Immunotherapy with dostarlimab for locally advanced or metastatic cancer (non-colorectal/non-endometrial) with tumor dMMR/MSI

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Jul 2024 → ongoing

Decision date (initial)

2024-03-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Institut National du Cancer (l'INCA) · GSK (GlaxoSmithKline)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy

To assess the activity in terms of progression-free survival (according to RECIST v1.1 per investigator) of dostarlimab compared to standard of care (SOC) as first-line therapy for dMMR/MSI non resectable metastatic or locally advanced non-colorectal and non-endometrial cancers.

Secondary objectives 9

1. To assess treatment efficacy in both arms in terms of Objective Response Rate (ORR)
2. To assess treatment efficacy in both arms in terms of duration of response
3. To assess treatment efficacy in both arms in terms of overall Survival
4. To assess treatment efficacy in both arms in terms of Progression-Fee Survival 2 (PFS2)
5. To assess treatment efficacy in both arms in terms of Objective response rate after initiation of new anti-cancer therapy (ORR2)
6. To assess the PFS in crossover patients treated with dostarlimab as a second line therapy (PFS-c)
7. To study association between the evolution of ctDNA levels and progression-free survival in the overall population.
8. To assess the safety of treatments
9. To evaluate the health-related quality of life by the EORTC QLQ-C30 questionnaire in both arms before second line treatment initiation.

Conditions and MedDRA coding

Patients with dMMR/MSI (non-colorectal/non-endometrial) locally advanced or metastatic cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. Patient must have signed a written informed consent form prior any trial specific procedures.
2. 18 years or older patients.
3. Documented locally advanced or metastatic disease with no previous systemic anticancer treatment in these settings and not suitable for complete surgical resection.
4. Histologically proven, dMMR/MSI-H solid tumors that are not colorectal or endometrial cancers and including one of the following: duodenum and small bowel adenocarcinoma, gastric and oeso-gastric junction adenocarcinoma with CPS<5, pancreatic adenocarcinoma, biliary tract carcinoma including ampulla of Vater adenocarcinoma, adrenocortical carcinoma, carcinoma of unknown primary site, neuroendocrine carcinoma (Grade 3) all primary, and soft tissue sarcoma except Gastro-Intestinal stromal tumor (GIST).
5. If patient received adjuvant therapy for non-metastatic disease, this therapy should be completed more than 6 months before the diagnosis of metastatic or recurrent disease.
6. Availability of minimum 1 block of tumor tissue or 20 slides (archival (<2 years) or fresh biopsy specimen of primary and or metastasis) for centralized confirmation of MMR/MSI status by IHC or NGS/PCR, and for Translational Research.
7. Patients with dMMR/MSI tumor analyzed by IHC, PCR (for Gastric and OGJ adenocarcinoma, and duodenum and small bowel adenocarcinoma only), and/or NGS at the recruiting center should be confirmed by central review within 24h (every anonymized patient analysis reporting will be provided for central review). Patients should not be included in the study until the dMMR/MSI status is confirmed by the review committee.
8. Presence of at least one measurable lesion within 28 days before the start of treatment according to RECIST v1.1.
9. Eastern Cooperative Oncology Group Performance status (ECOG PS) 0-1.
10. Haematological status: absolute neutrophil count (ANC) ≥1.5 x 109/L; platelets ≥100 x 109/L; haemoglobin ≥9 g/dL.
11. Adequate renal function: serum creatinine level <120 μM, or clearance >50 ml/min (Modification of the Diet in Renal Disease [MDRD] or Cockcroft and Gault).
12. Adequate liver function: serum bilirubin ≤1.5 x upper normal limit (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN, unless liver metastases are present, in which case they must be ≤ 5× ULN
13. For patients not taking warfarin: INR <1.5 or PT <1.5 x ULN and either PTT or aPTT <1.5 x ULN. Participants taking warfarin may be included on a stable dose with a therapeutic INR <3.5
14. Women of childbearing potential must have a negative serum pregnancy test performed within 72 hours before the date of randomization.
15. Men, and women of childbearing potential (WOCBP) must agree to use adequate contraception for the duration of trial participation and for 4 months after the last dose of dostarlimab (used in first line or at crossover) or for at least 6 months after the last administration of the chemotherapy agent(s) used in the control arm if no crossover with dostarlimab (according to the current version of the SmPC of each chemotherapy agent). Men must also agree to not donate sperm and women must agree to not donate oocytes during the specified period.
16. Registration in a National Health Care System.
17. Patient is willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study.

Exclusion criteria 19

1. Colorectal and endometrial cancer and all primary tumor not listed in inclusion criterion #4.
2. Previous exposure to anti-PD-1 or PD-L1 or anti-CTL-4 antibodies or treatment with immunotherapy.
3. Previous exposure to any investigational drug within 4 weeks (6 weeks for monoclonal antibodies) before the first dose in the study.
4. Previous exposure to any systemic anti-cancer therapy or radiation therapy for the cancer for which the patient is being enrolled.
5. Active autoimmune disease: Active autoimmune disease requiring systemic treatment in the past 2 years (excluding replacement therapy) or any history of interstitial lung disease (patients with ancient auto-immune disease with stable endocrine oral substitution are eligible).
6. Uncontrolled central nervous system metastases or carcinomatous meningitis or other concurrent illness or ongoing or active infections.
7. Patients with HER2-positive gastric carcinoma.
8. Other serious and uncontrolled non-malignant disease or is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active infection requiring systemic therapy. Specific examples include, but are not limited to, active, non-infectious pneumonitis; uncontrolled ventricular arrhythmia; recent (within 90 days) myocardial infarction; uncontrolled major seizure disorder; unstable spinal cord compression; superior vena cava syndrome; or any psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study,
9. Prior allogeneic bone marrow transplantation or prior solid organ transplantation,
10. Has received treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis factor agents) within 2 weeks prior to the first dose of adjuvant treatment or is required to receive systemic immunosuppressive medications during the study. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
11. Other concomitant or previous malignancy other than the disease under study, except : i. adequately treated in-situ carcinoma of the uterine cervix, ii. basal or squamous cell carcinoma of the skin, iii. cancer from which the patients was in complete remission for >2 years.
12. Known Human Immunodeficiency Virus (HIV) infection.
13. Received live vaccine within 14 days.
14. Known active hepatitis, including the following: Participant has an acute hepatitis and untreated chronic hepatitis B at the pre-inclusion visit. i. Chronic HBV carriers (HBsAg positive, HBcAb positive) can be included provided that they receive effective antiviral therapy (i.e., with nucleos(t)ide analogs) for at least 14 days prior to first dose and are willing to continue for at least 6 months after treatment discontinuation or longer at the discretion of the treating hepatologist. HBV DNA must be adequately suppressed, per institutional or local guidelines, prior to initiation of study intervention. ii. Participants with past HBV infection (HBcAb positive, HBsAg negative) can be enrolled if HBV DNA is undetectable at screening.
15. Known prior severe hypersensitivity to investigational product or any component in its formulation
16. Pregnant or breast feeding women.
17. Participation in another clinical trial within 30 days prior to the first study treatment administration or concomitantly with the trial.
18. Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
19. Person deprived of their liberty or under protective custody or guardianship.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression-Free Survival (PFS) is defined per RECIST v1.1 as the time from randomization until disease progression or death from any cause, whichever occurs first. At the time of analysis, a patient alive and without disease progression will be censored at the date of the last valid tumor assessment.

Secondary endpoints 9

1. To assess in both arms the Objective Response Rate (ORR) is defined as the proportion of patients with best response of CR or PR according to RECIST v1.1.
2. To assess in both arms the Duration of response (DOR) will be evaluated in patients with either a complete response (CR) or partial response (PR). DOR is defined as the time from the first assessment of a CR or PR until the date of the first occurrence of progressive disease (PD) or death from any cause (if death occurred within predefined period), whichever occurs first.
3. To assess in both arms the Overall Survival (OS) is defined as the time from randomization until death from any cause. Patients who are alive at last follow-up news will be censored at this date. An additional OS sensitivity analysis will be performed with survival dates censored at the start of crossover to experimental treatment or the start of first subsequent immune checkpoint inhibitor treatment, whichever occurs first.
4. To assess in both arms the Progression-Free Survival 2 (PFS2) is defined as the time from randomization to second/subsequent disease progression after initiation of new anti-cancer therapy (including subsequent immune checkpoint inhibitor therapy), or death from any cause, whichever first.
5. To assess in both arms the Objective response rate after initiation of new anti-cancer therapy (ORR2) is defined as the proportion of patients with best response of CR or PR according to the investigator’s judgment.
6. PFS-c for crossover patients is defined as the time from crossover initiation to disease progression after initiation of new anti-cancer therapy, or death from any cause, whichever first.
7. The evolution of ctDNA level in patient’s blood during treatment will be correlated with PFS in the overall population to assess its biomarker potential.
8. The safety will be evaluated according to the incidence of adverse events (AEs) graded by NCI-CTCAE v5.0.
9. Health-related quality of life will be evaluated by the EORTC QLQ-C30 questionnaire with two prespecified exploratory endpoints before second line treatment initiation

Investigational products

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

Test 1

Comparator 16

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris Cedex 13

Postcode

75654

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Director of regulatory Affairs and Pharmacovigilance

Public contact point

Organisation

Unicancer

Contact name

Director of regulatory Affairs and Pharmacovigilance

Third parties 1

Locations

1 EU/EEA country · 26 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 29 files

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

Application history

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