This is a phase II, multicenter, randomized (2:1) controlled, clinical trial to evaluate the preliminary efficacy and safety of consolidation chemotherapy (XELOX) plus dostarlimab after standard long-course CRT (ARM A) compared to XELOX alone (ARM B) in patients with pMMR/MSS or MSI-Low LARC (cT3-4 cN0, any cT cN+) candidate to receive standard long course CRT followed by TME. After the surgery, the patients in ARM A will be randomized (1:1) to receive adjuvant dostarlimab (ARM A1) versus follow-up (ARM A2), and in ARM B only follow-up.
If clinical complete responses (cCR) are documented after consolidation treatment, the patient may choose not to proceed with surgery and pursue nonoperative management (NOM).
Histologically proven rectal adenocarcinoma with distal extension less 16 cm from the anal verge.
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)].
Proficient mismatch repair (pMMR)/microsatellite stable status (MSS) or microsatellite instability (MSI)-low (MSI-L)
ECOG-Performance Status 0-1
Subjects with active, known, or suspected autoimmune disease requiring systemic treatment (systemic steroids or immunosuppressive agents), except for 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.
Distant metastases documented.
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.
Participants have a current active history of pneumonitis or interstitial lung disease.
Parallel
XELOX (Capecitabine and Oxaliplatin)
DrugCapecitabine 1000mg/m2 BID + Oxaliplatin 130mg/m2 Q3W
Dostarlimab
DrugDostarlimab IV 500mg Q3W
Clinical complete response (cCR) at 12 months
To evaluate the clinical complete response (cCR) after 12 months of the end of consolidation treatment, 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), or the pathological complete response (pCR), in patients who undergo surgery, defined as an absence of viable tumor cells after full pathologic examination of the resected specimen (pT0N0M0)
Clinical complete response (cCR) at 24 and 36 months
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
Assessment of Organ Preservation Rate
To assess 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.
Disease Free Survival
To evaluate DFS
Overall Survival
To evaluate OS
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Gruppo Oncologico Italiano di Ricerca Clinica
Lead sponsor
GlaxoSmithKline
Collaborator
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