| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| GIST - unresectable/metastatic Gastrointestinal Stromal Tumor after failure of standard therapy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Gastrointestinal Stromal Tumor (GIST) |
|
| 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 | 10062427 |
| E.1.2 | Term | Gastrointestinal stromal tumor |
| 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 |
| To assess anti-tumor activity of avelumab in combination with axitinib in patients with unresectable/metastatic GIST after progression despite previous treatment with at least imatinib and sunitinib |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary goals include the assessment of progression-free survival, overall survival, the response rate according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumors), duration of response, disease control percentage, and CTCAE v.4.0 adverse event score (Common Terminology Criteria for Adverse Events), and the assessment of potential biomarkers of prognostic and predictive importance for the prognosis of patients |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent.
2. Male or female subjects aged ≥ 18 years.
3. Histologically proven locally advanced or metastatic GIST. C-Kit (CD117) positive tumors detected by immunohistochemistry
4. Known mutational status KIT or PDGFRA.
5. Documented disease progression (as per RECIST 1.1) within 3 months before study entry
6. No more than 3 previous lines of treatment, which must include imatinib and sunitinib .
7. Performance status ≤ 2 at trial entry and an estimated life expectancy of at least 3 months.
8. Disease must be measurable with at least 1 unidimensional measurable lesion by RECIST 1.1. Clinically and/or radiographically documented measurable disease within 21 days prior to registration
• CT-scan, physical exam ≥10 mm
• Chest X-ray ≥20 mm
• Lymph node short axis ≥15 mm
All radiology studies must be performed within 21 days prior to registration.
9. Adequate hematological function defined by the following laboratory tests results, obtained within 14 days prior to initiation of study treatment
- white blood cell (WBC) count ≥ 3 × 109/L with absolute neutrophil count (ANC) ≥ 1.5 × 109/L,
- lymphocyte count ≥ 0.5 × 109/L,
- platelet count ≥ 100 × 109/L,
- hemoglobin ≥ 9 g/dL (patients may be transfused).
10. Adequate hepatic function defined by
- total bilirubin level ≤ 1.5 × the upper limit of normal range (ULN),
- an AST level ≤ 2.5 × ULN, and an ALT level ≤ 2.5 × ULN or, for subjects with documented metastatic disease to the liver, AST and ALT levels ≤ 5 × ULN.
11. Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 ml/min on the basis of the Cockroft- Gault glomerular filtration rate estimation:
(140-age) x (weight in kg) x (0,85 if female)/72x(serum creatinine in mg/dl)
12. No clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), Uncontrolled hypertension (systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg , unstable angina, congestive heart failure (≥2 New York Heart Association Classification medication) serious cardiac arrhythmia. All other significant diseases (e.g., inflammatory bowel disease), which, in the opinion of the investigator, might impair the subject’s tolerance of trial treatment;
13. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
14. Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) >1.5 or an activated partial thromboplastin time (aPTT) >1.5 x ULN within 7 days prior to first study treatment. Note: Patients receiving full dose oral or parenteral anticoagulants may be included in the study as long as anticoagulant dosing has been stable for at least 2 weeks prior to study entry and the appropriate coagulation monitoring tests are within local therapeutic limits;
15. Effective contraception for both male and female subjects if the risk of conception exists. (Note: The effects of the study drugs on the developing human fetus are unknown. Thus, women of childbearing potential and men must agree to use effective contraception, defined as 2 barrier methods e.g. implants, injectables, combined oral contraceptives in combination with a barrier method, some intrauterine contraceptive devices, sexual abstinence, or a vasectomized partner;)
16. Availability of representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks.
|
|
| E.4 | Principal exclusion criteria |
1. Concurrent anticancer treatment within 14 days before the start of trial treatment (e.g., cytoreductive therapy, radiotherapy [with the exception of palliative bone directed radiotherapy], immune therapy, or cytokine therapy except for erythropoietin); major surgery within 28 days before the start of trial treatment (excluding prior diagnostic biopsy); use of hormonal agents within 7 days before the start of trial treatment; or use of any investigational drug within 28 days before the start of trial treatment.
2. Patients with PDGFRA D842V mutations are not eligible for this study.
3. Previous treatment with anti-PD-1 or anti-PD-L1 antibodies, previous therapy with axitinib.
4. Persisting toxicity related to prior therapy Grade > 1 CTCAE v 4.0,
5. Major surgical procedure within 28 days prior to the first study treatment, or anticipation of the need for major surgery during the course of the study treatment; or minor surgical procedures, within 24 hours prior to the first study treatment;
6. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
7. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration except for adrenal replacement steroid. The use of inhaled corticosteroids for chronic obstructive pulmonary disease is allowed.
8. History of abdominal fistula, grade 4 bowel obstruction or gastrointestinal perforation, intra-abdominal abscess within 6 months of enrollment;
9. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan
10. Significant acute or chronic infections including, among others: positive testing for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS);
11. Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening. Patients with past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study.
12. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test and positive HCV RNA test at screening
13. Active tuberculosis
14. Severe infection within 2 weeks prior initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteriemia or severe pneumonia
15. Brain or leptomeningeal metastases, history of intracranial hemorrhage
16. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the course of the study
17. Known alcohol or drug abuse.
18. Inability or unwillingness to swallow pills
19. Pregnant or breastfeeding, or intending to become pregnant during the study. Woman of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.
20. Symptomatic brain metastases, history of intracranial hemorrhage
21. Previous enrollment in this study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Rate of Participants Achieving 3-Month Progression-Free Survival (PFSR) defined as a percentage of patients with a documented total, partial or stabilization response after 3 months of treatment according to the RECIST 1.1 criteria.
SAFETY
Toxicity levels according to common terminological criteria for adverse events developed by the National Cancer Institute of Common Terminology Criteria for Adverse Events, NCI-CTCAE, version 4.0 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary end-point of the study is progression free survival 3 months after start of therapy, measured as a binary variable. Patients will be considered as “success” if one radiological evaluation performed after 3 months therapy indicates a “stable disease” or a “response” as defined by the RECIST method; all other cases will be considered as failures. |
|
| E.5.2 | Secondary end point(s) |
• Overall survival (OS)
• Progression free survival (PFS)
• Disease control rate (DCR) [
• the percentage of responses to treatment and the duration of the response.
Exploring endpoints:
Collection of biological material for translational research projects to detect potential biomarkers of prognostic and predictive importance for the prognosis of patients |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PFS: [time from treatment initiation to date of first documentation of progression of disease assessed by the Investigator (by RECIST version 1.1) or death due to any cause]
OS:[time from the date of treatment initiation until the date of death from any cause]. The observation of patients still alive will be censored at the time of the last visit / contact
The assessment of adverse events according to the CTCAE v.4.0 classification (Common Terminology Criteria for Adverse Events) will take place at every medical visit (every 2 weeks)
Collection of biological material for translational research will take place:
- tumor tissue biopsy before treatment
- peripheral blood sampling before treatment, after 8 weeks of treatment, after confirmation of disease progression |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| 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 | No |
| 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 | No |
| E.8.1.7 | Other | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| LVLS (Last Visit Last Subject) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 20 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 20 |
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