| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| TREATMENT FOR REFRACTORY METASTATIC MICROSATELLITE STABLE COLORECTAL CANCER |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
To evaluate the safety and tolerability of avelumab associated to cetuximab and irinotecan separately in each cohort of RAS WT (cohort A) and RAS mutated (cohort B) metastatic CRC.
To evaluate in term of ORR the efficacy of avelumab associated to cetuximab and irinotecan separately in each cohort of RAS WT (cohort A) and RAS
mutated (cohort B) metastatic CRC |
|
| E.2.2 | Secondary objectives of the trial |
To further explore efficacy of avelumab combined with cetuximab and irinotecan.
To characterize the mechanistic pathways of mCRC immune response during treatment and potentially identify predictive biomarkers for mCRC response to avelumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female ≥ 18 years at time of study entry
2. Histologically proven metastatic colorectal adenocarcinoma, refractory to standard chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan) and anti-EGFR treatment (only for RAS WT tumor).
a. Patients who are received prior anti-angiogenic therapy (e.g, bevacizumab, aflibercept) are eligible
b. Patients must have had documented disease progression within 3 months of the last systemic therapy administration
c. Patients who were intolerant to prior systemic oxaliplatin-based chemotherapy regimens are eligible if there is documented evidence of
clinically significant intolerance despite adequate supportive measures.
d. For patients who had disease recurrence within 6 months of completing adjuvant chemotherapy, the adjuvant regimen can be considered as one chemotherapy regimen for metastatic disease
3. MSS tumor, BRAF V600E WT tumor.
4. Measurable disease according RECIST 1.1
5. Availability of protocol required screening tumor and blood samples:
Metastases must be accessible for sequential biopsies. Patient must consent
for metastasis biopsies
6. ECOG performance status of 0 or 1
7. Adequate normal organ and marrow function
For women who are not postmenopausal (≥ 12 months of non−therapyinduced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent (refrain from heterosexual intercourse) or use two highly efficient methods of contraception, including at least one method
with a failure rate of < 1% per year, during the treatment period and for at
least 6 months after the last dose of treatment. Examples of contraceptive
methods with a failure rate of < 1% per year include bilateral tubal ligation,
male sterilization, established, proper use of hormonal contraceptives that
inhibit ovulation, hormone-releasing intrauterine devices (IUDs), and copper
IUDs. The reliability of sexual abstinence should be evaluated in relation to
the duration of the clinical trial and the preferred and usual lifestyle of the
patient Periodic abstinence (e.g., calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of
contraception. Barrier methods must always be supplemented with the use of a spermicide.
9. Patients who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result prior to initiation of study drug
10. Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
11. A life expectancy of at least 4 months. |
|
| E.4 | Principal exclusion criteria |
1.BRAF V600E mutated tumor, MSI-High tumor
2. Patient has not received all of the standard chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan)
3.Previous treatment with regorafenib or TAS-102 (trifluridine/tipiracil)
4. Patients not consent for metastasis biopsy.
5. Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or anticipation of needing such procedure while receiving study treatment.
6. Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry.
a. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be
treated prior to start of study treatment.
b. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis
that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to the start
of study treatment.
7. Active or untreated CNS metastases are excluded. Patients with treated and asymptomatic CNS metastases are eligible with some criteria.
8. Any previous treatment with a PD1 or PD-L1 inhibitor (including avelumab), CD137 agonists or anti-CTLA4
9. Participation in another clinical study with an investigational product for any other indication until 4 weeks before study participation.
10. Receipt of the last dose of anti-cancer therapy (chemotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) ≤ 21 days prior to the first dose of study drug.
11. History of another primary malignancy except for exceptions (see protocol)
12. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving anyprevious immunotherapy agent, or any unresolved irAE >Grade 1
13. Current or prior use of immunosuppressive medication within 28 days beforethe first dose of avelumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
14. Treatment with systemic immunostimulatory agents (including but not limitedto interferons or IL-2) within 4 weeks or five half-lives of the drug(whichever is shorter) prior to start the study treatment.
15. Receipt of live attenuated vaccination within 30 days prior first avelumab planned administration.
16. Mean QT interval corrected for heart rate (QTc) ≥470 ms
17. Active or prior documented autoimmune disease within the past 2 years.
18. Active or prior documented inflammatory bowel disease.
19. History of idiopathic pulmonary fibrosis, of primary immunodeficiency, of allogeneic organ transplant, of hypersensitivity to avelumab or any excipient, of hypersensitivity or unacceptable toxicity to cetuximab (anaphylactic reaction) or irinotecan or any excipient.
20. History of primary immunodeficiency, of allogeneic organ transplant, of hypersensitivity to avelumab or any excipient, of hypersensitivity to avelumab or any excipient.
21. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
22. Subjects with uncontrolled seizures.
23. Known history of active tuberculosis
24. Female subjects who are pregnant, breast-feeding or female patients of reproductive potential who are not employing or willing to employ an effective method of birth control.
25. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study
results. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The overall tumor response rate (ORR) defined as the proportion of all included patient with a confirmed best overall tumor response of PR or CR according to irRECIST 1.1 occuring until 19 weeks after study treatment start. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| The safety and tolerability of the study treatment measured by the frequency and grade of Adverse Events, laboratory analysis and vital signs. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During all the clincial trial period |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | No |
| 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 | 2 |
| 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
|
| Accrual period of 24 months for the first stage of the study (cohort A and B). Expected whole study duration including second stage approximately 4 years. |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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