Acute Myeloid LeukemiaPhase 1/2NCT00045942

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)

A Phase 1/2 study testing Itraconazole and PKC412 in people with Acute Myeloid Leukemia and Myelodysplastic Syndromes, run by Novartis Pharmaceuticals at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 years and older
Conditions the study is for: Acute Myeloid Leukemia, Myelodysplastic Syndromes
What is being tested?: Itraconazole and PKC412
Type of treatment: Pill or oral medicine
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 144 participants
Where: 4 sitesUnited States
Study dates: 30 Jan 2002to 27 Mar 2008
Phase: Phase 1/2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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.

Trial locations and contacts

4 sites in 1 country.

United States4 sites

Dana-Farber Cancer Institute
Boston, Massachusetts, 02115
UCLA Medical Center
Los Angeles, California, 90095
New York Weill Cornell Medical Center
New York, New York, 10021
Memorial Sloan Kettering Cancer Center
New York, New York, 10065

Other trials in United States

About this study

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)

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.

Conditions: Acute Myeloid Leukemia, Myelodysplastic Syndromes
Being tested: Itraconazole, PKC412
Keywords: AML, MDS, high risk myelodysplastic syndrome
Medical subject headings: Leukemia, Myeloid, Acute, Myelodysplastic Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

ItraconazoleDrug
Itraconazole was commercially available.
PKC412Drug
Also called Midostaurin
PKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.

Study groups in NCT00045942
Study group	Role	What they receive
PKC412 (Core)	Experimental	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. Receives: Drug: PKC412
FLT3 mutated PKC412 100 mg/day (E1)	Experimental	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. Receives: Drug: PKC412
FLT3 mutated PKC412 200 mg/day (E1)	Experimental	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. Receives: Drug: PKC412
FLT3 wild type PKC412 100 mg/day (E1)	Experimental	Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. Receives: Drug: PKC412
FLT3 wild type PKC412 200 mg/day (E1)	Experimental	Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity. Receives: Drug: PKC412
FLT3 mutated PKC412 dose escalation	Experimental	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. Receives: Drug: PKC412
FLT3 mutated PKC+Itraconazole (E2)	Experimental	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. Receives: Drug: Itraconazole; Drug: PKC412
FLT3 wild type PKC412 dose escalation (E2)	Experimental	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. Receives: Drug: PKC412
FLT3 wild type PKC+Itraconazole (E2)	Experimental	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. Receives: Drug: Itraconazole; Drug: PKC412

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of Participants With Best Clinical Response (Core)
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.
Measured: from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003
Percent Decrease in Phospho-FLT3 Compared to Baseline (Core)
Measured: days 1, 28
Number of Participants With Overall Clinical Response (E1)
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.
Measured: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Percent Decrease in Phospho-FLT3 Compared to Baseline (E1)
Measured: days 1, 28
Percent Decrease in Phospho-FLT3 Compared to Baseline (E2)
Measured: 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)
Blood samples were collected for pharmacokinetic (PK) analysis.
Measured: Cycle 1: days 21, 22, 28
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2)
Blood samples were collected for pharmacokinetic (PK) analysis.
Measured: Cycle 1: days 21, 22, 28
Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2)
Blood samples were collected for PK analysis.
Measured: Cycle 1: days 21, 22, 28
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)
Blood samples were collected for PK analysis.
Measured: Cycle 1: days 21, 22, 28
Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2)
Blood samples were collected for PK analysis.
Measured: Cycle 1: days 21 and 22
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)
Blood samples were collected for pharmacokinetic (PK) analysis.
Measured: Cycle 1: days 21, 22, 28
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2)
Blood samples were collected for pharmacokinetic (PK) analysis.
Measured: Cycle 1: days 21, 22, 28
Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2)
Blood samples were collected for PK analysis.
Measured: Cycle 1: days 21, 22, 28
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)
Blood samples were collected for PK analysis.
Measured: Cycle 1: days 21, 22, 28
Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2)
Blood samples were collected for PK analysis.
Measured: Cycle 1: day 22,
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)
Blood samples were collected for pharmacokinetic (PK) analysis.
Measured: Cycle 1: days 21, 22, 28
Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2)
Blood samples were collected for pharmacokinetic (PK) analysis.
Measured: Cycle 1: days 21, 22, 28
Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2)
Blood samples were collected for PK analysis.
Measured: Cycle 1: days 21, 22, 28
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)
Blood samples were collected for PK analysis.
Measured: Cycle 1: days 21, 22, 28
Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2)
Blood samples were collected for analysis.
Measured: 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
Summary of CGP62221 Concentration (E2)
Blood samples were collected for analysis.
Measured: 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
Summary of CGP52421 Concentration (E2)
Blood samples were collected for analysis.
Measured: 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

Secondary outcomes (17)

Time to Disease Progression (TTP) (Core)
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.
Measured: from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003
Summary of Midostaurin Plasma Concentration (Core)
Blood samples were collected for analysis.
Measured: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
Summary of CGP62221 Plasma Concentration (Core)
Blood samples were collected for analysis.
Measured: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
Summary of CGP52421 Plasma Concentration (Core)
Blood samples were collected for analysis.
Measured: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
Time to Disease Progression (E1)
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.
Measured: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Overall Survival (OS) (E1)
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).
Measured: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Duration of Best Clinical Response (E1)
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.
Measured: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Event-free Survival (E1)
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
Measured: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1)
Blood samples were collected for analysis.
Measured: 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)
Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1)
Blood samples were collected for analysis.
Measured: 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)
Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1)
Blood samples were collected for analysis.
Measured: 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)
Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1)
Blood samples were collected for analysis.
Measured: 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)
Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1)
Blood samples were collected for analysis.
Measured: 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)
Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1)
Blood samples were collected for analysis.
Measured: 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)
Best Clinical Response (E2)
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.
Measured: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008
Time to Disease Progression (E2)
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
Measured: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008
Overall Survival (E2)
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)
Measured: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

30 Jan 200227 Mar 2008

First posted18 Sep 2002 (estimated)
Study start30 Jan 2002
Primary completion27 Mar 2008
Study completion27 Mar 2008

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Acute Myeloid LeukemiaStudies of the same condition, open and under way.
More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Single group
Masking: None (open label)
Enrolment: 144 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00045942
Sponsor's protocol ID: CPKC412A2104
Status last verified: Aug 2017
First submitted: 16 Sep 2002
Last updated: 11 Aug 2017
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Undecided

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Acute Myeloid Leukemia trials

Study at a glance

From the registry record, last updated by the sponsor on 11 Aug 2017. Recruitment status is as the sponsor reported it: confirm with the study team.

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)
ClinicalTrials.gov ID: NCT00045942
Acronym / sponsor ID: CPKC412A2104
Conditions: Acute Myeloid Leukemia, Myelodysplastic Syndromes
Keywords: AML, MDS, high risk myelodysplastic syndrome
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 144 participants (actual)
Lead sponsor: Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
Study start: 30 Jan 2002 (actual)
Primary completion: 27 Mar 2008 (actual)
Study completion: 27 Mar 2008 (actual)
First posted: 18 Sep 2002 (estimated)
Results: Posted 17 Jul 2017

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Single group
Masking: None (open label)
Number of arms: 9

Arm	Type	Receives
PKC412 (Core)	Experimental	Drug: PKC412Participants received 75 mg PKC412 three time daily (tid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
FLT3 mutated PKC412 100 mg/day (E1)	Experimental	Drug: PKC412Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
FLT3 mutated PKC412 200 mg/day (E1)	Experimental	Drug: PKC412Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
FLT3 wild type PKC412 100 mg/day (E1)	Experimental	Drug: PKC412Participants received 50 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
FLT3 wild type PKC412 200 mg/day (E1)	Experimental	Drug: PKC412Participants received 100 mg PKC412 twice daily (bid) orally on a continuous basis until disease progression or the occurrence of unacceptable treatment related toxicity.
FLT3 mutated PKC412 dose escalation	Experimental	Drug: PKC412Participants 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.
FLT3 mutated PKC+Itraconazole (E2)	Experimental	Drug: Itraconazole, Drug: PKC412Within 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.
FLT3 wild type PKC412 dose escalation (E2)	Experimental	Drug: PKC412Participants 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.
FLT3 wild type PKC+Itraconazole (E2)	Experimental	Drug: Itraconazole, Drug: PKC412Within 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.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (7 listed)

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

Key exclusion criteria (5 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
ItraconazoleItraconazole was commercially available.	Drug	FLT3 mutated PKC+Itraconazole (E2), FLT3 wild type PKC+Itraconazole (E2)
PKC412Also: MidostaurinPKC412 was supplied as soft gelatin capsules containing 25 mg PKC412.	Drug	FLT3 mutated PKC+Itraconazole (E2), FLT3 mutated PKC412 100 mg/day (E1), FLT3 mutated PKC412 200 mg/day (E1), FLT3 mutated PKC412 dose escalation, FLT3 wild type PKC+Itraconazole (E2), FLT3 wild type PKC412 100 mg/day (E1), FLT3 wild type PKC412 200 mg/day (E1), FLT3 wild type PKC412 dose escalation (E2), PKC412 (Core)

Primary outcome

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.

17 secondary outcomes

Time to Disease Progression (TTP) (Core)
Time frame: from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003
Summary of Midostaurin Plasma Concentration (Core)
Time frame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
Summary of CGP62221 Plasma Concentration (Core)
Time frame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
Summary of CGP52421 Plasma Concentration (Core)
Time frame: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,
Time to Disease Progression (E1)
Time frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Overall Survival (OS) (E1)
Time frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Duration of Best Clinical Response (E1)
Time frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
Event-free Survival (E1)
Time frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004
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)
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)
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)
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)
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)
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)
Best Clinical Response (E2)
Time frame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008
Time to Disease Progression (E2)
Time frame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008
Overall Survival (E2)
Time frame: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008

Results and safety

Results posted to the registry on 17 Jul 2017, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
PKC412 in FLT3 Mutated Participants (Core)	20	0
FLT3 Mutated PKC412 100 mg/Day (E1)	0	0
FLT3 Mutated PKC412 200 mg/Day (E1)	0	0
FLT3 Wild Type PKC412 100 mg/Day (E1)	0	0
FLT3 Wild Type PKC412 200 mg/Day (E1)	0	0
FLT3 Mutated PKC412 Dose Escalation (E2)	0	0
FLT3 Mutated PKC+Itraconazole (E2)	0	0
FLT3 Wild Type PKC412 Dose Escalation (E2)	0	0
FLT3 Wild Type PKC+Itraconazole (E2)	0	0

Primary outcome: 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. Number. Unit: Participants

Measure	PKC412 in FLT3 Mutated Participants (Core) n = 20
Value	0

Population analysed: Core primary efficacy population: The core primary efficacy population included all participants who were randomized.

Primary outcome: Percent Decrease in Phospho-FLT3 Compared to Baseline (Core)

Time frame: days 1, 28

Population analysed: This outcome measure was not analyzed. Assessment of FLT3 autophosphorylation in leukemic blasts was not possible at the planned time points because the blast reduction was rapid and occurred during the first week in some participants. Thus, by Day 28, the blast count in some participants were too low for autophosphorylation to be measured.

Primary outcome: Number of Participants With Overall Clinical Response (E1)

Time frame: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004. Number. Unit: Participants

Measure	FLT3 Mutated PKC412 100 mg/Day (E1) n = 18	FLT3 Mutated PKC412 200 mg/Day (E1) n = 17	FLT3 Wild Type PKC412 100 mg/Day (E1) n = 32	FLT3 Wild Type PKC412 200 mg/Day (E1) n = 25
Complete response	0	0	0	0
Partial response	0	1	0	0
Minor response	1	0	6	3
Blast response	11	12	15	8
Overall response	12	13	21	11

Population analysed: E1 primary efficacy population: all participants who received at least one dose of study medication, completed at least 8 days of therapy within Cycle 1 unless discontinued due to progressive disease and/or death due to any cause, and who were not considered to be associated with a protocol violation that was exclusionary from the population.

Primary outcome: Percent Decrease in Phospho-FLT3 Compared to Baseline (E1)

Time frame: days 1, 28

Population analysed: The analyses for this outcome measure were not performed due to technical challenges in measuring phosphorylated FLT3 in patient blast samples in an ex vivo setting.

17 secondary outcomes are reported in the full results.

Adverse events

Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
PKC412 Core	12 of 20 (60%)	20 of 20 (100%)	Not reported
FLT3 Mutated PKC412 100 mg/Day (E1)	16 of 18 (88.9%)	17 of 18 (94.4%)	Not reported
FLT3 Mutated PKC412 200 mg/Day (E1)	14 of 17 (82.4%)	16 of 17 (94.1%)	Not reported
FLT3 Wild Type PKC412 100 mg/Day (E1)	22 of 33 (66.7%)	32 of 33 (97%)	Not reported
FLT3 Wild Type PKC412 200 mg/Day (E1)	19 of 27 (70.4%)	27 of 27 (100%)	Not reported
FLT3 Mutated PKC412 Dose Escalation (E2)	7 of 9 (77.8%)	9 of 9 (100%)	Not reported
FLT3 Mutated PKC+Itraconazole (E2)	6 of 7 (85.7%)	6 of 7 (85.7%)	Not reported
FLT3 Wild Type PKC412 Dose Escalation (E2)	5 of 7 (71.4%)	7 of 7 (100%)	Not reported
FLT3 Wild Type PKC+Itraconazole (E2)	3 of 6 (50%)	6 of 6 (100%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 11 Aug 2017.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Individual participant dataSharing planned: Undecided

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Novartis Pharmaceuticals study director

Novartis Pharmaceuticals

4 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Itraconazole and PKC412 in people with Acute Myeloid Leukemia and Myelodysplastic Syndromes, run by Novartis Pharmaceuticals at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 11 Aug 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 17 Jul 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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). The study lists 22 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00045942.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Aug 2017.