Phase 1b/II Trial of Pembrolizumab Plus IMRT in Stage III/IV Carcinoma of Anus

NCT04046133 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: SPON 1529-16
• Study Type: interventional
• Target: 52
• Locations: 2 countries
• Sites: 11

Brief Summary

The CORINTH trial is for patients with more advanced (stage 3 and 4) anal cancer. The numbers of patients with anal cancer is increasing and only 65% patients with this later stage anal cancer have not had a recurrence 3 years after treatment. Anal cancer responds well to chemo-radiation (CRT) and this would be the treatment used for standard clinical care. The chemotherapy in CORINTH will be the same as standard of care (Mitomycin and 5FU or capecitabine) and the radiotherapy (RT) will be delivered using a technique where the dose intensity of RT can be modulated for different areas of the tumor (Intensity Modulated RT - IMRT). Translational samples (tissue blocks and blood) will be collected at baseline with further blood and tissue samples during and after treatment. Pembrolizumab, a relatively new drug, is a monoclonal antibody that enhances the body's immune response to cancer cells by acting on a receptor on the surface of T-cells called Programmed Death -1 (PD-1). The CORINTH study aims to see whether pembrolizumab, can be added safely to standard CRT. We will explore how safe the combination is and how well tolerated it is for patients with stage 3 and 4 anal cancer. If it is tolerable more patients will be treated to see if there is a similar or better clinical response. The trial is designed in 3 groups of patients. All patients will receive eight infusions of pembrolizumab at three weekly intervals. Each infusion lasts approximately 1 hour. The first group will not get pembrolizumab until they have already had 4 weeks of CRT (Day 29). As long as this is not found to cause too many extra side effects, the next group will have infusions at the beginning of the third week of CRT. The final group (cohort 3) will start their pembrolizumab with the first day of CRT i.e. Day 1. Initially each group will have 6 patients. Provided each group of patients finds the treatment tolerable and it is safe, more patients will be recruited into the group that receives the pembrolizumab earliest during their CRT. This will add further credence to the safety and tolerability of the combination and may provide a signal of how effective this treatment might be in improving outcomes for patients with more advanced anal cancer.

Conditions

Anal Cancer Stage III A; Anal Cancer Stage III B

Outcome Measures

Primary Outcomes (6)

• Safety and tolerability- 30 days post CRT

  To assess safety of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T 3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE - v.4.03) will be reported at 30 days post chemoradiotherapy.

  30 days post chemoradiotherapy

• Safety and tolerability- 6 weeks post CRT

  To assess the safety of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE v.4.03) will be reported at 6 weeks post chemoradiotherapy.

  6 weeks post chemoradiotherapy

• Safety and tolerability - 12 weeks post CRT

  To assess the safety of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE v.4.03) will be reported at 12 weeks post chemoradiotherapy.

  12 weeks post chemoradiotherapy

• Safety and tolerability - 6 months post CRT

  To assess the safety of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE v.4.03) will be reported at 6 months post chemoradiotherapy.

  6 months post chemoradiotherapy

• Safety and tolerability- 9 months post CRT

  To assess the safety and of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE Adverse Events v.4.03) will be reported at 9 months post chemo-radiotherapy.

  9 months post chemoradiotherapy

• Safety and tolerability- 12 months post CRT

  To assess the safety of different schedules of exposure to pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer. Grade 3 to 5 treatment related adverse events (CTCAE v.4.03) will be reported at 12 months post chemoradiotherapy.

  12 months post chemoradiotherapy

Secondary Outcomes (12)

• Adherence to protocol treatment

  Up to 6 months post chemoradiotherapy

• Recruitment

  2 years

• Retention

  Up to 12 months post chemoradiotherapy

• Study eligibility

  2 years

• Clinical response assessment - 3 months post CRT

  3 months post chemoradiotherapy

Study Arms (1)

pembrolizumab

EXPERIMENTAL

Patients with locally advanced (stage IIIA/B, T3/T4, any N, M0) anal cancer will receive pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT.

Drug: Pembrolizumab

Interventions

Pembrolizumab DRUG

Pembrolizumab, an immune checkpoint inhibitor, concomitantly with standard CRT in patients with locally advanced T3/4 anal cancer.

Also known as: Radiotherapy, Chemotherapy (Mytomycin or Mitomycin and Capecitabine)

pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible for participation in this trial, the subject must:
• Be willing and able to provide written informed consent/assent for the trial.
• Age 18 years or over on day of signing informed consent.
• Histologically proven Squamous Cell Cancer of Anus (SCCA) T3 / 4 N0 M0 or any N+ M0 or highly suspicious and confirmed by the MDT
• Be willing to provide tissue sample either archival or repeat biopsy to be tested for HPV and p16.
• Have a performance status of 0 or 1 on the ECOG Performance Scale.
• Demonstrate adequate organ function performed within 10 days of treatment initiation:
• Hematological: Absolute neutrophil count (ANC) ≥1.5 x 109/L, Platelets ≥100 x 109/L,
• Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants), Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants).
• Renal: Serum creatinine ≤1.5 x upper limit of normal (ULN) OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥60 mL/min for patient with creatinine levels \> 1.5 x institutional ULN
• Hepatic Serum total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels \> 1.5 ULN
• Female patient of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of trial medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Female patients of childbearing potential must be willing to use an adequate method of contraception for the course of the trial through 120 days after the last dose of trial medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
• Male patients must agree to use an adequate method of contraception starting with the first dose of trial therapy through 120 days after the last dose of trial therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.

You may not qualify if:

• The subject must be excluded from participating in the trial if the subject:
• Has malignant tumour of non-epithelial origin (sarcoma)
• Has any metastatic disease
• Is unsuitable for radical CRT for whatever reason
• Is currently participating and receiving trial therapy or has participated in a trial of an investigational agent and received trial therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency (see 18. For patients with HIV who may be eligible) or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has a known history of active TB (Bacillus Tuberculosis)
• Hypersensitivity to pembrolizumab or any of its excipients.
• Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
• Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer or previous VIN (vulval intra-epithelial neoplasia) or vulval cancer adequately treated, or previous adequately treated breast cancer / DCIS \> 5 years ago.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has known history of, or any evidence of active, non-infectious pneumonitis.

Sponsors & Collaborators

• Cardiff University: lead

Study Sites (11)

Oslo University Hospital

Oslo, NO-0424, Norway

Location

Aberdeen Royal Informary

Aberdeen, Scotland, AB25 2ZN, United Kingdom

Location

Cambridge University Hospitals NHS Foundation Trust

Cambridge, United Kingdom

Location

Velindre Cancer Centre

Cardiff, United Kingdom

Location

East Suffolk and North Essex NHS Foundation Trust

Colchester, United Kingdom

Location

The Leeds Teaching Hospitals NHS Trust

Leeds, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

Mount Vernon Cancer Centre

Northwood, HA6 2RN, United Kingdom

Location

Oxford University Hospitals NHS Foundation Trust

Oxford, United Kingdom

Location

Sheffield Teaching Hospitals NHS Foundation Trust

Sheffield, United Kingdom

Location

Swansea Bay University Local Health Board

Swansea, United Kingdom

Location

MeSH Terms

Conditions

Anus Neoplasms

Interventions

pembrolizumab; Radiotherapy; Drug Therapy; Mitomycin; Capecitabine

Condition Hierarchy (Ancestors)

Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Anus Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Mitomycins; Indolequinones; Quinones; Organic Chemicals; Azirines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Richard Adams, Prof

  Velindre University NHS Trust

  PRINCIPAL INVESTIGATOR

• Mark Harrison, Dr

  East and North Hertfordshire NHS Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 29, 2018
• First Posted: August 6, 2019
• Study Start: October 19, 2020
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): November 30, 2026
• Last Updated: August 5, 2025

Record last verified: 2025-07

Locations

NO (1); GB (10)