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

Study Overview
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Brief Summary
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The purpose of this study is to investigate dostarlimab monotherapy in participants with locally advanced Mismatch-repair deficient (dMMR)/Microsatellite instability-high (MSI-H) rectal cancer who have received no prior treatment. Participants who achieve complete clinical response (cCR) following dostarlimab treatment will undergo non-operative management (NOM), including close surveillance for recurrent disease. The goal of the study is to determine if Dostarlimab therapy alone is an effective treatment that can allow participants to avoid chemotherapy, radiation, and surgery.

Official Title
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A Phase 2, Single-Arm, Open-Label Study With Dostarlimab Monotherapy in Participants With Untreated Stage II/III dMMR/MSI-H Locally Advanced Rectal Cancer

Conditions
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Neoplasms, Rectal

Intervention / Treatment
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* Biological: Dostarlimab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has histologically confirmed Stage II to III (T3-T4, N0, or T any, N+), locally advanced rectal cancer Participant has radiologically and endoscopically evaluable disease. Participant has a tumor which can be categorized as dMMR or MSI-H by local or central assessment Exclusion Criteria: Participant has distant metastatic disease. Participant has received prior radiation therapy, systemic therapy, or surgery for management of rectal cancer. Participant has any history of interstitial lung disease or pneumonitis Participant 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. Participant 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. Participant 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. Participant has a history of severe allergic and/or anaphylactic reactions to chimeric, human or humanized antibodies, fusion proteins, or has known allergies to dostarlimab or its excipients. Has received or plans to receive an organ or stem cell transplant that uses donor stem cells (allogeneic stem cell transplant).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dostarlimab monotherapy<br> | Biological: Dostarlimab<br>* Dostarlimab will be administered.<br>* Other names: GSK4057190A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Sustained Complete Clinical Response for 12 Months (cCR12) as assessed by Independent Central Review (ICR) | cCR12 is achieved when a participant maintains complete clinical response (cCR) as assessed by ICR for 12 months following their post-intervention disease assessment (PIDA) | 18 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Sustained Complete Clinical Response for 24 Months (cCR24) as assessed by ICR | cCR24 is achieved when a participant maintains complete clinical response (cCR) as assessed by ICR for 24 months following their post-Intervention disease assessment (PIDA) | 30 Months | 
| Number of Participants with Sustained Complete Clinical Response for 36 Months (cCR36) as assessed by ICR | cCR36 is achieved when a participant maintains complete clinical response (cCR) as assessed by ICR for 36 months following their post-Intervention disease assessment (PIDA) | 42 Months | 
| Number of Participants with Event Free Survival at 3 years (EFS3) as assessed by Investigator | EFS3 is defined as participants who remained alive and free of disease progression precluding surgery, local recurrence, and distant recurrence at 3 years as assessed by Investigator | 3 years | 
| Event Free Survival (EFS) as assessed by Investigator | EFS is defined as time from the date of first dose of study intervention to any of the following events: progression of disease that precludes surgery, local recurrence, distant recurrence (all as assessed by the investigator), or death due to any cause | Up to 74 months | 
| Number of Participants with cCR12 as assessed by Investigator | cCR12 is achieved when a participant maintains complete clinical response (cCR) as assessed by Investigator for 12 months following their post-intervention disease assessment (PIDA) | 18 Months | 
| Number of Participants with cCR24 as assessed by Investigator | cCR24 is achieved when a participant maintains complete clinical response (cCR) as assessed by Investigator for 24 months following their post-intervention disease assessment (PIDA) | 30 Months | 
| Number of Participants with cCR36 as assessed by Investigator | cCR36 is achieved when a participant maintains complete clinical response (cCR) as assessed by Investigator for 36 months following their post-intervention disease assessment (PIDA) | 42 Months | 
| Objective Response Rate (ORR) assessed by ICR | ORR is defined as number of participants achieving a partial response (PR), near complete response (nCR) or complete clinical response (cCR) at PIDA or at least 4 weeks but no longer than 8 weeks after PIDA for participants with nCR or incomplete clinical response (iCR) (PIDA 2) as assessed by ICR | Up to 33 Weeks | 
| Objective Response Rate (ORR) as assessed by Investigator | ORR by Investigator, 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 | Up to 33 Weeks | 
| Organ Preservation Rate | Organ Preservation Rate defined as not undergoing Total Mesorectal Excision (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 | 3 years | 
| Disease-Specific Survival (DSS) | DSS is defined as time from the date of first dose of study intervention to death due to disease | Up to 74 months | 
| Disease-Specific Response at 5 years (DSS5) | DSS5 is defined as the number of participants not dying due to disease under study at 5 years from the first dose of study intervention | Up to 5 years | 
| Overall Survival (OS) | OS is defined as time from first dose of study intervention to death from any cause | Up to 74 months | 
| Overall Survival at 5 years (OS5) | OS is defined as number of participants as being alive at 5 years from first dose of study intervention | Up to 5 years | 
| Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs), Immune related Adverse Events (irAEs) based on Severity |  | Up to 74 months | 
| Number of Participants with discontinuation of study intervention |  | Up to 24 weeks | 
| Serum concentration of Dostarlimab |  | Up to 37 weeks | 
| Concentration at the end of infusion (C-EOI) of Dostarlimab |  | Up to 37 weeks | 
| Trough Concentration (C-trough) of Dostarlimab |  | Up to 37 weeks | 
| Number of Participants with Anti-Drug Antibodies against Dostarlimab |  | Up to 37 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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JEMPERLI, dostarlimab-gxly, GSK4057190A, Stage II/III rectal cancer, Neoadjuvant, dMMR, MSI-H