| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Indolent Systemic Mastocytosis (ISM) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10042949 |
| E.1.2 | Term | Systemic mastocytosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 27.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10056452 |
| E.1.2 | Term | Indolent systemic mastocytosis |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1 - to determine the RP2D of avapritinib in patients with ISM for use in Part 2 and Part 3 of the study.
Part 2 - to determine mean change in ISM-SAF TSS from baseline to C7D1, compared to placebo.
Part 3 - to assess the long-term safety and efficacy of avapritinib in ISM patients. |
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| E.2.2 | Secondary objectives of the trial |
Key Secondary (Part2 Only)
To determine the proportion of avapritinib-treated patients with ISM, from baseline to C7D1, compared to placebo:
- with a ≥50% reduction in serum tryptase
- with a ≥50% reduction in peripheral blood KIT D816V allele fraction or undetectable (<0.02%) for patients with detectable mutation at Baseline
- achieving ≥50% reduction in ISM-SAF TSS
- achieving ≥30% reduction in ISM-SAF TSS
- with a ≥50% reduction in bone marrow mast cells or no aggregates for patients with aggregates at Baseline
Additional Secondary
Assess change in:
- measures of mast cell burden in each treatment cohort (serum tryptase, KIT D816V allele burden in blood, bone marrow mast cells)
- best supportive care usage for SM symptoms
Assess change in other Patient-Reported Outcomes and Quality of Life measures
Assess the safety and tolerability of avapritinib, as assessed by AEs, vital signs, electrocardiograms, and laboratory tests
Assess the PK of avapritinib (Part 1 & 2 only) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients must be ≥ 18 years of age.
2. Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and central review of B- and C-findings by WHO diagnostic criteria.
3. Patient must have moderate-to-severe symptoms based on minimum mean TSS over the 14-day eligibility screening period for assessment of TSS. Minimum TSS for eligibility is ≥ 28.
4. Patient must have failed to achieve adequate symptom control for 1 or more Baseline symptoms, as determined by the Investigator, with at least 2 of the following symptomatic therapies: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
5. The patient’s symptomatic SM therapies (eg, H1 and H2 blockers) must be stable (same dose, no new medications ≥14 days before beginning the 14-day ISM-SAF eligibility TSS assessment).
6. If the patient is receiving corticosteroids, the dose must be ≤20 mg/day prednisone or equivalent, and the dose must be stable for ≥14 days before beginning the 14-day ISM-SAF eligibility TSS assessment.
7. Patient must have an ECOG-PS of 0 to 2.
8. Patient must be able to give written informed consent. |
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| E.4 | Principal exclusion criteria |
1. Patient has been diagnosed with any of the following WHO SM subclassifications: Cutaneous mastocytosis only, SM-AHN, SSM, ASM, MCL, MC sarcoma.
2. Patient has been diagnosed with another myeloproliferative disorder.
3. Patient has any of the following organ damage C-findings attributable to SM: Cytopenia, Hepatomegaly with ascites and impaired liver function, Palpable splenomegaly with hypersplenism, Malabsorption with hypoalbuminemia and significant weight loss, Skeletal lesions: large osteolytic lesions with pathologic fractures, Life-threatening organ damage in other organ systems that is caused by MC infiltration in tissues.
4. Patient meets any of the following laboratory criteria: Aspartate aminotransferase or alanine aminotransferase > 3.0 × ULN, Total bilirubin > 1.5 × ULN; > 3.0 × ULN if due to Gilbert's disease. (In the case of Gilbert’s disease, a direct bilirubin > 2.0 × ULN is an exclusion.) Albumin < 1 × LLN, eGFR < 30 mL/min/1.73 m^2 or creatinine clearance or creatinine > 1.5 × ULN
Absolute neutrophil count < 1.5 × 10^9/L, Hemoglobin < 10 g/dL, Platelet count < 100,000/μL
5. Patient has received any of the following medications, therapies, or procedures in the timeframes listed: Any prior treatment with avapritinib, Any TKI, including but not limited to masitinib and midostaurin, or investigational agent for < 14 days or 5 half-lives of the drug (whichever is longer) before beginning the 14-day ISM-SAF eligibility TSS assessment, Any antineoplastic drug therapy < 28 days or 5 half-lives of the drug (whichever is longer) before beginning the 14-day ISM-SAF eligibility TSS assessment,
Radiotherapy or PUVA therapy < 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment, Any hematopoietic growth factor < 14 days before beginning the 14-day ISM-SAF eligibility TSS assessment, Any major surgical procedure < 14 days before starting the ISM-SAF for determination of eligibility.
6. Patient requires therapy with a concomitant medication that is a strong inhibitor, strong inducer, or moderate inducer of CYP3A4 (see Appendix 9).
7. Patient has a history of a malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational agent may be included after approval by medical monitor.
8. Patient has a QTcF > 480 msec.
9. Patient has a history of a seizure disorder (eg, epilepsy) or requires antiseizure medication.
10. Patient has a history of a cerebrovascular accident or transient ischemic attacks within 12 months before the first dose of study drug.
11. Patient has a known risk or recent history (12 months before the first dose of study drug) of ICB (eg, brain aneurysm).
12. Patient has a primary brain malignancy or metastases to the brain.
13. Patient has clinically significant, uncontrolled cardiovascular disease, including Grade III or Grade IV congestive heart failure greater than New York Heart Association classification II; myocardial infarction or unstable angina within the previous 6 months; clinically significant, uncontrolled arrhythmias, or uncontrolled hypertension.
14. Female patients who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 6 weeks after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 6 weeks after the last dose of study drug.
15. Pregnant women, as documented by a β-hCG pregnancy test consistent with pregnancy obtained within 7 days before the first dose of study drug.
16. Women who are breastfeeding.
17. Patient is illiterate or otherwise unable or unwilling to complete daily ISM-SAF assessments in the eDiary.
18. Patients with known hypersensitivity to avapritinib or to any of the excipients.
19. Patients requiring anticoagulant therapy such as warfarin, or similar agents requiring therapeutic international normalized ratio (INR) monitoring.
20. Germany only: Patients who have previously experienced reactions to local anesthesia.
21. Germany only: Patient is not eligible for an MRI due to contraindications (eg, patients with implanted defibrillators or other metallic devices not approved for MRI). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
•The RP2D in patients with ISM.
Part 2
•Mean change in ISM-SAF TSS, from Baseline to C7D1.
Part 3
•The long-term safety and efficacy of avapritinib.
|
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1 - weekly for the first 4 weeks, then every 4 weeks
Part 2 - Patients will be assessed every 4 weeks through C7D1
Part 3 - All patients in Part 3 will have study visits every 4 weeks until C7D1, then every 8 weeks until C13D1. After C13D1, patients will have visits every 12 weeks for a total study duration of up to 5 years, inclusive of Part 1 and Part 2. |
|
| E.5.2 | Secondary end point(s) |
Key Secondary (Part 2 Only)
• Proportion of patients with a ≥50% reduction in serum tryptase.
• Proportion of patients with a ≥50% reduction in peripheral blood KIT D816V allele fraction or undetectable (<0.02%) for patients with detectable mutation at Baseline.
• Proportion of patients with ≥50% reduction in ISM-SAF TSS.
• Proportion of patients with ≥30% reduction in ISM-SAF TSS.
• Proportion of patients with a ≥50% reduction in bone marrow mast cells or no aggregates for patients with aggregates at Baseline.
Additional Secondary
• Change in measures of mast cell burden: serum tryptase, KIT D816V allele burden in blood, bone marrow mast cells.
• Change in best supportive care usage.
• Change in MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L.
• Safety and tolerability of avapritinib, as assessed by AEs, vital signs, electrocardiograms, and laboratory tests.
• Pharmacokinetics of avapritinib (Part 1 and 2 only)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Key Secondary (Part 2 Only): from Baseline to C7D1
• KIT D816V & Tryptase: C1D1/D15, C2D1, C4D1 (KIT), every visit through C4D1 (tryptase), every 4w until roll over (Part 1); every cycle through C7D1 (Part 2); every cycle through C7D1, every 8w during C7-13, and every 12w during C13 through EOT (Part 3)
• Bone marrow biopsy: Screening, C4D1 (Part 1), C7D1 (Part 2); optional at approx. 1 year after end of Part 1 & 2 biopsy (Part 3)
• ISM-SAF: daily through EOT
• QoL: each visit through EOT
• AE & BSC: throughout study
• Vital signs, hematology & chemistry: every visit until EOT
• ECG: Screening, D1 of every cycle (Part 1 & 2); D1 of every visit (Part 3)
• Sparse PK: before & after study drug dosing (Part 1 & 2) |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Switzerland |
| Canada |
| United Kingdom |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as the time that the last patient completes his/her last visit (Last Patient Last Visit), including assessments performed as part of safety follow-up, if the patient enters the safety follow-up period of the study or assessments performed as part of the LTFU.
Patients who have discontinued the study may reconsent to the LTFU. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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