Treatment of microstellite stable metastatic colorectal cancer presenting high immune infiltrate with chemotherapy (XELOX or FOLFOX Bevacizumab) and immunotherapy ( Pembrolizumab)

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

30 Jul 2024 → ongoing

Decision date (initial)

2024-07-30

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-515788-73-00

EudraCT number

2019-002407-18

ClinicalTrials.gov

NCT04262687

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Pharmacokinetic, Safety

To evaluate the efficacy of pembrolizumab in combination with XELOX or FOLFOX and bevacizumab as 1st line treatment of microsatellite stable (MSS) metastatic colorectal cancer (mCRC) with a high immune infiltrate. Efficacy will be determined by analysis of the number of patients alive and without radiological and/or clinical progression at 10 months (based on RECIST 1.1 criteria evaluated by the investigator).

Secondary objectives 16

1. Overall survival (median)
2. Serious adverse events evaluated according to NCI-CTC v4.0
3. Histological response in case of secondary resection (TRG criteria)
4. Secondary resection rate (R0 and R1)
5. Outcome of tumour markers (CEA and CA19.9)
6. Percentage of patients alive and without progression at 10 months (centralised review) Evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
7. Progression-free survival (median), evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
8. Time to progression, evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
9. Time to objective response, evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
10. Best response during treatment, evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
11. Depth of response, evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
12. Early tumour shrinkage at 9 weeks, evaluated according to the investigator and centralised review (according to RECIST V1.1 criteria)
13. Percentage of patients alive and without progression at 10 months, evaluated according to centralised review according to iRECIST criteria
14. Progression-free survival (median), evaluated according to centralised review according to iRECIST criteria
15. Time to progression, evaluated according to centralised review according to iRECIST criteria
16. Early tumour shrinkage at 9 weeks, evaluated according to centralised review according to iRECIST criteria

Conditions and MedDRA coding

MICROSATELLITE STABLE (MSS) METASTATIC COLORECTAL CANCER AND A HIGH IMMUNE INFILTRATE

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. ≥ 18 years
2. Both MSS and pMMR metastatic colorectal adenocarcinoma (metachronous or synchronous metastases), histologically proven
3. Patients who have had adjuvant/post-operative chemotherapy and/or post-operative radiotherapy for the treatment of their primary tumor or R0 resected metastatic lesions can be included if they have a recurrence more than 6 months after the end of this treatment
4. High immune response defined as the immune infiltration score obtained on the primary tumour (resection of primary tumour containing at least 2 mm of tumour-free margin between the tumour and nontumour area)
5. Unresectable cancer with at least one measurable metastatic target according to RECIST v1.1 criteria
6. WHO PS ≤ 1
7. Absence severe neuropathy (≥ grade 2) (chemo-induced or not)
8. Life expectancy > 3 months
9. Adequate haematological function: neutrophils > 1,500 /mm3, platelets > 100,000/mm3, Hb > 9 g/dL
10. Adequate liver function: AST/ALT ≤ 5xULN, total bilirubin ≤ 2xULN, Alkaline phosphatase ≤ 5xULN
11. Creatinine clearance > 50 mL/min according to the CKD-EPI formula
12. Proteinuria <2+ (dipstick urinalysis) or ≤1g/24hour
13. Patient who is a beneficiary of the social security system
14. Information provided to patient and signature of the informed consent form

Exclusion criteria 26

1. Active infection requiring intravenous antibiotics at day 1 of cycle 1
2. All uncontrolled progressive disorders during the last 6 months: hepatic insufficiency, renal insufficiency, respiratory insufficiency, arterial hypertension
3. History of an inflammatory digestive disease, obstruction or subobstruction not resolved with symptomatic treatment
4. Active or untreated central nervous system metastases
5. Peptic ulcer disease not healed before the treatment
6. Patient already enrolled in another therapeutic trial with an ongoing investigational drug or whose treatment ended less than 4 weeks before inclusion
7. Absence of effective contraception in patients (male and/or female patients) of childbearing potential, a pregnant or breastfeeding woman, women of childbearing potential and who have not had a pregnancy test
8. Impossibility to submit to medical follow-up of the trial due to geographic, social or psychological reasons
9. Patients who have had neo-adjuvant treatment (chemotherapy or radiotherapy) for the treatment of primary tumor can not be included
10. Another concomitant cancer or history of cancer during the last 5 years, except for carcinoma in situ of the uterine cervix or a basal cell or squamous cell skin carcinoma or any other carcinoma in situ considered as cured
11. Previous bone marrow allogenic stem cell transplantation or previous organ transplantation
12. Previous treatment with anti-PD1 or anti-PDL1 or another immunotherapy
13. History of idiopathic pulmonary fibrosis, medicinal product-related pneumonia or proof of active pneumonia or pneumonitis on a chest CTscan prior to therapy
14. HIV infection, active hepatitis B or C infection, active tuberculosis
15. Colorectal cancer with microsatellite instability (dMMR and/or MSI)
16. Patient eligible for curative treatment (resection and/or thermal ablation according to the opinion of the local multidisciplinary tumour meeting board) and patient with RAS wild-type tumour for whom a tumour shrinkage with an anti-EGFR is necessary to perhaps obtain a XML File Identifier: IjpoCuOJiXEw1TRpi8rHlb0n7yE= Page 27/63 downstaging for a secondary surgery (according to the opinion of the local multidisciplinary tumour meeting board and/or at investigator's discretion)
17. Patient with only primary tumour biopsies available or only a sample of a metastasis (no surgical resection of the primary tumour)
18. An auto-immune disease which may worsen during treatment with an immune-stimulating agent (patients with type I diabetes, vitiligo, psoriasis, hypo or hyperthyroidism not requiring immunosuppressant therapy are eligible)
19. Long-term immunosuppressant therapy (patients requiring corticosteroid therapy are eligible if administration at a dose ≤ 10 mg prednisone equivalent dose per day, administration of steroids by a route of administration resulting in minimal systemic exposure (cutaneous, rectal, ocular or inhalation) is authorised)
20. Known severe hypersensitivity to monoclonal antibodies, to one of the medicinal products used or to one of the excipients in the products used or a history of anaphylactic shock or of uncontrolled asthma
21. Vaccinations (live vaccine) within 30 days prior to start of treatment
22. Dihydropyrimidine Dehydrogenase (DPD) deficiency defined by uracilemy level ≥ 16 ng/mL
23. QT/QTc interval > 450 msec in men and > 470 msec in women
24. One of the following disorders during the 6 months prior to inclusion: myocardial infarction, unstable/severe angina pectoris, coronary artery bypass grafting, NYHA class II, III or IV congestive heart failure, stroke or transient ischaemic attack
25. Concomitant treatment with brivudine or brivudine within 4 weeks before capecitabine or 5FU initiation
26. Poor nutritional status

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is the percentage of patients alive and without progression at 10 months. Progression is defined by: - radiological progression evaluated by the investigator according to RECIST v1.1 criteria. - death, whatever the cause

Secondary endpoints 12

1. Overall survival: is defined as time between date of inclusion and date of death of patient (whatever the cause) or date of last news if patient is XML File Identifier: IjpoCuOJiXEw1TRpi8rHlb0n7yE= Page 28/63 alive
2. Grades 3 – 4 adverse events: will be evaluated according to NCI-CTC v4.0 criteria and described by maximum grade based on total duration of treatment and 30 days after treatment
3. Secondary resection rate (R0 and R1): is defined as the percentage of patients who underwent surgery on their metastatic lesions after the protocol treatment.
4. Histological response in case of secondary resection: is evaluated according to the TRG (Rubbia-Brandt L et al. Annals Oncol 2007), in patients who underwent a secondary resection. This response is evaluated according to the various categories: TRG1/TRG 2/TRG 3/TRG 4/TRG 5.
5. Outcome of tumour markers (CEA and CA19.9): the evolution of the markers will be analyzed by a graphic representation of the percentage change from baseline rate.
6. Progression-free survival, according to the investigator (RECIST criteria): defined as time between date of inclusion and date of a first radiological progression or date of death (whatever the cause). Patients alive without progression will be censured at date of last news. According to iRECIST criteria, progression will be considered as an event if it is confirmed. If the patient dies before confirmation, the event will be considered as unconfirmed progression.
7. The percentage of patients alive and without progression at 10 months (according to centralised review, RECIST and iRECIST criteria): progression is defined as radiological progression or death, whatever the cause. According to iRECIST criteria, the patient will be considered as in progression if progression is confirmed in the next 2 months.
8. Time to progression, according to the investigator (RECIST criteria) and in centralised review (RECIST and iRECIST criteria): is defined as the time between date of inclusion and date of first progression (RECIST v1.1 criteria) or date of suspected progression if confirmed (iRECIST criteria).
9. Time to an objective response (according to the investigator and in centralised review, RECIST criteria): is defined as the time between the date of inclusion and the date of a first objective response (complete response or partial response) during treatment. Patients with no imaging study (or if best response is not evaluable, or patients not treated) will not be taken into account in the analysis.
10. Best response during treatment (according to the investigator and in centralised review, RECIST criteria): the best response is described by a percentage according to different categories: complete response (CR), partial response (PR), stability (S), progression (P) and not evaluable (NE). The best objective response is evaluated during treatment based on different imaging studies and according to RECIST v1.1 criteria.
11. Depth of response (according to the investigator and in centralised review, RECIST criteria): is defined as the relative difference between the sum total of the largest diameters of target lesions in NADIR (RECIST v1.1: in the absence of new lesions or progression of non-target lesions) and the sum total of the largest diameters of target lesions at inclusion.
12. Early tumour shrinkage at 9 weeks, according to the investigator (RECIST criteria) and in centralised review (RECIST and iRECIST criteria): is defined as the relative difference between the sum of the largest diameters of the target lesions at 9 weeks and the sum of different targets at inclusion. Tumour shrinkage corresponds to a relative difference > 20% with RECIST v1.1 criteria and > 30% with iRECIST.

Investigational products

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

Test 6

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 Cedex

Postcode

21001

Country

France

Scientific contact point

Organisation

Fondation Franc.Cancerologie Digestive

Contact name

David TOUGERON

Public contact point

Organisation

Fondation Franc.Cancerologie Digestive

Contact name

Nathalie DECK

Locations

1 EU/EEA country · 87 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

Documents 13 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