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

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.

CORINTH is a multi center trial with a single arm. Patients will be recruited into 3 successive cohorts followed by an expansion of the final cohort. For each cohort the first dose of Pembrolizumab will be given at an earlier time point during the chemo-radiation (CRT).

Pemrolizumab will be given as an IV infusion every 21 days, and a total of 8 infusions per patient at 200mg per infusion. The first dose of Pemrolizumab will be given at the following times:

COHORT 1: beginning at Week 5 day 1 of CRT schedule COHORT 2: beginning at Week 3 day 1 of CRT schedule COHORT 3: beginning at Week 1 day 1 of CRT schedule\*\* Cohort 2 will be dependent on a Safety Review Committee (SRC) recommendation. If the SRC are concerned about toxicity in Cohort 1 but not sufficiently to stop the study, they are able to recommend that Cohort 2 can change to commence pembrolizumab at week 4. If the SRC are concerned about toxicity in Cohort 2 but not sufficiently to stop the study, they are able to recommend that Cohort 3 can change to commence pembrolizumab at week 2.

Potential participants will be under the care of a consultant who specializes in the treatment of anal cancer and the patient will have been identified as requiring CRT treatment for their anal cancer. They will be assessed for eligibility before being consented and allocated to the current cohort. # Patients will be monitored for Adverse Events which will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) 4.03. Treatment guidelines are given for any immune related or infusion related events. Adverse Event review will take place weekly during CRT and at every Pembrolizumab visit as well as key time during follow up.

Patient reported outcomes will be assessed using the European Organisation for Research and Treatment of Cancer (EORTC) tool during CRT, pembrolizumab treatment and follow up. Patients will be followed up for 12 months.

Eligibility Criteria:
Inclusion Criteria:

In order to be eligible for participation in this trial, the subject must:

1. Be willing and able to provide written informed consent/assent for the trial.
2. Age 18 years or over on day of signing informed consent.
3. Histologically proven Squamous Cell Cancer of Anus (SCCA) Stage IIIA or IIIB (T3 / 4 any N M0) anal cancer or highly suspicious and confirmed by the MDT
4. Be willing to provide tissue sample either archival or repeat biopsy to be tested for HPV and p16.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
6. Demonstrate adequate organ function performed within 10 days of treatment initiation.
7. Hematological: Absolute neutrophil count (ANC) ≥1.5 x 109/L, Platelets ≥100 x 109/L,
8. 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).
9. Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
10. Female subjects of childbearing potential must be willing to use an adequate method of contraception - Contraception and pregnancy, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
11. Male subjects of childbearing potential must agree to use an adequate method of contraception - Contraception and pregnancy, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

The subject must be excluded from participating in the trial if the subject:

1. Has malignant tumour of non-epithelial origin (sarcoma)
2. Has any metastatic disease
3. Is unsuitable for radical CRT for whatever reason
4. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
5. 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.
6. Has a known history of active TB (Bacillus Tuberculosis)
7. Hypersensitivity to pembrolizumab or any of its excipients.
8. 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.
9. 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.

   1. Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
   2. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
10. 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.
11. 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.
12. Has known history of, or any evidence of active, non-infectious pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
20. Has received a live vaccine within 30 days of planned start of study therapy. (Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.)