A Phase 2 interventional study of cytarabine and vismodegib in Myelodysplastic Syndromes, Myelogenous Leukemia, Acute, sponsored by Hoffmann-La Roche. Terminated at 14 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2015-12-15.
Sponsored by Hoffmann-La Roche · Phase 2, Interventional, and Treatment
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.
5,442 studies on the registry are indexed under Leukemia; 637 are open to participants now.
This study's enrollment of 38 is close to the median of 38 across 4,248 interventional studies indexed under Leukemia.
Browse Leukemia studies →Hoffmann-La Roche is the lead sponsor of 2,061 studies on the registry; 85 are open to participants now.
Of its 319 completed or terminated interventional studies of FDA-regulated products, 239 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
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
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
Drug: cytarabine · Drug: vismodegib
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
Cohorts 1 and 2: 150 mg orally daily
Also known as: RO5450815
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.
Time frame: Week 8
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.
Time frame: 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).
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: Predose, 0.25, 0.5, 1, 3, 6 hours post-dose on Days 1, 8 and 29
A total of 47 participants were screened; of which,7 participants failed screening and 2 participants were erroneously entered but did not receive study drug.A total of 38 participants were enrolled and treated. It was planned to enroll 2 cohorts; Cohort 1 (vismodegib) and Cohort 2 (vismodegib + cytarabine).
| Milestone | Poor Risk Cytogenetics | FLT-3 Mutation Positive | Neither Poor Risk Cytogenetics Nor FLT-3 |
|---|---|---|---|
| Started | 15 | 4 | 19 |
| Completed | 0 | 0 | 0 |
| Not completed | 15 | 4 | 19 |
| Withdrew: Death | 12 | 4 | 17 |
| Withdrew: Study terminated by sponsor | 3 | 0 | 2 |
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.
No measurements were reported for this outcome.
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.
| percentage of participants | Poor Risk Cytogenetics | FLT-3 Mutation Positive | Neither Poor Risk Cytogenetics Nor FLT3 |
|---|---|---|---|
| CR | 0 (0.00 to 22.51) | 0 (0.00 to 52.71) | 0 (0.00 to 19.75) |
| CRi | 0 (0.00 to 22.51) | 0 (0.00 to 52.71) | 6.3 (0.32 to 29.88) |
| MLFS | 0 (0.00 to 22.51) | 0 (0.00 to 52.71) | 0 (0.00 to 19.75) |
| PR | 0 (0.00 to 22.51) | 0 (0.00 to 52.71) | 6.3 (0.32 to 29.88) |
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).
| weeks | Poor Risk Cytogenetics | FLT-3 Mutation Positive | Neither Poor Risk Cytogenetics Nor FLT3 |
|---|---|---|---|
| DOR of participants with CRi (n=0,0,1) | — | — | 13 (NA to NA) |
| DOR of participants with PR (n=0,0,1) | — | — | 6.1 (NA to NA) |
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.
| months | Poor Risk Cytogenetics | FLT-3 Mutation Positive | Neither Poor Risk Cytogenetics Nor FLT-3 |
|---|---|---|---|
| Median Overall Survival (OS) Time | 3.38 (2.37 to 4.83) | 1.43 (0.33 to 3.94) | 3.65 (1.94 to 5.36) |
| percentage of participants | Poor Risk Cytogenetics | FLT-3 Mutation Positive | Neither Poor Risk Cytogenetics Nor FLT-3 |
|---|---|---|---|
| Percentage of Participants With an Event of Death During the Study | 80.0 | 100.0 | 89.5 |
PK data was planned to be reported only if the results of Cohort 2 are available.
No measurements were reported for this outcome.
PK data was planned to be reported only if the results of Cohort 2 are available.
No measurements were reported for this outcome.
Collected over From screening until study completion or early termination visit (Up to 14 months). Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Poor Risk Cytogenetics | — | 10/15 (66.7%) | 13/15 (86.7%) |
| FLT-3 Mutation Positive | — | 3/4 (75%) | 4/4 (100%) |
| Neither Poor Risk Cytogenetics Nor FLT-3 | — | 13/19 (68.4%) | 19/19 (100%) |
| Event | Poor Risk Cytogenetics | FLT-3 Mutation Positive | Neither Poor Risk Cytogenetics Nor FLT-3 |
|---|---|---|---|
| PyrexiaGeneral disorders | 0/15 | 1/4 | 6/19 |
| Febrile neutropeniaBlood and lymphatic system disorders | 2/15 | 1/4 | 4/19 |
| SepsisInfections and infestations | 0/15 | 1/4 | 1/19 |
| Lung infectionInfections and infestations | 3/15 | 0/4 | 1/19 |
| PneumoniaInfections and infestations | 1/15 | 0/4 | 3/19 |
| Abdominal painGastrointestinal disorders | 2/15 | 0/4 | 0/19 |
| Urinary retentionRenal and urinary disorders | 2/15 | 0/4 | 0/19 |
| ThrombocytopeniaBlood and lymphatic system disorders | 1/15 | 0/4 | 0/19 |
| Pericardial effusionCardiac disorders | 1/15 | 0/4 | 0/19 |
| HaemorrhoidsGastrointestinal disorders | 1/15 | 0/4 | 0/19 |
| Event | Poor Risk Cytogenetics | FLT-3 Mutation Positive | Neither Poor Risk Cytogenetics Nor FLT-3 |
|---|---|---|---|
| PyrexiaGeneral disorders | 3/15 | 3/4 | 5/19 |
| NauseaGastrointestinal disorders | 4/15 | 0/4 | 10/19 |
| LeukocytosisBlood and lymphatic system disorders | 0/15 | 2/4 | 2/19 |
| FatigueGeneral disorders | 1/15 | 2/4 | 5/19 |
| EpistaxisRespiratory, thoracic and mediastinal disorders | 1/15 | 0/4 | 8/19 |
| DysgeusiaNervous system disorders | 4/15 | 1/4 | 7/19 |
| DiarrhoeaGastrointestinal disorders | 1/15 | 0/4 | 6/19 |
| HypokalaemiaMetabolism and nutrition disorders | 1/15 | 1/4 | 6/19 |
| DizzinessNervous system disorders | 2/15 | 0/4 | 6/19 |
| Abdominal painGastrointestinal disorders | 4/15 | 0/4 | 1/19 |
Included all enrolled participants who received at least 1 dose of study drug.
| Age, Continuous(years) | Poor Risk Cytogenetics | FLT-3 Mutation Positive | Neither Poor Risk Cytogenetics Nor FLT-3 | Total |
|---|---|---|---|---|
| Mean | 61.5 ± 20.7 | 54.5 ± 5.9 | 66.2 ± 14.7 | 63.1 ± 16.9 |
| Sex: Female, Male(Participants) | Poor Risk Cytogenetics | FLT-3 Mutation Positive | Neither Poor Risk Cytogenetics Nor FLT-3 | Total |
|---|---|---|---|---|
| Female | 6 | 2 | 9 | 17 |
| Male | 9 | 2 | 10 | 21 |
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