjects may receive up to 2 cycles of induction with standard salvage chemotherapy followed by crenolanib. Each arm will enroll approximately 24 patients (72 total); stratification to each arm will be per physician's choice

Official Title
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Pilot Study of Crenolanib Combined With Standard Salvage Chmetherapy in Subjects With Relapsed/Refractory Acute Myeloid Leukemia

Conditions
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Relapsed/Refractory Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Crenolanib
* Drug: Mitoxantrone
* Drug: Cytarabine
* Drug: Etoposide
* Drug: Fludarabine
* Drug: G-CSF
* Drug: Idarubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Confirmed diagnosis of AML, including treatment-related secondary AML (except prior MDS) according to World Health Organization (WHO) 2008 classification at treating institution Subjects who are refractory* or who have relapsed** following first line AML therapy with cytarabine/anthracycline based chemotherapy, with or without a tyrosine kinase inhibitor. *Refractory to induction therapy is defined as never achieving CR, CRi or CRp (according to International Working Group criteria) after one line of intensive regimen for AML (re-induction, consolidation and/or transplant allowed) including at least one cytarabine containing induction block with a total dose no less than 700mg/m² per cycle and 3 days of an anthracycline with or without a TKI. or **First relapse is defined as untreated hematologic relapse (according to International Working Group criteria) after one line of intensive regimen for AML (re-induction, consolidation and/or transplant allowed) including at least one cytarabine containing induction block with a total dose no less than 700mg/m² per cycle and 3 days of an anthracycline with or without a TKI that induced a CR/CRi/CRp. Subjects are allowed to receive induction, consolidation, transplant and/or maintenance prior to achieving their first CR/CRi/CRp. Subjects considered eligible for intensive chemotherapy ECOG performance status ≤ 2 Age ≥ 18 years Adequate liver function within 72 hours of enrollment, defined as: Normal total serum bilirubin ALT and AST ≤ 2.0 x ULN Adequate renal function, defined as serum creatinine ≤ 1.5x ULN Women of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 72 hours prior to enrollment Woman of childbearing potential is defined as any woman who has not undergone a hysterectomy and who has had menses at any time in the preceding 24 consecutive months Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin one acceptable method of birth control (IUD, tubal ligation, or partner's vasectomy) while on crenolanib and for 3 months following the last dose of crenolanib. Hormonal contraception alone is not an acceptable method of birth control for the purpose of this trial. Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 3 month after the last dose of crenolanib). Willing to adhere to protocol specific requirements 12. Following receipt of verbal and written information about the study, the subject must provide signed informed consent before any study related activity is carried out. 13. Clinically significant toxic effects of prior therapy (expect hydroxyuria) resolved to Grade ≤ 1 before the start of study. Exclusion Criteria < 5% blasts in blood or marrow at screening, except if measurable extramedullary AML is confirmed Acute promyelocytic leukemia (APL) Known clinically active CNS leukemia Clinically active or unstable graft-versus-host disease (GvHD) requiring treatment which precludes administration of chemotherapy as defined in this protocol Prior anti-leukemia therapy within 14 days of enrollment for classical cytotoxic agents, and within 5x the half-life for other investigational agents Prior use of hydroxyurea or isolated doses of cytarabine for palliation (i.e., control of WBC) are allowed but should be discontinued at least 24 hrs prior to enrollment. Other agents used strictly with palliative intent might be allowed during this period after discussing with principal investigator Pre-existing liver disease (e.g. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, sclerosing cholangitis) Known HIV infection. Evidence of ongoing, uncontrolled systemic infection or an uncontrolled local infection requiring therapy at the start of study. Currently active second malignancy (other than non-melanoma skin cancer, carcinoma in situ of the cervix or prostatic intraepithelial neoplasia within 1 year). Subjects are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within 1 year. Concurrent participation in another therapeutic clinical trial. Pregnant or breastfeeding women Subjects of childbearing potential not willing to use adequate contraception during study and 3 months after last dose of crenolanib Subject with uncontrolled cardiac disease including congestive heart failure class III or IV by the NYHA, unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months) or myocardial infarction within the past 6 months Subject with concurrent severe and/or uncontrolled medical or psychiatric conditions that in the opinion of the investigator may impair the participation in the study or the evaluation of safety and/or efficacy Inability to give an informed consent

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: Arm A<br>Mitoxantrone Cytarabine Crenolanib | Drug: Crenolanib<br> <br> Drug: Mitoxantrone<br> <br> Drug: Cytarabine<br> <br> * Other names: cytosine arabinoside;|
| Experimental: Arm B<br>Fludarabine Cytarabine G-CSF Idarubicin Crenolanib | Drug: Crenolanib<br> <br> Drug: Cytarabine<br> <br> * Other names: cytosine arabinoside;Drug: Fludarabine<br> <br> * Other names: Fludarabine monophosphate;Drug: G-CSF<br> <br> Drug: Idarubicin<br> <br> |
| Experimental: Arm C<br>Mitoxantrone Etoposide Cytarabine Crenolanib | Drug: Crenolanib<br> <br> Drug: Mitoxantrone<br> <br> Drug: Cytarabine<br> <br> * Other names: cytosine arabinoside;Drug: Etoposide<br> <br> * Other names: Etoposide phosphate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response to Crenolanib With Standard Salvage Chemotherapy | To determine the response rate to crenolanib. 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 have either platelet recovery or ANC recovery. CRh response included all CR criteria met, except subject only has partial platelet recovery and ANC recovery. Complete CR (CRc) response includes all subjects who achieve a CR, CRi and CRh. Partial Response (PR) response included a decrease of ≥50% in % blasts in the BM aspirate or biopsy from baseline but >5%. Morphologic Leukemia-Free State (MLFS) response included ≤5% in % blasts in the BM aspirate or biopsy. | 1 year |