Description:
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.
Title
- Brief Title: A Study To Evaluate PF-04449913 With Chemotherapy In Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome
- Official Title: A PHASE 1B/2 STUDY TO EVALUATE THE SAFETY AND EFFICACY OF PF-04449913, AN ORAL HEDGEHOG INHIBITOR, IN COMBINATION WITH INTENSIVE CHEMOTHERAPY, LOW DOSE ARA-C OR DECITABINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA OR HIGH-RISK MYELODYSPLASTIC SYNDROME
Clinical Trial IDs
- ORG STUDY ID:
B1371003
- SECONDARY ID:
2012-000684-24
- NCT ID:
NCT01546038
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| PF-04449913 | | Arm A (Phase 1B) |
| Low dose ARA-C (LDAC) | | Arm A (Phase 1B) |
| PF-04449913 | | Arm B (Phase 1B) |
| Decitabine | | Arm B (Phase 1B) |
| PF-04449913 | | Arm C (Phase 1B) |
| Daunorubicin | | Arm C (Phase 1B) |
| Cytarabine | | Arm C (Phase 1B) |
| PF-04449913 | | P2 Fit (Phase 2 Single Arm) |
| Daunorubicin | | P2 Fit (Phase 2 Single Arm) |
| Cytarabine | | P2 Fit (Phase 2 Single Arm) |
| PF-04449913 | | P2 Unfit (Phase 2 Randomized) |
| Low dose ARA-C (LDAC) | | P2 Unfit (Phase 2 Randomized) |
Purpose
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.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Arm A (Phase 1B) | Experimental | PF-04449913 in combination with low dose ARA-C (LDAC) | - PF-04449913
- Low dose ARA-C (LDAC)
|
| Arm B (Phase 1B) | Experimental | PF-04449913 in combination with Decitabine | |
| Arm C (Phase 1B) | Experimental | PF-04449913 in combination with intensive chemotherapy: PF-04449913 administered continuously for 28 days. Daunorubicin given using 60 mg/m2 for 3-days together with cytarabine 100 mg/m2 on days 1 through 7 followed by cytarabine 1g/m2 on days 1, 3, and 5 during 2-4 cycles of consolidation therapy. | - PF-04449913
- Daunorubicin
- Cytarabine
|
| P2 Fit (Phase 2 Single Arm) | Experimental | PF-04449913 in combination with intensive chemotherapy: PF-04449913 administered continuously for 28 days. Daunorubicin given using 60 mg/m2 for 3-days together with cytarabine 100 mg/m2 on days 1 through 7 followed by cytarabine 1g/m2 on days 1, 3, and 5 during 2-4 cycles of consolidation therapy. | - PF-04449913
- Daunorubicin
- Cytarabine
|
| P2 Unfit (Phase 2 Randomized) | Other | Patients will be randomized 2:1 (low dose ARA-C in combination with PF-04449913: low dose ARA-C alone). | - PF-04449913
- Low dose ARA-C (LDAC)
|
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Number of Participants With Dose-limiting Toxicities (DLTs) at Phase 1B |
| 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 |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | Overall Survival (OS) at Phase 1B |
| Time Frame: | First dose to Follow-up (4 years) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Overall Survival (OS) at Phase 2 Fit |
| Time Frame: | First dose to Follow-up (4 years) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Percentage of Participants With CR / Complete Response With Incomplete Blood Count Recovery (CRi) at Phase 1B |
| Time Frame: | 4 years |
| Safety Issue: | |
| Description: | 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). |
| Measure: | Percentage of Participants With Complete Response (CR) at Phase 2 Unfit |
| Time Frame: | 4 years |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Percentage of Participants With Disease-specific Efficacy for Acute Myeloid Leukemia (AML) at Phase 2 Fit and Unfit |
| Time Frame: | 4 years |
| Safety Issue: | |
| Description: | 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). |
| Measure: | Percentage of Participants With Disease-specific Efficacy for Myelodysplastic Syndrome (MDS) at Phase 2 Fit and Unfit |
| Time Frame: | 4 years |
| Safety Issue: | |
| Description: | 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). |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 |
| 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | AUCtau of Cytarabine and Ara-U in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 |
| Time Frame: | Pre-dose, 6 and 24 hours post start of cytarabine infusion on Induction Cycle 1/Day 3 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Cmax of Daunorubicin and Daunorubicinol in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 |
| Time Frame: | Pre-dose, 0.25, 0.5, 1, 4, 6, 24 hours post administration of daunorubicin on Induction Cycle 1/Day 3 |
| Safety Issue: | |
| Description: | Daunorubicinol is the major metabolite of daunorubicin, which has anti-neoplastic activity. Cmax values of daunorubicin and daunorubicinol are reported. |
| Measure: | Tmax of Daunorubicin and Daunorubicinol in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 |
| Time Frame: | Pre-dose, 0.25, 0.5, 1, 4, 6, 24 hours post administration of daunorubicin on Induction Cycle 1/Day 3 |
| Safety Issue: | |
| Description: | Daunorubicinol is the major metabolite of daunorubicin, which has anti-neoplastic activity. Tmax values of daunorubicin and daunorubicinol are reported. |
| Measure: | AUCtau of Daunorubicin and Daunorubicinol in Participants Receiving Glasdegib and Cytarabine/Daunorubicin at Phase 1B on Induction Cycle 1/Day 3 |
| Time Frame: | Pre-dose, 0.25, 0.5, 1, 4, 6, 24 hours post administration of daunorubicin on Induction Cycle 1/Day 3 |
| Safety Issue: | |
| Description: | Daunorubicinol is the major metabolite of daunorubicin, which has anti-neoplastic activity. AUCtau values of daunorubicin and daunorubicinol are reported. |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | 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 |
| Safety Issue: | |
| Description: | |
| Measure: | Number of Participants With Disease-related Gene Mutations at Phase 1B |
| 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Serum Levels of Circulating Protein Analytes at Phase 1B - Baseline |
| Time Frame: | Baseline (Induction Cycle 1/Day -3 pre-dose) |
| Safety Issue: | |
| Description: | Serum levels were determined for 38 circulating proteins. Values showing statistically significant, ≥2-fold difference compared with baseline are reported here. |
| Measure: | Serum Levels of Circulating Protein Analytes at Phase 1B - Induction Cycle 1/Day 3 |
| Time Frame: | Induction Cycle 1/Day 3, 1 Hour Post dose |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Serum Levels of Circulating Protein Analytes at Phase 1B - Induction Cycle 1/Day 10 |
| Time Frame: | Induction Cycle 1/Day 10, 1 Hour Post dose |
| Safety Issue: | |
| Description: | Serum levels were determined for 38 circulating proteins. Values showing statistically significant, ≥2-fold difference compared with baseline are reported here. |
| Measure: | Baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 1B |
| 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 1B - Induction Cycle 1/Lead-In |
| Time Frame: | Induction Cycle 1/Lead-in, 1 Hour Post dose |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 1B - Induction Cycle 1/Day 3 |
| Time Frame: | Induction Cycle 1/Day 3, 1 Hour Post dose |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Disease-related Gene Mutations at Phase 2 Fit and Unfit |
| Time Frame: | Baseline (Induction Cycle 1/Day -3 pre-dose for Phase 2 Fit; Cycle 1/Day 1 pre-dose for Phase 2 Unfit) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Induction Cycle 1/Day 3 |
| Time Frame: | Induction Cycle 1/Day 3, 1 Hour Post dose |
| Safety Issue: | |
| Description: | Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant difference compared with baseline are reported here. |
| Measure: | Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Induction Cycle 1/Day 10 |
| Time Frame: | Induction Cycle 1/Day 10, 1 Hour Post dose |
| Safety Issue: | |
| Description: | Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant difference compared with baseline are reported here. |
| Measure: | Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Consolidation Cycle 1/Day 1 |
| Time Frame: | Consolidation Cycle 1/Day 1, 1 Hour Post dose |
| Safety Issue: | |
| Description: | Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant difference compared with baseline are reported here. |
| Measure: | Serum Levels of Circulating Protein Analytes at Phase 2 Fit - Consolidation Cycle 1/Day 10 |
| Time Frame: | Consolidation Cycle 1/Day 10, Pre-dose |
| Safety Issue: | |
| Description: | Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant difference compared with baseline are reported here. |
| Measure: | Serum Levels of Circulating Protein Analytes at Phase 2 Fit - End of Treatment |
| 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) |
| Safety Issue: | |
| Description: | Serum levels were determined for 38 circulating proteins. Selected values showing statistically significant difference compared with baseline are reported here. |
| Measure: | Baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit |
| Time Frame: | Baseline (Induction Cycle 1/Day -3 pre-dose) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit - Induction Cycle 1/Day 3 |
| Time Frame: | Induction Cycle 1/Day 3, 1 Hour Post dose |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit - Induction Cycle 1/Day 10 |
| Time Frame: | Induction Cycle 1/Day 10, 1 Hour Post dose |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Fit - End of Treatment |
| 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Serum Levels of Circulating Protein Analytes at Phase 2 Unfit - Cycle 1/Day 1 |
| Time Frame: | Cycle 1/Day 1, 1 Hour Post dose |
| Safety Issue: | |
| Description: | Serum levels were determined for 38 circulating proteins. Selected value showing statistically significant difference compared with baseline is reported here. |
| Measure: | Serum Levels of Circulating Protein Analytes at Phase 2 Unfit - Cycle 1/Day 10 |
| Time Frame: | Cycle 1/Day 10, Pre-dose |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Unfit |
| Time Frame: | Baseline (Cycle 1/Day 1 pre-dose) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Unfit - Cycle 1/Day 1 |
| Time Frame: | Cycle 1/Day 1, 1 Hour Post-dose |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Post-baseline Levels of Serum Circulating Protein Analytes Associated With Best Overall Response at Phase 2 Unfit - End of Treatment |
| 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Ratios of mRNA Levels to Baseline at Phase 2 Fit - Induction Cycle 1/Day 3 |
| Time Frame: | Baseline (Induction Cycle 1/Day -3 pre-dose); Induction Cycle 1/Day 3, 1 Hour Post dose |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Ratios of mRNA Levels to Baseline at Phase 2 Fit - End of Treatment |
| 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Ratios of mRNA Levels to Baseline at Phase 2 Unfit - End of Treatment |
| 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) |
| Safety Issue: | |
| Description: | Whole blood mRNA analyses were performed on 21 mRNA candidates. Only the analytes showing statistically significant change from baseline are reported here. |
| Measure: | Baseline mRNA Levels Associated With Best Overall Response at Phase 2 Fit |
| Time Frame: | Baseline (Induction Cycle 1/Day -3 pre-dose) |
| Safety Issue: | |
| Description: | 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). |
| Measure: | Baseline mRNA Levels Associated With Best Overall Response at Phase 2 Unfit |
| Time Frame: | Baseline (Cycle 1/Day 1 pre-dose) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Ratios of mRNA Levels to Baseline Associated With Best Overall Response at Phase 2 Fit |
| 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) |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Ratios of mRNA Levels Associated With Best Overall Response at Phase 2 Unfit |
| Time Frame: | Baseline (Cycle 1/Day 1 pre-dose); Cycle 1/Day 1, 1 Hour Post dose |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Corrected QT Interval Using Fridericia's Formula (QTcF) Values Meeting Predefined Criteria at Phase 1B |
| Time Frame: | 1 year |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Corrected QT Interval Using Fridericia's Formula (QTcF) Values Meeting Predefined Criteria at Phase 2 Fit and Unfit |
| Time Frame: | 1 year |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Treatment-emergent Adverse Events (AEs) at Phase 1B (All Causality) |
| Time Frame: | 4 years |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Treatment-emergent AEs at Phase 1B (Treatment-related) |
| Time Frame: | 4 years |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Treatment-emergent AEs Categorized by Seriousness at Phase 1B |
| Time Frame: | 4 years |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Treatment-emergent AEs at Phase 2 Fit and Unfit (All Causality) |
| Time Frame: | 4 years |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Treatment-emergent AEs at Phase 2 Fit and Unfit (Treatment-related) |
| Time Frame: | 4 years |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Number of Participants With Treatment-emergent AEs Categorized by Seriousness at Phase 2 Fit and Unfit |
| Time Frame: | 4 years |
| Safety Issue: | |
| Description: | 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. |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Pfizer |
Trial Keywords
- Hedgehog Inhibitor
- Acute Myeloid Leukemia
- Myelodysplastic syndrome
- Intensive chemotherapy
- LDAC
- glasdegib
Last Updated
March 3, 2020
