Nivolumab, Chemoradiotherapy, and Surgery-2

JRCT ID: jRCT2031220484

Registered date:02/12/2022

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Resectable Stage II/III and Stage I rectal cancer with dMMR/MSI-H
• Date of first enrollment: 23/01/2023
• Target sample size: 55
• Study type: Interventional

Intervention(s)

Patients must begin protocol treatment within 2 weeks of enrollment (by the same day of the week 2 weeks after the date of enrollment).

Patients will be evaluated by endoscopy, thoracoabdominal pelvic CT, and pelvic MRI (MRI only at the end of 6 courses) at the end of 3 and 6 courses (1st evaluation) of nivolumab (240 mg/body intravenously at 2-week intervals), respectively. If there is disease progression, the patient is transferred to CRT if the disease is considered resectable without distant metastasis, and protocol treatment is terminated if the disease is considered unresectable due to distant metastasis or other reasons. If there is no disease progression, 6 courses of nivolumab (240 mg/body intravenously at 2-week intervals) will be administered, and at the end of the 12 courses, a comprehensive evaluation will be conducted using endoscopy, thoracoabdominal pelvic CT and pelvic MRI (second evaluation), including the investigator or subinvestigator and a physician from the Clinical Research Coordinating Committee. Patients who are judged to have clinical complete response (cCR) or near CR by the comprehensive evaluation will be followed up with up to 12 additional courses of nivolumab (240 mg/body every 2 weeks) (24 courses in total). If the disease does not progress to cCR or near CR, or if there is progression but no distant metastasis and the disease is considered resectable, the patient is moved to CRT within 4 weeks (by the same day 4 weeks later) after the 12th course of nivolumab.

Patients will receive 50.4 Gy (45 Gy/25 pelvic irradiations and 5.4 Gy/3 boost irradiations to the primary tumor) with capecitabine (1650 mg/m2 equivalent x 5 days/week) as CRT. Patients who do not achieve cCR or near CR within 12 weeks of CRT completion (by the same day 12 weeks later) will undergo salvage surgery.

In case of re-enlargement during non-operative management (NOM), salvage surgery should be performed within 8 weeks (by the same day of the week 8 weeks later) from the date of confirmation of re-enlargement. No postoperative treatment is specified.

In case of re-enlargement during the NOM of the protocol treatment period, patients who have not undergone CRT should undergo CRT, and those who have undergone CRT should undergo salvage surgery.

Outcome(s)

• Primary Outcome: Percentage of 2-year clinical complete response (cCR) as judged by the investigator or sub-investigator for nivolumab alone

Secondary Outcome

1.2-year cCR rate for all protocol treatments
2.2-year cCR + pathological complete response (pCR) rate
3.2-year cCR rate for nivolumab alone by central adjudication
4.Percentage of patients who completed protocol treatment
5.Recurrence form
6.Progression-free survival (PFS)
7.Event-free survival (EFS)
8.Disease-free survival (DFS)
9.2-year total mesorectal excision (TME)-free rate
10.TME-free survival
11.TME-free progression-free survival
12.Distant metastasis free survival (DMFS)
13.Local recurrence free survival (LRFS)
14.Overall survival (OS)
15.Ratio of treatment-related adverse events as determined by CTCAE ver. 5.0
16.Perioperative safety assessment of patients who underwent surgery (intraoperative complications as determined by CTCAE ver5.0 and postoperative complications as determined by CTCAE ver5.0 and Clavien-Dindo classification)
17.Quality of life assessment during treatment and up to 5 years after treatment
18.Circulating tumor DNA (ctDNA) negative rate

For patients who underwent NOM
1.Local regrowth rate
2.Time to local regrowth
3.Percentage of radical resection to cases of salvage surgery

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Histopathologically diagnosed adenocarcinoma.
2. Rectal cancer with the inferior margin of the tumor within 12 cm of the anal verge (AV).
3. deficient mismatch repair (dMMR/MSI-H) on examination of tissue or blood specimen.
4. Age >18 years at the time of enrollment.
5. Clinical stage II/III (T3-4 N-any M0, T1-2N1-2M0) in the primary analysis part. In the exploratory part, the clinical stage is Stage I (T1-2 N0 M0), which cannot be cured by endoscopic or local resection.

6. Patients with considered to be amenable of radical resection by diagnostic imaging.
7. Patient's written informed consent has been obtained.
8. Patients with an ECOG Performance Status (PS) of 0 or 1 at the time of enrollment.
9. No history of radiation to the pelvic region.

10. Women with childbearing potential (including patients who are not menstruating for medical reasons, such as chemical menopause) must have dual contraceptive coverage from the time of consent for at least 5 months after the last dose of nivolumab (or during chemoradiotherapy and for at least 7 months after the last dose of capecitabine, if chemoradiotherapy is administered) Patients who have consented to double contraception and restricted egg donation (including the harvesting of eggs for their own use) for at least 5 months after the last dose of nivolumab. Patients who also agree not to breastfeed from the time consent is obtained for at least 5 months after the last dose of nivolumab (or during chemoradiotherapy and for at least 7 months after the last dose of capecitabine if chemoradiotherapy is administered).
11. Men who, if receiving chemoradiotherapy, will use appropriate contraception as specified in this trial during chemoradiotherapy and for at least 7 months after the last dose of capecitabine. And patients who agree not to cryopreserve or donate sperm.
12. Patients with adequate organ function at the time of enrollment.

Exclude criteria

1.Patients diagnosed with active multiple cancers (concurrent multiple cancers and multiple cancers with a disease-free interval of 5 years or less from the time of enrollment).
However, active duplications do not include intraepithelial or intramucosal carcinomas that are considered curable with local treatment. Patients with duplicate cancer of the colon or rectum are eligible if there is no distant metastasis and all lesions are considered surgically resectable.
2.Patients with a history of inflammatory bowel disease.
3.Patients with a history of pneumonia or interstitial lung disease (ILD).
4.Patients with concomitant autoimmune disease or a history of chronic or recurrent autoimmune disease.
5.Patients who require systemic corticosteroids (except for prophylactic administration for laboratory or allergic reactions or temporary use to reduce edema associated with radiation therapy) or immunosuppressive agents, or who have received such treatment within 14 days prior to enrollment in this study.

6.Patients with a history or findings of cardiovascular risk.
7.Patients with poorly controlled diabetes mellitus or other conditions that may interfere with toxicity assessment.
8.Patients with positive HIV-1 and HIV-2 antibody tests, HTLV-1 antibody test, HBs antigen test or HCV antibody test. Patients with a negative HBs antigen test but a positive HBs antibody test or HBc antibody test and an HBV-DNA quantitative test with a detection sensitivity of greater than or equal to 0.05. Patients with a negative HBs antigen test but a positive HBs antibody test or HBc antibody test. If the HCV antibody test is positive but the HCV-RNA is negative, enrollment is acceptable.
9.Pregnant, lactating, or possibly pregnant patients.
10.Patients suffering from a serious or unstable psychiatric or other medical condition that may interfere with the safety of the subject, the obtaining of consent, or compliance with study procedures.

11.Patients with a history of prior therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 or anti-CTLA-4 antibodies or other antibody or drug therapies for T-cell control.
12.Patients who have received live or attenuated vaccination within 28 days prior to enrollment in this study.
13.Patients who are unwilling or unable to comply with the procedures specified in the study protocol.
14.Patients who are judged by the investigator to be unsuitable for the clinical trial.

Related Information

• Primary Sponsor: Bando Hideaki
• Source(s) of Monetary Support: Japan Agency for Medical Research and Development