A window-of-opportunity trial with high-dose vitamin C to enhance neoadjuvant immune checkpoint therapy in mismatch repair proficient colorectal cancer: the ALFEO pilot study

Prior treatment

• Prior major surgery, open biopsy, or significant traumatic injury within 28 days prior to randomization. Any wound-related AE(s) must have been resolved prior to randomization
• History of gastrointestinal perforation or abscess within 6 months prior to enrollment
• Prior cytotoxic treatment for CC or prior radiotherapy
• Participants who received cancer-related Investigational Products (IPs) within 28 days or 5 half-lives, whichever is longer, prior to randomization
• Participants who have received a live/attenuated vaccine within 30 days of randomization (e.g., varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella [MMR])
• Treatment with botanical preparations (e.g. herbal supplements or traditional Chinese medicines) intended to treat the disease under study within 2 weeks prior to randomization
• A positive pregnancy test at enrollment or prior to administration of study medication
• Active or prior history of chronic or acute renal insufficiency or kidney stones
• Prior or active interstitial lung disease or pneumonitis
• Any medical contraindication to undergo radical surgical resection of the primary CC and/or metastatic liver lesions
• Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease

Other illness

• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured (for example squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast)
• Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results
• Clinically significant cardiovascular disease. Pre-existing hypertension should be adequately controlled to < 140/90 mmHg
• Clinically significant bleeding diathesis or coagulopathy
• History of thromboembolic or cerebrovascular events within the last 6 months, including transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary embolism
• Non-healing wound, ulcer, or bone fracture
• Participants with an active, known, or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enrol
• Any positive test result for hepatitis B virus or hepatitis C virus indicating the presence of the virus, eg, HBsAg, Australia antigen positive, or hepatitis C antibody (anti-HCV) positive (except if HBV DNA or HCV RNA negative)
• History of allergy or hypersensitivity to study drug components
• History or known allergy to ascorbate acidic or citrus fruits
• Known history of a positive test for HIV or known AIDS
• Known diagnosis of Lynch syndrome
• Obstructing primary CC assessed by endoscopy and/or impossibility to pass through the tumor with the colonoscope and/or stricturing disease at imaging tumor staging

Lab values

• Clinically significant cardiac disease including: congestive heart failure requiring treatment (NYHA grade ≥ 2), Left ventricular ejection fraction (LVEF) < 45% as determined by echocardiogram; history or presence of clinically significant ventricular arrhythmias or atrial fibrillation; clinically significant resting bradycardia; unstable angina pectoris ≤ 3 months prior to starting study drug; acute myocardial infarction ≤ 3 months prior to starting study drug; QTcF > 480 msec
• Abnormal organ or bone marrow functions, defined as: Neutrophils < 1500/L; Platelets < 100 10^3/L Hemoglobin < 9.0 g/dL (transfusion to achieve the level of haemoglobin 9 g/dL is not permitted within 7 days of this laboratory assessment) PT/INR and PTT > 1.5 ULN unless participants are receiving anticoagulant therapy and their INR is stable and within the recommended range for the desired level of anticoagulation; Serum creatinine > 1.5 × ULN, or creatinine clearance (CLcr) lower than 40 mL/minute (measured or calculated using the Cockcroft-Gault formula); AST or ALT > 3.0 ULN; Total bilirubin > 1.5 ULN (except participants with Gilbert syndrome who must have a total bilirubin level of < 3.0 ULN);
• Known glucose-6-phosphate dehydrogenase (G6PD) deficit

Other

• Known CC MSI or dMMR status as per standard practice

• Histologically confirmed diagnosis of colon carcinoma (CC)
• Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception
• The absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
• Stage cT4N0-TxN1-2 CC patients who are candidates for upfront surgery as per standard of care or stage IV oligometastatic liver-limited CC patients, as well candidates for upfront surgery on both primary and metastatic tumor sites, after multidisciplinary evaluation; according to ESMO guidelines in low-risk CLM (easy surgery, and Excellent/Good prognosis based on oncological criteria, such as the absence of extrahepatic disease, <5 lesions, no clinical signs of rapid tumor progression)
• Patients eligible for radical surgical resection of the primary CC and liver metastasis in case of oligometastatic stage IV disease
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Age ≥ 18 years
• Written informed consent to present study
• Written informed consent to AlfaOmega observational study
• ECOG performance status < 2
• Negative serum pregnancy test within 1 week prior to the first study dose in all women of childbearing potential