Cladribine Based Induction Therapy With All-Trans Retinoic Acid and Midostaurin in Relapsed/Refractory AML

Study Overview
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Brief Summary
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This study will evaluate the investigational drug Midostaurin in various doses given with ATRA and CLAG chemotherapy. Midostaurin is a FLT3 inhibitor that is activated or overexpressed in a significant proportion of AML patients. Research has shown that midostaurin and drugs like midostaurin may work better in combination with chemotherapy, like CLAG. CLAG is a combination of cladribine, cytarabine, and G-CSF which is approved by the FDA and used to treat AML.

Detailed Description
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The main purpose of this study is to gather information about the use of a drug called midostaurin when given with ATRA and CLAG chemotherapy. Midostaurin is an investigational drug. It is a drug that inhibits FLT3 that is mutated or overexpressed in a significant proportion of AML patients. Research has shown that midostaurin and drugs like midostaurin may work better in combination with chemotherapy, like CLAG. ATRA is known to promote myeloid differentiation and has also been shown to augment cancer cell death in combination with chemotherapy. CLAG is a combination of cladribine, cytarabine, and G-CSF which is approved by the FDA and used to treat AML. This study will look at how safe this combination is, how you tolerate the treatment, and to see what dose of midostaurin is appropriate.

Official Title
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Phase 1 Study of Cladribine Based Induction Therapy (CLAG) With ATRA (All-Trans Retinoic Acid) and Midostaurin in Relapsed/Refractory AML

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: Granulocyte colony-stimulating factor (G-CSF)
* Drug: Cladribine
* Drug: Cytarabine
* Drug: All-Trans Retinoic Acid (ATRA)
* Drug: Midostaurin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be ≥18 of age. Because no dosing or adverse event data are currently available on the use of midostaurin in combination with ATRA and CLAG in patients <18 years of age, children are excluded from this study but will be eligible for future pediatric phase 2 combination trials. Patient must be diagnosed with refractory or relapsed AML. For the purpose of the study, refractory AML is defined as failure to achieve CR after 2 cycles of induction chemotherapy or persistent > 40% bone marrow blasts after one cycle of chemotherapy induction. Relapsed AML is defined as any evidence of disease recurrence after achieving CR. Early relapse is defined as relapse occurring earlier than 12 months and late relapse is defined as relapse occurring later than 12 months. Patient must have a Karnofsky Performance Status of ≥ 70% (unless poor performance status is related to the disease). Patient must have the following laboratory values: AST and ALT ≤ 1.5 x Upper Limit of Normal (ULN), Serum Bilirubin ≤ 1.5 x ULN, Serum Creatinine ≤ 1.5 x ULN. Laboratory values can be outside this range if secondary to AML disease. Patient must able to understand and willing to sign a written informed consent document prior to registration on study. Exclusion Criteria: Patient must not have newly diagnosed AML. Patient must not have acute promyelocytic leukemia Patient must not have known CNS leukemia Patient must not have a history of allergic reactions to compounds of similar chemical or biologic composition to midostaurin or other agents used in the study. Patient must not have any uncontrolled or intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction within 6 months, poorly controlled hypertension, uncontrolled diabetes, chronic renal disease, or psychiatric illness/social situation that would limit compliance with study requirements. Patient must not have any condition, including the presence of laboratory abnormalities, which places him/her at unacceptable risk if s/he were to participate in the study or confounds the ability to interpret data from the study. Patient may not concurrently use other anti-cancer agents or treatments (with the exceptions of hydroxyurea, steroids, and leukopheresis). Female patients must not be pregnant or breastfeeding. Adults of reproductive potential must employ an effective method of birth control. Barrier contraceptives must be used throughout the study in both sexes. Women of childbearing potential must have a negative serum pregnancy test 48 hours prior to administration of midostaurin. Women considered not of childbearing potential include any of the following: no menses for at least 5 years; menses within 5 years but amenorrheic for at least 2 months and luteinizing hormone (LH) and follicular stimulating hormone (FSH) values within normal range (according to definition of postmenopausal for laboratory used); bilateral oophorectomy amenorrheic for at least 3 months. Patient must not have impaired cardiac function including any of the following: Screening ECG with a QTc > 450 msec Patients with congenital long QT syndrome History or presence of sustained ventricular tachycardia Any history of ventricular fibrillation or torsades de pointes Bradycardia defined as HR < 50 bpm Right bundle branch block + left anterior hemiblock (bifascicular block) Patients with myocardial infarction or unstable angina < 6 months prior to starting study drug CHF NY Heart Association class III or IV Patients with an ejection fraction < 50% assessed by MUGA or ECHO scan within 14 days of Day 1. Patients must not have a known confirmed diagnosis of HIV infection or active viral hepatitis. Patient may not have received any investigational agent within 30 days prior to Day 1. Patient may not be receiving any other investigational agents while on this trial. Patients must not have had any surgical procedure, excluding central venous catheter placement or other minor procedures (e.g. skin biopsy) within 14 days of Day 1. Patients must not have any pulmonary infiltrate, including those suspected to be of infectious origin. In particular, patients with resolution of clinical symptoms of pulmonary infection but with residual pulmonary infiltrates on chest x-ray are not eligible until pulmonary infiltrates have completely resolved.

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 1<br>GCSF 300 mcg SC Days 1-6 Cladribine 5 mg/m2 IV Days 2-6 Cytarabine 2 mg/m2 IV Days 2-6 ATRA 15 mg/m2 PO QD Days 7-20 Midostaurin 25 mg PO BID Days 7-20 | Drug: Granulocyte colony-stimulating factor (G-CSF)<br> <br> * Other names: Filgrastim;Drug: Cladribine<br> <br> * Other names: Movectro;Drug: Cytarabine<br> <br> * Other names: Depocyt;Drug: All-Trans Retinoic Acid (ATRA)<br> <br> * Other names: Tretinoin;Drug: Midostaurin<br> <br> * Other names: PKC412;|
| Experimental: Arm 2<br>GCSF 300 mcg SC Days 1-6 Cladribine 5 mg/m2 IV Days 2-6 Cytarabine 2 mg/m2 IV Days 2-6 ATRA 15 mg/m2 PO QD Days 7-20 Midostaurin 50 mg PO BID Days 7-20 | Drug: Granulocyte colony-stimulating factor (G-CSF)<br> <br> * Other names: Filgrastim;Drug: Cladribine<br> <br> * Other names: Movectro;Drug: Cytarabine<br> <br> * Other names: Depocyt;Drug: All-Trans Retinoic Acid (ATRA)<br> <br> * Other names: Tretinoin;Drug: Midostaurin<br> <br> * Other names: PKC412;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability of midostaurin + ATRA given with CLAG chemotherapy |  | 28 days following completion of therapy | 
| Dose limiting toxicity (DLT) of midostaurin + ATRA with CLAG chemotherapy |  | 28 days following completion of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response | To determine the response rate 3, morphologic leukemia-free state, morphologic complete remission rate (CRm), cytogenetic CR (CRc) rate, CR with incomplete blood counts 1 rate, and partial remission 48 rate (PR) of patients treated with midostaurin + ATRA given with CLAG chemotherapy | 1 year | 
| Survival | To determine the duration of response and survival including disease-free survival (DFS), event-free survival (EFS), and overall survival (OS) in these patients | 1 year | 
| Toxicity profile of midostaurin + ATRA |  | 28 days following completion of treatment | 
| Pharmacokinetics of midostaurin |  | Cycle 1 Day 7, Cycle 1 Day 14, and Cycle 1 Day 20 |