Trial Title:
Dostarlimab for Locally Advanced or Metastatic Cancer (non-colorectal/non-endometrial) with Tumor DMMR/MSI
NCT ID:
NCT06333314
Condition:
Pancreatic Adenocarcinoma
Ampulla of Vater Carcinoma
Adrenocortical Carcinoma
Neuroendocrine Carcinoma
Soft Tissue Sarcoma
Small Bowel Adenocarcinoma
Duodenum Adenocarcinoma
Gastric Adenocarcinoma
Conditions: Official terms:
Carcinoma
Adenocarcinoma
Sarcoma
Neoplasm Metastasis
Carcinoma, Neuroendocrine
Adrenocortical Carcinoma
Dostarlimab
Conditions: Keywords:
Immunotherapy
locally advanced or metastatic cancer
dMMR/MSI (non-colorectal/non-endometrial) cancer
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Randomized, multicenter, comparative phase II trial
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Dostarlimab
Description:
Anti-PD-1 monoclonal antibody
Arm group label:
Dostarlimab
Intervention type:
Drug
Intervention name:
Chemotherapy
Description:
- mFOLFOX6 or FOLFIRI or XELOX regimen
- FOLFOX or XELOX or TFOX regimen
- FOLFIRINOX or gemcitabine-nab-paclitaxel or gemcitabine monotherapy.
- Cisplatin and gemcitabine cisplatin or CAPOX or mFOLFOX6.
- Etoposide-cisplatin-doxorubicin or mitotane
- Cisplatin and gemcitabine or carboplatin and paclitaxel
- Etoposide-cisplatin or etoposide-carboplatin
- Doxorubicin and ifosfamide or doxorubicin monotherapy or doxorubicin and
trabectedin.
Arm group label:
Standard of care
Summary:
The goal of this open-label randomized, multicenter, comparative phase II trial is to
evaluate the efficacy of the immunotherapy, dostarlimab, as first-line treatment for
deficient mismatch repair (dMMR)/microsatellite instability (MSI) non-resectable
metastatic or locally advanced non-colorectal and non-endometrial cancers compared to the
standard of care chemotherapy.
Adult patients (aged ≥18 years) with histologically confirmed dMMR/MSI duodenum and small
bowel adenocarcinoma, gastric and oeso-gastric junction (OGJ) adenocarcinoma with
combined positive score (CPS)<5, pancreatic adenocarcinoma, ampulla of vater
adenocarcinoma, adrenocortical carcinoma, carcinoma of unknown primary site,
neuroendocrine carcinoma (Grade3) all primary, and soft tissue sarcoma (except
Gastro-Intestinal Stromal Tumor) will be included in this study. They will be randomized
and treated with either dostarlimab (experimental arm A), or chemotherapy (control arm
B).
Patients with documented disease progression following the first line chemotherapy (Arm
B) may be eligible for crossover to be treated with dostarlimab, with the same schedule
as arm A.
Detailed description:
Following signature of the informed consent form, patients will enter the pre-inclusion
period (maximum 28 days prior to start of treatment) during which all examinations
required to assess their eligibility will be performed, including dMMR/MSI status,
demographic data collection, tumor evaluation, and clinical and laboratory evaluations. A
centralized confirmation of MMR/MSI status by immunohistochemistry (IHC) or
next-generation sequencing (NGS)/polymerase chain reaction (PCR) is mandatory to include
the patient.
Patients will be randomized 1:1 to receive either dostarlimab intravenously 500 mg every
3 weeks for 4 cycles followed by 1000 mg every 6 weeks for all cycles thereafter
(experimental arm A) or chemotherapy (control arm B) as per standard of care (SOC) until
disease progression, unacceptable toxicity, death, investigator's decision, withdrawal of
consent or for a maximum of 24 months.
Randomization will be stratified by:
- Primary tumor (Duodenum and Small Bowel/Gastric/OGJ vs Pancreas/ Ampulla of Vater vs
Other),
- Age (<70 years vs ≥70 years)
- Stage: Locally advanced vs Metastatic.
Patients randomized to Arm B may be eligible to participate in the crossover phase after
documentation of disease progression by investigator evaluation according to response
evaluation criteria in solid tumors version 1.1 (RECIST v1.1). Crossover patients may
then be treated with dostarlimab for up to 2 years, according to the schedule defined for
experimental arm A. These patients may not initiate treatment with dostarlimab any
earlier than 28 days after their last dose of chemotherapy (washout period) regardless of
the time of progression. Patients who discontinue dostarlimab treatment after crossover
will enter the follow-up phase until the last follow-up visit of the last randomized
patient. Crossover is optional and is at the discretion of the investigator (with
coordinating investigator's agreement).
In both arms, tumor evaluation will be done by local investigator at inclusion and
post-randomization visits as follow:
- Treatment period: every 6 weeks (+/- 7 days) for the first year then every 12 weeks
(+/- 7 days) for the second year.
- Follow-up period: every 16 weeks (+/- 7 days) up to one year after the last
follow-up of the last randomized patient.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
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
anti-cancer 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, 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.
NB: In case of ambiguous result of IHC (lack of positive internal control,
heterogeneous loss of MMR protein expression, ambiguous loss of only one protein
including HMSH6 and PMS2), the MSI-H status will be assessed by PCR or NGS for
gastric and OGJ adenocarcinoma, and duodenum and small bowel adenocarcinoma, and by
NGS for other primary. Based on IHC and PCR or NGS results (NGS will be centrally
performed in this case ), the sponsor will decide if inclusion is possible;
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: International normalised ratio (INR) <1.5 or
prothrombin time (PT) <1.5 x ULN and either partial thromboplastin time (PTT) or
activated PTT (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 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 summary of
product characteristics (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:
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
anti-tumor 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.
Note 1: Patients who have received acute, low-dose, systemic immunosuppressant
medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled into
the study after approval of the Medical Contact.
Note 2: patients are permitted the use of topical, ocular, intra-articular,
intranasal, and inhalational corticosteroids (with minimal systemic absorption).
Adrenal replacement steroid doses including doses >10 mg daily prednisone are
permitted. A brief (less than 3 weeks) course of corticosteroids for prophylaxis
(e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g.,
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted.
11. Other concomitant or previous malignancy other than the disease under study, except
as noted below:
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. Patient has documented presence of HBsAg [or HBcAb] at pre-inclusion visit or within
3 months prior to first dose of study intervention.
Participant has a positive hepatitis C virus (HCV) antibody test result at
pre-inclusion visit or within 3 months prior to first dose of study intervention.
Note: Participants with a positive HCV antibody test result due to prior resolved
disease can be enrolled, only if a confirmatory negative HCV RNA test is obtained.
Participant has a positive HCV RNA test result at pre-inclusion visit or within 3
months prior to first dose of study intervention. Note: The HCV RNA test is optional
and participants with negative HCV antibody test are not required to undergo HCV RNA
testing as well
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.
Patient randomized to receive SOC (Arm B) may crossover to receive dostarlimab (Arm A) in
case of documented progressive disease according to RECIST v1.1.
Inclusion and exclusion are the same for the crossover except for the inclusion criteria
#3 and #4.
The criterion #3 for crossover is: Patient included in the protocol and randomized in the
arm "standard of care" with documented progressive disease by RECIST v1.1 on standard of
care (defined in the protocol).
The criterion #4 for crossover is: Previous exposure to chemotherapy for locally advanced
or metastatic disease.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Institut de Cancérologie de l'Ouest
Address:
City:
Angers
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Victor SIMMET, MD
Facility:
Name:
Institut du Cancer Avignon-Provence
Address:
City:
Avignon
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Clémence TOULLEC, MD
Facility:
Name:
CHU Jean Minjoz
Address:
City:
Besançon
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Angélique VIENOT, MD
Facility:
Name:
CHU Morvan
Address:
City:
Brest
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Pierre-Guillaume POUREAU, MD
Facility:
Name:
Centre François Baclesse
Address:
City:
Caen
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Elodie COQUAN, MD
Facility:
Name:
Centre Jean Perrin
Address:
City:
Clermont-Ferrand
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Florence OSAER-POLYCARPE, MD
Facility:
Name:
CHU - Henri Mondor
Address:
City:
Créteil
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Christophe TOURNIGAND, MD
Facility:
Name:
Centre Georges François Leclerc
Address:
City:
Dijon
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
François GHIRINGHELLI, MD
Facility:
Name:
Centre Léon Bérard
Address:
City:
Lyon
Country:
France
Status:
Recruiting
Contact:
Last name:
Clélia COUTZAC, MD
Facility:
Name:
Hôpital la Timone
Address:
City:
Marseille
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Laëtitia DAHAN, MD
Facility:
Name:
Institut Paoli Calmettes
Address:
City:
Marseille
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Christelle DE LA FOUCHARDIERE, MD
Facility:
Name:
Institut de Cancérologie de Lorraine
Address:
City:
Nancy
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Aurélien LAMBERT, MD
Facility:
Name:
Institut Mutualiste Montsouris
Address:
City:
Paris
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Raphaël COLLE, MD
Facility:
Name:
CHU de Bordeaux - Hôpital Haut -Lèvêque
Address:
City:
Pessac
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Denis SMITH, MD
Facility:
Name:
CHU de Poitiers
Address:
City:
Poitiers
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
David TOUGERON, MD
Facility:
Name:
Institut Jean Godinot
Address:
City:
Reims
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Damien BOTSEN, MD
Facility:
Name:
Centre Eugène Marquis
Address:
City:
Rennes
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Héloïse BOURIEN, MD
Facility:
Name:
CHU de Rouen
Address:
City:
Rouen
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Frédéric DI FIORE, MD
Facility:
Name:
Institut de Cancérologie de l'Ouest
Address:
City:
Saint-Herblain
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Sandrine HIRET, MD
Facility:
Name:
CHU de Toulouse Hôpital Rangueil
Address:
City:
Toulouse
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Rosine GUIMBAUD, MD
Facility:
Name:
Gustave Roussy Grand Paris
Address:
City:
Villejuif
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Cristina SMOLENSCHI, MD
Facility:
Name:
Hôpital Saint-Antoine
Address:
City:
Paris
Country:
France
Status:
Not yet recruiting
Contact:
Last name:
Thierry ANDRE, MD
Start date:
July 23, 2024
Completion date:
September 2030
Lead sponsor:
Agency:
UNICANCER
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute, France
Agency class:
Other
Collaborator:
Agency:
GlaxoSmithKline
Agency class:
Industry
Source:
UNICANCER
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06333314
