Phase 2
Completed N=255
A Study To Evaluate PF-04449913 With Chemotherapy In Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome
Source: ClinicalTrials.gov NCT01546038 ↗Enrolled (actual)
255
Serious AEs
69.9%
Results posted
May 2018
Primary outcomePrimary: Number of Participants With Dose-limiting Toxicities (DLTs) at Phase 1B — 0; 0; 0; 0 Participants
Summary
This is a study to evaluate PF-04449913 (an inhibitor of the Hedgehog pathway) in Acute Myeloid Leukemia and high-risk Myelodysplastic Syndrome in combination with standard agents used to treat these diseases.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Dose-limiting Toxicities (DLTs) at Phase 1B |
0; 0; 0; 0; 1; 0 | — |
| PRIMARY Percentage of Participants With Complete Response (CR) at Phase 2 Fit |
42.0; 36.7; 77.8 | — |
| PRIMARY Overall Survival (OS) at Phase 2 Unfit |
8.8; 4.9 | 0.0020 sig |
| SECONDARY Overall Survival (OS) at Phase 1B |
4.4; 11.5; 37.8 | — |
| SECONDARY Overall Survival (OS) at Phase 2 Fit |
14.9; 14.7; NA | — |
| SECONDARY Percentage of Participants With CR / Complete Response With Incomplete Blood Count Recovery (CRi) at Phase 1B |
8.7; 28.6; 54.5 | — |
| SECONDARY Percentage of Participants With Complete Response (CR) at Phase 2 Unfit |
18.2; 2.3 | 0.0112 sig |
| SECONDARY Percentage of Participants With Disease-specific Efficacy for Acute Myeloid Leukemia (AML) at Phase 2 Fit and Unfit |
10.9; 5.1; 2.6; 7.8; 2.6; 0.0 | — |
| SECONDARY Percentage of Participants With Disease-specific Efficacy for Myelodysplastic Syndrome (MDS) at Phase 2 Fit and Unfit |
0.0; 10.0; 0.0; 0.0; 0.0; 0.0 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) of Glasdegib in Participants Receiving Glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21 |
1074; 1942; 1242; 2577 | — |
| SECONDARY Time to Cmax (Tmax) of Glasdegib in Participants Receiving Glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21 |
1.75; 4.00; 1.34; 4.00 | — |
| SECONDARY Area Under the Plasma Concentration-time Profile From Time 0 to Dosing Interval (AUCtau) of Glasdegib in Participants Receiving Glasdegib and LDAC at Phase 1B on Cycle 1/Day 10 and Cycle 1/Day 21 |
15020; 28600; 16660; 31400 | — |
| SECONDARY Cmax of Glasdegib in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1 |
1718; 2381; 1826; NA | — |
| SECONDARY Tmax of Glasdegib in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1 |
2.00; 2.05; 1.03; NA | — |
| SECONDARY AUCtau of Glasdegib in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1 |
NA; 28380; 17060; NA | — |
| SECONDARY Cmax of Glasdegib in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10 |
674.2; 1622; 1135; 2371 | — |
| SECONDARY Tmax of Glasdegib in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10 |
5.99; 6.00; 4.08; 1.04 | — |
| SECONDARY AUCtau of Glasdegib in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10 |
9332; 22840; 16300; 26370 | — |
| SECONDARY Cmax of LDAC and Ara-U in Participants Receiving Glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10 |
58.50; 100.1; 63.01; 132.5; 379.5; 569.7 | — |
| SECONDARY Tmax of LDAC and Ara-U in Participants Receiving Glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10 |
0.250; 0.250; 0.325; 0.250; 3.97; 4.00 | — |
| SECONDARY Area Under the Plasma Concentration-time Profile From Time 0 to Infinity (AUCinf) of LDAC in Participants Receiving Glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10 |
71.10; 89.35; 92.28; 143.9 | — |
| SECONDARY Area Under the Plasma Concentration-time Profile From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of LDAC and Ara-U in Participants Receiving Glasdegib and LDAC at Phase 1B on Cycle 1/Day 2 and Cycle 1/Day 10 |
62.55; 87.49; 65.56; 134.8; 2036; 3050 | — |
| SECONDARY Cmax of Decitabine in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2 |
113.4; 174.2; 127.9; 121.7 | — |
| SECONDARY Tmax of Decitabine in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2 |
0.75; 0.53; 0.58; 0.53 | — |
| SECONDARY AUCinf of Decitabine in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2 |
133.4; 251.5; NA; NA | — |
| SECONDARY AUCtau of Cytarabine and Ara-U in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 |
1070; NA; 28420; NA | — |
| SECONDARY Cmax of Daunorubicin and Daunorubicinol in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 |
275.3; 341.0; 195.4; 233.4 | — |
| SECONDARY Tmax of Daunorubicin and Daunorubicinol in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 |
0.500; 0.492; 1.00; 0.642 | — |
| SECONDARY AUCtau of Daunorubicin and Daunorubicinol in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 |
499.3; 424.9; 2152; 2712 | — |
| SECONDARY Pre-dose Plasma Concentration (Ctrough) of Glasdegib in Phase 2 Fit on Induction Cycle 1/Day 10 |
308.7 | — |
| SECONDARY Cmax of Glasdegib in Participants Receiving Glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10 |
1252 | — |
| SECONDARY Tmax of Glasdegib in Participants Receiving Glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10 |
1.67 | — |
| SECONDARY AUCtau of Glasdegib in Participants Receiving Glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10 |
17210 | — |
| SECONDARY Number of Participants With Disease-related Gene Mutations at Phase 1B |
3; 0; 2; 0; 2; 0 | — |
| SECONDARY Serum Levels of Circulating Protein Analytes at Phase 1B - Baseline |
10200; 10.7; 1200; 0.00; 88.00; 180.5 | — |
| SECONDARY Serum Levels of Circulating Protein Analytes at Phase 1B - Induction Cycle 1/Day 3 |
20000 | — |
| SECONDARY Serum Levels of Circulating Protein Analytes at Phase 1B - Induction Cycle 1/Day 10 |
37.00; 200; 99.00; 51.00; 684.00; 0.00 | — |
| SECONDARY Baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 1B |
2275.00; 3275.00 | — |
| SECONDARY Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 1B - Induction Cycle 1/Lead-In |
8.90; 10.50 | — |
| SECONDARY Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 1B - Induction Cycle 1/Day 3 |
2510.00; 3260.00 | — |
| SECONDARY Number of Participants With Disease-related Gene Mutations at Phase 2 Fit and Unfit |
6; 3; 3; 5; 0; 3 | — |
| SECONDARY Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Induction Cycle 1/Day 3 |
318000; 700; 21000; 28.00; 14.00 | — |
| SECONDARY Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Induction Cycle 1/Day 10 |
8.50; 17.00; 292500; 300; 69.00; 594.00 | — |
| SECONDARY Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Consolidation Cycle 1/Day 1 |
226.00; 7000; 232.50; 9.90; 41.50 | — |
| SECONDARY Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Consolidation Cycle 1/Day 10 |
239.50; 581.00; 12000; 11.00; 4.10 | — |
| SECONDARY Serum Levels of Circulating Protein Analytes at Phase 2 Fit - End of Treatment |
338.00; 133.00; 277.00 | — |
| SECONDARY Baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit |
323.00; 362.00 | — |
| SECONDARY Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit - Induction Cycle 1/Day 3 |
3.20; 10.90 | — |
| SECONDARY Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit - Induction Cycle 1/Day 10 |
1.20; 6.60 | — |
| SECONDARY Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit - End of Treatment |
9.70; 6.70; 700; 600 | — |
| SECONDARY Serum Levels of Circulating Protein Analytes at Phase 2 Unfit - Cycle 1/Day 1 |
483.00 | — |
| SECONDARY Serum Levels of Circulating Protein Analytes at Phase 2 Unfit - Cycle 1/Day 10 |
500; 200; 7.5; 0.00 | — |
| SECONDARY Baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Unfit |
2000; 900; 128000; 161000; 223.50; 318.00 | — |
| SECONDARY Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Unfit - Cycle 1/Day 1 |
311500; 234500; 0.00; 6.80 | — |
| SECONDARY Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Unfit - End of Treatment |
0.00; 9.40 | — |
| SECONDARY Ratios of mRNA Levels to Baseline at Phase 2 Fit - Induction Cycle 1/Day 3 |
2.40; 4.80; 0.60; 0.20 | — |
| SECONDARY Ratios of mRNA Levels to Baseline at Phase 2 Fit - End of Treatment |
0.80; 0.80; 0.70 | — |
| SECONDARY Ratios of mRNA Levels to Baseline at Phase 2 Unfit - End of Treatment |
0.70; 0.40; 0.40 | — |
| SECONDARY Baseline mRNA Levels Associated With Best Overall Response at Phase 2 Fit |
10.9; 14.80 | — |
| SECONDARY Baseline mRNA Levels Associated With Best Overall Response at Phase 2 Unfit |
0.20; 0.40; 0.20; 0.10 | — |
| SECONDARY Ratios of mRNA Levels to Baseline Associated With Best Overall Response at Phase 2 Fit |
0.60; 1.10; 0.90; 0.50 | — |
| SECONDARY Ratios of mRNA Levels Associated With Best Overall Response at Phase 2 Unfit |
1.60; 0.50 | — |
| SECONDARY Number of Participants With Corrected QT Interval Using Fridericia's Formula (QTcF) Values Meeting Predefined Criteria at Phase 1B |
16; 2; 14; 5; 3; 6 | — |
| SECONDARY Number of Participants With Corrected QT Interval Using Fridericia's Formula (QTcF) Values Meeting Predefined Criteria at Phase 2 Fit and Unfit |
41; 60; 12; 21; 19; 4 | — |
| SECONDARY Number of Participants With Treatment-emergent Adverse Events (AEs) at Phase 1B (All Causality) |
1; 1; 0; 2; 0; 3 | — |
| SECONDARY Number of Participants With Treatment-emergent AEs at Phase 1B (Treatment-related) |
3; 2; 2; 2; 0; 7 | — |
| SECONDARY Number of Participants With Treatment-emergent AEs Categorized by Seriousness at Phase 1B |
17; 6; 4; 3; 16; 6 | — |
| SECONDARY Number of Participants With Treatment-emergent AEs at Phase 2 Fit and Unfit (All Causality) |
0; 2; 0; 1; 4; 1 | — |
| SECONDARY Number of Participants With Treatment-emergent AEs at Phase 2 Fit and Unfit (Treatment-related) |
0; 4; 4; 4; 9; 6 | — |
| SECONDARY Number of Participants With Treatment-emergent AEs Categorized by Seriousness at Phase 2 Fit and Unfit |
69; 84; 41; 35; 68; 32 | — |
Eligibility Criteria
Inclusion Criteria
- Patients with AML or RAEB 2 High Risk MDS who are newly diagnosed according to the WHO 2008 Classification and previously untreated.
- Patients with AML (arising from an antecedent hematologic disease [AHD]) or MDS who may have had one prior regimen with commercially available agents for the treatment of their prior hematologic disease. The patients may not have had a prior therapy for their AML.
- AML patients include de novo AML, AML evolving from MDS or other AHD and AML after previous cytotoxic therapy or radiation (secondary AML)
- For a diagnosis of AML, a bone marrow blast count of 20% or more is required.
- For a diagnosis of high-risk Myelodysplastic Syndrome RAEB 2 the patient must have 10-19% bone marrow blasts
- Adequate Organ Function
- ECOG Performance Status 0, 1, or 2
Exclusion Criteria
- AML M3 Acute Promyelocytic Leukemia (APL) or patients with a t(9:22) cytogenetic translocation.
- Patients with known active uncontrolled central nervous system (CNS) leukemia.
Data sourced from ClinicalTrials.gov (NCT01546038). 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. Informational only — not medical advice.