| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally Advanced Unresectable or Metastatic Gastrointestinal Stromal Tumor (GIST) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Gastrointestinal Tumours and Solid Tumours |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10051066 |
| E.1.2 | Term | Gastrointestinal stromal tumour |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to demonstrate the efficacy of avapritinib based on progression-free survival (PFS) determined by central radiological assessment per modified Response Evaluation Criteria in Solid Tumors (mRECIST), version 1.1 in patients with advanced GIST following 2 or 3 prior TKI therapies, including imatinib, compared to patients treated with regorafenib. |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives:
• To evaluate objective response rate (ORR) determined by central radiology assessment per mRECIST, version 1.1 in patients with advanced GIST treated with avapritinib compared to patients treated with regorafenib.
• To evaluate overall survival (OS) in patients with advanced GIST treated with avapritinib compared to patients treated with regorafenib. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients who are ≥ 18 years of age.
2. Patients who have GIST, which is histologically confirmed metastatic and/or
unresectable (confirmed to be unresectable by a qualified surgeon).
3. Patients who have received imatinib and 1 or 2 other TKIs for the treatment of GIST, including TKIs used for adjuvant therapy. Each different TKI is counted once
regardless of how often it was used, and if 2 different TKIs are used in combination, both TKIs are counted. Patients must have disease progression prior to enrollment. Prior use of other systemic and local therapies is not restricted.
4. Patients who have an ECOG PS of 0 to 1.
5. Patient, or legal guardian if permitted by local regulatory authorities, who provides informed consent to participate in the study |
|
| E.4 | Principal exclusion criteria |
1. Patients who have received prior treatment with avapritinib or regorafenib.
2. Patients who have previously received more than 3 different TKIs for the treatment of GIST, including TKIs used for adjuvant therapy. Each different TKI is counted once regardless of how often it was used, and if 2 different TKIs are used in combination, both TKIs are counted.
3. Patients who are known to be both KIT and PDGRFα wild type.
4. Patients who received any systemic anticancer therapy within 1 week before the first dose of study drug. Prior radiotherapy (including stereotactic radiotherapy) to major organs within 2 weeks of the first dose of study drug, or focal radiotherapy, (including stereotactic radiotherapy), such as to bones, limbs, or other areas not involving major organs, within 3 days.
5. Patients who have clinically significant, uncontrolled, cardiovascular disease, including congestive heart failure Grades II, III or IV according to the New York Heart Association classification, myocardial infarction or unstable angina within the previous 6 months, or uncontrolled hypertension.
6. Patients who have experienced arterial thrombotic or embolic events such as cerebrovascular accident within 6 months before the first dose of study drug, or venous thrombotic events such as pulmonary embolism or deep vein thrombosis within 14 days before the first dose of study drug. Patients with venous thrombotic events such as pulmonary embolism or deep vein thrombosis ≥ 14 days before the first dose of study drug are not excluded provided they are on stable doses of anticoagulation, or have completed the planned anti-coagulation regimen.
7. Patients who have experienced any hemorrhage or bleeding event NCI CTCAE version 5.0 Grade 3 or higher within 4 weeks before the first dose of study drug.
8. Patients who have a known risk of intracranial bleeding, such as a brain aneurysm that has not been removed or repaired, or a history of intracranial bleeding within one year prior to the first dose of study drug.
9. Patients who have a symptomatic non-healing wound, ulcer, gastrointestinal perforation, or bone fracture.
10. Patients who have poor organ function as defined by one or more laboratory parameters, as described in the Protocol.
11. Patients who have received neutrophil growth factor support within 14 days of the first dose of study drug.
12. Patients who require therapy with a concomitant medication that is a strong inhibitor or strong or moderate inducer of CYP3A4.
13. Patients who have had a major surgical procedure within 14 days of the first dose of study drug. Patient has significant traumatic injury within 28 days before the first dose of study drug.
14. Patients who have a history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of study drug.
15. Patients who have a history of a seizure disorder requiring anti-seizure medication.
16. Patients who have metastases to the brain.
17. Patients who are unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions.
18. Patients who have a QT interval corrected using Fridericia's formula (QTcF) of > 450 msec
19. Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of the first dose of study drug and for at least 60 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 from the time of the first dose of study drug and for at least 90 days after the last dose of study drug.
20. Women who are pregnant, as documented by a serum beta human chorionic gonadotropin (βhCG ) pregnancy test consistent with pregnancy, obtained within 7 days before the first dose of study drug.
21. Women who are breastfeeding.
22. Patients who have prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s opinion, could put the patient at an unacceptably high risk for toxicities, or alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.
23. Patients with a known hypersensitivity to avapritinib, regorafenib, or the excipients in either study drug. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is progression-free survival (PFS), based on central radiological assessment per mRECIST, version 1.1, in patients with advanced GIST. PFS is defined as time from randomization to disease progression, or death due to any cause, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis for PFS is based on the central radiological assessment of progressive disease (PD) per mRECIST, version 1.1 in the ITT population. Patients without disease progression or death at the time of analysis will be censored at their last date of tumor evaluation. Patients who withdraw from the study and receive subsequent antineoplastic therapy without documented PD will be censored at the time of the last adequate (CT or MRI scan available) disease assessment.
For PD documented between scheduled evaluations, the actual date of PD will be used not the date of the next scheduled evaluation. For death or PD after no more than 1 missed evaluation, the date of the event will be the date of PD or death, whichever occurs first. |
|
| E.5.2 | Secondary end point(s) |
• Objective response rate defined as the percentage of patients whose best response is complete response (CR) or partial response (PR) as assessed by central radiology using mRECIST, version 1.1.
• Overall survival defined as the time from date of randomization to death due to any cause.
• All individual EORTC QLQ-C30 scores, eg, physical functioning score, pain score, role functioning score, appetite loss score, etc.
• Adverse events, serious AEs (SAEs), and changes in safety laboratory parameters, 12-lead ECG evaluations, and Eastern Cooperative Oncology Group Performance Status (ECOG PS). The intensity of AEs will be assessed by the NCI CTCAE, version 5.0.
• Response as assessed by Investigator per mRECIST, version 1.1. and assessed by central radiology per Choi criteria.
• Disease control is defined as the rate of CR, or PR of any duration, or SD lasting for at least 16 weeks per mRECIST, version 1.1.
• Duration of response defined as the time from first documentation of tumor response to disease progression or death due to any cause.
• Plasma drug concentration at specified time points.
• Abdominal pain, as measured by a numeric rating scale (0-10). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The Kaplan-Meier method will be used to estimate the distribution of PFS for each treatment group. The primary treatment comparison is based on a stratified log-rank test in the intent-to-treat population. The hazard ratio, and its 95% confidence interval (CI), are to be estimated based on a stratified Cox's model with treatment as the explanatory variable. Stratification factors include treatment regimen (third vs. fourth), geographic region (Asia vs. rest of the world), and mutation status measured in ctDNA or a tumor sample (PDGFRα D842V mutation present vs absent ).
One interim analysis for futility and efficacy will be performed at approximately 50% of the information fraction (ie, 132 PFS events). |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Singapore |
| Spain |
| Sweden |
| 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 PFS follow-up, if the patient enters the PFS follow-up part of the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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