A Study of Vismodegib in Patients With Relapsed/Refractory Acute Myelogenous Leukemia and Relapsed Refractory High-Risk Myelodysplastic Syndrome

Study Overview
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Brief Summary
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This study will assess the safety and efficacy of vismodegib in patients with relapsed/refractory acute myelogenous leukemia (AML) and relapsed/refractory high-risk myelodysplastic syndrome (MDS). Patients in Cohort 1 will receive single-agent vismodegib 150 mg orally daily. In Cohort 2, patients will receive vismodegib 150 mg orally daily in combination with cytarabine 20 mg subcutaneously for 10 days. Anticipated time on study treatment is until disease progression, intolerable toxicity, or patient withdrawal of consent.

Official Title
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A PHASE IB/II STUDY TO EVALUATE THE SAFETY AND EFFICACY OF VISMODEGIB IN RELAPSED/REFRACTORY ACUTE MYELOGENOUS LEUKEMIA (AML) AND RELAPSED/REFRACTORY HIGH-RISK MYELODYSPLASTIC SYNDROME (MDS)

Conditions
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Myelodysplastic Syndromes, Myelogenous Leukemia, Acute

Intervention / Treatment
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* Drug: cytarabine
* Drug: vismodegib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, >/= 18 years of age Patients with documented relapsed or refractory AML, except acute promyelocytic leukemia (APL [M3 subtype]), or relapsed or refractory high-risk MDS (high-risk MDS defined as International Prognostic Scoring System (IPSS) Int-2 or high and >/= 10% blasts in bone marrow) Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 Negative serum pregnancy test for women of childbearing potential and use of two forms of contraception while enrolled in the study and for 7 months after the patient discontinues from study Male patients with female partners of childbearing potential must agree to use a latex condom and to advise their female partner to use an additional method of contraception during the study and for 2 months after the last dose of vismodegib All non-hematological adverse events of any prior chemotherapy, surgery, or radiotherapy must have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade </= 2 prior to starting therapy Adequate hepatic and renal function Exclusion Criteria: Prior treatment with a Hh pathway inhibitor Prior therapy for the treatment of malignancy within 14 days of Day 1, with the exception of: Hydroxyurea in patients who need to continue this agent to maintain white blood cell (WBC) counts </= 50,000/mL. Hydroxyurea must be discontinued by Day 14 of the study Current evidence of active central nervous system (CNS) leukemia Any other active malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix) Any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as: Unstable angina, symptomatic or otherwise uncontrolled arrhythmia requiring medication (does not include stable, lone atrial fibrillation), or myocardial infarction </= 6 months before study treatment start Any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study Pregnant or breast-feeding women Patients who refuse to potentially receive blood products and/or have a severe hypersensitivity to blood products

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vismodegib<br> | Drug: cytarabine<br>* Cohort 2: 20 mg sc daily for 10 days starting Day 1, with a possible further cycle of 20 mg sc daily for 5 days starting no earlier than Day 29<br>Drug: vismodegib<br>* Cohorts 1 and 2: 150 mg orally daily<br>* Other names: RO5450815;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Complete Response (CR) or CR With Incomplete Blood Count Recovery (CRi) or Morphologic Leukemia Free State (MLFS) or Partial Response (PR) at Week 8 | CR was defined as achieved if the neutrophils count was greater than (>) 1000 cells per microliter (µL), platelets count >100000/µL, bone marrow blasts percentage (%) less than (<) 5, no Auer rods (clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts), no transfusion requirements and no signs of extra medullary disease (EMD). CRi was defined if either of the cell (neutrophil or platelet) lineage was not recovered (neutrophils >1000 cells/µL or Not applicable [NA] or platelets count >100000/µL or NA), bone marrow blasts <5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. MLFS (neutrophil and platelet criteria were NA) was defined as bone marrow blasts <5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. PR was defined as neutrophils count >1000 cells/µL, platelets count >100000/µL, and >50% decrease from baseline to a range of 5-25% of bone marrow blasts or blasts <5% with Auer rods. | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | CR was defined as achieved if the neutrophils count >1000 cells/µL, platelets count >100000/µL, bone marrow blasts <5%, no Auer rods (clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of leukemic blasts), no transfusion requirements and no signs of EMD. CRi was defined if either of the cell (neutrophil or platelet) lineage was not recovered (neutrophils > 1000 cells/µL or NA or platelets count >100000/µL or NA, bone marrow blasts <5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. MLFS (neutrophil and platelet criteria were NA) was defined as bone marrow blasts <5% with no Auer rods and confirmed by flow cytometry with no signs of EMD. PR was defined as neutrophils count >1000 cells/µL, platelets count >100000/µL, and >50% decrease from baseline to a range of 5-25% of bone marrow blasts or blasts <5% with Auer rods. The 95% confidence intervals (CI) were constructed using Blyth-Still-Cassella method. | Up to 30 days of last dose of study drug (maximum treatment duration = 225 days) | 
| Duration of Overall Response (DOR) | DOR is defined as the time from the first occurrence of a documented overall response to the time of relapse, as determined by the investigator using International Working Group (IWG) criteria (Participants not falling under any of the response criteria [CR or CRi or MLFS or PR] described under outcome measure 1 were considered as non-responders) or death from any cause during the study (defined as death within 30 days after the last dose of study drug). | Up to 30 days of last dose of study drug (maximum treatment duration = 225 days) | 
| Median Overall Survival (OS) Time | OS was defined as the time from start of study drug to death from any cause. OS was estimated using Kaplan-Meier analysis. Participants alive at the last date known to be alive were censored for the analysis. | Up to death or 30 days of last dose of study drug (maximum treatment duration = 225 days) | 
| Percentage of Participants With an Event of Death During the Study |  | Up to death or 30 days of last dose of study drug (maximum treatment duration = 225 days) | 
| Pharmacokinetics (PK): Steady-state Plasma Concentration of Vismodegib | PK data was planned to be reported only if the results of Cohort 2 are available. | Predose on Days 8, 29 and 57 | 
| Area Under the Concentration-time Curve (AUC) of Cytarabine | PK data was planned to be reported only if the results of Cohort 2 are available. | Predose, 0.25, 0.5, 1, 3, 6 hours post-dose on Days 1, 8 and 29 |