DOSTARLIMAB for Locally advanced rectal cancer (pMMR/MSS or MSI-Low)

Inclusion criteria

• {"criterion_text":"- Histologically proven rectal adenocarcinoma with distal extension less 16 cm from the anal verge.\n- Signed written informed consent.\n- Subjects aged 18 years or older.\n- Stage cT3-4 cN0 cM0, any cT cN+ M0 [N+ stage, three or more lymph nodes of diameter >/=0.5 cm measured by endorectal ultrasound, or one or more lymph nodes of diameter >/=1 cm measured by magnetic resonance (MRI)].\n- Proficient mismatch repair (pMMR)/microsatellite stable status (MSS) or microsatellite instability (MSI) – low (MSI-L)\n- ECOG-Performance Status 0-1\n- No previous treatment with chemotherapy or radiation therapy.\n- No prior exposure to immune-mediated therapy, excluding therapeutic anticancer vaccines.\n- Neutrophil count >1,500/mL, platelet count >100.000/mL, hemoglobin >9.0 g/dL, AST and ALT ≤2.5 x Upper Limit Normal (ULN); bilirubin less than or equal to 1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%); serum creatinine ≤1.5×ULN.\n- For participants not taking warfarin: INR <1.5 or PT <1.5 x ULN and either PTT or aPTT <1.5 x ULN. Participants taking warfarin may be included on a stable dose with a therapeutic INR <3.5.\n- A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: - Is not a woman of childbearing potential (WOCBP) or - Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), from the Screening Visit through at least 120 days after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for reproduction during this period. The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment. - A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 72 hours prior to the first dose of study treatment. The Investigator is responsible for reviewing medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy."}

Exclusion criteria

• {"criterion_text":"- Subjects with active, known, or suspected autoimmune disease requiring systemic treatment (systemic steroids or immunosuppressive agents) except subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune conditions only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.\n- Subjects that are receiving other anticancer therapies.\n- Participant has an active infection requiring systemic steroid therapy within 1 week before the anticipated first dose of study treatment.\n- Participants have received systemic steroid therapy (>10 mg daily prednisone or equivalent) within 7 days prior to the first dose of the study treatment or are receiving any other form of immunosuppressive medication. Replacement therapy (adrenal or pituitary insufficiency) is not considered a form of systemic therapy. Use of inhaled corticosteroids, local steroid injection, or steroid eye drops is allowed.\n- Pre-existing/active conditions: - Participant has experienced any of the following with prior immunotherapy: any immune related AE (irAE) of Grade 3 or higher, 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 drug reaction with eosinophilia and systemic symptoms [DRESS] syndrome), or myocarditis of any grade. Non-clinically significant laboratory abnormalities are not exclusionary.\n- Malignancies: - Participant has an additional malignancy or a history of prior malignancy, except adequately treated basal or squamous skin cancer, cervical carcinoma in situ, superficial bladder cancer without evidence of disease, other in situ cancers, or had a malignancy treated with curative intent and with no evidence of disease recurrence for 2 years since the initiation of that therapy.\n- Partecipants has cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, or persistent jaundice.\n- Participant has any history of interstitial lung disease or pneumonitis\n- Participant has clinically significant cardiovascular disease within 6 months of enrollment.\n- Distant metastases documented.\n- Participants have received a live vaccine within 30 days of the planned start of study therapy. COVID- 19 vaccines that do not contain live viruses are allowed. Note: mRNA and adenoviral-based COVID- 19 vaccines are considered non-live.\n- Participants have a current active history of pneumonitis or interstitial lung disease.\n- Hypersensitivity: Participant has a history of severe allergic and/or anaphylactic reactions to chimeric, human, or humanized antibodies or fusion proteins, sensitivity to any of the study treatments or components thereof, or a history of drug or other allergy that, in the opinion of the Investigator or GSK Medical Monitor, contraindicates their participation.\n- Patient is pregnant or breastfeeding or expecting to conceive children, starting with the Screening Visit through 120 days after the last dose of study treatment.\n- Known HIV infection (section 9.1 says HIV-positive patients will be excluded)\n- Hepatitis: - Has documented presence of HBsAg [or HBcAb] at Screening or within 3 months before the first dose of study intervention. Participants with antibody foies HBsAg and HBcAg are eligible only if HBV DNA is negative. - Has a positive HCV antibody test result at Screening or within 3 months prior to the 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 by PCR is obtained. - Has a positive HCV RNA test result at Screening or within 3 months before the first dose of the 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."}

Primary endpoints

• {"endpoint_text":"- Clinical complete response (cCR) is defined as an absence of residual disease on digital and endoscopic rectal examination, as well as the absence of residual disease on rectal MRI, with no restricted diffusion on T2-weighted imaging (cT0N0M0). cCR will be evaluate according to criteria by MSKCC Regression Scheme. Pathological complete response (pCR) is defined as an absence of viable tumor cells after full pathologic examination of the resected specimen (pT0N0M0).","definition_or_measurement_approach":"cCR: absence of residual disease on digital and endoscopic rectal examination and absence on rectal MRI with no restricted diffusion on T2-weighted imaging; evaluated according to MSKCC Regression Scheme. pCR: absence of viable tumor cells after full pathologic examination of resected specimen (pT0N0M0)."}

Secondary endpoints

• {"endpoint_text":"- Pathological downstaging is defined as pathological stage after surgery compared with the clinical stage at diagnosis.\n- Organ Preservation Rate is 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.\n- DFS is defined as the time from randomization to recurrence of a tumor.\n- OS is defined as the time from initiation of study treatment to death from any cause.\n- QoL is measured as pre-defined PRO endpoints in this study are mean changes from baseline in the EORTC-QLQ-CR29 questionnaire administered at baseline, after chemoradiation, after consolidation therapy, before starting adjuvant therapy and at the end of adjuvant therapy.\n- Safety will be evaluated in terms of incidence, nature, frequency and severity of Adverse Events (AEs) and laboratory abnormalities graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.\n- ctDNA prognostic value will be evaluated at the end of chemo/radiation, at the end of consoldation treatment, after surgery (or restaging in NOM), and after the end of adjuvant dostarlimab therapy (or 6 months in other patients)\n- To evaluate cCR at 24 and 36 months defined as an absence of residual disease on digital and endoscopic rectal examination, as well as the absence of residual disease on rectal MRI, with no restricted diffusion on T2- weighted imaging.","definition_or_measurement_approach":"Pathological downstaging: compare pathological stage after surgery vs clinical stage at diagnosis. Organ Preservation Rate: not undergoing TME or not having a permanent colostomy up to 3 years. DFS: time from randomization to tumor recurrence. OS: time from initiation of study treatment to death from any cause. QoL: mean changes from baseline in EORTC-QLQ-CR29 at prespecified timepoints. Safety: incidence, nature, frequency, severity of AEs and lab abnormalities graded by NCI CTCAE v5.0. ctDNA: measured at specified timepoints (end of chemo/radiation, end of consolidation, after surgery/restaging, after adjuvant dostarlimab or 6 months). cCR at 24/36 months: assessed as for primary cCR (digital/endoscopic exam and rectal MRI, no restricted diffusion on T2)."}

Italy

Earliest CTIS Part Ii Submission Date

01-09-2025

Latest Decision Or Authorization Date

23-12-2025

Processing Time Days

113

Number Of Sites

30

Number Of Participants

270

Primary sponsor

Full Name

G.O.I.R.C. Gruppo Oncologico Italiano Di Ricerca Clinica

Organisation Type

Patient organisation/association

Country Of Registered Address

Italy

Contract research organisations

Name

Almac Clinical Services Limited

Responsibilities

Codes: 14; 15 - secondary labelling/packaging and the QP release activities.

Name

Fullcro S.r.l.

Responsibilities

Codes: 1; 5; 6; 7; 8; 9 (roles indicated by sponsor duties codes in record)

Third parties

• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"Sponsor duties codes: 14; 15 (secondary labelling/packaging and the QP release activities.)","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Fullcro S.r.l.","duties_or_roles":"Sponsor duties codes: 1; 5; 6; 7; 8; 9","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Guardant Health Inc.","duties_or_roles":"Sponsor duties code: 4","organisation_type":"Laboratory/Research/Testing facility"}