GLAD-AML - Glasdegib (Pf-04449913) With Two Standard Decitabine Regimens for Older Patients With Poor-risk Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This multi-center, randomized phase 2 study is designed to evaluate the complete remission (including complete remission with incomplete count recovery) rates of glasdegib in combination with either decitabine on a 5-day or 10-day schedule in patients with newly-diagnosed poor-risk AML who either refuse or are ineligible for intensive therapy.

Detailed Description
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The primary objective of this multi-center, randomized phase 2 study is to determine the response rates, complete remission (CR) and complete remission with incomplete count recovery (CRi), of glasdegib/DAC5 and glasdegib/DAC10 in patients with newly-diagnosed PrAML. There are two secondary objectives for this study. The first secondary objective is to evaluate the toxicity and safety profiles of glasdegib/DAC5 and glasdegib/DAC10 in patients with newly-diagnosed PrAML. The other secondary objective is to determine the event-free survival (EFS), relapse-free survival (RFS), overall survival (OS), duration of response, bone marrow mutational clearance, and remission clonality of glasdegib/DAC5 and glasdegib/DAC10 in patients with newly-diagnosed PrAML.

Official Title
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A Randomized, Parallel-arm, Phase 2 Clinical Trial of the Combination of Glasdegib (Pf-04449913) With Two Standard Decitabine Regimens for Older Patients With Poor-risk Acute Myeloid Leukemia Who Are Unfit for or Refuse Intensive Chemotherapy (GLAD-AML)

Conditions
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ACUTE MYELOID LEUKEMIA

Intervention / Treatment
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* Drug: Glasdegib
* Drug: Decitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a morphologically-confirmed diagnosis of AML according to WHO 2016 classification with poor-risk disease as defined by the cytogenetic or molecular abnormalities (excluding FLT3-mutated AML). Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2. Adequate Renal Function: a. Calculated creatinine clearance (determined by MDRD) ≥50mL/min/1.73m2, or serum creatinine <1.5x upper limit of normal (ULN); Adequate Liver Function: Total serum bilirubin ≤ 2.0 x ULN (unless the bilirubin is principally unconjugated and there is strong suspicion of sub-clinical hemolysis or the patient has documented Gilbert's disease); Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 3.0 x ULN; Alkaline phosphatase ≤ 3.0 x ULN. Serum or urine pregnancy test (for female patients of childbearing potential) with a minimum sensitivity of 25 IU/L or equivalent units of human chorionic gonadotropin (HCG) negative at screening. Males and female patients both of childbearing potential and at risk for pregnancy must agree to use two highly effective method(s) of contraception throughout the study and for 180 days after the last dose of decitabine and the last dose of glasdegib, whichever occurs later. Female patients who are not of childbearing potential (i.e. meet at least 1 of the following criteria): Have undergone a documented hysterectomy and/or bilateral oophorectomy; Have medically confirmed ovarian failure; Have achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle stimulating hormone (FSH) level within the laboratory's reference range for postmenopausal women. Exclusion Criteria: Patients who are candidates for and willing to receive intensive induction chemotherapy. Prior use of a hypomethylating agent. Prior use of cytotoxic chemotherapy for any myeloid malignancy (prior immunosuppressive therapy is permitted provided that treatment is stopped within 8 weeks from study entry; hydroxyurea is allowed through the end of cycle 1 on study). Previous hematopoietic stem cell transplant. Prior treatment with a licensed or experimental smoothened inhibitor (SMOi) and/or hypomethylating agent (HMA). Participation in a clinical study involving an investigational drug(s) (Phases 1-4) within 4 weeks prior to study entry or within 5 half-lives of the investigational agent, whichever is greater. Major surgery or radiation within 12 weeks prior to study entry. Patients known to be refractory to platelet or packed red cell transfusions as per institutional guidelines, or who are known to refuse or who are likely to refuse blood product support. Treatment with hematopoietic growth factors including: erythropoietin, granulocyte colony stimulating factor (G-CSF), and granulocyte macrophage colony stimulating factor (GM-CSF), or thrombopoietin receptor agonists within 3 weeks prior to study entry. Any ongoing medical condition requiring chronic use of moderate to high dose steroids (defined as ≥10 mg/day of prednisone or equipotent dose of another corticosteroid). Any anti-cancer treatment within 2 weeks prior to study entry (including hydroxyurea as above). Current use or anticipated requirement for drugs that are known moderate to strong CYP3A4 inducers (Appendix 2). Presence of concurrent active malignancy requiring active systemic therapy Patients with known active, uncontrolled bacterial, fungal or viral infection, including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV), or acquired immunodeficiency syndrome (AIDS) related illness. Known uncontrolled central nervous system (CNS) involvement. Poorly-controlled active medical conditions that as per investigator judgement would interfere with the conduct of the study. Active cardiac dysrhythmias of NCI CTCAE Grade ≥2 (e.g. atrial fibrillation) or QTcF interval >470 msec. Pregnant or breastfeeding female patients.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DAC5<br>Glasdegib will be administered at the starting dose of 100 mg orally once daily and continuously in combination with either DAC5 (decitabine 20 mg/m2 IV on a 5-day schedule) or DAC10 (decitabine 20 mg/m2 IV on a 10-day schedule) as per randomization. Treatment will be administered in 28-day cycles. | Drug: Glasdegib<br>* Glasdegib will be administered at the starting dose of 100 mg orally once daily.<br>Drug: Decitabine<br>* Decitabine will be administered per local label and will be administered by IV infusion at a dose of 20 mg/m2/day for either 5 days or 10 days as determined by randomization. Each cycle will be every 28 days.<br>|
| Experimental: DAC10<br>Glasdegib will be administered at the starting dose of 100 mg orally once daily and continuously in combination with either DAC5 (decitabine 20 mg/m2 IV on a 5-day schedule) or DAC10 (decitabine 20 mg/m2 IV on a 10-day schedule) as per randomization. Treatment will be administered in 28-day cycles. | Drug: Glasdegib<br>* Glasdegib will be administered at the starting dose of 100 mg orally once daily.<br>Drug: Decitabine<br>* Decitabine will be administered per local label and will be administered by IV infusion at a dose of 20 mg/m2/day for either 5 days or 10 days as determined by randomization. Each cycle will be every 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CR/CRi | The complete remission (CR) and complete remission with incomplete count recovery (CRi) combined rate will be defined by the 2017 European LeukemiaNet (ELN) AML response criteria. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OS | Overall survival (OS) is defined as the time from date of first study treatment to date of death due to any cause. | Up to 2 years | 
| EFS | Event-free survival (EFS) will be monitored up to 2 years. | Up to 2 years | 
| RFS | Relapse-free survival (RFS) will be monitored up to 2 years. | Up to 2 years | 
| Time to CR/CRi | The time to complete remission (CR) and complete remission with incomplete count recovery (CRi) will be collected as a secondary outcome. | Up to 2 years | 
| Duration of CR/CRi | The duration of complete remission (CR) and complete remission with incomplete count recovery (CRi) will be collected as a secondary outcome. | Up to 2 years | 
| Bone Marrow Mutational Clearance | Bone marrow mutational clearance of frequently-mutated genes in AML (e.g. NPM1, CEBPA, DNMT3A, RUNX1, TET2, IDH1/2) via next-generation DNA sequencing will be monitored up to 2 years. | Up to 2 years |