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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
255
PF-04449913 administered orally and continuously for 28-days.
Low dose ARA-C (LDAC) administered at 20 mg SQ, BID on Days 1 through 10.
PF-04449913 administered orally and continuously for 28 days.
Number of Participants With Dose-limiting Toxicities (DLTs) at Phase 1B
A DLT was any of the following adverse events (AEs) in Cycle 1 and considered by the investigator possibly related to glasdegib in combination with chemotherapy: (1) Grade \>= 3 non-hematologic toxicity, excluding Grade \>= 3 infection, fever (including febrile neutropenia), infusion related AEs, electrolyte abnormalities and ALT/AST elevation that returned to Grade \<= 1 or baseline within 7 days; (2) prolonged myelosuppression that lasted longer than 42 days from the point of detection, defined as absolute neutrophil count (ANC) \< 500/microliter(mcL) or platelet count \< 10 \*10\^9/L with a normal bone marrow (\<5% blasts and no evidence of disease or dysplasia); (3) inability to deliver at least 80% of the planned study doses for all agents in a combination due to non-hematologic toxicities; (4) Delay of \>28 days in receiving the next scheduled cycle due to persisting non-hematologic toxicities. Arm A: Glasdegib+LDAC; Arm B: Glasdegib+Decitabine; Arm C: Glasdegib+Cytarabine/Daunorubicin.
Time frame: Arms A and B: Cycle 1, Day 1 to Day 28; Arm C: Cycle 1, Day -3 to Day 21 or to Day 28 depending on when the next chemotherapy cycle was started
Percentage of Participants With Complete Response (CR) at Phase 2 Fit
For AML participants:CR were those with repeat bone marrow showing \<5% myeloblasts,spicules present and no Auer rods, peripheral blood showing neutrophils\>=1000/mcL and platelets\>=100,000/mcL, transfusion independent and no extramedullary disease. For MDS participants:CR were those with repeat bone marrow showing \<=5% myeloblasts, peripheral blood showing neutrophils\>=1000/mcL, platelets\>=100,000/mcL, 0% blast and hemoglobin (Hgb)\>= 11 g/dL, normal maturation of all cell lines.
Time frame: 4 years
Overall Survival (OS) at Phase 2 Unfit
OS was defined as duration from the date of randomization to the date of death from any cause. Kaplan-Meier (KM) method was used to estimate median OS. In this method, every participant had a follow-up time which was associated with an indicator, 1=event (death in our case), and 0 =censored. If the participants were not known to have died, time to date of last known to be alive was used as to calculate the follow-up time and indicator was 0 for these participants. KM method estimates the median OS based on the K-M curve. The K-M curve only drops when we had an event and censor data are the ticks in the graph. To estimate median OS, the K-M curve usually will be smoothed first and a line will be drawn at 50%. The median OS is the point when K-M curve and the horizontal hit. Survival status was collected every month for the first 2 months after discontinuation of study treatment and thereafter every 2 months until death or 4 years from time of randomization for each participant.
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Decitabine given at 20 mg/m2 over 1 hour infusion for 5-days
PF-04449913 administered orally and continuously for 28 days
Daunorubicin given using 60 mg/m2 for 3-days
Cytarabine 100 mg/m2 on days 1 through 7
PF-04449913 administered orally and continuously for 28 days
Daunorubicin given using 60 mg/m2 for 3-days
Cytarabine 100 mg/m2 on days 1 through 7
PF-04449913 administered orally and continuously for 28 days (if randomized to receive PF-04449913)
Low dose ARA-C (LDAC) administered at 20 mg SQ, BID on Days 1 through 10.
University of Alabama at Birmingham
Birmingham, Alabama, United States
University of Alabama at Birmingham
Birmingham, Alabama, United States
University of Alabama at Birmingham
Birmingham, Alabama, United States
UC San Diego Moores Cancer Center - Investigational Drug Services
La Jolla, California, United States
UC San Diego Medical Center - La Jolla
La Jolla, California, United States
UC San Diego Moores Cancer Center
La Jolla, California, United States
Keck Hospital of USC
Los Angeles, California, United States
LAC & USC Medical Center
Los Angeles, California, United States
USC/Norris Comprehensive Cancer Center / Investigational Drug Services
Los Angeles, California, United States
USC/Norris Comprehensive Cancer Center
Los Angeles, California, United States
...and 71 more locations
Time frame: Randomization to Follow-up (4 years)
Overall Survival (OS) at Phase 1B
OS was defined as duration from the date of randomization to the date of death from any cause. Kaplan-Meier (KM) method was used to estimate median OS. In this method, every participant had a follow-up time which was associated with an indicator, 1=event (death in our case), and 0 =censored. If the participants were not known to have died, time to date of last known to be alive was used as to calculate the follow-up time and indicator was 0 for these participants. KM method estimates the median OS based on the K-M curve. The K-M curve only drops when we had an event and censor data are the ticks in the graph. To estimate median OS, the K-M curve usually will be smoothed first and a line will be drawn at 50%. The median OS is the point when K-M curve and the horizontal hit. Survival status was collected every month for the first 2 months after discontinuation of study treatment and thereafter every 2 months until death or 4 years from each participant's first dose.
Time frame: First dose to Follow-up (4 years)
Overall Survival (OS) at Phase 2 Fit
OS was defined as duration from the date of randomization to the date of death from any cause. Kaplan-Meier (KM) method was used to estimate median OS. In this method, every participant had a follow-up time which was associated with an indicator, 1=event (death in our case), and 0 =censored. If the participants were not known to have died, time to date of last known to be alive was used as to calculate the follow-up time and indicator was 0 for these participants. KM method estimates the median OS based on the K-M curve. The K-M curve only drops when we had an event and censor data are the ticks in the graph. To estimate median OS, the K-M curve usually will be smoothed first and a line will be drawn at 50%. The median OS is the point when K-M curve and the horizontal hit. Survival status was collected every month for the first 2 months after discontinuation of study treatment and thereafter every 2 months until death or 4 years from each participant's first dose.
Time frame: First dose to Follow-up (4 years)
Percentage of Participants With CR / Complete Response With Incomplete Blood Count Recovery (CRi) at Phase 1B
For AML participants:CR were those with repeat bone marrow showing \<5% myeloblasts,spicules present and no Auer rods, peripheral blood showing neutrophils\>=1000/mcL and platelets\>=100,000/mcL, transfusion independent and no extramedullary disease. For MDS participants:CR were those with repeat bone marrow showing \<=5% myeloblasts, peripheral blood showing neutrophils\>=1000/mcL, platelets\>=100,000/mcL, 0% blast and hemoglobin (Hgb)\>= 11 g/dL, normal maturation of all cell lines.For AML and MDS participants, complete response with incomplete blood count recovery(CRi)were those with repeat bone marrow showing \<5% myeloblasts with either platelets or neutrophils not recovered (platelets \<100,000/mcL or neutrophils \<1000/mcL).
Time frame: 4 years
Percentage of Participants With Complete Response (CR) at Phase 2 Unfit
For AML participants:CR were those with repeat bone marrow showing \<5% myeloblasts,spicules present and no Auer rods, peripheral blood showing neutrophils\>=1000/mcL and platelets\>=100,000/mcL, transfusion independent and no extramedullary disease. For MDS participants:CR were those with repeat bone marrow showing \<=5% myeloblasts, peripheral blood showing neutrophils\>=1000/mcL, platelets\>=100,000/mcL, 0% blast and hemoglobin (Hgb)\>= 11 g/dL, normal maturation of all cell lines.
Time frame: 4 years
Percentage of Participants With Disease-specific Efficacy for Acute Myeloid Leukemia (AML) at Phase 2 Fit and Unfit
AML participants,disease specific efficacy measures included:CRi;Morphologic Leukemia Free State(MLFS)(bone marrow\<5%myeloblasts with spicules and no blasts with auer rods,neutrophils\<1000/mcL and platelets\<100,000/mcL);partial remission(PR)(bone marrow myeloblasts decrease to 5-25\&\>=50%decrease from start, neutrophils\>=1000/mcL, platelets\>=100,000/mcL);PR with incomplete blood count recovery(PRi)(bone marrow myeloblasts decrease to 5-25\&\>=50%decrease from start,neutrophils\<1000/mcL or platelets\<100,000/mcL);minor response(MR)(bone marrow myeloblasts decrease to\>=25% from start);stable disease(SD)(bone marrow myeloblasts stable+/-25% from screening value);cytogenetic complete response(CRc)(bone marrow\<5%myeloblasts, neutrophils\>1000/mcL, platelets\>100,000/mcL and normal cytogenetics),molecular complete response(CRm)(bone marrow\<5%myeloblasts, neutrophils\>1000/mcL, platelets\>100,000/mcL and molecular-negative).
Time frame: 4 years
Percentage of Participants With Disease-specific Efficacy for Myelodysplastic Syndrome (MDS) at Phase 2 Fit and Unfit
For all MDS participants, disease specific efficacy measures included: CRi (bone marrow showing \<5% myeloblasts with platelets \<100,000/mcL or neutrophils \<1000/mcL, including confirmed and unconfirmed responses); PR (repeat bone marrow myeloblasts showing decreased by \>= 50% decrease but still \>5%, peripheral blood showing neutrophils \>= 1,000/mcL, platelets \>= 100,000/mcL and Hgb\>=11g/dL; including confirmed and unconfirmed responses); SD (including confirmed and unconfirmed responses, failure to achieve PR and no evidence of progression for \>8 weeks); marrow complete response (mCR) (bone marrow showing \<=5% myeloblasts and decreased by \>= 50%), partial cytogenetic response (\>=50% reduction of chromosomal abnormality) and complete cytogenetic response (CRc) (disappearance of chromosomal abnormality with no appearance of now ones).
Time frame: 4 years
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
Time frame: Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10 and Cycle 1/Day 21
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
Time frame: Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10 and Cycle 1/Day 21
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
Time frame: Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10 and Cycle 1/Day 21
Cmax of Glasdegib in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1
Time frame: Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10; pre-dose, 0.5, 1, 2, 6 and 24 hours post-dose on Cycle 2/Day 1
Tmax of Glasdegib in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1
Time frame: Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10; pre-dose, 0.5, 1, 2, 6 and 24 hours post-dose on Cycle 2/Day 1
AUCtau of Glasdegib in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 10 and Cycle 2/Day 1
Time frame: Pre-dose, 0.5, 1, 2, 4, 6 and 24 hours post-dose on Cycle 1/Day 10; pre-dose, 0.5, 1, 2, 6 and 24 hours post-dose on Cycle 2/Day 1
Cmax of Glasdegib in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10
Time frame: Pre-dose, 0.5, 1, 6 and 24 hours post-dose on Induction Cycle 1/Day 3; pre-dose, 0.5, 1, 4, 6 and 24 hours post-dose on Induction Cycle 1/Day 10
Tmax of Glasdegib in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10
Time frame: Pre-dose, 0.5, 1, 6 and 24 hours post-dose on Induction Cycle 1/Day 3; pre-dose, 0.5, 1, 4, 6 and 24 hours post-dose on Induction Cycle 1/Day 10
AUCtau of Glasdegib in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 and Day 10
Time frame: Pre-dose, 0.5, 1, 6 and 24 hours post-dose on Induction Cycle 1/Day 3; pre-dose, 0.5, 1, 4, 6 and 24 hours post-dose on Induction Cycle 1/Day 10
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
Ara-U is the major metabolite of cytarabine. LDAC (low dose cytarabine) is rapidly degraded to the stable metabolite Ara-U, Cmax levels of both LDAC and Ara-U were reported.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4 and 6 hours post-dose on Cycle 1/Day 2 and Cycle 1/Day 10
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
Ara-U is the major metabolite of cytarabine. LDAC (low dose cytarabine) is rapidly degraded to the stable metabolite Ara-U, Tmax levels of both LDAC and Ara-U were reported.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4 and 6 hours post-dose on Cycle 1/Day 2 and Cycle 1/Day 10
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
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4 and 6 hours post-dose on Cycle 1/Day 2 and Cycle 1/Day 10
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
Ara-U is the major metabolite of cytarabine. LDAC (low dose cytarabine) is rapidly degraded to the stable metabolite Ara-U. Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) levels of both LDAC and Ara-U were reported.
Time frame: Pre-dose, 0.25, 0.5, 1, 2, 4 and 6 hours post-dose on Cycle 1/Day 2 and Cycle 1/Day 10
Cmax of Decitabine in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2
Time frame: Pre-dose, 0.5 hour from start of infusion, 1 hour (at end of infusion) and 2, 3 and 4 hours from start of infusion on Cycle 1/Day 1 and Cycle 1/Day 2
Tmax of Decitabine in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2
Time frame: Pre-dose, 0.5 hour from start of infusion, 1 hour (at end of infusion) and 2, 3 and 4 hours from start of infusion on Cycle 1/Day 1 and Cycle 1/Day 2
AUCinf of Decitabine in Participants Receiving Glasdegib and Decitabine at Phase 1B on Cycle 1/Day 1 and Cycle 1/Day 2
Time frame: Pre-dose, 0.5 hour from start of infusion, 1 hour (at end of infusion) and 2, 3 and 4 hours from start of infusion on Cycle 1/Day 1 and Cycle 1/Day 2
AUCtau of Cytarabine and Ara-U in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3
Ara-U is the major metabolite of cytarabine. LDAC (low dose cytarabine) is rapidly degraded to the stable metabolite Ara-U, levels of both cytarabine and Ara-U were reported.
Time frame: Pre-dose, 6 and 24 hours post start of cytarabine infusion on Induction Cycle 1/Day 3
Cmax of Daunorubicin and Daunorubicinol in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3
Daunorubicinol is the major metabolite of daunorubicin, which has anti-neoplastic activity. Cmax values of daunorubicin and daunorubicinol are reported.
Time frame: Pre-dose, 0.25, 0.5, 1, 4, 6, 24 hours post administration of daunorubicin on Induction Cycle 1/Day 3
Tmax of Daunorubicin and Daunorubicinol in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3
Daunorubicinol is the major metabolite of daunorubicin, which has anti-neoplastic activity. Tmax values of daunorubicin and daunorubicinol are reported.
Time frame: Pre-dose, 0.25, 0.5, 1, 4, 6, 24 hours post administration of daunorubicin on Induction Cycle 1/Day 3
AUCtau of Daunorubicin and Daunorubicinol in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3
Daunorubicinol is the major metabolite of daunorubicin, which has anti-neoplastic activity. AUCtau values of daunorubicin and daunorubicinol are reported.
Time frame: Pre-dose, 0.25, 0.5, 1, 4, 6, 24 hours post administration of daunorubicin on Induction Cycle 1/Day 3
Pre-dose Plasma Concentration (Ctrough) of Glasdegib in Phase 2 Fit on Induction Cycle 1/Day 10
Time frame: Pre-dose, 1 and 4 hours post-dose on Induction Cycle 1/Day 10
Cmax of Glasdegib in Participants Receiving Glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10
Time frame: Pre-dose, 1, 2, 4, and 6 hour post-dose on Cycle 1/Day 10
Tmax of Glasdegib in Participants Receiving Glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10
Time frame: Pre-dose, 1, 2, 4, and 6 hour post-dose on Cycle 1/Day 10
AUCtau of Glasdegib in Participants Receiving Glasdegib and LDAC at Phase 2 Unfit on Cycle 1/Day 10
Time frame: Pre-dose, 1, 2, 4, and 6 hour post-dose on Cycle 1/Day 10
Number of Participants With Disease-related Gene Mutations at Phase 1B
Peripheral blood and bone marrow aspirate were collected for baseline mutational analyses. Genetic abnormalities frequently associated with AML were analyzed. These genetic abnormalities included known mutations in the genes NPM1, CEBPA, FLT3, RUNX1, IDH1, IDH2, KIT, K Ras, N Ras and WT1. Additional genes with mutations known to be associated with AML and MDS such as TET2 and DNMT3A were also evaluated.
Time frame: Baseline (Cycle 1/Day 1 pre-dose for Glasdegib + LDAC and Glasdegib + Decitabine Arms; Induction Cycle 1/Day -3 pre-dose for Glasdegib +Cytarabine/Daunorubicin Arm)
Serum Levels of Circulating Protein Analytes at Phase 1B - Baseline
Serum levels were determined for 38 circulating proteins. Values showing statistically significant, ≥2-fold difference compared with baseline are reported here.
Time frame: Baseline (Induction Cycle 1/Day -3 pre-dose)
Serum Levels of Circulating Protein Analytes at Phase 1B - Induction Cycle 1/Day 3
Serum levels were determined for 38 circulating proteins. Values showing statistically significant, ≥2-fold difference compared with baseline are reported here. Statistically significant, \>=2-fold baseline difference was only seen for MMP-3 (Matrix metalloproteinase-3) at Induction Cycle 1/Day 3.
Time frame: Induction Cycle 1/Day 3, 1 Hour Post dose
Serum Levels of Circulating Protein Analytes at Phase 1B - Induction Cycle 1/Day 10
Serum levels were determined for 38 circulating proteins. Values showing statistically significant, ≥2-fold difference compared with baseline are reported here.
Time frame: Induction Cycle 1/Day 10, 1 Hour Post dose
Baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 1B
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response in Arm C are reported. Baseline levels statistically associated with best overall response was only seen in SDF-1 (stromal cell-derived factor 1) in glasdegib+cytarabine/daunorubicin arm.
Time frame: Baseline (Cycle 1/Day 1 pre-dose for Glasdegib + LDAC and Glasdegib + Decitabine Arms; Induction Cycle 1/Day -3 pre-dose for Glasdegib +Cytarabine/Daunorubicin Arm)
Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 1B - Induction Cycle 1/Lead-In
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response are reported. Post-baseline levels statistically significant associated with best overall response was only seen for MMP-3 (Matrix metalloproteinase-3) at Induction Cycle 1/Lead-in.
Time frame: Induction Cycle 1/Lead-in, 1 Hour Post dose
Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 1B - Induction Cycle 1/Day 3
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response are reported. Post-baseline levels statistically significant associated with best overall response was only seen for SDF-1 (Stromal cell-derived factor 1) at Induction Cycle 1/Day 3.
Time frame: Induction Cycle 1/Day 3, 1 Hour Post dose
Number of Participants With Disease-related Gene Mutations at Phase 2 Fit and Unfit
Peripheral blood and bone marrow aspirate were collected for baseline mutational analyses. Genetic abnormalities frequently associated with AML were analyzed. These genetic abnormalities included known mutations in the genes NPM1, CEBPA, FLT3, RUNX1, IDH1, IDH2, KIT, K Ras, N Ras and WT1. Additional genes with mutations known to be associated with AML and MDS such as TET2 and DNMT3A were also evaluated.
Time frame: Baseline (Induction Cycle 1/Day -3 pre-dose for Phase 2 Fit; Cycle 1/Day 1 pre-dose for Phase 2 Unfit)
Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Induction Cycle 1/Day 3
Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant difference compared with baseline are reported here.
Time frame: Induction Cycle 1/Day 3, 1 Hour Post dose
Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Induction Cycle 1/Day 10
Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant difference compared with baseline are reported here.
Time frame: Induction Cycle 1/Day 10, 1 Hour Post dose
Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Consolidation Cycle 1/Day 1
Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant difference compared with baseline are reported here.
Time frame: Consolidation Cycle 1/Day 1, 1 Hour Post dose
Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Consolidation Cycle 1/Day 10
Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant difference compared with baseline are reported here.
Time frame: Consolidation Cycle 1/Day 10, Pre-dose
Serum Levels of Circulating Protein Analytes at Phase 2 Fit - End of Treatment
Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant difference compared with baseline are reported here.
Time frame: End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, participant refusal or unacceptable toxicity occurred, whichever came first, an average of 1 year)
Baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. Selected data of analyte for which the serum level showed statistically significant correlation with clinical response are reported.
Time frame: Baseline (Induction Cycle 1/Day -3 pre-dose)
Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit - Induction Cycle 1/Day 3
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. Selected data of analyte for which the serum level showed statistically significant correlation with clinical response are reported.
Time frame: Induction Cycle 1/Day 3, 1 Hour Post dose
Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit - Induction Cycle 1/Day 10
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. Selected data of analyte for which the serum level showed statistically significant correlation with clinical response are reported.
Time frame: Induction Cycle 1/Day 10, 1 Hour Post dose
Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit - End of Treatment
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. Selected data of analytes for which the serum level showed statistically significant correlation with clinical response are reported.
Time frame: End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, participant refusal or unacceptable toxicity occurred, whichever came first, an average of 1 year)
Serum Levels of Circulating Protein Analytes at Phase 2 Unfit - Cycle 1/Day 1
Serum levels were determined for 38 circulating proteins. Selected value showing statistically significant difference compared with baseline is reported here.
Time frame: Cycle 1/Day 1, 1 Hour Post dose
Serum Levels of Circulating Protein Analytes at Phase 2 Unfit - Cycle 1/Day 10
Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant differences compared with baseline are reported here. ITAC (Interferon-inducible T-cell α chemoattractant) level in LDAC alone arm at Cycle 1/Day 10 exhibited non-significant change from baseline but similar trends as in Glasdegib 100 mg+LDAC arm.
Time frame: Cycle 1/Day 10, Pre-dose
Baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Unfit
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. The data of analytes for which the serum level showed statistically significant correlation with clinical response are reported.
Time frame: Baseline (Cycle 1/Day 1 pre-dose)
Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Unfit - Cycle 1/Day 1
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. Selected data of analytes for which the serum level showed statistically significant correlation with clinical response are reported.
Time frame: Cycle 1/Day 1, 1 Hour Post-dose
Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Unfit - End of Treatment
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. A total of 38 proteins were analyzed. Selected data of analyte for which the serum level showed statistically significant correlation with clinical response are reported.
Time frame: End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, participant refusal or unacceptable toxicity occurred, whichever came first, an average of 1 year)
Ratios of mRNA Levels to Baseline at Phase 2 Fit - Induction Cycle 1/Day 3
Whole blood mRNA analyses were performed on 21 mRNA candidates. Values showing statistically significant, ≥2-fold differences compared with baseline are reported here. CDKN1A: cyclin-dependent kinase inhibitor 1A; SMO: mRNA encoding the glasdegib target Smoothened; PTCH2: Patched 2; MYCN: Neuroblastoma Myc oncogene.
Time frame: Baseline (Induction Cycle 1/Day -3 pre-dose); Induction Cycle 1/Day 3, 1 Hour Post dose
Ratios of mRNA Levels to Baseline at Phase 2 Fit - End of Treatment
Whole blood mRNA analyses were performed on 21 mRNA candidates. Selected values showing statistically significant differences compared with baseline are reported here. CCND2:G1/S-Specific Cyclin D2; MSI2: Musashi RNA Binding Protein 2; PTCH2: Patched 2.
Time frame: Baseline (Induction Cycle 1/Day -3 pre-dose); End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, participant refusal or unacceptable toxicity occurred, whichever came first, an average of 1 year)
Ratios of mRNA Levels to Baseline at Phase 2 Unfit - End of Treatment
Whole blood mRNA analyses were performed on 21 mRNA candidates. Only the analytes showing statistically significant change from baseline are reported here.
Time frame: Baseline (Cycle 1/Day 1 pre-dose); End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, participant refusal or unacceptable toxicity occurred, whichever came first, an average of 1 year)
Baseline mRNA Levels Associated With Best Overall Response at Phase 2 Fit
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. Whole blood mRNA analyses were performed on 21 mRNA candidates. Baseline mRNA level showing statistically significant correlation with clinical response are reported. Baseline mRNA levels statistically significant associated with best overall response was only seen for CCND2 (G1/S-Specific Cyclin D2).
Time frame: Baseline (Induction Cycle 1/Day -3 pre-dose)
Baseline mRNA Levels Associated With Best Overall Response at Phase 2 Unfit
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. Whole blood mRNA analyses were performed on 21 mRNA candidates. Baseline mRNA level showing statistically significant correlation with clinical response are reported. FOXM1: Forkhead box M1; PTCH1: Patched 1.
Time frame: Baseline (Cycle 1/Day 1 pre-dose)
Ratios of mRNA Levels to Baseline Associated With Best Overall Response at Phase 2 Fit
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. Whole blood mRNA analyses were performed on 21 mRNA candidates. Ratios of mRNA level to baseline showing statistically significant correlation with clinical response are reported.
Time frame: Baseline (Induction Cycle 1/Day -3 pre-dose); End of Treatment (maximum of 12 cycles from start of therapy or until disease progression or relapse, participant refusal or unacceptable toxicity occurred, whichever came first, an average of 1 year)
Ratios of mRNA Levels Associated With Best Overall Response at Phase 2 Unfit
Responders were AML participants who achieved CR, CRi, MLFS, PR or PRi based on investigator-reported best overall response and MDS participants who achieved CR, mCR, PR or SD based on investigator-reported best overall response. Whole blood mRNA analyses were performed on 21 mRNA candidates. Ratios of mRNA level to baseline showing statistically significant correlation with clinical response are reported. Ratios of mRNA levels to baseline statistically significant associated with best overall response was only seen for MYCN (Neuroblastoma Myc oncogene) at Cycle 1/Day 1.
Time frame: Baseline (Cycle 1/Day 1 pre-dose); Cycle 1/Day 1, 1 Hour Post dose
Number of Participants With Corrected QT Interval Using Fridericia's Formula (QTcF) Values Meeting Predefined Criteria at Phase 1B
Maximum absolute values and increases from baseline were summarized for QTcF interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole corrected for heart rate using Fridericia's formula). Number of participants with QTcF meeting the following criteria is presented: QTcF interval:\<450 msec; QTcF interval: 450 to \<480 msec; QTcF interval: 480 to \<500 msec; QTcF interval \>=500 msec; QTcF interval increase from baseline: \<30 msec; QTcF interval increase from baseline: 30 to \<60 msec; QTcF interval increase from baseline \>=60 msec. Arms in the time frame description are defined as: Arm A, Glasdegib +LDAC; Arm B, Glasdegib + Decitabine; Arm C, Glasdegib + Cytarabine/Daunorubicin. End of treatment in the time frame were defined as: maximum of 12 cycles from start of therapy or until disease progression or relapse, participant refusal or unacceptable toxicity occurred, whichever came first.
Time frame: 1 year
Number of Participants With Corrected QT Interval Using Fridericia's Formula (QTcF) Values Meeting Predefined Criteria at Phase 2 Fit and Unfit
Maximum absolute values and increases from baseline were summarized for QTcF interval (time from the beginning of Q wave to the end of T wave corresponding to electrical systole corrected for heart rate using Fridericia's formula). Number of participants with QTcF meeting the following criteria is presented:QTcF interval:\<450 msec; QTcF interval: 450 to \<480 msec; QTcF interval: 480 to \<500 msec; QTcF interval \>=500 msec; QTcF interval increase from baseline: \<30 msec; QTcF interval increase from baseline: 30 to \<60 msec; QTcF interval increase from baseline \>=60 msec. End of treatment in the time frame were defined as: maximum of 12 cycles from start of therapy or until disease progression or relapse, participant refusal or unacceptable toxicity occurred, whichever came first.
Time frame: 1 year
Number of Participants With Treatment-emergent Adverse Events (AEs) at Phase 1B (All Causality)
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE.
Time frame: 4 years
Number of Participants With Treatment-emergent AEs at Phase 1B (Treatment-related)
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. Treatment-related AEs were AEs related to glasdegib and/or backbone chemotherapy. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE.
Time frame: 4 years
Number of Participants With Treatment-emergent AEs Categorized by Seriousness at Phase 1B
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. An serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect.
Time frame: 4 years
Number of Participants With Treatment-emergent AEs at Phase 2 Fit and Unfit (All Causality)
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE.
Time frame: 4 years
Number of Participants With Treatment-emergent AEs at Phase 2 Fit and Unfit (Treatment-related)
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. Treatment-related AEs were AEs related to glasdegib and/or backbone chemotherapy. AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 : Grade 1: mild AE; Grade 2: moderate AE; Grade 3: severe AE; Grade 4: life-threatening consequences, urgent intervention indicated; Grade 5: death related to AE.
Time frame: 4 years
Number of Participants With Treatment-emergent AEs Categorized by Seriousness at Phase 2 Fit and Unfit
An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a product or medical device; the event did not necessarily had a causal relationship with the treatment or usage. Treatment Emergent AEs were those with initial onset or increasing in severity after the first dose of study medication and occurred within 28 days post last dose. An serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death; was life threatening (immediate risk of death); required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); resulted in congenital anomaly/birth defect.
Time frame: 4 years