Untreated Stage II/III dMMR/MSI-H locally advanced rectal cancer 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) 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)
Conditions
Sponsors
GlaxoSmithKline Research & Development Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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. To be eligible for participation in the study, participants must meet the full inclusion and exclusion criteria presented in Section 5.1.2 and Section 5.2, respectively, after completing the Prescreening Period. Age 1. Is at least 18 years of age (or the local legal age of consent) 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 adenocarcinoma. 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 (or the local legal age of consent) at the time of signing the ICF. 2. Has histologically confirmed Stage II to III (T3-T4, N0, or T any, N+), locally advanced rectal adenocarcinoma. 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 MMR; 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 locally. 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,or EPCAM) may be 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. 8. Has an ECOG performance status of 0 or 1. 9. Has adequate organ function, as defined in Table 8. (NOTE: A complete blood count test should be obtained without transfusion or receipt of colony-stimulating factors within 2 weeks of obtaining the sample.) For a full list of Inclusion criteria please refer to the Study Protocol Section 5.1 Inclusion Criteria Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 50 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 50
Exclusion criteria
Exclusion criteria: Exclusion criteria Participants are excluded from the study if any of the following criteria apply: 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, orimmunosuppressive 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. 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. 9. Has undergone any major surgical procedure, open biopsy, or experienced significant traumatic injury within 28 days prior to enrollment. 15. Is receiving immunosuppressive medication. 16. 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. 18. Has received or plans to receive an organ or stem cell transplant that uses donor stem cells (allogeneic stem cell transplant). For a full list of Exclusion criteria please refer to the Study Protocol Section 5.2
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): • cCR24 as assessed by ICR, defined as maintenance of cCR for 24 months. The 24-month period starts from the first disease assessment after last dose of study intervention that demonstrates cCR by ICR. • 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 • cCR24 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 • Organ preservation rate at 3 years, defined as not undergoing TME, either as primary management or for local recurrence, or who did not have a permanent colostomy created, at any time up to 3 years • 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 intervent | — |
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