Untreated Stage II/III dMMR/MSI-H locally advanced rectal cancer MedDRA version: 21.0 Level: PT Classification code 10038050 Term: Rectal cancer stage III System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.0 Level: PT Classification code 10038049 Term: Rectal cancer stage II System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Jemperli
Product Name: Dostarlimab
Product Code: [TSR-042, GSK4057190A]
Pharmaceutical Form: Concentrate for solution for injection/infusion
INN or Proposed INN: Dostarlimab
CAS Number: 20
Sponsors
GLAXOSMITHKLINE RESEARCH AND DEVELOPMENT
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: (Prescreening Period) - A Prescreening Period will only be available at sites/countries where local dMMR/MSI-H testing is not available. The Prescreening Period is not required for participants whose dMMR/MSI-H status has been previously determined. Prior to Screening, participants without must meet the Prescreening criteria below. *Age Is at least 18 years of age at the time of signing the ICF. *Type of participant and disease characteristics 1. Has histologically confirmed Stage II to III (T3-T4, N0, or T any, N+), locally advanced rectal cancer. 2. Has radiologically and endoscopically evaluable disease. Inclusion criteria (Screening Period) Participants are eligible to be included in the study only if all the following criteria apply: *Age 1. Is at least 18 years of age at the time of signing the ICF. * Type of participant and disease characteristics 2. Has histologically confirmed Stage II to III (T3-T4, N0, or T any, N+), locally advanced rectal cancer. 3. Has radiologically and endoscopically evaluable disease. 4. Has a tumor demonstrating the presence of either: a. dMMR status; MMR status must be assessed by IHC for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of 1 or more proteins indicates dMMR; MMR status may be determined either locally or by the central reference laboratory; or b. MSI-H phenotype as determined by polymerase chain reaction or by tissue next-generation sequencing; MSI-H may be determined either locally or by the central reference laboratory. NOTE: Participants who are known to have Lynch syndrome and have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2) are eligible to participate. 5. Has an archival FFPE tissue sample that must be available and submitted to the central reference laboratory for testing at Screening. If no archival tissue is available, a fresh baseline biopsy will be required. *Sex and contraceptive/barrier requirements Is willing to use adequate contraception. • Contraceptive use by female participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Female participants: • A female participant is eligible to participate if she is not pregnant or breastfeeding, and 1 of the following conditions applies: • Is a WONCBP as defined in Appendix 4. OR • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Appendix 4, during the Intervention Period and for at least 120 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention. • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention. • If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. • Additional requirements for pregnancy testing during and after study intervention as defined in Appendix 4. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early u
Exclusion criteria
Exclusion criteria: * Medical conditions 1. Has distant metastatic disease. 2. Has received prior radiation therapy, systemic therapy, or surgery for management of rectal cancer. Note: Endoscopy guided biopsy is not considered surgery. 3. Has a tumor that, in the investigator’s judgment, is causing symptomatic bowel obstruction or otherwise requires urgent/emergent local intervention. 4. Has a known additional malignancy that progressed or required active treatment within the past 2 years. Exceptions include adequately treated superficial skin cancers, superficial bladder cancers, and other in situ cancers. 5. Is immunocompromised in the opinion of the investigator. 6. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. 7. Is unable to undergo MRI. 8. Has experienced any of the following with prior immunotherapy: any irAE of Grade =3, immune-related severe neurologic events of any grade (e.g., myasthenic syndrome/myasthenia gravis, encephalitis, Guillain-Barré Syndrome, or transverse myelitis), exfoliative dermatitis of any grade (Stevens-Johnson Syndrome, toxic epidermal necrolysis, or DRESS syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary. * Prior/concomitant therapy 9. Is receiving any other anticancer or experimental therapy. No other experimental therapies (including but not limited to chemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, or other experimental drugs) of any kind are permitted while the participant is receiving study intervention. 10. Is receiving immunosuppressive medication. 11. Has received systemic corticosteroids (>10 mg daily prednisone or equivalent) within 7 days of first dose of study intervention. Use of inhaled steroids, local injection of steroids, topical steroids, and steroidal eye drops are allowed. 12. Has received any live vaccine within 30 days prior to enrollment. Vaccination against COVID-19 using vaccines that are authorized via the appropriate regulatory mechanisms (e.g., Emergency Use Authorization, Conditional Marketing Authorization, or Marketing Authorization Application) are not exclusionary. Note: mRNA and adenoviral-based COVID-19 vaccines are considered non-live. If a COVID-19 vaccine is administered at any time, the date of COVID-19 vaccination must be entered in the eCRF. 13. Is considered, in investigator’s opinion, 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: 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 (including obtaining informed consent). *Diagnostic assessments and other criteria 14. Has documented presence of HBsAg at Screening or within 3 months prior to first dose of study intervention. 15. Has a positive HCV antibody test result at Screening or within 3 months prior to first dose of study intervention. NOTE: Participants with a positive HCV ant
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To estimate the efficacy of dostarlimab in participants with Stage II/III (locally advanced) dMMR/MSI-H rectal cancer that has not been previously treated;Secondary Objective: - To further estimate the efficacy of dostarlimab in participants with Stage II/III (locally advanced) dMMR/MSI-H rectal cancer that has not been previously treated - To assess the safety and tolerability of dostarlimab in participants with Stage II/III (locally advanced), dMMR/MSI-H rectal cancer that has not been previously treated - To describe the PK of dostarlimab in participants with Stage II/III (locally advanced), dMMR/MSI-H rectal cancer that has not been previously treated - To determine the immunogenicity of dostarlimab in participants with Stage II/III (locally advanced), dMMR/MSI-H rectal cancer that has not been previously treated;Primary end point(s): - cCR12 as assessed by ICR, defined as maintenance of cCR for 12 months. The 12-month period starts from the first disease assessment after last dose of study intervention that demonstrates cCR by ICR.;Timepoint(s) of evaluation of this end point: - cCR12 as assessed by ICR, defined as maintenance of cCR for 12 months. The 12-month period starts from the first disease assessment after last dose of study intervention that demonstrates cCR by ICR. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - cCR36 as assessed by ICR, defined as maintenance of cCR for 36 months. The 36-month period starts from the first disease assessment after last dose of study intervention that demonstrates cCR by ICR. - EFS3 as assessed by investigator assessment, defined as remaining alive and free of 1) disease progression precluding surgery, 2) local recurrence, and 3) distant recurrence, as assessed by investigator at 3 years from the first dose of study intervention. EFS by investigator assessment defined as time from the date of first dose of study intervention to any of the following events: 1) progression of disease that precludes surgery, 2) local recurrence, 3) distant recurrence (all as assessed by the investigator), or 4) death due to any cause • cCR12 by investigator assessment • cCR36 by investigator assessment • ORR by ICR, defined as achieving a PR, nCR, or cCR at PIDA or at least 4 weeks but no longer than 8 weeks after PIDA for participants with nCR or iCR (PIDA 2) • ORR at PIDA by investigator assessment • TME at 3 years, defined as undergoing TME, either as primary management or for local recurrence • DSS, Disease-Specific Survival, defined as time from the date of first dose of study intervention to death due to disease under study • DSS5, defined as not dying due to disease under study at 5 years from the first dose of study intervention • OS, defined as time from first dose of study intervention to death from any cause • OS5, defined as being alive at 5 years from first dose of study intervention - Frequency and severity of AEs, SAEs, irAEs, and AEs leading to death or discontinuation of study intervention - Serum concentrations and PK parameters (C-EOI and Ctrough) for dostarlimab - Incidence of ADA against dostarlimab;Timepoint(s) of evaluation of this end point: - cCR36 as assessed by ICR, defined as maintenance of cCR for 36 months. The 36-month period starts from the first disease assessment after last dose of study intervention | — |
Countries
Canada, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Spain, United Kingdom, United States
Contacts
Public ContactGSK Clinical Support Help Desk
GlaxoSmithKline Research & Development Ltd
Outcome results
None listed