| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Systemic Mastocytosis (AdvSM) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056453 |
| E.1.2 | Term | Aggressive systemic mastocytosis |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| The primary objective is to determine adjudicated ORR (CR/ CRh + PR + CI) based on modified IWG-MRT-ECNM consensus response criteria in patients with AdvSM treated with avapritinib and enrolled in Cohort 1. |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objective: Assess mean change from baseline in AdvSM-SAF TSS
Additional secondary objectives
• Determine local investigator determined ORR based on modified IWG-MRT-ECNM response criteria, using C-findings when present at baseline
• Determine time-to-event outcomes including time-to-response (TTR), DOR, PFS, and OS
• Determine morphologic response (CR/CRh+ PR) based on Pure Pathological Response criteria.
• Determine ORR and other clinical outcome measures (DOR, PFS, OS) analyzed by prior therapy and by genotype
• Assess changes in the following individual measures of MC burden: BM MCs, serum tryptase, KIT mutation burden in PB and BM, liver and spleen volume by imaging
• Assess additional PROs using the AdvSM-SAF and changes in QoL measures
• Assess safety and PK of avapritinib
• Correlate avapritinib exposure with safety and efficacy endpoints |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients who are ≥ 18 years of age.
2. Patients must have 1 of the following diagnoses as confirmed by WHO diagnostic criteria (Appendix 4, Appendix 5, and Appendix 6). Before enrollment, the SSC must confirm the diagnosis of AdvSM (based on Central Pathology Laboratory assessment of BM).
o ASM.
o SM-AHN.
The AHN must be myeloid, with the following exceptions that are excluded:
• AML.
• Myelodysplastic syndrome that is very high- or high-risk, as defined by the International Prognostic Scoring System for Myelodysplastic Syndromes (Greenberg et al, 2012).
• A myeloid AHN with ≥ 10% BM or PB blasts.
• Philadelphia chromosome-positive malignancies.
Incidental indolent, low-grade lymphoid AHNs (eg, chronic lymphocytic leukemia) not requiring treatment are eligible.
o MCL, including diagnoses with an AHN component.
3. Patients with SM-AHN should have received prior treatment for the AHN component of disease if, in the opinion of the Investigator, such therapy was appropriate.
4. Patient must have a BM biopsy taken within 56 days of C1D1, assessed by the Central Pathology Laboratory.
5. Cohort 1 only: Patient must have at least 1 of the following measurable C-findings, per modified IWG-MRT-ECNM criteria, attributed to SM (Appendix 6, unless diagnosis is MCL, which does not require a C-finding). Laboratory abnormality C-findings should not be assessed until the required washout period from last cytoreductive therapy has been met. If a C-finding improves during the Screening period, prior to dosing, and no longer meets criteria for evaluability, it can no longer be counted as a C-finding. In addition,
• Patients must have documented evidence of mast cell aggregates in the bone marrow or other extracutaneous organ based on central pathology.
• Patient must be willing to have follow up biopsies of affected organ(s) to document response.
Measurable C-findings:
o Cytopenias:
• ANC < 1.0 × 10^9/L or
• Hemoglobin < 10 g/dL or
• Platelet count < 75 × 109/L.
NOTE: Cytopenias attributable to prior cytoreductive therapy or causes other than SM may not be used as C-findings.
o Symptomatic ascites or pleural effusion requiring medical intervention such as:
• Use of diuretics (Grade 2) or
• ≥ 2 therapeutic paracenteses or thoracenteses (Grade 3) at least 28 days apart over the 12 weeks before
C1D-8 and 1 of the procedures is performed during the 6 weeks before C1D-8.
o ≥ Grade 2 abnormalities in direct bilirubin (> 1.5 × upper limit of normal [ULN]), aspartate aminotransferase (AST; > 3.0 × ULN), alanine aminotransferase (ALT; > 3.0 × ULN), or alkaline phosphatase (> 2.5 × ULN) with 1 of the following present:
• Ascites or
• Clinically relevant portal hypertension or
• Liver MC infiltration that is biopsy-proven or
• No other identified cause of abnormal liver function.
o ≥ Grade 2 hypoalbuminemia (< 3.0 g/dL).
o A spleen that is palpable ≥ 5 cm below the left costal margin.
o Transfusion-dependent anemia defined as:
• Transfusion of ≥ 6 units packed red blood cells (PRBCs) in the 12 weeks before C1D-8 and
• Most recent transfusion occurring during the 4 weeks before C1D-8 and
• Transfusion administered for hemoglobin ≤ 8.5 g/dL and
• Reason for transfusion is not bleeding, hemolysis, or therapy-related.
6. Patient must have a serum tryptase ≥ 20 ng/mL.
7. Patients receiving cytoreductive therapy within the preceding 12 weeks must have discontinued therapy due to disease progression, refractory disease, lack of efficacy, or intolerance.
8. Patient’s non-antineoplastic SM therapies (ie, BSC; eg, H1 and H2 blockers) must be stable (same dose, no new medications for SM) for ≥ 14 days C1D-8. This criterion is not applicable if a patient has progressive disease and it is in the patient’s best interest to enroll in the study rapidly with Medical Monitor approval.
9. If the patient is receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent and dose must be stable for ≥ 14 days before C1D-8. This criterion is not applicable if the patient has progressive disease, and it is in the patient’s best interest to enroll in the study rapidly with Medical Monitor approval.
10. Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 3.
11. Patient must be able to give written informed consent. |
|
| E.4 | Principal 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. If the patient has progressive disease and it is in the patient’s best interest to enroll in the study rapidly, cytoreductive therapy may be discontinued 1 day before the screening BM biopsy with approval from the Medical Monitor. Cytoreductive therapy may not be restarted during Screening or while on study.
3. Patient has received prior radiotherapy within 14 days before the screening BM biopsy, unless given to palliate specific sites of disease (eg, bone lesion).
4. Patient received any hematopoietic growth factor within 14 days of screening BM biopsy.
5. Patient requires therapy with a concomitant medication that is a strong inhibitor, strong inducer, or moderate inducer of CYP3A4 (Appendix 13).
6. Patient has had a major surgical procedure within 14 days of the first dose of study drug. Surgical procedures such as central venous catheter placement, BM biopsy, and feeding tube placement are considered minor surgical procedures.
7. Patient is a candidate for allogeneic hematopoietic stem cell transplantation for treatment of SM, in the opinion of the Investigator.
8. 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 PCR.
9. Patient has history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug.
10. Patient meets any of the following laboratory criteria:
o AST or ALT > 3.0 × ULN; no restriction if due to suspected liver infiltration by MCs.
o Bilirubin > 1.5 × ULN; no restriction if due to suspected liver infiltration by MCs or Gilbert’s disease. (In the case of Gilbert’s disease, a direct bilirubin > 2.0 × ULN would be an exclusion.)
o Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 or creatinine> 1.5 × ULN.
oPlatelet count < 50,000/µL (within 4 weeks of the first dose of study drug) or receiving platelet transfusion(s)
11. Patient has a QT interval corrected using Fridericia’s formula (QTcF) > 480 msec.
12. Patient has a history of a seizure disorder (eg, epilepsy) or requirement for antiseizure medication.
13. Patient has a history of a cerebrovascular accident or transient ischemic attacks within 1 year before the first dose of study drug.
14. 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).
15. Patient has a primary brain malignancy or metastases to the brain.
16. 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.
17. Patient is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.
18.Female patients who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the first dose of study drug 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 from the first dose of study drug and for at least 6 weeks after the last dose of study drug. Refer to Section 9.6.1 for acceptable methods of contraception.
19. Female patients who are pregnant, as documented by a serum beta human chorionic gonadotropin (β-hCG) pregnancy test consistent with pregnancy obtained within 15 days before the first dose of study drug.
20. Women who are breast feeding.
21. Patient has a prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the opinion of the Investigator, 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.
22. Hypersensitivity to avapritinib or to any of the excipients.
23. Patient is participating in another interventional study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Adjudicated ORR (CR/CRh + PR + CI) based on modified IWG-MRT-ECNM criteria, confirmed 12 weeks after initial response in patients in Cohort 1 only. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At C1D15, C2D1, C3D1, C7D1 and C11D1 and then every 6 cycles. Also performed 12 weeks (± 4 weeks) after documentation of CR or PR to confirm response and 4 weeks after SM and/or AHN PD or clinical progression to confirm PD. Performed at EOT if patient discontinues for reasons other than PD or initiation of alternative cytoreductive therapy. |
|
| E.5.2 | Secondary end point(s) |
• Mean change from baseline in AdvSM-SAF TSS in patients in Cohorts 1 and 2.
Additional secondary endpoints for patients in Cohorts 1 and 2:
• Local Investigator assessed ORR (CR/CRh + PR + CI) based on modified IWG MRT ECNM criteria, using C-findings when present, confirmed 12 weeks after initial response.
• Objective response rate (CR/CRh + PR) based on Pure Pathological Response criteria
• Time-to-event outcomes including TTR, DOR, PFS, and OS.
• CR/CRh + PR and clinical benefit (CR/CRh + PR + CI + SD) based on modified IWG-MRT-ECNM criteria.
• Overall response rate and other clinical outcome measures (DOR, PFS, OS) analyzed by prior therapy and by genotype.
• Changes in BM MCs, serum tryptase, KIT mutation burden (eg, D816V) in PB and BM, and liver and spleen volume by imaging.
• Mean change from baseline in AdvSM-SAF domain and individual symptom scores.
• Changes in PGIS and EORTC QLQ-C30 (global health status, functional scales, and symptom scales/items) score.
• Safety of avapritinib, as assessed by AEs, changes in vital signs, ECGs, and laboratory testing.
• PK of avapritinib.
• Correlations between avapritinib exposure and safety and efficacy endpoints. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•AdvSM-SAF: daily from C1D7 to C17 or until pt stops
•OS: until death or loss to F/U
•BM biopsy/aspirate: screening, C3D1, C7D1, C11D1, every 6 cycles, EoT, PD F/U
•Serum tryptase: screening, C1D15, C2D1, C3D1, C7D1, C11D1, every 6 cycles, EoT, PD F/U
•Liver/spleen imaging: screening, C3D1, C7D1, C11D1, every 6 cycles, EoT
•KIT D816V mutant allele burden: screening, C1D1/D15, C2D1, C3D1, C7D1, C11D1, every 6 cycles, EoT, PD F/U
•Resp: C1D15, C2D1, C3D1, C7D1, C11D1, every 6 cycles, EoT, PD F/U
•PGIS, EORTC-QLQ-C30: each visit through C17, EoT
•AE: from C1D1 to Safety F/U
•Vital signs, ECG: each visit through EoT
•Lab: screening, each visit from C1D15 to EoT, PD F/U
•Std PK: C1D1/D15, C2D1, C3D1, C5D1
•Intensive PK (subset of 15 pts): C1D1/D2/D3/D15/D16/D17, C2D1, C3D1, C5D1
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 20 |
| 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 |
| Canada |
| United States |
| Austria |
| Denmark |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 follow-up for OS, if the patient enters the OS follow-up period of the study. |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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