Neoadjuvant ADG126 and Pembrolizumab in Locally Advanced Colorectal Cancer

This is a single site, open-label, single-arm phase II study to determine feasibility, tolerability, and preliminary efficacy of neoadjuvant ADG126 and pembrolizumab in stage II or III colorectal cancer.

This clinical trial aims to enrol patients with stage II or III colorectal cancer. At least 16, and up to 20 patients will be recruited. Patients will be given two cycles of neoadjuvant immunotherapy (ADG 126 and pembrolizumab). They will be assessed for response at 4 weeks or if they develop clinical symptoms of progression. Patients will undergo surgery 2 weeks (± 1 week) after the second dose of study treatment and within 8 weeks of study enrolment.

Eligibility Criteria:
Inclusion Criteria:

1. Willing and able to provide written informed consent for the trial.
2. Be ≥ 21 years of age on the date of signing informed consent.
3. ECOG performance status of 0 or 1.
4. Histologically confirmed colorectal adenocarcinoma. Rectal cancers allowed if the treatment plan was upfront surgery with no need for any neoadjuvant chemotherapy or radiation.
5. Clinical stage II (T3-4, N-) or stage III (Tany, N+).
6. No evidence of distant metastases.
7. Radiologically measurable or clinically evaluable disease.
8. Negative pregnancy test done 72 hours before registration, for women of childbearing potential.

   Subjects of childbearing potential must be willing to use an adequate method of contraception. Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormone contraceptives, or double barrier method (diaphragm plus condom). Contraception, for the course of the study starting with the first dose of study medication through 150 days after the last dose of study medication. Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

   Non-childbearing potential is defined as follows:
   * ≥45 years of age and has not had a menstrual period for \>1 year
   * Patients who have been amenorrhoeic for \<2 years without a history of hysterectomy and oophorectomy must have a follicle-stimulating hormone value in the postmenopausal range upon screening evaluation
   * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure; otherwise, the patient must be willing to use 2 adequate barrier methods throughout the study.
9. Demonstrate adequate organ function as defined below, all screening labs should be performed within 28 days of treatment initiation.

   1. Haematological

      * Absolute neutrophil count (ANC) greater than or equal to 1,500/mcL.
      * Platelets greater than or equal to 100,000/mcL.
      * Haemoglobin greater than or equal to 9 g/dL.
   2. Renal

      · Serum creatinine OR Measured or calculated creatinine clearance (by Cockcroft-Gault equation), Serum creatinine less than or equal to 1.5 x upper limit of normal (ULN) OR creatinine clearance greater than or equal to 60 mL/min for subject with creatinine levels greater than 1.5 x ULN
   3. Hepatic

      * Serum total bilirubin less than or equal to 1.5 x ULN OR Direct bilirubin less than or equal to ULN for subjects with total bilirubin levels greater than 1.5 x ULN.
      * AST and ALT less than or equal to 2.5 x ULN.
   4. Coagulation · International Normalised Ratio (INR) or Prothrombin Time (PT) or Activated Partial Thromboplastin Time (aPTT). For patients not taking warfarin: INR less than or equal to 1.5 or PT less than or equal to 1.5 x ULN; and either PTT or aPTT less than or equal to 1.5 x ULN. Patients on warfarin may be included on a stable dose with a therapeutic INR less than 3.5.

Exclusion Criteria:

1. Recurrent colorectal cancer.
2. Prior radiation therapy, chemotherapy, immunotherapy, or surgery for colorectal cancer.
3. Tumour is causing symptomatic bowel obstruction (patients who have a temporary diverting stoma are eligible).
4. Other invasive malignancy ≤5 years prior to registration.
5. Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form of non-physiologic dose immunosuppressive therapy within 7 days prior to first dose of trial treatment.
6. Active autoimmune disease requiring systemic treatment within the past 2 years or documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents at non-physiologic doses.
7. Active infection requiring systemic therapy.
8. Received prior therapy with an antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
9. Experienced ≥ Grade 3 immune-related adverse event with prior immunotherapy, with the exception of non-clinically significant lab abnormalities.
10. Other anticancer or experimental therapy. No other experimental therapies (including chemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, or other experimental drugs) of any kind are permitted while the patient is receiving study treatment.
11. Known history of Human Immunodeficiency Virus.
12. Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
13. Women who are pregnant or breastfeeding, or men expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening visit through 150 days after the last dose of study medication.
14. Concurrent medical or psychiatric condition or disease which, in the investigator's judgement, would make them inappropriate candidates for entry into the study. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, chronic obstructive pulmonary disease, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent.
15. Received a live vaccine within 30 days of planned start of study medication.
16. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrolment.
17. History of interstitial lung disease.
18. Known hypersensitivity to ADG126 or pembrolizumab components or excipients.