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

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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:
Information provided by (Responsible Party):
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.


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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 38 participants
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


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




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.



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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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01880437


Locations
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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
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Study Director: Clinical Trials Hoffmann-La Roche

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01880437     History of Changes
Other Study ID Numbers: GO28852
2013-001570-14 ( EudraCT Number )
First Posted: June 19, 2013    Key Record Dates
Results First Posted: December 15, 2015
Last Update Posted: December 15, 2015
Last Verified: November 2015
Additional relevant MeSH terms:
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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