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

• ClinicalTrials.gov Identifier: NCT01880437
• Recruitment Status: Terminated
• First Posted: June 19, 2013
• Results First Posted: December 15, 2015
• Last Update Posted: December 15, 2015
• Sponsor: Hoffmann-La Roche
• Information provided by (Responsible Party): Hoffmann-La Roche

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Myelodysplastic Syndromes, Myelogenous Leukemia, Acute	Drug: cytarabine; Drug: vismodegib	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Study Start Date: September 2013
• Actual Primary Completion Date: November 2014
• Actual Study Completion Date: November 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Vismodegib	Drug: cytarabine; 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; Drug: vismodegib; Cohorts 1 and 2: 150 mg orally daily; Other Name: RO5450815

Outcome Measures

Primary Outcome Measures :

1. 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 [ Time Frame: 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 :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, California

Stanford, California, United States, 94305

United States, Michigan

Ann Arbor, Michigan, United States, 48109

United States, Missouri

Kansas City, Missouri, United States, 64131

United States, New York

New York, New York, United States, 10065

United States, Texas

Houston, Texas, United States, 77030

Canada, Alberta

Edmonton, Alberta, Canada, T6L5X8

Canada, Ontario

Toronto, Ontario, Canada, M5G 2M9

Canada, Quebec

Montreal, Quebec, Canada, H1T 2M4

Montreal, Quebec, Canada, H3T 1E2

Germany

Braunschweig, Germany, 38114

Essen, Germany, 45122

Hamburg, Germany, 20246

Heidelberg, Germany, 69120

Münster, Germany, 48149

Sponsors and Collaborators

Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

More Information

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01880437
• Other Study ID Numbers: GO28852; 2013-001570-14 ( EudraCT Number )
• First Posted: June 19, 2013
• Results First Posted: December 15, 2015
• Last Update Posted: December 15, 2015
• Last Verified: November 2015

Additional relevant MeSH terms:

Leukemia; Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Syndrome; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Cytarabine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs