Brachytherapy Followed by Nivolumab Prior to Surgery in Rectal Cancer

Official title

Pilot Evaluation of the Immunogenic Potentiation of Neo-adjuvant Brachytherapy Followed by Nivolumab Immunotherapy Without Chemotherapy in Stage II/III Locally Advanced Mismatch Repair Proficient Rectal Cancer

Overview

This is a small Phase II study testing whether targeted internal radiation treatment (HDREBT) followed by two doses of the immunotherapy drug Nivolumab is safe, practical, and potentially effective before patients undergo surgery (TME) to remove rectal cancer.

Interventions

• Drug Nivolumab
  2 doses of nivolumab 3 mg/kg mg IV every 2 weeks
• Device HDRBET
  26 Gy in 4 fractions Administered over Days 1-4 as per institutional standard
• Procedure Total Mesorectal Excision (TME)
  Targeted to take place 6-8 weeks post completion of HDREBT (maximum 12 weeks)

Primary outcome measures

• Pathologic complete response (pCR) [Time frame: This is assessed at the time of total mesorectal excision surgery, occurring approximately 12 weeks after enrollment.]

Secondary outcome measures (2)

• Incidence and severity of adverse events, as per CTCAE criteria v6.0 [Time frame: From time of first treatment through 90 days following last treatment with nivolumab]
• Assess feasibility of treatment sequence [Time frame: This is assessed from the time of enrollment until the time of surgery, approximately 12 weeks after enrolment.]

Eligibility criteria

Inclusion criteria

• Age ≥18 years at the time of consent.
• Histologically confirmed rectal adenocarcinoma arising within 5 to 15 cm of the anal verge as measured by sigmoidoscopy or MRI.
• Rectal cancer staging:

• Clinical Stage cT2 or cT3 based on high resolution pelvic MRI;
• No evidence of distant metastases (cM0) on contrast -enhanced CT of chest, abdomen and pelvis (or PET/CT if clinically indicated);
• Disease deemed technically resectable with curative intent by multidisciplinary tumor board (MDT)\*. No radiologic evidence of unresectable local disease (e.g., tumor fixation or invasion of adjacent unresectable structures).
• At least one of the following adverse prognostic features observed on baseline MRI:

• Node-positive disease (cN+);
• Threatened mesorectal fascia (MRF) defined as distance from tumor to mesorectal fascia < 1mm on pelvic MRI;
• Extramural venous invasion (EMVI+).
• Proficient mismatch repair (pMMR) status, as determined by immunohistochemistry and/or microsatellite instability-low (MSI-L) status by next-generation sequencing
• Planned management includes neoadjuvant therapy with radiotherapy followed by curative-intent TME.
• Prior external beam pelvic radiation for other malignancy (prostate, gynecology, lymphoma, bladder) are acceptable, provided the colorectal surgeon deems the patient as a candidate for TME surgery.
• ECOG performance status of 0-2
• Adequate organ function, defined by:

• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L
• Hemoglobin ≥ 90 g/L
• Estimated creatinine clearance ≥ 30 mL/min
• Total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's syndrome who may only be included with total bilirubin ≤ 3.0 x ULN)
• Aspartate transaminase (AST) ≤ 3.0 x ULN
• Alanine transaminase (ALT) ≤ 3.0 x ULN
• INR ≤ 1.5 ULN
• aPTT and PT ≤ 1.5 ULN
• Albumin ≥ 25 g/L
• Ability to understand, willing to provide written informed consent, and to comply with study requirements.

Exclusion criteria

• Prior anticancer therapy for rectal cancer.
• Contraindication to safe MRI imaging.
• Evidence of bowel obstruction on MRI or clinical evaluation.
• Evidence of distant metastasis.
• Medical or surgical contraindications to major pelvic surgery
• Active autoimmune disease requiring systemic immunosuppressive therapy.
• Active/uncontrolled infection. Infectious screening for HIV, Hepatitis B (HBV), Hepatitis C (HBC) and tuberculosis will be performed at screening:

• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks; and have undetectable HBV viral load prior to starting treatment. Participants should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
• Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening. Note: Participants must have completed curative anti-viral therapy at least 4 weeks prior to start of treatment.
• HIV-infected participants must have well-controlled HIV on antiretroviral treatment (ART), defined as:

i. have a CD4+ T-cell count ≥ 0.35 x109 cells/L at the time of screening. ii. must have achieved and maintained virologic suppression defined as confirmed HIV ribonucleic acid (RNA) level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening.

iii. must not have had any AIDS-defining opportunistic infections within the past 12 months.

iv. must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before start of treatment and agree to continue ART throughout the study.

• Known allergy or hypersensitivity to nivolumab or any of its excipients.
• Patients with other psychiatric, social or severe or uncontrolled medical conditions that in the opinion of the investigator may compromise their compliance with the protocol or may represent an unacceptable risk to their safety (e.g. uncontrolled diabetes, active or uncontrolled infection, uncontrolled clinically significant cardiovascular disease).
• Requirement for prohibited concomitant medication, as outlined in section 8.4 within 14 days prior to first brachytherapy treatment.
• Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 28 days of first neo-adjuvant treatment.
• Patients who are pregnant or breastfeeding or WOCBP not employing an effective method of birth control.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 1 center

• Jewish General Hospital — Montreal

Publications

• Vuong T, Devic S, Podgorsak E. High dose rate endorectal brachytherapy as a neoadjuvant treatment for patients with resectable rectal cancer. Clin Oncol (R Coll Radiol). 2007 Nov;19(9):701-5. doi: 10.1016/j.clon.2007.07.006. Epub 2007 Aug 22. PMID 17714925
• Lin ZY, Zhang P, Chi P, Xiao Y, Xu XM, Zhang AM, Qiu XF, Wu JX, Yuan Y, Wang ZN, Qu XJ, Li X, Nie X, Yang M, Cai KL, Zhang WK, Huang Y, Sun Z, Hou ZG, Ma C, Cheng FZ, Tao KX, Zhang T. Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial. Ann Oncol. 2024 Oct;35(10):882-89 PMID 38964714

Identifiers

NCT: NCT07645118 · IMPERIA-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗