Multicenter Randomized Phase Ii Study Comparing the Effectiveness and Tolerance of Avelumab Versus Standard 2ND Line Treatment Chemotherapy in Patients with Colorectal Metastatic Cancer with Microsatellite Instability (Msi)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondation Franc.Cancerologie Digestive

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Apr 2018 → 7 May 2025

Decision date (initial)

2024-09-27

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck

External identifiers

EU CT number

2024-517362-41-00

EudraCT number

2016-004575-49

ClinicalTrials.gov

NCT03186326

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Compare between the two arms PFS assessed by the investigator according to RECIST v1.1 criteria

Secondary objectives 8

1. Time to progression assessed by investigator
2. Overall survival (median)
3. Time to best response
4. Response rate
5. Toxicity according to NCI-CTC v4.0
6. Secondary resection rate (R0 and R1)
7. Quality of life (QLQ-C30)
8. Evolution of tumor markers (CEA)

Conditions and MedDRA coding

COLORECTAL METASTATIC CANCER WITH MICROSATELLITE INSTABILITY

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Histologically proven colorectal adenocarcinoma with metastasis(es) non-resectable
2. Total bilirubin < 25 µmol/L, ASAT < 3 x LSN, ALAT < 3 x LSN (ASAT , ALAT < 5 x LSN in case of hepatic metastasis) , PT >60% , PAL<2.5 x LSN ( < 5 x LSN in case of hepatic metastasis)
3. Creatinine clearance > 50 ml/min according to MDRD formula
4. Patient belonging to a social security scheme
5. Patient information and signature of the informed consent
6. MSI-H determined by immunohistochemistry (loss of expression of MLH1, MSH2, MSH6 and/or PMS2) and by molecular biology
7. At least one measurable target (primary tumour or metastasis) according to RECIST v1.1
8. Mutational status RAS and BRAF
9. Age ≥ 18
10. WHO ≤ 2
11. Life expectancy ≥ 3 months
12. Patient failure (progression or unacceptable toxicity) of chemotherapy containing fluoropyrimidine (capecitabine or 5FU) +/- irinotecan +/- oxaliplatin with or without cetuximab, bevacizumab ,panitumumab or aflibercept (patients in progression during or within 6 months after discontinuation of adjuvant chemotherapy are eligible)
13. PNN > 1500/mm3, platelets > 100 000/mm3, Hb > 9 g/dL
14. Tumor block available

Exclusion criteria 26

1. patient eligible for curative therapy (surgical and/or percutaneous) after discussion in PCM
2. Patient having progressed under 1st line treatment with FOLFIRINOX or FOLFOXIRI
3. Cerebral metastasis
4. Previous treatment with anti-PD1 or anti-PDL1
5. Autoimmune disease that might be aggravated during treatment with an immuno-stimulating agent (patients with type I diabetes, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible)
6. Immunosuppressive long-term treatment. Patients necessitating hormone replacement corticosteroids are eligible if the steroids are administered to target hormone therapy and the dose < or = 10 mg or the equivalent of 10 mg of prednisone by daily administration of steroids by pathway resulting in minimal systemic exposure (local, intra-anal, intraocular or inhalation) are eligible
7. Transplant patients (including stem cell transplants), HIV positive or other immune deficiency syndromes
8. Active infection by HBV or HCV
9. Known severe hypersensitivity to monoclonal antibodies or history of anaphylactic shock, or uncontrolled asthma
10. Any known specific contraindication or allergy to the treatments used in the study (oxaliplatin, irinotecan, leucovorin, 5-fluorouracil and targeted therapy of choice [bevacuzimab, aflibercept, cetuximab or panitumumab]. In order to check the contraindications, please refer to the updated versions of the SmPCs presented in Appendix 8 of the protocol
11. Peripheral sensory neuropathy with functional impairment
12. Persistence of toxicities related to chemotherapy 1st line > 2 (NCI-CT v4.0) (except alopecia and neuropathy sequelae of oxaliplatin)
13. Vaccination during the 4 weeks preceding the start of treatment
14. QT/QTc interval > 450 msec for men and > 470 msec for women
15. K+ < LIN, Mg2+ < LIN, Ca2+ < LIN
16. Following alterations in the 6 months prior to inclusion: myocardial infarction, angina, severe/unstable angina, coronary artery bypass surgery, congestive heart failure NYHA class II, III or IV, stroke or transient ischemic attack
17. Any progressive pathology not stabilised over the past 6 months: hepatic failure, renal failure, respiratory failure
18. Patient with interstitial pneumonitis or pulmonary fibrosis or any other known severe respiratory insufficiency
19. History of inflammatory bowel disease, or unresolved occlusion or sub-occlusion in symptomatic treatment
20. History of malignant pathologies during the past 5 years except basocellular skin carcinoma or in situ cervical carcinoma, properly treated
21. Patient already included in another clinical trial with an experimental molecule for L2 or treatment during the last 4 weeks before inclusion
22. Lack of effective contraception in patients (men and/or women) of childbearing age, pregnant or breastfeeding women, women of childbearing age not having had a pregnancy test
23. Persons deprived of freedom or under guardianship.
24. Impossibility of undergoing medical monitoring during the trial for geographic, social or psychological reasons
25. Active tuberculosis
26. Partial or complete DPD deficiency (Uracilemia ≥ 16 ng/ml)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is radiographic progression-free survival (PFS). The progression will assessed by the investigator according to RECIST v1.1 criteria in arm A and B, PFS is defined by the time between the date of randomization and the date of the first radiological progression or the date of death (for whatever reason). Patients alive without radiological progression will be censored on the date of their last CT-scan.

Secondary endpoints 12

1. Time To Progression (TTP): This time is defined by the time between the date of randomization and the date of the first radiological progression. Patients alive or dead without radiological progression will be censored on the date of their latest CT-scan
2. Overall survival (OS): OS is defined by the time between the date of randomization and the date of death (regardless of the cause). Alive patients will be censored at the date of their last news.
3. Objective Response Rate : Objective Response rate is defined by patients with partial or complete response.
4. Time to Best Response (TBR) This time is defined as the time from the date of randomization and the date of best response under treatment. Patients without imaging (better response non-evaluable, untreated patients) will not be taken into account in the analysis.
5. The best response under treatment: The best tumor response will be evaluated throughout the treatment. The response is evaluated according to the various categories: complete, partial, stability, progression or non-evaluable response.
6. Toxicities: Toxicity will be evaluated according to NCI-CTC v4.0.
7. Early tumor shrinkage at 8 weeks: This endpoint is defined as the relative difference between the sum of the largest diameters of target lesions at 8 weeks and this sum at baseline. Early decrease corresponds to a relative difference of > 20% and > 30% in RECIST v1.1.
8. Depth of response: This criterion is defined as the relative difference between the sum of the largest diameters of target lesions in the NADIR (in the absence of new lesions or progression of non-target lesions) and the sum of the largest diameters of the target lesions at inclusion
9. Secondary resection rate: This rate is defined as the proportion of patients who could benefit from surgery of their metastases (optionally combined with a surgery of the primary tumor) during 2nd line treatment.
10. Histological response if resection: This endpoint will be evaluated according to the TRG (Rubbia-Brandt L et al. Annals Oncol 2007), in patients who underwent a secondary resection of their metastases (possibly associated with surgery of the primary tumor). This response is evaluated according to the various categories: TRG1/TRG 2/TRG 3/TRG 4/TRG 5.
11. Evolution of CEA markers: The markers will be collected at each treatment cycle. The evolution of the markers will be analysed by a graphic representation of the percentage change from baseline rate.
12. Quality of life: Quality of life will be assessed according to the questionnaire of EORTC QLQ-C30.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondation Franc.Cancerologie Digestive

Sponsor organisation

Fondation Franc.Cancerologie Digestive

Address

7 Boulevard Jeanne D Arc

City

Dijon

Postcode

21000

Country

France

Scientific contact point

Organisation

Fondation Franc.Cancerologie Digestive

Contact name

Julien Taieb

Public contact point

Organisation

Fondation Franc.Cancerologie Digestive

Contact name

Julien Taieb

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 18 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications