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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)

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ClinicalTrials.gov Identifier: NCT00045942
Recruitment Status : Completed
First Posted : September 18, 2002
Results First Posted : July 17, 2017
Last Update Posted : August 11, 2017
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE September 16, 2002
First Posted Date  ICMJE September 18, 2002
Results First Submitted Date  ICMJE May 3, 2017
Results First Posted Date  ICMJE July 17, 2017
Last Update Posted Date August 11, 2017
Actual Study Start Date  ICMJE January 30, 2002
Actual Primary Completion Date March 27, 2008   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 15, 2017)
  • 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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 15, 2017)
  • 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)
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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)
Official Title  ICMJE 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)
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Myeloid Leukemia
  • Myelodysplastic Syndromes
Intervention  ICMJE
  • Drug: Itraconazole
    Itraconazole was commercially available.
  • Drug: PKC412
    PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.
    Other Name: Midostaurin
Study Arms  ICMJE
  • 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.
    Intervention: Drug: PKC412
  • 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.
    Intervention: Drug: PKC412
  • 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.
    Intervention: Drug: PKC412
  • 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.
    Intervention: Drug: PKC412
  • 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.
    Intervention: Drug: PKC412
  • 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.
    Intervention: Drug: PKC412
  • 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.
    Interventions:
    • Drug: Itraconazole
    • Drug: PKC412
  • 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.
    Intervention: Drug: PKC412
  • 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.
    Interventions:
    • Drug: Itraconazole
    • Drug: PKC412
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 15, 2017)
144
Original Enrollment  ICMJE
 (submitted: June 23, 2005)
24
Actual Study Completion Date  ICMJE March 27, 2008
Actual Primary Completion Date March 27, 2008   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00045942
Other Study ID Numbers  ICMJE CPKC412A2104
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP