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Study to Nivolumab Following Preoperative Chemoradiotherapy

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ClinicalTrials.gov Identifier: NCT02948348
Recruitment Status : Unknown
Verified September 2021 by Takayuki Yoshino, National Cancer Center Hospital East.
Recruitment status was:  Recruiting
First Posted : October 28, 2016
Last Update Posted : September 16, 2021
Sponsor:
Collaborator:
Ono Pharmaceutical Co. Ltd
Information provided by (Responsible Party):
Takayuki Yoshino, National Cancer Center Hospital East

Study Description
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Brief Summary:
This is a phase Ib/II, open-label, single-arm, multicenter study to investigate the safety, efficacy, and proof of concept (POC) of monotherapy with nivolumab, an anti-PD-1 antibody drug, as a sequential therapy following chemoradiotherapy (CRT) with capecitabine and subsequent surgical therapy in patients with locally advanced resectable rectal cancer.

Condition or disease Intervention/treatment Phase
Cancer of Rectum Drug: Nivolumab Drug: Ipilimumab Phase 1 Phase 2

Detailed Description:

[Phase Ib]

After preoperative CRT, to sequentially administer nivolumab in combination for patients with locally advanced resectable rectal cancer. To evaluate the safety of nivolumab in sequential combination therapy, the onset of dose-limiting toxicity (DLT) and the safety of subsequent surgical therapy, and to decide on a recommended dose (RD) for the phase II part.

[Phase II] PhaseⅡ is composed of 4 cohorts.

Cohort A: First-onset rectal cancer cohort (42 cases) To evaluate the efficacy and safety of nivolumab (at the RD determined in Phase Ib) in sequential combination with surgery, administered following preoperative CRT.

And to search for biomarkers related to therapeutic effects in first-onset cases. Evaluate the safety of surgical treatment.

Cohort B: Rectal cancer with localized recurrence cohort (10 cases) To conduct an exploratory evaluation of the efficacy and safety of nivolumab (at the RD determined in Phase Ib) in sequential combination with surgery, administered after preoperative CRT.

Search for biomarkers related to therapeutic effects in localized recurrence cases. Conduct an exploratory evaluation on the safety of surgical treatment.

Cohort C: Rectal cancer with resectable lung/liver metastasis cohort (10 cases) To conduct an exploratory evaluation of the efficacy and safety of nivolumab (at the RD determined in Phase Ib) in sequential combination with surgery, administered after preoperative CRT.

Search for biomarkers related to therapeutic effects in resectable lung/liver metastasis cases. Conduct an exploratory evaluation on the safety of surgical treatment.

Cohort D: First-onset rectal cancer using ipilimumab-nivolumab combination cohort (25 cases) To conduct an exploratory evaluation of the efficacy and safety of nivolumab (240 mg/body at two-week intervals) and ipilimumab (1 mg/kg at six-week intervals) after preoperative CRT, and search for biomarkers related to therapeutic effects in first-onset cases. Conduct an exploratory evaluation on the safety of surgical treatment.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Multicenter Study to Investigate the Safety, Efficacy and Proof of Concept (POC) of Nivolumab Monotherapy as a Sequential Therapy Following Preoperative Chemoradiotherapy Patients With Locally Advanced Resectable Rectal Cancer
Study Start Date : October 2016
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : August 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Nivolumab & Ipilimumab(Only Cohort D)
chemoradiotherapy with capecitabine+ Nivolumab + Ipilimumab(Only Cohort D) + surgical therapy
 Drug: Nivolumab
Capecitabine:Dose of 1650mg/m2,14days, Radiation:45Gy/25 fractions, Nivolumab :240mg on day1 of each cycle, Surgical therapy:The resection (LAR), intersphincteric resection (ISR), or abdominoperineal resection (APR).
Other Names:
  • Opdivo
  • Chemoradiotherapy with capecitabine
  • Surgical therapy

Drug: Ipilimumab
For only Cohort D,1 mg/kg at six-week intervals
Other Name: Yervoy


Outcome Measures
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Primary Outcome Measures :
  1. Pathological complete response [ Time Frame: 1 year ]
    Pathological complete response will be evaluated with American Joint Committee on Cancer (AJCC) Cancer Staging


Secondary Outcome Measures :
  1. Objective response rate [ Time Frame: 1 year ]
    Evaluation Criteria In Solid Tumors (RECIST)

  2. Recurrence pattern (local or distant) [ Time Frame: 1 year ]
  3. Disease-free survival (DFS) [ Time Frame: 5years ]
    Evaluation Criteria In Solid Tumors (RECIST)

  4. Overall survival (OS) [ Time Frame: 5years ]
    Evaluation Criteria In Solid Tumors (RECIST)

  5. Incidence of adverse events (AEs) [ Time Frame: 1 year ]
    Safety will be evaluated with CTCAE v4.0

  6. Rate of completing the protocol therapy [ Time Frame: 1 year ]
  7. Rate of radical resection [ Time Frame: 1 year ]
  8. Safety evaluation [ Time Frame: 5years ]
    Safety will be evaluated with CTCAE v4.0

  9. macroscopic evaluation of (rectal cancer) resected specimen [ Time Frame: 1 year ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   20 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

(A. Phase Ib and Cohorts A and D only)

A1. Rectal cancer patients who have not undergone treatment for pre-CRT tumors situated 12 cm or less from the lower edge of the AV.

A2. The primary rectal lesion is histopathologically diagnosed as adenocarcinoma.

A3. Pre-CRT clinical stage is clinical T3-4 N-any M0.

A4. Macroscopic radical resection is deemed possible on pre-CRT image diagnosis.

A5. Aged between 20 and 80 years at the time of enrollment.

(B. Cohort B only)

B1. Clinically diagnosed with local recurrence after rectal surgery.

B2. The main site of recurrence is limited to the pelvis by pre-CRT imaging diagnosis.

B3. Macroscopic radical resection is deemed possible on pre-CRT imaging diagnosis.

B4. Aged between 20 and 75 years at the time of enrollment.

(C. Cohort C only)

C1. Rectal cancer patients who have not undergone pretreatment for a pre-CRT tumor which is 12 cm or less from the lower AV.

C2. The primary rectal lesion is histopathologically diagnosed as adenocarcinoma.

C3. The pre-CRT clinical stage is clinical T3-4 N-any M1a (liver) M1a (lungs).

C4. Macroscopic curative resection of the primary rectal lesion is deemed possible on pre-CRT imaging diagnosis.

C5. A metastatic liver tumor or a metastatic lung tumor has been diagnosed as clinically resectable prior to CRT and during clinical trial enrollment.

(D. Common to all cohorts in Phase Ib and Phase II)

D1. Patients who have provided consent through a consent form.

D2. Patients whose Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is 0 or 1 at the time of enrollment.

D3. CRT was administered:

D4. Patients whose CRT adverse events have recovered to Grade 1 or lower based on CTCAE ver.4.0. within 14 days after the end of CRT, and are expected to be able to take nivolumab (patient is still eligible even if adverse events are not restored to Grade 1, provided that the blood cell count satisfies the eligibility criteria specified in point D8).

D5. Patients with no remote metastases as confirmed by imaging at the end of CRT (testing is allowed from 14 days before the end of CRT to the trial enrollment date).

D6. For women who may become pregnant (including patients who are not menstruating due to chemically-induced menopause among other medical reasons), patients who agree to use contraception for at least 23 weeks after the last administration of the investigational drug, starting from the day they provide consent (30 days (ovulation cycle) plus five times the elimination half-life of the investigational drug).

D7. For men, patients who agree to use contraception for at least 31 weeks after the last administration of the investigational drug, starting from the day they provide consent (90 days (spermatogenesis cycle) plus five times the elimination half-life of the investigational drug).

D8. Patients who have the sufficient organ function at the time of enrollment.

Exclusion criteria

  1. Patients diagnosed with active double cancer (synchronous double cancer and double cancer with disease-free period within five years from enrollment).

    However, lesions equivalent to intraepithelial or mucosal carcinoma deemed cured by localized treatment are not classified as active double cancer.

  2. Patients with a history of pelvic irradiation prior to this rectal cancer treatment.
  3. Patients who have not given consent through the informed consent form.
  4. Patients deemed by the investigator to be ineligible for the trial.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02948348


Contacts
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Contact: Hideaki Bando, Dr +81-52-762-6111 voltage_core@east.ncc.go.jp
Contact: Yuichiro Tsukada, Dr +81-4-7133-1111 ext 92331 voltage_core@east.ncc.go.jp

Locations
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Japan
National Cancer Center Hospital East Recruiting
Kashiwa, Chiba, Japan
Hokkaido University Recruiting
Sapporo, Hokkaido, Japan
Osaka National Hospital Recruiting
Osaka, Japan
Sponsors and Collaborators
Takayuki Yoshino
Ono Pharmaceutical Co. Ltd
Investigators
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Study Chair: Takayuki Yoshino, Dr Gastrointestinal Oncology Division National Cancer Center Hospital East
More Information
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Responsible Party: Takayuki Yoshino, Director of Gastrointestinal Oncology Division, National Cancer Center Hospital East
ClinicalTrials.gov Identifier: NCT02948348    
Other Study ID Numbers: EPOC1504
First Posted: October 28, 2016    Key Record Dates
Last Update Posted: September 16, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
 Rectal Diseases
Capecitabine
Nivolumab
Ipilimumab
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors