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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

ASST Grande Ospedale Metropolitano Niguarda

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

2 May 2023 → ongoing

Decision date (initial)

2023-03-22

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Fondazione Oncologia Niguarda · Ministero della Salute - PNRR-MAD-2022-12376593

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To assess the activity of Ipilimumab + Nivolumab + high dose Vitamin C in a pre-operative setting in colorectal cancer

Secondary objectives 1

1. Safety and feasibility

Conditions and MedDRA coding

pMMR/MSS

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Histologically confirmed diagnosis of colon carcinoma (CC)
2. 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)
3. Patients eligible for radical surgical resection of the primary CC and liver metastasis in case of oligometastatic stage IV disease
4. Stated willingness to comply with all study procedures and availability for the duration of the study
5. Age ≥ 18 years
6. Written informed consent to present study
7. Written informed consent to AlfaOmega observational study
8. ECOG performance status < 2
9. Negative serum pregnancy test within 1 week prior to the first study dose in all women of childbearing potential
10. 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
11. 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.

Exclusion criteria 28

1. Known CC MSI or dMMR status as per standard practice
2. 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
3. Prior or active interstitial lung disease or pneumonitis
4. Known history of a positive test for HIV or known AIDS
5. Known diagnosis of Lynch syndrome
6. Any medical contraindication to undergo radical surgical resection of the primary CC and/or metastatic liver lesions
7. Known glucose-6-phosphate dehydrogenase (G6PD) deficit
8. 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
9. 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
10. 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)
11. 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
12. 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
13. Clinically significant cardiovascular disease. Pre-existing hypertension should be adequately controlled to < 140/90 mmHg
14. Clinically significant bleeding diathesis or coagulopathy
15. History of thromboembolic or cerebrovascular events within the last 6 months, including transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary embolism
16. 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
17. Non-healing wound, ulcer, or bone fracture
18. History of gastrointestinal perforation or abscess within 6 months prior to enrollment
19. Prior cytotoxic treatment for CC or prior radiotherapy
20. Participants who received cancer-related Investigational Products (IPs) within 28 days or 5 half-lives, whichever is longer, prior to randomization
21. 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])
22. 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
23. 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);
24. A positive pregnancy test at enrollment or prior to administration of study medication
25. 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)
26. Active or prior history of chronic or acute renal insufficiency or kidney stones
27. History of allergy or hypersensitivity to study drug components
28. History or known allergy to ascorbate acidic or citrus fruits

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Pathological response rate

Secondary endpoints 1

1. Adverse events rate

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

ASST Grande Ospedale Metropolitano Niguarda

Sponsor organisation

ASST Grande Ospedale Metropolitano Niguarda

Address

Piazza Dell'ospedale Maggiore 3

City

Milan

Postcode

20162

Country

Italy

Scientific contact point

Organisation

ASST Grande Ospedale Metropolitano Niguarda

Contact name

Oncologia Molecolare

Public contact point

Organisation

ASST Grande Ospedale Metropolitano Niguarda

Contact name

Clinical Trial Unit

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications