| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients with advanced or metastatic digestive solid tumors |
| Patients porteurs de tumeurs solides digestives localement avancées et/ou métastatiques |
|
| E.1.1.1 | Medical condition in easily understood language |
| Adult patients with advanced or metastatic digestive solid tumors |
| Patients porteurs de tumeurs solides digestives localement avancées et/ou métastatiques |
|
| 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 | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| 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 | 20.0 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10017991 |
| E.1.2 | Term | Gastrointestinal neoplasms malignant and unspecified |
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073073 |
| E.1.2 | Term | Hepatobiliary cancer |
| 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 |
Phase I :
Primary objective of the phase I trial is to establish the recommended phase II dose (RP2D), the maximum tolerated dose (MTD) evaluated on the first cycle (D1 to D28), the safety profile, and the dose limiting toxicities (DLT) of Regorafenib when prescribed in association with Avelumab (no dose escalation for Avelumab) in patients treated for advanced digestive solid tumors.
Phase II :
To investigate the antitumor activity of Regorafenib when prescribed in association with Avelumab, independently for 4 cohorts of patients (Colorectal cancer not MSIH or MMR-deficient / GIST / Oesophageal or gastric carcinoma / Biliary tract cancer, hepatocellular carcinoma). Antitumoral activity will be assessed in terms of objective response under treatment as per RECIST 1.1 after in-stream centralized radiological review. |
Phase I :
Définir la dose recommandée pour la phase II (RP2D), la dose maximale tolérée (MTD) évaluée sur le premier cycle de traitement (J1 à J28), le profil de tolérance et les toxicités doses limitantes (DLT) du Regorafenib prescrit en association avec l’Avelumab chez des patients traités pour des tumeurs solides digestives avancées.
Phase II :
Evaluer l’activité anti-tumorale du Regorafenib prescrit en association avec l’Avelumab, indépendamment pour 4 cohortes de patients (cancer colorectal non MSI-High ou MMR-déficient / GIST / carcinome oesophagien ou gastrique / cancer des voies biliaires, carcinome hépatocellulaire). L’activité anti-tumorale sera évaluée en termes de réponse objective sous traitement, selon les critères RECIST v1.1 et après relecture radiologique centralisée en temps réel. |
|
| E.2.2 | Secondary objectives of the trial |
Phase I :
- Evaluate preliminary signs of anti-tumor activity of Regorafenib in association with Avelumab in terms of 6-month objective response, 6-month progression-free status, best overall response, objective response under treatment, growth modulation index, 1-year progression free survival and 1 year overall survival.
- Describe the pharmacokinetics of Regorafenib in association with Avelumab.
Phase II :
- Evaluate the antitumor activity of Regorafenib in association with Avelumab in terms of 6-month objective response, 6-month progression-free status, best overall response, growth modulation index, 1-year progression-free survival and 1 year overall survival.
- Evaluate the Regorafenib safety profile in association with Avelumab.
Phase I and II :
- Biomarkers analysis as well as predictive biomarkers analysis (levels of angiogenic and immunologic biomarkers in blood/tissue at baseline and different study time points). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histology:
- Dose escalation part: histologically confirmed non MSI-H or MMR-deficient colorectal cancer, or GIST, or oesophageal or gastric carcinoma or hepatobiliary cancers,
- Expansion cohort : histologically confirmed non MSI-H or MMR-deficient colorectal cancer (cohort A), or GIST (cohort B), or oesophageal or gastric carcinoma (cohort C) or hepatobiliary cancers (cohort D),
As recommended by INCa, patients with GIST must have diagnosis histologically confirmed by central review, except if it has been already confirmed by the RRePS Network.
2. Advanced non resectable / metastatic disease,
3. Age ≥ 18 years,
4. ECOG, Performance status ≤ 1,
5. Measurable disease according to RECIST (outside any previously irradiated field). At least one site of disease must be uni-dimensionally ≥ 10 mm,
6. Life expectancy > 3 months,
7. ≥ 1 previous line (s) of systemic therapy
8. Adequate hematological, renal, metabolic and hepatic functions:
a. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 109/l and platelet count ≥ 100 x 109/l, lymphocytes ≥ 1000/mm3.
b. Alkaline phosphatase (AP), alanine aminotransferase (ALT) and aspartate aminotransferase (ASP) ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of extensive skeletal involvement for AP exclusively and ≤ 5 x ULN in case of liver metastasis for AST and ALT).
c. Total bilirubin ≤ 1.5 x ULN.
d.Albumin ≥ 25g/l.
e. Calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft and Gault formula).
f. Creatine phosphokinase (CPK) ≤ 2.5 x ULN
g. INR < 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
h. aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
i. Lipase ≤ 1.5 X ULN
j. Cohort specific criteria: Patients with hepatocellular carcinoma must have a correct hepatocellular function, id est Child-Pugh A.
9. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in situ transitional bladder cell carcinoma,
10. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy,
11. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment, excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (according to the National Cancer Institute Common Terminology Criteria for Adverse Event (NCI-CTCAE, version 4.0)),
12. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
13. Both women and men must agree to use an highly effective method of contraception throughout the treatment period and for eight weeks after discontinuation of treatment. Acceptable methods for contraception include intrauterine device (IUD), oral contraceptive, subdermal implant and double barrier. Subjects of childbearing potential are those who have not been surgically sterilized (e.g., vasectomy for males and hysterectomy for females) or have not been free from menses for ≥ 1 year.
14. Voluntary signed and dated written informed consents prior to any specific study procedure,
15. Patients with a social security in compliance with the French law. |
1. Histologie :
- Phase d’escalade de dose : diagnostic histologiquement confirmé de cancer colorectal non MSI-H ou MMR-déficient, ou GIST, ou carcinome oesophagien ou gastrique, ou cancer des voies biliaires/hépatocarcinome,
- Cohortes d’expansion : diagnostic histologiquement confirmé cancer colorectal non MSI-H ou MMR-déficient (cohorte A), ou GIST (cohorte B), or carcinome oesophagien ou gastrique (cohorte C) ou cancer des voies biliaires/hépatocarcinome (cohorte D),
Selon les recommandations de l’INCa, les patients avec une GIST doivent avoir un diagnostic histologique confirmé par relecture centralisé sauf si ce dernier a été vu/revu par le réseau RRePS.
2. Maladie localement avancée non opérable / maladie métastatique,
3. Age ≥ 18 ans,
4. ECOG, Performance status ≤ 1,
5. Maladie mesurable selon les critères RECIST (en dehors de champs d’irradiation). Existence d’au moins une lésion (plus grand diamètre) ≥ 10 mm,
6. Espérance de vie > 3 mois,
7. ≥ 1 ligne(s) de traitement antérieur systémique,
8. Fonctions hématologiques, rénales, métaboliques et hépatiques:
a. Hémoglobine ≥ 9 g/dl (les transfusions préalable de globules rouges sont autorisées); taux de neutrophiles ≥ 1.5 x 109/l et taux de plaquettes ≥ 100 x 109/l.
b. Phosphatase alcaline (AP), alanine aminotransférase (ALT) et aspartate aminotransférase (ASP) ≤ 2.5 x limite normale supérieure (ULN) (≤ 5 en cas de
métastases osseuses pour AP exclusivement et ≤ 5 x ULN en cas de métastases hépatiques pour AST et ALT).
c. Bilirubine totale ≤ 1.5 x ULN.
d.Albumine ≥ 25g/l.
e. Clairance de la créatinine (CrCl) ≥ 30 ml/min (selon la formule de Cockroft and Gault).
f. Créatine phosphokinase (CPK) ≤ 2.5 x ULN
g. INR < 1.5 x ULN à moins que le patient ne reçoive un traitement anticoagulant, auquel cas PT ou PTT doivent restent dans la fenêtre thérapeutique d’utilisation des anticoagulants
h. aPTT ≤ 1.5 X ULN à moins que le patient ne reçoive un traitement anticoagulant, auquel cas PT ou PTT doivent restent dans la fenêtre thérapeutique d’utilisation des anti-coagulants.
i. Lipase ≤ 1.5 X ULN
j. Critère spécifique à la cohorte D : les patients avec un carcinome hépatocellulaire doivent avoir une fonction hépatique correcte, id est Child-Pugh A.
9. Pas de pathologie maligne antérieure ou concomitante, diagnostiquée ou traitée au cours des deux dernières années, à l’exception des carcinomes in situ du col utérin, carcinomes basocellulaires / spinocellulaires de la peau ou les carcinomes in situ de la vessie,
10. Au moins 3 semaines de wash-out depuis la dernière chimiothérapie, immunothérapie ou tout autre traitement pharmacologique et/ou radiothérapie,
11. Retour à un grade ≤ 1 de toxicité suite à un traitement antérieur (sauf alopécie quel que soit le grade et pour les neuropathies périphériques non douloureuses de grade ≤ 2) selon la classification NCI-CTCAE version 4.0,
12. Les femmes susceptibles d’être enceintes doivent avoir un test de grossesse (sérique) négatif, dans les 72 heures avant le début du traitement,
13. Les hommes et les femmes doivent utiliser une méthode de contraception hautement efficace Durant toute la période de l’étude et jusqu’à 8 semaines après l’arrêt. Les méthodes acceptables de contraception sont : les dispositifs intra-utérins (IUD), les contraceptifs oraux, l’implant sub dermique et la double barrière.Ne sont pas concernés par ces précautions, les personnes stérilisées chirurgicalement (ex : vasectomie pour les hommes et hystérectomie pour les femmes) ou les femmes en amménorrhée depuis ≥ 1 an.
14. Consentement éclairé (daté et signé) avant toute procédure spécifique à l’étude,
15. Affiliation à un régime de sécurité sociale en accord avec la loi française. |
|
| E.4 | Principal exclusion criteria |
1. Previous treatment with Avelumab or Regorafenib,
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways),
3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases,
4. Men or women of childbearing potential who are not using an effective method of contraception as previously described; women who are pregnant or breast feeding,
5. Participation to a study involving a medical or therapeutic intervention in the last 30 days,
6. Previous enrolment in the present study,
7. Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons,
8. Known hypersensitivity to any involved study drug or of its formulation components,
9. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:
a. Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
b. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day
c. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment,
11. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan or interstitial lung disease with ongoing signs and symptoms at inclusion. History of radiation pneumonitis in the radiation field (fibrosis) is permitted,
12. Has known active hepatitis B or hepatitis C,
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV1/2 antibodies) or known acquired immunodeficiency syndrome (AIDS)
14. Persistent proteinuria < 3.5 g/24 hours measured by urine protein-creatinine ratio from a random urine sample (≥ Grade 3, NCI-CTCCAE v 4.0),
15. Major surgical procedure or significant traumatic injury within 28 days before start of study medication,
16. Non-healing wound, non-healing ulcer, or non-healing bone fracture,
17. Patients with evidence or history of any bleeding diathesis, irrespective of severity,
18. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication,
19.Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before the start of study medication (except for adequately treated catheter-related venous thrombosis occurring more than one month before the start of study medication),
20. Ongoing infection > Grade 2 as per NCI CTCAE v4.0,
21. Uncontrolled hypertension (Systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg) despite optimal medical management,
22. Congestive heart failure ≥ New York Heart Association (NHYA) class 2,
23. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months),
24. Myocardial infarction less than 6 months bedfore start of study drug
25. Uncontrolled cardiac arrhythmias,
26. Pregnant or breast-feeding patients
27. Individuals deprived of liberty or placed under legal guardianship,
28. Prior organ transplantation, including allogeneic stem-cell transplantation,
29. Known alcohol or drug abuse
30. Vaccination within 4 weeks of the first dose of Avelumab and while on trial is prohibited except for administration of inactivated vaccines.
31. Patients with any condition that impairs their ability to swallow and retain tablets,
32. Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study..
33. Patient with oral anticoagulation therapy,
34. Suspected or known intraabdominal fistula. |
1. Traitement antérieur par Avelumab ou Regorafenib,
2. Traitement antérieur par un anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, ou anticytotoxique T-lymphocyte-associated antigen-4 (CTLA-4) (incluant l’ipilimumab ou tout autre anticorps ou molécule ciblant spécifiquement la costimulation des cellules T ou d’autres points de contrôle immunitaires)
3. Preuve de l’existence de métastases progressives ou symptomatiques du système nerveux central ou leptoméningées,
4. Hommes ou femmes susceptibles d’être enceintes n’utilisant pas de méthode de contraception telle que précédemment décrite ; femmes enceintes ou allaitantes,
5. Participation à un autre essai Clinique médicament et traités par un médicament à l’étude dans les 30 derniers jours,
6. Précédente inclusion dans cette étude,
7. Facteurs géographiques, sociaux ou psychologiques rendant le patient incapable de se soumettre au suivi et aux procédures de l’étude,
8. Hypersensibilité connue à l’un des produits de l’étude ou à l’un de ses composants,
9. Maladie auto-immune active qui pourrait s’aggraver avec l’utilisation d’un agent immune-suppresseur:
a. Les patients avec un diabète de type I, vitiligo, psoriasis, hypo- ou hyperthyroïdie ne nécessitant pas de traitement immunosuppresseur sont éligibles
b. Les patients nécessitant un traitement par hormones de substitution avec corticostéroïdes sont éligibles si ces derniers sont administrés dans le cadre du traitement par hormone de substitution et à des doses ≤ 10 mg ou 10 mg d’équivalent prednisone par jour
c. L’administration de stéroïdes par une voie connue pour induire une exposition systémique minimale (cutanée, intra-nasale, intraocculaire ou inhalation) sont acceptables
10. Patient avec un diagnostic d’immunodéficience ou recevant un traitement systémique par stéroïdes ou tout autre traitement immunosuppresseur dans les 7 jours avant le début du traitement,
11. Antécédent de fibrose pulmonaire idiopathique (incluant les pneumopathies), de pneumopathie médicamenteuse, de pneumopathie organisée, de pneumopathie active sur le scanner thoracique ou de maladie pulmonaire interstitielle en cours et symptomatique au moment de l’inclusion. Un antécédent de pneumopathie post radique dans le champ d’irradiation est autorisé.
12. Hépatite B ou C active connue,
13. Antécédent connu de VIH (anticorps HIV1/2) ou syndrome d’immunodéficience acquise (AIDS),
14. Protéinurie persistante < 3.5 g/24 heures mesurée par le ratio protéine/créatinine urinaire sur un échantillon urinaire aléatoire (≥ Grade 3, NCICTCCAE v 4.0),
15. Procédure chirurgicale majeure ou traumatisme significatif dans les 28 jours avant le début du traitement,
16. Blessure non cicatrisée, ulcère non cicatrisé ou fracture osseuse non cicatrisée,
17. Patients aux antécédents connus et/ou actuels de diathèse hémorragique, quelle que soit la sévérité,
18. Toute hémorragie ou saignement ≥ CTCAE Grade 3 dans les 4 semaines avant le début du traitement,
19. Thrombose veineuse ou artérielle, évènements emboliques tells qu’un accident vasculaire cérébral (incluant une attaque ischémique transitoire), thrombose veineuse profonde ou embolie pulmonaire dans les 6 mois avant le début du traitement (exception faite des thromboses veineuses reliée à un cathéter adéquatement traitée et survenues plus d’un mois avant le début du traitement),
20. Infection active > Grade 2 selon la NCI CTCAE v4.0,
21. Hypertension non contrôlée (pression sanguine systolique > 140 mmHg ou pression diastolique > 90 mmHg) malgré une prise en charge médicamenteuse adéquate,
22. Insuffisance cardiaque congestive ≥ New York Heart Association (NHYA) class 2,
23. Angor instable (symptomatique au repos), angor débutant (dans les 3 derniers mois),
24. Infarctus du myocarde moins de 6 mois avant le début du traitement,
25. Arythmies cardiaques non contrôlées,
26. Femmes enceintes ou allaitantes,
27. Personne sous protection judiciaire ou privée de liberté,
28. Antécédent de transplantation d’organe, incluant la greffe allogénique de cellules souches,
29. Alcoolisme connu ou consommation de drogues,
30. Vaccination dans les 4 semaines avant la première dose d’Avelumab, et interdite durant le traitement, à l’exception des vaccins inactivés,
31. Incapacité d’avaler et/ou d’assimiler des comprimés,
32. Toute autre condition médicale, sévère, aigue, ou chronique, incluant: colite auto immune, maladie inflammatoire de l’intestin, pneumopathie auto immune, fibrose pulmonaire, pathologie psychiatrique incluant des idées suicidaires actives ou récentes (< 1 an), des anomalies biologiques augmentant le risque associé à la participation du patient dans l’étude, ou à l’administration du traitement, ou pouvant interférer avec l’interprétation des résultats de l’étude, ou rendant d’après le jugement de l’investigateur l’inclusion du patient dans l’étude inappropriée.
33. Traitement par anticoagulants oraux,
34. Fistule intra-abdominale suspectée ou connue. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PHASE I TRIAL/ DOSE ESCALATION PART :
- Toxicity graded using the common toxicity criteria from the NC-CTCAE v4.03
- Incidence rate of DLT at each dose level during the first 28 days.
PHASE II TRIALS (4 cohorts) :
Objective response under treatment defined as for the phase I trial, except that data from in-stream centralized radiological review will be used. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PHASE I TRIAL / DOSE ESCALATION PART :
- Toxicity: During the first cycle (cycle= 28 days)
- Incidence rate of DLTs: During the first cycle (cycle= 28 days)
PHASE II TRIALS (4 cohorts) :
- Objective Response under treatment: An average of 6 months |
|
| E.5.2 | Secondary end point(s) |
PHASE I TRIAL/ DOSE ESCALATION PART :
- Preliminary signs of antitumor activity in terms of :
a. Best overall response defined as the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation as per RECIST v1.1 criteria.
b. Objective response rate (ORR) defined as the proportion of patients with complete response or partial response, as per RECIST 1. ORR under treatment and 6-month ORR will be reported.
c. Progression-free rate (PFR) at 6 months defined as the proportion of patients with complete response, partial response or stable disease more than 24 weeks as per RECIST v1.1 criteria.
d. Progression-free survival (PFS) defined as the time from study treatment initiation to the first occurrence of disease progression or death (of any cause), whichever occurs first. 1-year PFS rate and median PFS will be reported.
e. Overall Survival (OS) defined as the time from study treatment initiation to death (of any cause). 1-year OS rate and median OS will be
reported.
f. Growth modulation index (GMI): GMI will be defined for each patient as the ratio of its PFS on Regorafenib + Avelumab treatment to its PFS on the previous line of therapy. This method accounts for inter-patient variability, the patient serving as his/her own control and implies by the natural history of the disease that the PFS tends to become shorter in successive lines of therapy. It is thought that an anti-cancer agent should be considered effective if the GMI is greater than 1.3
- PK measurements expressed as AUC, half-life and concentration peak for Regorafenib
- Pharmacodynamic activity: Predictive biomarkers analysis and pharmacodynamic (PD)/mechanism of action (MOA) in blood (levels of angiogenic and immunologic biomarkers in blood at baseline and different study time points), potentially including but not limited to :
a. Serum/plasma cytokines levels (ELISA)
b. Treg, CD4+, CD8+ and DR lymphocytes subpopulations (flow cytometry)
c. Archived tumor tissue will be collected for assessment of tumor VEGFR, PDGFR, HIF1alpha expression and lymphocytes, TAM and MDSC tumor infiltrates (IHC)
d. In additional, for all patients, optional biopsy at baseline and after 4 weeks of treatment will be proposed for mechanisms of action documentation : tumor VEGFR, PDGFR, HIF1alpha expression as well as PD-L1/PD1, lymphocytes, TAM, MDSC tumor infiltrates (IHC) and mutational burden.
PHASE II TRIALS (4 cohorts) :
- Best overall response, ORR at 6 months, PFR at 6 months, GMI, PFS: defined as for the phase I trial, except that data from in-stream centralized radiological review will be used.
- OS: defined as for the phase I trial
- Assessment of the safety profile of the association Regorafenib + Avelumab: Toxicity will be graded using the common toxicity criteria from the NCI v4.0.
- Pharmacodynamic activity: defined as for the phase I trial. Avelumab |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PHASE I TRIAL:
-Preliminary signs of antitumor activity:
1-Objective Response under treatment/Best overall response: average of 6 months
2-6-months Objective Response/6-month non-progression: 6 months
3-1-year PFS/1-year OS: 1 year
4-GMI: 1 year
-PK measurements: C1D15,C2D1,C2D15
-Pharmacodynamic activity:
1-Predictive biomarkers: C1D1,C2D1,C4D1,C6D1,at progression
2-Tumor samples: baseline,C2D15
PHASE II TRIALS:
-Preliminary signs of antitumor activity in terms of:
1-Best overall response: average of 6 months
2-6-months Objective Response/6-month non-progression: 6 months
3-1-year PFS/1-year OS: 1 year
4-GMI: 1 year
-Toxicity: average of 6 months
-Pharmacodynamic activity:
1-Predictive biomarkers: C1D1,C2D1,C4D1,C6D1,at progression
2-Tumor samples: baseline,C2D15 |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
Biomarkers study
Translational research |
Etude de biomarqueurs
Etude translationnelle |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation |
| Escalade de dose |
|
| 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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 3 |
| 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 | 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
|
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
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