| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Indolent and Smoldering Systemic Mastocytosis (ISM & SSM) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10042949 |
| E.1.2 | Term | Systemic mastocytosis |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056452 |
| E.1.2 | Term | Indolent systemic mastocytosis |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 in patients with ISM for use in Part 2 and Part 3 of the study.
Part 2 - to determine the effect of avapritinib in reducing symptoms in ISM and SSM patients, as compared to placebo.
Part 3 - to assess the long-term safety and efficacy of avapritinib in ISM and SSM patients. |
|
| E.2.2 | Secondary objectives of the trial |
Part 1 and Part 2, assess:
Change in measures of MC burden, cutaneous disease and BSC usage; Change from baseline to wk 12 for ISM-SAF "lead symptom" score, proportion of patients with and time to achieve 5, 10 and 15-pt reductions in TSS and domain scores, and change in individual symptom scores; Change in other PROs based on the MC-QoL, PGIS, SF-12, PGIC and the EQ 5D-5L questionnaires; Change in the frequency of anaphylactic episodes; Safety and tolerability of avapritinib, as assessed by AEs, vital signs, ECGs and lab tests; PK of avapritinib; Correlate exposure with safety and efficacy endpoints
Part 3, assess:
Change in the measures of MC burden, cutaneous disease and BSC usage; Change in ISM-SAF "lead symptom" score, TSS, domain scores and individual symptom from Part 3 baseline to wk 12, 24, 36 and 52; Time to achieve those reductions; Change in other PROs as in part 2; Change in the frequency of anaphylactic episodes; Safety and tolerability of avapritinib, as in part 2 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients who are ≥ 18 years of age.
2. Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and ISM or SSM subtype, as confirmed by WHO diagnostic criteria. In Part 1 of the study, only patients with a diagnosis of ISM are eligible.
3. Patient must have moderate-to-severe symptoms based on minimum mean TSS over the 14-day eligibility screening period for assessment of TSS and ≥ 1 symptom in skin or GI domains of the ISM-SAF at Baseline. Minimum TSS for eligibility is ≥ 28.
4. Patient must have failed to achieve symptom control for 1 or more Baseline symptoms measured by ISM-SAF, as determined by the Investigator, with at least 2 of the following symptomatic therapies administered at optimal (approved) dose and for a minimum of 28 days before starting the ISM-SAF for determination of eligibility: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
5. Patient must have symptom management optimized with symptomatic therapies (eg, H1 and H2 blockers) and the dose must be stable for ≥ 14 days before starting the ISM-SAF for determination of eligibility.
6. If the patient is receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days before starting the ISM-SAF for determination of eligibility.
7. Patient must have an Eastern Cooperative Oncology Group Performance Status of 0 to 2.
8. Patient must give written informed consent. |
|
| E.4 | Principal exclusion criteria |
1. Patient has been diagnosed with any of the following WHO SM subclassifications: CM only, SM-AHN, 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, Albumin < 1 × LLN, eGFR < 30 mL/min/1.73 m^2 or creatinine clearance calculated by Cockcroft-Gault equation < 40 mL/min, Absolute neutrophil count < 1.5 × 10^9/L, Hemoglobin < 10 g/dL, Platelet count < 100 × 10^9/L.
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 < 14 days before starting the ISM-SAF for determination of eligibility, Any antineoplastic drug therapy < 28 days before starting the ISM-SAF for determination of eligibility, Radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before starting the ISM-SAF for determination of eligibility, Any hematopoietic growth factor < 14 days before starting the ISM-SAF for determination of eligibility, 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 cytochrome P450 3A4 (CYP3A4).
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. 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.
8. Patient has a QTcF > 450 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 intracranial bleeding (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 IV congestive heart failure according to the New York Heart Association classification; myocardial infarction or unstable angina within the previous 6 months; clinically significant, uncontrolled arrhythmias, or uncontrolled hypertension.
14. Patient is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures, including mandatory BM and skin biopsies, and study restrictions.
15. 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 30 days 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 90 days after the last dose of study drug.
16. Pregnant women, as documented by a β-hCG pregnancy test consistent with pregnancy obtained within 7 days before the first dose of study drug. Women with β-hCG values that are within the range for pregnancy but are not pregnant (false-positives) may be enrolled with written approval of the Sponsor after pregnancy has been excluded. Women of nonchildbearing potential (postmenopausal, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) do not require a serum β-hCG pregnancy test.
17. Women who are breast feeding.
18. Patient has a prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's opinion, could affect the safety of the patient, alter the absorption, distribution, metabolism or excretion of the study drug, or impair the assessment of study results.
19. Patient is illiterate or otherwise unable or unwilling to complete daily ISM-SAF assessments in the eDiary. Patient must be fluent in the language(s) available for the ISM-SAF and other QoL questionnaires. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1 - RP2D in patients with ISM.
Part 2 - mean change in ISM-SAF TSS.
Part 3 - long-term safety and efficacy of avapritinib. |
|
| 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 - from Baseline to Week 12
Part 3 - weekly for 4 weeks, then every 4 weeks for 5 months, and then every 3 months, for a total of 2 years from C1D1; patients still on study after 2 years will have visits every 6 months (24 weeks) for a total study duration of 5 years, inclusive of Part 1 and Part 2 |
|
| E.5.2 | Secondary end point(s) |
Part 1 and Part 2
• Change in measures of MC burden:
o Serum tryptase.
o KIT D816V allele burden in blood.
o BM MCs.
o Skin MCs in patients with baseline CM.
• Change in percent body surface area (BSA) involved by CM and change in pigmentation of cutaneous lesions in patients with baseline CM.
• Change in BSC concomitant medication usage.
• Change in "lead symptom" score of ISM-SAF from Baseline to Week 12.
• Proportion of patients with at least 5-point, 10-point, and 15-point reductions in TSS and domain scores of ISM-SAF from Baseline to Week 12.
• Time to achieve 5-point, 10-point, 15-point, and maximum reductions in TSS and domain scores of ISM-SAF.
• Change in domain scores and individual symptom scores of ISM-SAF from Baseline to Week 12.
• Change in MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L.
• Change in number of episodes of anaphylaxis, based on epinephrine use.
• Safety and tolerability of avapritinib, as assessed by AEs, vital signs, ECGs, and laboratory tests.
• Pharmacokinetics of avapritinib.
• Correlations between avapritinib exposure and safety and efficacy endpoints.
Part 3
• Change in the following measures of MC burden:
o Serum tryptase.
o KIT D816V allele burden in blood.
o BM MCs (optional).
o Skin MCs in patients with baseline CM (optional).
• Change in BSA involved by CM and change in pigmentation of cutaneous lesions in patients with baseline CM.
• Change in BSC concomitant medication usage.
• Change in "lead symptom" score of ISM-SAF.
• Change in TSS, domain scores, and individual symptom scores of ISM-SAF from Part 3 baseline (and from Part 1 and Part 2 baseline for patients receiving same dose of avapritinib in both study parts) to Weeks 12, 24, 36, and 52.
• Time to achieve 5-point, 10-point, and 15-point, and maximum reductions in TSS and domain scores of ISM-SAF from Part 3 baseline (and from Part 1 and Part 2 baseline for patients receiving same dose of avapritinib in both study parts).
• Changes in MC-QoL, PGIS, SF-12, PGIC, and EQ-5D-5L.
• Change in number of episodes of anaphylaxis, based on epinephrine use.
• Safety and tolerability of avapritinib, as assessed by AEs, vital signs, ECGs, and laboratory tests. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Tryptase: Screening, every visit through C3D8 (P1-2); every visit (P3)
•KIT D816V allele burden: Screening, C1D1/D15, C2D1, C3D8 (P1-2), every 4W until P3 (P1); C1D1, C3D1, every 12W during C6-25, every 24W during C26 through end of study (P3)
•BM & skin biopsy: Screening, between C3D8 & D15 (P1-2); optional at W52 (P3)
•Skin photo: Screening, between C3D8 & D15, every 12W until W52 in P3
•ISM-SAF: daily from baseline to W12 (P1-2); from P3 baseline to W12/24/36/52
•QoL: each visit through P3 W52
•Anaphylaxis episode: Screening, throughout study
•AE & BSC: throughout study
•Vital signs, hematology & chemistry: every visit until EOT
•ECG: Screening, C1D1, C2D1, C3D8 (P1-2), between C3D8 & D15, D1 of every C (P1); D1 of every P3 visit
•PK: before & after study drug dosing (P1-2) |
|
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| 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 |
| Belgium |
| Canada |
| Denmark |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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 (LPLV), including assessments performed as part of safety follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 28 |
| 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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