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PKC412 in Participants With Acute Myeloid Leukemia or With Myelodysplastic Syndrome (CPKC412A2104 Core); and PKC412 in Participants With Acute Myeloid Leukemia or With Myelodysplastic Syndrome With Either Wild Type or Mutated FMS-like Tyrosine Kinase 3 (FLT3) (CPKC412A2104E1 and CPKC412A2104E2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00045942
First received: September 16, 2002
Last updated: June 15, 2017
Last verified: June 2017
  Purpose
CPKC412A2104 core had a 2 stage design. In stage 1, eight participants were treated. If at least one participant showed a clinical response, four more participants were recruited to stage 2. The trial was to be stopped if no participants showed a response in stage 1. POC was achieved if at least 2 participants out of 12 responded. In PKC412A2104E1, participants with AML or high risk MDS with wild-type or mutant FTL3 who had not previously received a FLT3 inhibitor were randomized to receive continuous twice daily oral doses of either 50 or 100 mg midostaurin in 1 28-day cycle regimen. Participants were to be treated until disease progression or the occurrence of unacceptable treatment-related toxicity. PKC412A2104 E2 contained 2 dosing regimens: 1) intra-participant midostaurin dose escalation and 2) midostaurin with itraconazole in participants with AML and high risk MDS irrespective of FLT3 status. Eligible participants were alternately assigned to the regimens. At the Investigator's discretion, intra-participant dose escalation was allowed for any previously enrolled CPKC412A2104E1 participant receiving midostaurin at the time of the approval of amendment 4. Participants were treated until the time of disease progression.

Condition Intervention Phase
Acute Myeloid Leukemia Myelodysplastic Syndromes Drug: Itraconazole Drug: PKC412 Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: An Open-label Phase II (Proof of Concept (POC)) Trial of PKC412 Monotherapy in Participants With Acute Myeloid Leukemia (AML) and Participants With High Risk Myelodysplastic Syndrome (MDS) (CPKC412A2104 Core); An Open-label, Randomized Phase II POC Trial in PKC412 in Participants With AML and Participants With High Risk MDS With Either Wild Type or Mutated FLT3 (CPKC412A2104E1); and An Open-label, Randomized Phase 1/II POC Trial in PKC412 in Participants With AML and Participants With High Risk MDS With Either Wild Type or Mutated FLT3 (CPKC412A2104E2)

Resource links provided by NLM:


Further study details as provided by Novartis ( Novartis Pharmaceuticals ):

Primary Outcome Measures:
  • Number of Participants With Best Clinical Response (Core) [ Time Frame: from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003 ]
    Best clinical response was defined as complete response (CR) or partial response (PR), according to NCI definitions for AML and the guidelines for defining responses in MDS.

  • Percent Decrease in Phospho-FLT3 Compared to Baseline (Core) [ Time Frame: days 1, 28 ]
  • Number of Participants With Overall Clinical Response (E1) [ Time Frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 ]
    Overall clinical response was defined as CR, PR, minor response (MR) or blast response (BR). CR and PR was defined according to NCI definitions, and MR and BR was defined according to the guidelines for defining hematologic improvement in MDS.

  • Percent Decrease in Phospho-FLT3 Compared to Baseline (E1) [ Time Frame: days 1, 28 ]
  • Percent Decrease in Phospho-FLT3 Compared to Baseline (E2) [ Time Frame: Days 1, 28 ]
  • Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for PKC412 Plasma in the PKC + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for pharmacokinetic (PK) analysis.

  • Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for pharmacokinetic (PK) analysis.

  • Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for PK analysis.

  • Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for PK analysis.

  • Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21 and 22 ]
    Blood samples were collected for PK analysis.

  • Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for CGP62221 Plasma in the PKC + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for pharmacokinetic (PK) analysis.

  • Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for pharmacokinetic (PK) analysis.

  • Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for PK analysis.

  • Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for CGP622221 in the PKC412 + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for PK analysis.

  • Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2) [ Time Frame: Cycle 1: day 22, ]
    Blood samples were collected for PK analysis.

  • Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) for CGP52421 Plasma in the PKC + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for pharmacokinetic (PK) analysis.

  • Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for pharmacokinetic (PK) analysis.

  • Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for PK analysis.

  • Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) [ Time Frame: Cycle 1: days 21, 22, 28 ]
    Blood samples were collected for PK analysis.

  • Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) [ Time Frame: Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15 ]
    Blood samples were collected for analysis.

  • Summary of CGP62221 Concentration (E2) [ Time Frame: Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15 ]
    Blood samples were collected for analysis.

  • Summary of CGP52421 Concentration (E2) [ Time Frame: Cycle 1: days 1, 2 (24 hr post day 1), 3, 8, 15, 16 (24 hr post day 15), 17, 22; Cycle 2: days 1, 2 (24 hr post day 1), 3, 8, 15 ]
    Blood samples were collected for analysis.


Secondary Outcome Measures:
  • Time to Disease Progression (TTP) (Core) [ Time Frame: from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003 ]
    TTP was defined as the time from first dose date to date of disease progression which is identified as study completion date for unsatisfactory treatment effect or date of death from any cause within the 28 day cutoff post treatment.

  • Summary of Midostaurin Plasma Concentration (Core) [ Time Frame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1, ]
    Blood samples were collected for analysis.

  • Summary of CGP62221 Plasma Concentration (Core) [ Time Frame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1, ]
    Blood samples were collected for analysis.

  • Summary of CGP52421 Plasma Concentration (Core) [ Time Frame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1, ]
    Blood samples were collected for analysis.

  • Time to Disease Progression (E1) [ Time Frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 ]
    TTP was defined as the time from the first dose date to the date of disease progression (defined as the study completion date for unsatisfactory treatment effect, date of response assessment of progressive disease, or date of death from any cause). One participant from the wild type 200 mg group did not have any assessment on treatment and therefore was not taken into account for TTP.

  • Overall Survival (OS) (E1) [ Time Frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 ]
    OS was measured from the date of the first dose of treatment to the date of death from any cause or to the last date that the patient was known to be alive (a censored observation).

  • Duration of Best Clinical Response (E1) [ Time Frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 ]
    Duration of best clinical response was measured from the time that the measurement criteria were met for CR, PR, MR (with or without blast reduction) or BR until the first date that recurrent disease was documented (event) or until the date of last follow up.

  • Event-free Survival (E1) [ Time Frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004 ]
    Event-free survival was defined as the time from date of start of treatment to the date of death from any cause, treatment failure or relapse

  • Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) [ Time Frame: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h) ]
    Blood samples were collected for analysis.

  • Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) [ Time Frame: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h) ]
    Blood samples were collected for analysis.

  • Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) [ Time Frame: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h) ]
    Blood samples were collected for analysis.

  • Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) [ Time Frame: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h) ]
    Blood samples were collected for analysis.

  • Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) [ Time Frame: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h) ]
    Blood samples were collected for analysis.

  • Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) [ Time Frame: Cycle 1: days 1 (0h, 4h, 24 h), 3 (0h), 8 (0h); cycle 2: days 1 (0h); cycle 3: day 1 (0h); cycle 4: day 1 (0h); cycle 5: day 1 (0h) and cycle 6: day 1 (0h) ]
    Blood samples were collected for analysis.

  • Best Clinical Response (E2) [ Time Frame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008 ]
    Best clinical response was defined as CR, PR, MR, MR+BR, or BR . CR and PR was defined according to NCI definitions, and MR and BR was defined according to the guidelines for defining hematologic improvement in MDS.

  • Time to Disease Progression (E2) [ Time Frame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008 ]
    TTP was defined as the time from the first dose date to the date of disease progression, which was defined as the study completion date for unsatisfactory treatment effect, the date of response assessment of progressive disease, or the date of death from any cause

  • Overall Survival (E2) [ Time Frame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008 ]
    OS was measured from the date of the first dose of treatment to the date of death from any cause or the last date the patient was known to be alive (censored observation)


Enrollment: 144
Actual Study Start Date: January 30, 2002
Study Completion Date: March 27, 2008
Primary Completion Date: March 27, 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PKC412 (Core)
Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Drug: PKC412
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
Other Name: Midostaurin
Experimental: FLT3 mutated PKC412 100 mg/day (E1)
Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Drug: PKC412
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
Other Name: Midostaurin
Experimental: FLT3 mutated PKC412 200 mg/day (E1)
Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Drug: PKC412
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
Other Name: Midostaurin
Experimental: FLT3 wild type PKC412 100 mg/day (E1)
Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Drug: PKC412
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
Other Name: Midostaurin
Experimental: FLT3 wild type PKC412 200 mg/day (E1)
Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
Drug: PKC412
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
Other Name: Midostaurin
Experimental: FLT3 mutated PKC412 dose escalation
Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.
Drug: PKC412
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
Other Name: Midostaurin
Experimental: FLT3 mutated PKC+Itraconazole (E2)
Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Drug: Itraconazole
Itraconazole was commercially available.
Drug: PKC412
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
Other Name: Midostaurin
Experimental: FLT3 wild type PKC412 dose escalation (E2)
Participants were treated with PKC412 orally starting at a dose of 100 mg bid. A dose increase up to 300 mg bid was allowed. Participants were treated until time of disease progression, doubling of the bone marrow blast percentage from baseline, or the occurrence of unacceptable toxicity.
Drug: PKC412
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
Other Name: Midostaurin
Experimental: FLT3 wild type PKC+Itraconazole (E2)
Within a cycle of 28 days, participants received a loading dose of PKC412 100 mg bid on days 1-2, followed by PKC412 50 mg bid for 3 weeks from days 3-21. On day 22, itraconazole 100 mg bid was added to the treatment regimen. The combinations of PKC412 and Itraconazole continued until disease progression, unacceptable toxicity, or withdrawal of consent.
Drug: Itraconazole
Itraconazole was commercially available.
Drug: PKC412
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
Other Name: Midostaurin

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  1. Patients:

    with AML who are not candidates for myelosuppressive chemotherapy or with AML who have relapsed disease or are refractory to standard therapy and not likely to require cytoreductive therapy within one month or with MDS subtypes refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T) or chronic myelomonocytic leukemia (CMML).

  2. Patients with a relevant FLT3-ITD mutation or D835Y point mutation
  3. Patients at least 18 years or older
  4. Patients with WHO performance status of 0 to 2 with a life expectancy of at least 3 months
  5. Patients must not be treated within 4 weeks after any prior therapy
  6. Written informed consent obtained according to local guidelines

Exclusion criteria:

Patients meeting any of the following criteria during screening will be excluded from entry into the study:

  1. Patients who had prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell transplant less than 2 months previously.
  2. Female patients who are pregnant or breast feeding, or adults of childbearing age not employing an effective method of birth control.
  3. Concurrent severe and/or uncontrolled medical or psychiatric condition which may interfere with the completion of the study.
  4. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PKC412.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00045942

Locations
United States, California
UCLA Medical Center
Los Angeles, California, United States, 90095
United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New York
New York Weill Cornell Medical Center
New York, New York, United States, 10021
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT00045942     History of Changes
Obsolete Identifiers: NCT00045578, NCT00977782
Other Study ID Numbers: CPKC412A2104
Study First Received: September 16, 2002
Results First Received: May 3, 2017
Last Updated: June 15, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
AML
MDS
high risk myelodysplastic syndrome

Additional relevant MeSH terms:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Itraconazole
Hydroxyitraconazole
4'-N-benzoylstaurosporine
Staurosporine
Antifungal Agents
Anti-Infective Agents
14-alpha Demethylase Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Steroid Synthesis Inhibitors
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 CYP3A Inhibitors
Antineoplastic Agents
Protein Kinase Inhibitors

ClinicalTrials.gov processed this record on July 26, 2017