XELOX Plus DoSTARlimab Versus XELOX Alone as Consolidation Treatment After Standard Chemoradiation in pMMR/MSS or MSI-Low Locally Advanced Rectal Cancer (LARC) Patients

Phase 2Not Yet RecruitingNCT07381777

Gruppo Oncologico Italiano di Ricerca Clinica270 enrolled

Overview

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).

This is a phase II, multicenter, randomized (2:1) controlled, clinical trial to evaluate the preliminary efficacy and safety of consolidation chemotherapy (XELOX) plus anti-PD-1 antibody (dostarlimab) after standard long-course CRT followed by adjuvant dostarlimab versus follow-up (ARM A) compared to XELOX alone as consolidation (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. Subsequent randomization into a ratio 1:1 will be performed after surgery, only for patients randomized in ARM A, to receive adjuvant dostarlimab for a maximum of 8 cycles (ARM A1) versus only follow-up (ARM A2), and in ARM B only follow-up (Figure 1). If clinical complete responses (cCR) are documented after restaging, the patient may choose not to proceed with surgery and pursue nonoperative management (NOM) (Figure 1). The patients before randomization will be stratified as follows: * cT4 or \< cT4 stage; * positive or negative lymph nodes.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

270

Eligibility

Sex: ALL

Medical Language ↔ Plain English

Inclusion Criteria: * 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 * No previous treatment with chemotherapy or radiation therapy. * No prior exposure to immune-mediated therapy, excluding therapeutic anticancer vaccines. * Neutrophil count \>1,500/mL, platelet count \>100.000/mL, hemoglobin \>9.0 g/dL, serum creatinine \<1.5 3 upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase 2.5 3 ULN, total bilirubin \<1.5 3 ULN. * Signed written informed consent. Exclusion Criteria: * 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.

Locations (30)

Ospedale San Donato - UOC Oncologia Medica dell'Aretino, Casentino, Valtiberina, Valdichiana Aretina

Arezzo, Italy

Oncologia medica e prevenzione oncologica - Centro di Riferimento Oncologico

Aviano, Italy

UOC Oncologia Medica IRCCS Azienda Ospedaliero-Universitaria di Bologna

Bologna, Italy

Oncologia Medica Fondazione Poliambulanza Istituto Ospedaliero

Brescia, Italy

UOC Oncologia Medica - ARNAS Garibaldi PO Nesima

Catania, Italy

Outcomes

Primary Outcomes

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)

Time frame: After 12 months of the end of the consolidation therapy

Secondary Outcomes

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

Time frame: After 24 and 36 months of the end of the consolidation therapy

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.

Time frame: From the enrollmentat to any time up to 3 years

Disease Free Survival

To evaluate DFS

Time frame: From randomization to recurrence of a tumor up to 3 years

Overall Survival

To evaluate OS

Time frame: From initiation of study treatment to death from any cause up to 3 years

Pathological Downstaging Rate

Pathological downstaging defined as a reduction in tumor stage comparing post-surgical pathological TNM stage (ypTNM) with baseline clinical TNM stage (cTNM).

Time frame: Perioperative period (at surgical resection).

Improvement of Quality of Life

To assess the QoL 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 to start adjuvant therapy and at the end of adjuvant therapy

Time frame: Baseline, during treatment, and at the end of adjuvant therapy (approximately 12 months).

Adverse Events

To evaluate safety 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.

Time frame: From first dose of study treatment through study completion, an average of 3 years

Association Between ctDNA Status and Clinical Outcomes

ctDNA status (positive vs negative) assessed at predefined time points and its association with clinical outcomes, including disease recurrence and treatment decisions.

Time frame: From ctDNA assessment during treatment through follow-up, up to 3 years.