Back to resultsA Study of Vismodegib in Patients With Relapsed/Refractory Acute Myelogenous Leukemia and Relapsed Refractory High-Risk Myelodysplastic Syndrome
Primary Purpose
Myelodysplastic Syndromes, Myelogenous Leukemia, Acute
Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
cytarabine
vismodegib
Sponsored by
About this trial
This is an interventional treatment trial for Myelodysplastic Syndromes, Myelogenous Leukemia, Acute
Eligibility 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
Sites / Locations
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Vismodegib
Arm Description
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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).
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.
Percentage of Participants With an Event of Death During the Study
Pharmacokinetics (PK): Steady-state Plasma Concentration of Vismodegib
PK data was planned to be reported only if the results of Cohort 2 are available.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01880437
Brief Title
A Study of Vismodegib in Patients With Relapsed/Refractory Acute Myelogenous Leukemia and Relapsed Refractory High-Risk Myelodysplastic Syndrome
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 Type
Interventional
2. Study Status
Record Verification Date
November 2015
Overall Recruitment Status
Terminated
Study Start Date
September 2013 (undefined)
Primary Completion Date
November 2014 (Actual)
Study Completion Date
November 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hoffmann-La Roche
4. Oversight
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelodysplastic Syndromes, Myelogenous Leukemia, Acute
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
38 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Vismodegib
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
cytarabine
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
vismodegib
Other Intervention Name(s)
RO5450815
Intervention Description
Cohorts 1 and 2: 150 mg orally daily
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Week 8
Secondary Outcome Measure Information:
Title
Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment
Description
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.
Time Frame
Up to 30 days of last dose of study drug (maximum treatment duration = 225 days)
Title
Duration of Overall Response (DOR)
Description
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).
Time Frame
Up to 30 days of last dose of study drug (maximum treatment duration = 225 days)
Title
Median Overall Survival (OS) Time
Description
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.
Time Frame
Up to death or 30 days of last dose of study drug (maximum treatment duration = 225 days)
Title
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)
Title
Pharmacokinetics (PK): Steady-state Plasma Concentration of Vismodegib
Description
PK data was planned to be reported only if the results of Cohort 2 are available.
Time Frame
Predose on Days 8, 29 and 57
Title
Area Under the Concentration-time Curve (AUC) of Cytarabine
Description
PK data was planned to be reported only if the results of Cohort 2 are available.
Time Frame
Predose, 0.25, 0.5, 1, 3, 6 hours post-dose on Days 1, 8 and 29
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Trials
Organizational Affiliation
Hoffmann-La Roche
Official's Role
Study Director
Facility Information:
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64131
Country
United States
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6L5X8
Country
Canada
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H1T 2M4
Country
Canada
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1E2
Country
Canada
City
Braunschweig
ZIP/Postal Code
38114
Country
Germany
City
Essen
ZIP/Postal Code
45122
Country
Germany
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
City
Münster
ZIP/Postal Code
48149
Country
Germany
12. IPD Sharing Statement
Learn more about this trial
A Study of Vismodegib in Patients With Relapsed/Refractory Acute Myelogenous Leukemia and Relapsed Refractory High-Risk Myelodysplastic Syndrome
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