PKC412, Daunorubicin, and Cytarabine in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia

Study Overview
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Brief Summary
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RATIONALE: PKC412 may stop the growth of cancer cells by blocking the enzymes necessary for their growth. It may also increase the effectiveness of daunorubicin and cytarabine by making cancer cells more sensitive to the drugs. Drugs used in chemotherapy, such as daunorubicin and cytarabine, work in different ways to stop cancer cells from dividing so they stop growing or die. Combining PKC412 with chemotherapy may kill more cancer cells. PURPOSE: This phase I trial is studying the side effects and best way to give PKC412 when given either after or together with daunorubicin and cytarabine in treating patients with newly diagnosed acute myeloid leukemia.

Detailed Description
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OBJECTIVES: Primary Determine the safety and tolerability of PKC412 administered sequentially or concurrently with induction chemotherapy comprising daunorubicin and cytarabine followed by consolidation therapy comprising high-dose cytarabine in patients with newly diagnosed acute myeloid leukemia. Compare the pharmacokinetics of these regimens in these patients. Secondary Determine the efficacy of these regimens, in terms of response rate, disease-free survival, and overall survival, in these patients. Correlate genetic variation in drug metabolism genes, leukemia genes, and drug target genes with response in patients treated with these regimens. OUTLINE: This is an open-label, multicenter study. Patients are alternately assigned to 1 of 2 induction treatment groups. Induction therapy: Group I (sequential therapy): Patients receive daunorubicin IV over 30 minutes on days 1-3, cytarabine IV continuously on days 1-7, and oral PKC412 twice daily on days 8-21 in the absence of disease progression or unacceptable toxicity. Group II (concurrent therapy): Patients receive daunorubicin and cytarabine as in group I and oral PKC412 twice daily on days 1-7 and 15-21 in the absence of disease progression or unacceptable toxicity. In both groups, patients are evaluated on day 28. Patients with persistent disease receive a second induction course comprising daunorubicin IV over 30 minutes on days 1 and 2, cytarabine IV continuously on days 1-5, and oral PKC412 on the same schedule as their assigned treatment group. Patients with a complete response after course 1 or course 2 proceed to consolidation therapy. Consolidation therapy: Patients in both groups receive high-dose cytarabine IV over 3 hours twice daily on days 1, 3, and 5 and oral PKC412 on the same schedule as their assigned treatment group. Treatment repeats every 28-42 days for 3 courses in the absence of disease progression or unacceptable toxicity. After completion of consolidation therapy, patients in both groups continue to receive PKC412 alone, according to their assigned treatment group, every 28-42 days for up to 3 years in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months.

Official Title
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A Phase IB, Open-Label Study to Determine the Safety and Pharmacokinetics of Twice Daily Oral Dosing of PKC412 Administered in Combinations Sequentially and Concomitantly With Daunorubicin and Cytarabine for Standard Induction Therapy, and High Dose Cytarabine for Consolidation in Patients With Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: cytarabine
* Drug: daunorubicin hydrochloride
* Drug: midostaurin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed acute myeloid leukemia (AML) Newly diagnosed disease No history of or newly diagnosed myelodysplastic syndromes, history of myeloproliferative disease, or secondary AML No CNS malignancy PATIENT CHARACTERISTICS: Age 18 to 60 Performance status Karnofsky 70-100% Life expectancy Not specified Hematopoietic Not specified Hepatic AST and ALT ≤ 1.5 times upper limit of normal (ULN) Bilirubin ≤ 1.5 times ULN No active viral hepatitis Renal Creatinine ≤ 1.5 times ULN No chronic renal disease Cardiovascular Ejection fraction ≥ 50% by MUGA or echocardiogram No congestive heart failure No myocardial infarction within the past 6 months No poorly controlled hypertension No other cardiovascular disease Pulmonary No pulmonary infiltrate, including those suspected to be infectious Patients with pulmonary infection whose clinical symptoms have resolved are eligible provided there are no residual pulmonary infiltrates on chest x-ray Other No gastrointestinal impairment or disease that would preclude absorption of study drugs No uncontrolled diabetes No active uncontrolled infection No other disease, except carcinoma in situ, that would preclude study participation No other severe or uncontrolled medical condition that would preclude study participation HIV negative Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for 3 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy At least 5 days since prior growth factors No concurrent biological response modifiers Chemotherapy No prior chemotherapy No other concurrent chemotherapy Endocrine therapy Not specified Radiotherapy No prior radiotherapy except radiation castration No concurrent radiotherapy Surgery More than 14 days since prior surgical procedure except central venous catheter placement or other minor procedure (e.g., skin biopsy) Other More than 30 days since prior investigational agents No other concurrent anticancer agents No other concurrent investigational drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: PKC412 administered sequentially<br>twice daily oral dosing of PKC412 administered sequentially | Drug: midostaurin<br> <br> * Other names: PKC412;|
| Experimental: PKC412 administered concomitantly<br>PKC412 administered concomitantly with standard induction daunorubicin and cytarabine therapy followed by high-dose consolidation therapy with cytarabine | Drug: cytarabine<br> <br> Drug: daunorubicin hydrochloride<br> <br> 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 |
| --- | --- | --- |
| Complete Response (CR) rate | cycle = between 28 days and 42 days in duration | cycle 1, day 14, cycle day 21 - 28, end of each cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR rate by FLT3 mutation and treatment arm |  | CR:cycle 1, day 14, cycle day 21 - 28, end of each cycle, FLT3: monthly | 
| Overall survival by FLT3 mutation status |  | time of death of any cause(FLT# - minthly) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult acute myeloid leukemia with 11q23 (MLL) abnormalities, adult acute myeloid leukemia with inv(16)(p13;q22), adult acute myeloid leukemia with t(15;17)(q22;q12), adult acute myeloid leukemia with t(16;16)(p13;q22), adult acute myeloid leukemia with t(8;21)(q22;q22), untreated adult acute myeloid leukemia