Advanced Systemic Mastocytosis, Aggressive Systemic Mastocytosis, Mast Cell Leukemia, Systemic Mastocytosis With an Associated Hematologic Neoplasm
Conditions
Brief summary
This is an open-label, single arm, Phase 2 study evaluating the efficacy and safety of avapritinib (BLU-285) in patients with advanced systemic mastocytosis (AdvSM), including patients with aggressive SM (ASM), SM with associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL)
Interventions
DRUGAvapritinib
Avapritinib tablet
Sponsors
Blueprint Medicines Corporation
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
Key Inclusion Criteria: 1. Patient must have a diagnosis of aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) or mast cell leukemia (MCL) based on World Health Organization diagnostic criteria. Before enrollment, the Study Steering Committee must confirm the diagnosis of AdvSM (based on Central Pathology Laboratory assessment of bone marrow). 2. Patient must have a serum tryptase ≥ 20 ng/mL. 3. Patient must have Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 3. Key
Exclusion criteria
1. Patient has received prior treatment with avapritinib. 2. Patient has received any cytoreductive therapy (including midostaurin and other TKIs, hydroxyurea, azacitidine) or an investigational agent less than 14 days, and for cladribine, interferon alpha, pegylated interferon and any antibody therapy (eg, brentuximab vedotin) less than 28 days before obtaining screening BM biopsy for this study. 3. Patient has eosinophilia and known positivity for the FIP1L1 PGDFRA fusion, unless the patient has demonstrated relapse or PD on prior imatinib therapy. Patients with eosinophilia (\> 1.5 × 10\^9/L), who do not have a detectable KIT D816 mutation, must be tested for a PDGFRA fusion mutation by fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR). 4. Patient has history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug. The following are exempt from the 3-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site. 5. Patient has a QT interval corrected using Fridericia's formula (QTcF) \> 480 msec. 6. Patient has a known risk or recent history (12 months before the first dose of study drug) of intracranial bleeding (eg, brain aneurysm, concomitant vitamin K antagonist use). 7. Platelet count \< 50,000/μL (within 4 weeks of the first dose of study drug) or receiving platelet transfusion(s). 8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>3 x the upper limit of normal (ULN); no restriction if due to suspected liver infiltration by mast cells. 9. Bilirubin \>1.5 × ULN; no restriction if due to suspected liver infiltration by mast cells or Gilbert's disease. (In the case of Gilbert's disease, a direct bilirubin \>2 × ULN would be an exclusion.) 10. Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73m2 or creatinine \> 1.5 × ULN. 11. Patient has a primary brain malignancy or metastases to the brain. 12. Patient has a history of a seizure disorder (eg, epilepsy) or requirement for antiseizure medication.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Based on Modified International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (mIWG-MRT-ECNM) Response Criteria | Baseline through Month 65 | ORR was defined as the percentage of participants with a confirmed best response of complete remission (CR), complete remission with partial recovery of peripheral blood counts (CRh), partial remission (PR), or clinical improvement (CI) by mIWG-MRT-ECNM criteria. The mIWG-MRT-ECNM criteria were based on findings from bone marrow biopsy and aspirate, and peripheral blood smear; bone marrow cytogenetics; other extracutaneous tissue biopsies (when available); liver and spleen imaging; and other clinical and laboratory parameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Advanced Systemic Mastocytosis-Symptom Assessment Form (AdvSM-SAF) Total Symptom Score (TTS) | Baseline up to Month 6 (Cycle 6, Day 1) | The AdvSM-SAF is a 10-item questionnaire that assesses eight symptoms specific to AdvSM. All eight symptoms are scored on a scale of 0 (absence of symptoms) to 10 (more severe symptoms) (up to 80 points maximum). Each symptom contributes to the TSS equally. The TSS was generated based on average scores for each 7-day period. An increase in score from 0 (no symptoms) to 80 (worst symptoms represents a worse symptoms outcome. Participants completed the AdvSM-SAF daily using an electronic diary (eDiary). Each cycle is 28 days long. |
| ORR Based on mIWG-MRT-ECNM Response Criteria as Assessed by Local Investigator | Baseline through Month 19 | ORR was defined as the percentage of participants with a confirmed best response of CR, CRh, PR, or CI by mIWG-MRT-ECNM criteria. The mIWG-MRT-ECNM criteria were based on findings from bone marrow biopsy and aspirate, and peripheral blood smear; bone marrow cytogenetics; other extracutaneous tissue biopsies (when available); liver and spleen imaging; and other clinical and laboratory parameters. |
| Time-to-Response (TTR) | Baseline through Month 65 | TTR was defined as the time from first dose to the time of initial evaluation of clinical improvement (CI) or better. Here, 'Overall Number of Participants Analyzed' signifies those participants with a confirmed best response of CR, CRh, PR, and CI by mIWG-MRT-ECNM criteria. |
| Duration of Response (DOR) | Baseline through Month 65 | DOR was defined as the time from initial documentation of a CI or better to the time of initial documentation of confirmed progressive disease (PD) or death due to any cause, whichever occurred first. For responders who had not progressed or died at the time of analysis, DOR was censored at the last response assessment that was stable disease (SD) or better. Here, 'Overall Number of Participants Analyzed' signifies those participants with a confirmed best response of CR, CRh, PR, and CI by mIWG-MRT-ECNM criteria. |
| Progression-free Survival (PFS) | Baseline through Month 65 | PFS was defined as time from first dose to the time of initial documentation of confirmed PD or death due to any cause, whichever occurred first. Participants who had not progressed or died at the time of analysis were censored at the last response assessment that was SD or better. |
| Overall Survival (OS) | Baseline through Month 65 | OS was defined as time from first dose to the time of death due to any cause. Participants who were known to be alive or are lost to follow-up were censored at the last time point they were known to be alive. |
| Objective Response Rate | Baseline through Month 65 | The objective response rate was defined as the number of participants with a confirmed best response of morphologic complete remission, morphologic complete remission with partial recovery of peripheral blood counts, or morphologic partial remission by pure pathologic response (PPR) criteria. The PPR criteria are a modification of the mIWG-MRT-ECNM criteria that define deep responses where direct measure of the disease burden determined the response and focus on objective changes (bone marrow mast cell burden, serum tryptase, and complete blood count). |
| Clinical Benefit Rate | Baseline through Month 65 | The clinical benefit rate was defined as the percentage of participants with a confirmed best response of CR, CRh, PR, CI, and SD by mIWG-MRT-ECNM criteria. |
| Percent Change From Baseline in Bone Marrow Mast Cells | Baseline up to Month 65 | Bone marrow biopsies and aspirates and peripheral blood smears were obtained for systemic mastocytosis response assessment according to mIWG-MRT-ECNM criteria. Each cycle is 28 days long. |
| Percent Change From Baseline in Serum Tryptase | Baseline up to Month 65 | Blood samples were collected to characterize the change in serum tryptase concentration during treatment with avapritinib. Each cycle is 28 days long. |
| Percent Change From Baseline in V-kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog Aspartate 816 Valine (KIT D816V) Mutation Burden | Baseline up to Month 65 | Bone marrow aspirate and PB samples were collected to characterize the KIT D816V mutation allele fraction. Each cycle is 28 days long. |
| Percent Change From Baseline in Liver Volume by Imaging | Baseline up to Month 65 | Assessment of liver volume was performed using serial imaging with magnetic resonance imaging (MRI). Response was defined as resolution of palpable hepatomegaly (CR). Each cycle is 28 days long. |
| Percent Change From Baseline in Spleen Volume by Imaging | Baseline up to Month 65 | Assessment of spleen volume was performed using serial imaging with MRI. Response was defined as ≥35% reduction in spleen volume (PR) or resolution of palpable splenomegaly (CR). Each cycle is 28 days long. |
| Mean Change From Baseline in AdvSM-SAF Skin and Gastrointestinal Domain Scores at Month 10 | Baseline, Month 10 | The AdvSM-SAF is a 10-item questionnaire that assesses symptoms and functional domains specific to AdvSM. Eight symptoms are scored on a scale of 0 to 10 for severity and 2 symptoms (vomiting and diarrhea) are scored for number of episodes. The skin domain is scored on a scale of 0-30, where 0 represents an absence of symptoms and 30 the most severe symptom experience. Similarly, the gastrointestinal domain is scored on a scale of 0-40, where 0 represents an absence of symptoms and 40 the most severe symptom experience. Skin and gastrointestinal domain scores were generated based on average scores for each 7-day period. An increase in score represents a worse symptoms outcome. Participants completed the AdvSM-SAF daily using an eDiary. |
| Mean Change From Baseline in AdvSM-SAF Individual Symptom Scores (Severity) at Month 10 | Baseline, Month 10 | The AdvSM-SAF is a 10-item questionnaire that assesses symptoms and functional domains specific to AdvSM. Individual symptom scores are generated based on average scores for each 7-day period. Eight symptoms are scored on a scale of 0 to 10 for severity. An increase in score represents a worse symptoms outcome. Participants completed the AdvSM-SAF daily using an eDiary. |
| Mean Change From Baseline in AdvSM-SAF Individual Symptom Scores (Episodes) at Month 10 | Baseline, Month 10 | The AdvSM-SAF is a 10-item questionnaire that assesses symptoms and functional domains specific to AdvSM. Individual symptom scores are generated based on average scores for each 7-day period. Two symptoms (vomiting and diarrhea) are scored for number of episodes. An increase in score represents a worse symptoms outcome. Participants completed the AdvSM-SAF daily using an eDiary. |
| Change From Baseline in Patient's Global Impression of Symptom Severity (PGIS) | Baseline, Cycle 1, Day 15 and Day 1 of Cycle 2, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11, Cycle 14, and Cycle 17 (28 days/cycle) | The PGIS is a single-item scale that assesses a participant's perception of disease symptoms at a point in time. Scores range from 0 to 4 points, with higher values representing worse symptom outcomes. It is widely used to evaluate a participant's overall sense of whether a treatment has been beneficial. Each cycle is 28 days long. |
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Baseline, Cycle 1, Day 15 and Day 1 of Cycle 2, Cycle 3, Cycle 5, Cycle 7, Cycle 9, Cycle 11, Cycle 14, and Cycle 17 (28 days/cycle) | Quality of life was assessed using EORTC QLQ-C30, which is a 30-item questionnaire that includes 5 functional domains (physical, cognitive, role, emotional, and social) and a global health status scale. Twenty-eight questions are scored from 1 (not at all) to 4 (very much), while the other 2 are scored from 1 (very poor) to 7 (excellent). The calculated average is standardized using a linear transformation to a standardized scale of 0 to 100, with a decrease in score representing a decrease in quality of life. Each cycle is 28 days long. |
| Number of Participants Experiencing Treatment-emergent Adverse Events (TEAE) | Baseline through Month 65 | A TEAE was defined as any adverse events that occurred between the first dose of a study drug through 30 days after the last dose of any study drug. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Maximum Plasma Concentration (Cmax) of a Single Dose of Avapritinib | Day 1 of Cycle 1 (1 hour postdose) (28 days/cycle) | Blood samples were collected at specified timepoints. Results reported as nanograms/milliliter (ng/mL). |
| Correlation Between TSS and Serum Tryptase | Baseline, Month 10 | The change in baseline for AdvSM-SAF TSS was correlated with the change in baseline for serum tryptase. Spearman correlation coefficients were performed with corresponding scatter plots on change from baseline. |
Countries
Austria, Canada, Denmark, France, Germany, Italy, Netherlands, Norway, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
The Avapritinib group (N=107) includes all participants treated at a starting dose of 200 milligrams (mg) once daily (N=105) and 2 participants treated at a starting dose of 100 mg once daily. One participant was treated at a starting dose of 100 mg per previous protocol amendment, and 1 participant was treated at a starting dose of 100 mg per principal investigator decision.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 67.1 Years STANDARD_DEVIATION 10.38 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 91 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 14 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 15 Participants |
| Race (NIH/OMB) White | 91 Participants |
| Sex: Female, Male Female | 45 Participants |
| Sex: Female, Male Male | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 33 / 105 |
| other Total, other adverse events | 2 / 2 | 104 / 107 |
| serious Total, serious adverse events | 2 / 2 | 67 / 105 |
Outcome results
None listed