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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT00093600
Collaborator
(none)
69
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Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
69 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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)
Study Start Date :
Feb 1, 2004
Actual Primary Completion Date :
Jun 1, 2011
Actual Study Completion Date :
Jun 1, 2011

Arms and Interventions

Arm Intervention/Treatment
Experimental: PKC412 administered sequentially

twice daily oral dosing of PKC412 administered sequentially

Drug: midostaurin
Other Names:
  • PKC412
  • Experimental: PKC412 administered concomitantly

    PKC412 administered concomitantly with standard induction daunorubicin and cytarabine therapy followed by high-dose consolidation therapy with cytarabine

    Drug: cytarabine

    Drug: daunorubicin hydrochloride

    Drug: midostaurin
    Other Names:
  • PKC412
  • Outcome Measures

    Primary Outcome Measures

    1. Complete Response (CR) rate [cycle 1, day 14, cycle day 21 - 28, end of each cycle]

      cycle = between 28 days and 42 days in duration

    Secondary Outcome Measures

    1. CR rate by FLT3 mutation and treatment arm [CR:cycle 1, day 14, cycle day 21 - 28, end of each cycle, FLT3: monthly]

    2. Overall survival by FLT3 mutation status [time of death of any cause(FLT# - minthly)]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Jonsson Comprehensive Cancer Center at UCLA Los Angeles California United States 90095-1781
    2 Dana Faber Cancer Institute Boston Massachusetts United States 02115
    3 Wayne State University/Karmanos Cancer Institute Detroit Michigan United States 48201-2014
    4 MD Anderson Cancer Center/University of Texas Houston Texas United States 77030
    5 Novartis Investigative Site Dresden Germany
    6 Novartis Investigative Site Mainz Germany

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Investigative Site, MD, Novartis Investigative Site

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT00093600
    Other Study ID Numbers:
    • NOVARTIS-CPKC412A2106
    • UCLA-0308139-01
    • CDR0000389242
    First Posted:
    Oct 8, 2004
    Last Update Posted:
    Dec 19, 2020
    Last Verified:
    Mar 1, 2015

    Study Results

    No Results Posted as of Dec 19, 2020