Myelodysplastic Syndromes, Myelogenous Leukemia, Acute
Conditions
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.
Interventions
DRUGcytarabine
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
DRUGvismodegib
Cohorts 1 and 2: 150 mg orally daily
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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. |
| 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 an Event of Death During the Study | Up to death or 30 days of last dose of study drug (maximum treatment duration = 225 days) | — |
Countries
Canada, Germany, United States
Participant flow
Recruitment details
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).
Pre-assignment details
Based on lower-than-expected efficacy observed in interim data review, study was terminated prior to initiation of Cohort 2. Results are reported as per subgroups of Cohort 1: Poor Risk Cytogenetics, FLT-3 Mutation Positive, Neither Poor Risk Cytogenetics Nor FLT-3, unless otherwise specified.
Participants by arm
| Arm | Count |
|---|---|
| Poor Risk Cytogenetics Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'poor risk cytogenetics' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent. | 15 |
| FLT-3 Mutation Positive Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling under 'FLT-3 mutation positive' subgroup received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent. | 4 |
| Neither Poor Risk Cytogenetics Nor FLT-3 Participants with relapsed/refractory AML or relapsed/refractory high-risk MDS falling neither under 'poor risk cytogenetics' nor 'FLT-3 mutation positive' subgroup were included in this group and received oral 150 mg dose of vismodegib capsule once daily until disease progression, intolerable toxicity most probably attributable to vismodegib, or participant withdrawal of consent. | 19 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 12 | 4 | 17 |
| Overall Study | Study terminated by Sponsor | 3 | 0 | 2 |
Baseline characteristics
| Characteristic | Poor Risk Cytogenetics | FLT-3 Mutation Positive | Neither Poor Risk Cytogenetics Nor FLT-3 | Total |
|---|---|---|---|---|
| Age, Continuous | 61.5 years STANDARD_DEVIATION 20.7 | 54.5 years STANDARD_DEVIATION 5.9 | 66.2 years STANDARD_DEVIATION 14.7 | 63.1 years STANDARD_DEVIATION 16.9 |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 9 Participants | 17 Participants |
| Sex: Female, Male Male | 9 Participants | 2 Participants | 10 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 15 | 4 / 4 | 19 / 19 |
| serious Total, serious adverse events | 10 / 15 | 3 / 4 | 13 / 19 |
Outcome results
Primary
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
Population: As the primary efficacy time-point (Week 8) was not reached for all participants due to study termination based on interim data analysis, the analysis of this outcome measure could not be performed, as per planned analysis.
Secondary
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
Population: No participants were enrolled as the study was terminated prior to the initiation of Cohort 2.
Secondary
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)
Population: Efficacy population including participants who were considered as responders.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neither Poor Risk Cytogenetics Nor FLT3 | Duration of Overall Response (DOR) | DOR of participants with CRi (n=0,0,1) | 13 weeks |
| Neither Poor Risk Cytogenetics Nor FLT3 | Duration of Overall Response (DOR) | DOR of participants with PR (n=0,0,1) | 6.1 weeks |
Secondary
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)
Population: Efficacy analysis population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Poor Risk Cytogenetics | Median Overall Survival (OS) Time | 3.38 months |
| FLT-3 Mutation Positive | Median Overall Survival (OS) Time | 1.43 months |
| Neither Poor Risk Cytogenetics Nor FLT3 | Median Overall Survival (OS) Time | 3.65 months |
Secondary
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)
Population: Efficacy analysis population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Poor Risk Cytogenetics | Percentage of Participants With an Event of Death During the Study | 80.0 percentage of participants |
| FLT-3 Mutation Positive | Percentage of Participants With an Event of Death During the Study | 100.0 percentage of participants |
| Neither Poor Risk Cytogenetics Nor FLT3 | Percentage of Participants With an Event of Death During the Study | 89.5 percentage of participants |
Secondary
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)
Population: Efficacy analysis population included all enrolled participants. Here number of participants analyzed included participants who were evaluable for tumor response at anytime during the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Poor Risk Cytogenetics | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | CR | 0 percentage of participants |
| Poor Risk Cytogenetics | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | CRi | 0 percentage of participants |
| Poor Risk Cytogenetics | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | MLFS | 0 percentage of participants |
| Poor Risk Cytogenetics | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | PR | 0 percentage of participants |
| FLT-3 Mutation Positive | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | PR | 0 percentage of participants |
| FLT-3 Mutation Positive | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | CR | 0 percentage of participants |
| FLT-3 Mutation Positive | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | MLFS | 0 percentage of participants |
| FLT-3 Mutation Positive | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | CRi | 0 percentage of participants |
| Neither Poor Risk Cytogenetics Nor FLT3 | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | PR | 6.3 percentage of participants |
| Neither Poor Risk Cytogenetics Nor FLT3 | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | CRi | 6.3 percentage of participants |
| Neither Poor Risk Cytogenetics Nor FLT3 | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | MLFS | 0 percentage of participants |
| Neither Poor Risk Cytogenetics Nor FLT3 | Percentage of Participants With CR, CRi, MLFS or PR at Anytime During Study Treatment | CR | 0 percentage of participants |
Secondary
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
Population: As the study was terminated prior to Cohort 2 enrollment, PK analysis could not be performed, as planned.