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

Phase 2

Terminated

Conditions: Myelodysplastic Syndromes, Myelogenous Leukemia, Acute

Interventions: Drug: cytarabine
Drug: vismodegib

Registration Number: NCT01880437

Lead Sponsor: Hoffmann-La Roche

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 38

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Vismodegib	cytarabine	-
Vismodegib	vismodegib	-

Primary Outcome Measures

Name	Time	Method
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	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.

Secondary Outcome Measures

Name	Time	Method
Duration of Overall Response (DOR)	Up to 30 days of last dose of study drug (maximum treatment duration = 225 days)	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).
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)
Area Under the Concentration-time Curve (AUC) of Cytarabine	Predose, 0.25, 0.5, 1, 3, 6 hours post-dose on Days 1, 8 and 29	PK data was planned to be reported only if the results of Cohort 2 are available.
Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment	Up to 30 days of last dose of study drug (maximum treatment duration = 225 days)	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.
Pharmacokinetics (PK): Steady-state Plasma Concentration of Vismodegib	Predose on Days 8, 29 and 57	PK data was planned to be reported only if the results of Cohort 2 are available.
Median Overall Survival (OS) Time	Up to death or 30 days of last dose of study drug (maximum treatment duration = 225 days)	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.