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Completed

NCT Number: NCT00045942

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)

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.

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Key information

Conditions

Acute Myeloid Leukemia Bone Marrow Diseases Hematologic Diseases Hemic and Lymphatic Diseases Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Myelodysplastic Syndromes Neoplasms Neoplasms by Histologic Type

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

UCLA Medical Center, Los Angeles, California, United States

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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).

  • Patients with a relevant FLT3-ITD mutation or D835Y point mutation
  • Patients at least 18 years or older
  • Patients with WHO performance status of 0 to 2 with a life expectancy of at least 3 months
  • Patients must not be treated within 4 weeks after any prior therapy
  • 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:

  • Patients who had prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell transplant less than 2 months previously.
  • Female patients who are pregnant or breast feeding, or adults of childbearing age not employing an effective method of birth control.
  • Concurrent severe and/or uncontrolled medical or psychiatric condition which may interfere with the completion of the study.
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PKC412.

Treatment and study plan

Itraconazole

Drug

Itraconazole was commercially available.

PKC412

Drug

PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.

Other names: Midostaurin

Primary outcomes

  1. 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.

  2. Percent Decrease in Phospho-FLT3 Compared to Baseline (Core)

    Time frame: days 1, 28

  3. 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.

  4. Percent Decrease in Phospho-FLT3 Compared to Baseline (E1)

    Time frame: days 1, 28

  5. Percent Decrease in Phospho-FLT3 Compared to Baseline (E2)

    Time frame: Days 1, 28

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

  22. 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 outcomes

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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).

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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)

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study 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)

Important dates

Study start
2002
Primary completion
2008
Study completion
2008
First posted
Sep 18, 2002
Registry last updated
Aug 11, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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