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Report for Clinical Trial NCT00045942

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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.

NCT00045942 Acute Myeloid Leukemia Myelodysplastic Syndromes
MeSH: Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Preleukemia Myelodysplastic Syndromes Syndrome
HPO: Acute megakaryocytic leukemia Acute myeloid leukemia Leukemia Myelodysplasia Myeloid leukemia

2 Interventions

Name: Itraconazole

Description: Itraconazole was commercially available.

Type: Drug

FLT3 mutated PKC+Itraconazole (E2) FLT3 wild type PKC+Itraconazole (E2)

Name: PKC412

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

Type: 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 Outcomes

Description: 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.

Measure: Number of Participants With Best Clinical Response (Core)

Time: from date of first patient first visit (FPFV), 29-Jan-2002, to date of last participant last visit (LPLV), 04-Sep-2003

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

Time: days 1, 28

Description: 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.

Measure: Number of Participants With Overall Clinical Response (E1)

Time: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

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

Time: days 1, 28

Measure: Percent Decrease in Phospho-FLT3 Compared to Baseline (E2)

Time: Days 1, 28

Description: Blood samples were collected for pharmacokinetic (PK) analysis.

Measure: 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: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for pharmacokinetic (PK) analysis.

Measure: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for PKC412 in the PKC + Itraconazole Combination Arm (E2)

Time: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for PK analysis.

Measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax) for PKC412 in the PKC412 + Itraconazole Combination Arm (E2)

Time: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for PK analysis.

Measure: 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: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for PK analysis.

Measure: Terminal Elimination Half-life (T1/2) for PKC412 in the PKC + Itrconazole Combination Arm (E2)

Time: Cycle 1: days 21 and 22

Description: Blood samples were collected for pharmacokinetic (PK) analysis.

Measure: 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: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for pharmacokinetic (PK) analysis.

Measure: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP62221 in the PKC + Itraconazole Combination Arm (E2)

Time: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for PK analysis.

Measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP62221 in the PKC412 + Itraconazole Combination Arm (E2)

Time: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for PK analysis.

Measure: 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: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for PK analysis.

Measure: Terminal Elimination Half-life (T1/2) for CGP62221 in the PKC + Itrconazole Combination Arm (E2)

Time: Cycle 1: day 22,

Description: Blood samples were collected for pharmacokinetic (PK) analysis.

Measure: 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: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for pharmacokinetic (PK) analysis.

Measure: Observed Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax) for CGP52421 in the PKC + Itraconazole Combination Arm (E2)

Time: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for PK analysis.

Measure: Time to Reach the Maximum Concentration After Drug Administration (Tmax) for CGP52421 in the PKC412 + Itraconazole Combination Arm (E2)

Time: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for PK analysis.

Measure: 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: Cycle 1: days 21, 22, 28

Description: Blood samples were collected for analysis.

Measure: Summary of Midostaurin Concentration in the PKC412 Dose Escalation Arms(E2)

Time: 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

Description: Blood samples were collected for analysis.

Measure: Summary of CGP62221 Concentration (E2)

Time: 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

Description: Blood samples were collected for analysis.

Measure: Summary of CGP52421 Concentration (E2)

Time: 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

Description: 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.

Measure: Time to Disease Progression (TTP) (Core)

Time: from date of FPFV, 29-Jan-2002, to date of LPLV, 04-Sep-2003

Description: Blood samples were collected for analysis.

Measure: Summary of Midostaurin Plasma Concentration (Core)

Time: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,

Description: Blood samples were collected for analysis.

Measure: Summary of CGP62221 Plasma Concentration (Core)

Time: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,

Description: Blood samples were collected for analysis.

Measure: Summary of CGP52421 Plasma Concentration (Core)

Time: Cycle 1: days 1 (24 hour), 3, 8; Cycle 2: day 1,

Description: 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.

Measure: Time to Disease Progression (E1)

Time: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

Description: 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).

Measure: Overall Survival (OS) (E1)

Time: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

Description: 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.

Measure: Duration of Best Clinical Response (E1)

Time: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

Description: 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

Measure: Event-free Survival (E1)

Time: from date of FPFV, 27-Mar-2003, to date of LPLV, 06-Sep-2004

Description: Blood samples were collected for analysis.

Measure: Summary of PKC412 Plasma Concentration for 50 mg Twice Daily (Bid) Arm (E1)

Time: 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)

Description: Blood samples were collected for analysis.

Measure: Summary of CGP62221 Plasma Concentration for 50 mg Bid Arm (E1)

Time: 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)

Description: Blood samples were collected for analysis.

Measure: Summary of CGP52421 Plasma Concentration for 50 mg Bid Arm (E1)

Time: 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)

Description: Blood samples were collected for analysis.

Measure: Summary of PKC412 Plasma Concentration for 100 mg Bid Arm (E1)

Time: 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)

Description: Blood samples were collected for analysis.

Measure: Summary of CGP62221 Plasma Concentration for 100 mg Bid Arm (E1)

Time: 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)

Description: Blood samples were collected for analysis.

Measure: Summary of CGP52421 Plasma Concentration for 100 mg Bid Arm (E1)

Time: 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)

Description: 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.

Measure: Best Clinical Response (E2)

Time: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008

Description: 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

Measure: Time to Disease Progression (E2)

Time: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008

Description: 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)

Measure: Overall Survival (E2)

Time: date of FPFV, 21-Aug-2003, to date of LPLV, 27-Mar-2008

Purpose: Treatment

Allocation: Randomized

Single Group Assignment


There is one SNP

SNPs


1 D835Y

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. --- D835Y ---



HPO Nodes


HPO:
Acute megakaryocytic leukemia
Genes 1
GATA1
Acute myeloid leukemia
Genes 50
KIT DDX41 SBDS LPP ETV6 DNMT3A TERT JAK2 NUP214 CEBPA BRCA2 TCIRG1 DNAJC21 TET2 FLT3 TET2 JAK2 SRP54 SF3B1 SRP54 SH3GL1 KRAS EFL1 PIGA MLLT10 SRP54 DNAJC21 DKC1 RUNX1 RUNX1 MPL CBFB NSD1 THPO ELANE NPM1 ASXL1 CHIC2 MLF1 DNAJC21 ERBB3 GFI1 GFI1 SRSF2 KIT PICALM RPS14 GATA2 SBDS TET2
Leukemia
Genes 190
ATM KRAS KIT RPS15A NF1 MPL RPL35A RPL11 RPL18 DDX41 SBDS LPP ETV6 BUB1B F13A1 DNMT3A JAK2 NUP214 FANCD2 MSH6 FANCA PIGL NRAS TCIRG1 BUB1 TET2 FLT3 TAL1 ATRX TREX1 PDGFRA SRP54 RPS29 PTPN11 CALR FANCE WIPF1 SF3B1 GATA2 GLI1 STS SH3GL1 XRCC4 MPL SH2B3 EFL1 PIGA TREM2 CBL MPL RUNX1 MPL PIGL THPO FANCG NSD1 BRD4 NSUN2 SH2B3 RARA GATA2 NPM1 CBL CHIC2 ERBB3 GFI1 TERT KIT BCR ARHGAP26 DYNC2LI1 EVC SCN10A GATA1 ELANE RNASEH2B RPS14 SH2B3 JAK2 RPL15 SBDS NRAS RPL26 RPL27 ADA2 RPS7 TYROBP F13B MSH2 BCR WAS TERC TP53 TRIP13 MYD88 NUTM1 RPS24 GNB1 TP53 DNMT3A TERT NUMA1 NUP214 RPL5 SAMD9L TET2 CFTR POT1 FANCC RPS10 EP300 EVC2 BUB1B CEBPA BRCA2 DNAJC21 CALR SCN9A LIG4 ADAR BLM TET2 JAK2 SMPD1 RNASEH2C SCN11A GATA2 BUB3 PRSS1 KIF11 BCR RPL35 TAL2 SRP54 IFIH1 ABL1 PDGFRB KRAS RNASEH2A TET2 MLLT10 SRP54 DNAJC21 DKC1 RUNX1 APC LIG4 CBFB BLM THPO CALR NBN JAK2 MLH1 RPS19 ELANE SAMD9L RPL31 PMS2 ASXL1 TSR2 MLF1 PIK3CA DNAJC21 RUNX1 GFI1 SRSF2 SETBP1 HAX1 RPS26 RPS17 FLT3 RPS27 PIK3R1 KRAS CEP57 PICALM CREBBP GATA2 CTRC MYD88 TET2 RPS28 ABL1 RB1 SPINK1 GATA1 NBN JAK2 SAMHD1
Myelodysplasia
Genes 93
NAGS MPL SLX4 TET2 TERT TRIP13 DDX41 SBDS TP53 ATRX TET2 SF3B1 BUB1B TCIRG1 DNAJC21 RFWD3 BUB1 TET2 FANCL ATRX ASXL1 TET2 JAK2 SAMD9 SRP54 RPS14 PALB2 GINS1 SMARCD2 GATA2 SF3B1 BUB3 GATA2 SRP54 TET2 FANCB FANCE TET2 FANCM RFWD3 EFL1 RAD51 PIGA SRP54 DNAJC21 RAF1 DKC1 MPL RUNX1 MPL FANCD2 BRAF LIG4 FANCG RECQL4 THPO NBEAL2 CALR JAK2 TERC ERCC4 FANCI ELANE GATA2 SRP72 FANCG ASXL1 FANCC BRCA1 ERBB3 PTPN11 BRIP1 GFI1 SRSF2 HSPA9 KIT HAX1 GFI1B MAD2L2 CEP57 RPS14 FANCF SH2B3 XRCC2 RPS19 TINF2 SBDS TET2 BRCA2 RAD51C UBE2T JAK2 FANCA
Myeloid leukemia
Genes 20
KIT SETBP1 NF1 ARHGAP26 CBL TET2 KRAS PTPN11 F13A1 SAMD9L SAMD9L GATA2 CBL ASXL1 DNMT3A F13B NRAS SRSF2 TERC TERT