A Trial of Regorafenib Plus Lorigerlimab as Neoadjuvant Therapy for Patients With pMMR/MSS, Resectable, Lung-limited Metastatic Colorectal Cancer

Concomitant extrapulmonary metastatic cancer at the time of study screening . A history of extrapulmonary metastases is permitted only if the participant has undergone definitive treatment (e.g., resection, radiation, ablation etc.) and remains without evidence of disease recurrence and/or progression within 6 months of study registration.

Systemic anti-cancer treatment within 14 days or less than 5 half-lives (whichever is shorter) of the first dose of study treatment.

Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.

Prior treatment with regorafenib or fruquintinib.

Non-palliative radiotherapy \< 12 weeks before the first dose of study treatment.

Treatment with any investigational drug within 30 days prior to enrollment or 5 investigational agent half-lives (whichever is longer).

An active condition requiring systemic treatment with either corticosteroids (\> 10 mg prednisone or equivalents) or other immunosuppressive medications within 14 days of registration. Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). Replacement steroid autoimmune disease. A brief (less than 3 weeks) course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayedtype hypersensitivity reaction caused by a contact allergen) is permitted.

Impairment of gastrointestinal function or disease, at the discretion of the treating provider or PI that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption).

A history of GI perforation (note: tumor-related perforation of a resected primary tumor is not applicable), GI bleeding within 4 weeks prior to study registration, or clinically significant diverticulitis or flare-up within 4 weeks prior to study registration).

A history of inflammatory bowel disease, (including ulcerative colitis and Crohn's disease), symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis \[scleroderma\], systemic lupus erythematosus, autoimmune vasculitis \[e.g., Wegener's Granulomatosis\]); CNS or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and myasthenia gravis, multiple sclerosis).

Note: participants with Graves' disease that is controlled on thyroid supplement/replacement, type 1 insulin-dependent diabetes mellitus that is controlled on insulin therapy, or any other autoimmune disease that is controlled at the discretion of the treating provider or PI while on steroid replacement therapy are allowed to participate.

A history of pneumonitis that has required oral or IV steroids within the last 12 months.

A history of a Grade 3 or 4 allergic reaction attributed to humanized or human monoclonal antibody therapy.

A history of a prior allogeneic tissue or solid organ transplant.

A history of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) within 6 months prior to study registration.

A history of myocarditis.

Persistent proteinuria of NCI-CTCAE Grade 3. Urine dipstick result of 3+ or abnormal, based on type of urine test strip used, is allowed if protein excretion (estimated by urine protein/creatinine ratio on a random urine sample) is \<3.5 g/24 hr.

History of uncontrolled intercurrent illness including but not limited to:

* Uncontrolled active infection requiring antibiotics at the time of initiation of study treatment.

* Uncontrolled cardiac arrythmias.

Non-healing wound or non-healing ulcer.

Major surgical procedure or significant traumatic injury within 28 days before start of study medication. If participants received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.

Other co-existing malignancies or previous malignant disease (other than colorectal cancer) within the last 3 years except for thyroid cancer (papillary or follicular), nonmelanoma skin cancers, the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, breast, or melanoma and any malignancy deemed in complete remission prior to study entry for which no additional therapy is required or anticipated to be required during the study period.

Administration of a live, attenuated vaccine within 120 days prior to start of study treatment or anticipation that such a live attenuated vaccine will be required during the study.

Administration of live, attenuated vaccines is therefore prohibited during study treatment.

Inactivated vaccines are allowed (for example, inactivated influenza vaccines).

Planned treatment with other systemic anti-cancer agents (e.g., chemotherapy, hormonal therapy, immunotherapy) or other treatments not part of protocol-specified anti-cancer therapy including concurrent investigational agents of any type.

Coexisting separate disease, metabolic disorder, clinically significant laboratory result, or any other condition that treating provider or PIs suspect may (a) prohibit use of the investigational product, or (b) put the patient at undue risk of harm.

Active pregnancy or nursing. Pregnant women are excluded from this study because: a) effects of regorafenib on pregnancy and lactation in humans are unknown but its use is advised against since there is preclinical evidence of reproductive toxicity and fetal harm and harm to breast-fed children cannot be excluded; b) reproductive and developmental toxicology studies have not yet been conducted with lorigerlimab consistently with the expectations for this early phase of clinical development in accordance with ICH S6(R1) (2011) and ICH M3(R2) (2009).

Concomitant or prior use within 2 weeks before start of study treatment of strong inhibitors and inducers of CYP3A4 activity (listed in APPENDIX B).

Note: inducers and inhibitors of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce or inhibit CYP3A4, should be considered.

Therapeutic anticoagulation with Vitamin-K antagonists (e.g., warfarin) or with heparins and heparinoids. Note: prophylactic anticoagulation as follows is allowed: low dose warfarin (1 mg orally, once daily) with PT-INR . 1.5 x ULN is permitted. Infrequent bleeding or elevations in PT-INR have been reported in some subjects taking warfarin while on regorafenib therapy. Therefore, subjects taking concomitant warfarin should be monitored regularly for changes in PT, PT-INR or clinical bleeding episodes; low dose aspirin (.

100 mg daily); prophylactic doses of heparin.

Use of any herbal remedy that may unsafely interact with study drugs at the discretion of the treating provider or PI (e.g. St. John's wort \[Hypericum perforatum\]).

* Known active viral hepatitis B (i.e., HBsAg positive prior to enrollment) or hepatitis C infection. Patients with past or resolved hepatitis B virus infection (i.e., HBsAg negative, anti-HBc positive, and HBV DNA negative tests prior to enrollment) are eligible for this trial. Anti-HCV antibody positive will be eligible only if PCR is negative for HCV RNA.

* Known active tuberculosis (history of exposure or history of positive TB test plus presence of clinical symptoms, physical or radiographic findings).

* Known positivity to the human immunodeficiency virus (HIV) or active acquired immunodeficiency syndrome (AIDS). Patients on effective anti-retroviral therapy with undetectable viral load and CD4 count \>200/unit are eligible for this trial.

* Known hypersensitivity to recombinant proteins, polysorbate 80, or any excipient contained in the Lorigerlimab drug formulation.

What this study is about