Phase 2 Study of Dostarlimab in Untreated dMMR/MSI-H Locally Advanced Rectal Cancer

Phase 1

• Conditions: ntreated Stage II/III dMMR/MSI-H locally advanced rectal cancer; MedDRA version: 21.0Level: PTClassification code 10038049Term: Rectal cancer stage IISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: PTClassification code 10038050Term: Rectal cancer stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2022-003289-18-NL
• Lead Sponsor: GlaxoSmithKline Research & Development Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-01-10
• Last Update Posted: 22 April 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 150

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 (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.
* Type of participant and disease characteristics
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, or EPCAM) 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 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 ECPAM) 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 r

Exclusion Criteria

Participants are excluded from the study if any of the following 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.
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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified