Phase 2
N=20
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)
Acute Myeloid Leukemia · Myelodysplastic Syndromes
Bottom Line
View on ClinicalTrials.gov: NCT00045942 ↗Enrolled (actual)
20
Serious AEs
72.2%
Results posted
Jul 2017
Primary outcome: Primary: Number of Participants With Best Clinical Response (Core) — 0 Participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Itraconazole (Drug); PKC412 (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Novartis Pharmaceuticals
- Primary completion
- Mar 2008
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Best Clinical Response (Core) |
— | — |
| PRIMARY Percent Decrease in Phospho-FLT3 Compared to Baseline (Core) |
— | — |
| PRIMARY Number of Participants With Overall Clinical Response (E1) |
0; 0; 0; 0; 0; 1 | — |
| PRIMARY Percent Decrease in Phospho-FLT3 Compared to Baseline (E1) |
— | — |
| PRIMARY Percent Decrease in Phospho-FLT3 Compared to Baseline (E2) |
— | — |
| PRIMARY 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) |
22261.53; 37578.85; 35630.45 | — |
| PRIMARY Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2) |
3945.00; 3968.70; 3931.25 | — |
| PRIMARY Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2) |
1.6; 1.9; 2.2 | — |
| PRIMARY 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) |
32120.58; 34684.6; 33020.17 | — |
| PRIMARY Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2) |
18.13; 13.23 | — |
| PRIMARY 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) |
30217.82; 23824.69; 31545.54 | — |
| PRIMARY Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2) |
3259.30; 3221.40; 3032.25 | — |
| PRIMARY Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2) |
3.7; 2.3; 3.3 | — |
| PRIMARY 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) |
31699.93; 31182.90; 26688.60 | — |
| PRIMARY Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2) |
14.37 | — |
| PRIMARY 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) |
40258.65; 42950.76; 49758.77 | — |
| PRIMARY Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2) |
4173.00; 4293.00; 4875.00 | — |
| PRIMARY Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2) |
3.5; 2.1; 2.2 | — |
| PRIMARY 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) |
38899.84; 41035.50; 44447.05 | — |
| PRIMARY Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2) |
0; 2565.0; 3100.0; 1640.0; 744.5; 836.0 | — |
| PRIMARY Summary of CGP62221 Concentration (E2) |
0; 1320.0; 2750.0; 2380.0; 1505.0; 1425.0 | — |
| PRIMARY Summary of CGP52421 Concentration (E2) |
0; 684.0; 1185.0; 2835.0; 3845.0; 3830.0 | — |
| SECONDARY Time to Disease Progression (TTP) (Core) |
63.0 | — |
| SECONDARY Summary of Midostaurin Plasma Concentration (Core) |
3801.0; 7152.86; 5154.44; 1873.17 | — |
| SECONDARY Summary of CGP62221 Plasma Concentration (Core) |
1636.00; 3143.71; 4873.33; 2816.67 | — |
| SECONDARY Summary of CGP52421 Plasma Concentration (Core) |
951.70; 1846.57; 6342.22; 12978.33 | — |
| SECONDARY Time to Disease Progression (E1) |
77.0; 50.0; 62.0; 54.0 | — |
| SECONDARY Overall Survival (OS) (E1) |
99.0; 93.0; 145.0; 159.0 | — |
| SECONDARY Duration of Best Clinical Response (E1) |
57.0; 29.0; 56.0; 58.0 | — |
| SECONDARY Event-free Survival (E1) |
60.0; 50.0; 58.0; 1.0 | — |
| SECONDARY Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1) |
0.000; 1198.000; 1735.974; 2585.471; 3576.467; 1756.500 | — |
| SECONDARY Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1) |
0.000; 367.079; 808.182; 1400.476; 2868.933; 1930.000 | — |
| SECONDARY Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1) |
0.000; 203.013; 436.282; 1188.359; 2840.833; 6467.591 | — |
| SECONDARY Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1) |
0.000; 2087.088; 2849.731; 3756.483; 4447.583; 1226.333 | — |
| SECONDARY Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1) |
0.000; 471.635; 1134.764; 1944.069; 2898.708; 1828.667 | — |
| SECONDARY Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1) |
0.000; 257.391; 666.194; 1394.062; 4447.500; 9196.667 | — |
| SECONDARY Best Clinical Response (E2) |
0; 0; 0; 1; 0; 0 | — |
| SECONDARY Time to Disease Progression (E2) |
49.0; 26.0; 169.0; 78.0 | — |
| SECONDARY Overall Survival (E2) |
116.0; 75.0; 372.0; 220.0 | — |
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.
Eligibility Criteria
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.
Data sourced from ClinicalTrials.gov (NCT00045942). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.