Phase 1b/2 dose-escalation trial of OMTX705, an anti-fibroblast activation protein antibody-drug conjugate, in combination with regorafenib and tislelizumab in patients with advanced/metastatic colorectal cancer

Prior treatment

• Prior treatment with OMTX705, regorafenib, or RTK inhibitors (other than fruquintinib) for CRC. Combination with tislelizumab only. Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies including anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies.
• Treatment with systemic anticancer treatments, investigational products, or major surgery within four weeks before the first dose of study drug or 5 half-lives, whichever is shorter. Patients should have recovered from previous treatment toxicity to Grade 1, baseline (excluding anemia, lymphopenia, alopecia, skin pigmentation, and neurotoxicity).
• Known hepatitis B virus surface antigen seropositive or detectable hepatitis C infection viral load. Note: Patients who have positive hepatitis B surface antigen antibody can be included but must have an undetectable hepatitis B viral load. Patients receiving antiviral therapy for hepatitis B for any reason are excluded.
• Patients with previous history or evidence of liver cirrhosis.
• Known or suspected allergies to study treatment or related products, and specifically patients with a prior history of life-threatening reaction to polysorbate 20 or for regorafenib, if they have allergy to soya-derived lecithin.
• Combination with tislelizumab only. Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks) within 6 months before the start of study medication. Active pulmonary emboli or deep vein thrombosis that are significant or not adequately controlled on anticoagulation regimen
• Combination with tislelizumab only. Patient who discontinued prior treatment with any immune checkpoint due to irAEs, irrespective of grade, recovery, or need for continued steroid therapy. Also, patients without formal contraindication due to previous irAE are not eligible if the AE has not resolved to Grade 1 or better and/or still requires steroids (>10 mg of prednisone equivalent per day) for ongoing management.
• Combination with tislelizumab only. Patients with a history of pneumonitis/ILD, patients who received live vaccines within 30 days of enrollment, and patients who discontinued prior immune checkpoint inhibitors due to Grade 2 myocarditis.
• Exclusions related to regorafenib: 1. Patients requiring strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort)(Section 15.4.). 2. Patients that require strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole)(Section 15.4.). 3. Not being able to swallow and absorb oral tablets.
• History of uncontrolled brain metastasis. Patients with brain metastases are allowed if they are previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery and have new brain imaging confirming that brain metastasis are stable (without evidence of progression by imaging using the identical imaging modality for each assessment, either MRI or CT and considered controlled with ≤10 mg/day prednisone equivalent at the time of receiving the first dose of OMTX705). For asymptomatic participants, brain image screening is not required.
• Patient has received extended field radiotherapy ≤4 weeks before the start of treatment (≤1 week for limited field radiation for palliation), and who has not recovered to Grade 1 or better from related side effects of such therapy (except for alopecia).
• Major surgical procedure or significant traumatic injury ≤28 days prior to the planned first dose of OMTX705
• Drainage of ascitic or pleural fluid two or more times in the four weeks prior to the first dose of study drug or permanent drain in place (e.g., PleurX®) for ascites or pleural effusion symptom management

Other illness

• Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or compromised ability to provide written informed consent
• Patients with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 3 years prior to the study entry and no additional therapy is required or anticipated to be required during the study period.
• Cardiac arrhythmias that require anti-arrhythmic therapy (excluding controlled atrial fibrillation). Note: pacemakers, beta-blockers, or digoxin are permitted.
• Uncontrolled hypertension: systolic BP >160 mmHg or diastolic pressure > 100 mmHg despite optimal medical management.
• Patients with a history of arterial aneurysms or artery dissection.
• Patients with unstable angina or new onset angina (within 3 months of enrollment), recent myocardial infarction (within 6 months of enrollment) and those with cardiac failure New York Heart Association (NYHA) classification II or higher
• Active infection that requires parenteral or oral antibiotics. Antibiotics given for prophylaxis are allowed. They are also allowed for minor localized infections like cystitis, amygdalates or localized skin infections.
• History of organ allograft (including corneal transplant).
• Non-healing wound, ulcer, or bone fracture including fistulae (e.g., Chron’s disease)
• Renal failure that requires hematological (hemo-) or peritoneal dialysis
• Significant acute gastrointestinal disorders with diarrhea as a major symptom, e.g., Chron’s disease, malabsorption, or ≥ National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 2 diarrhea of any etiology.
• Evidence of serious uncontrolled medical disorder that, in the opinion of the Investigator or Medical Monitor, makes it unwise for the patient to participate in the study or that might jeopardize compliance with the protocol.

Lab values

• Patients positive for human immunodeficiency virus (HIV) are not excluded from this study, but HIV-positive patients must meet the following criteria: 1. Have CD4+ T-cell (CD4+) counts ≥350 cells/µL. 2. Have not had an opportunistic infection within the past 12 months. Patients on prophylactic antimicrobials can be included in the trial. 3. Should be on established antiretroviral therapy for at least four weeks. 4. Have an HIV viral load of less than 400 copies/mL prior to enrollment. 5. Known history of any other relevant congenital or acquired immunodeficiency other than HIV infection.

Other

• Women who are pregnant, breastfeeding, or trying to become pregnant.
• Male patients wishing to father children, planning for future sperm banking, or expressing concerns about sterility.

• Capable of giving signed informed consent as described in Section 12.2 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Signed informed consent must be obtained prior to conducting any study specific procedures.
• Women of childbearing potential (WOCBP) and men with sexual partners who are WOCBP must be willing to adhere to contraceptive requirements.
• Suitable venous access for safe drug administration and the study-required drug concentration and pharmacodynamics sampling.
• A valid archival tumor sample as defined in Section 7.20.1.
• Pretreatment fresh biopsy is optional in Part 1. In Part 2, participants must be eligible to provide a non-significant risk fresh pretreatment biopsy and commit to an on-treatment biopsy. Notes: (i) In some circumstances, the Medical Monitor can waive the obtention of paired treatment biopsies upon request from the Investigator. The rationale for the decision needs to be documented in writing. (ii) A patient receiving treatment can decline the on-treatment biopsy without providing any explanation and continue on study. If it is the Investigator who decides to skip the on-treatment biopsy, the rationale needs to be discussed with the Medical Monitor and documented in writing. (Section 7.20.2).
• Male and female patients aged 18 years and older.
• Patients should have documented progression to the last line of therapy or, in the opinion of the Investigator, require a change in the therapy. This latter situation must be discussed and approved explicitly by the Sponsor’s Medical Monitor.
• Patients must have histologically or cytologically confirmed adenocarcinoma of the colon or rectum, who had disease progression on or after receiving all the following SoC systemic therapies for advanced or metastatic disease* (if approved and locally available/reimbursed in the respective country/region/hospital) or were intolerant to those therapies: 1. Fluoropyrimidine, oxaliplatin, and irinotecan 2. Anti-VEGF therapy (e.g., bevacizumab) 3. Anti-EGFR therapy (e.g., cetuximab, panitumumab) if RAS (KRAS/NRAS) wild type 4. BRAF inhibitor (e.g., dabrafenib, encorafenib) if BRAF V600E mutation In addition, patients may have received up to 2 additional lines of therapy for advanced or metastatic disease with any of the following drugs: trifluridine/tipiracil (TAS-102) with or without anti-VEGF therapy, fruquintinib, or other drugs approved in the country (except regorafenib), or investigational drugs that do not share mechanism of action with regorafenib (i.e., unspecific tyrosine kinase receptor inhibitors). *Neoadjuvant/adjuvant chemotherapy is included if disease had recurred during treatment or within six months after the last administration of neoadjuvant/adjuvant therapy
• Microsatellite stable or pMMR CRC per previous local assessment.
• Known extended RAS and BRAF status as per local SoC.
• Measurable disease by RECIST 1.1 criteria on computerized tomography (CT), FAPI PET/CT (if available), fluorodeoxyglucose positron emission tomography (FDG-PET)/CT or magnetic resonance imaging (MRI) scan. Imaging tests outside the screening period are valid if performed no more than 2 weeks before consent signature and otherwise fulfill protocol criteria.
• Easter Cooperative Oncology Group Performance (ECOG) performance status 0-1.
• Adequate bone marrow, hepatic and renal function: 1. Total bilirubin ≤1.5 times the upper limit of normal (ULN) or total bilirubin <3.0×ULN with direct bilirubin within the normal range in patients with documented Gilbert’s syndrome*. *Regorafenib is a uridine diphosphate glucuronosyl transferase 1A1 inhibitor. Mild, indirect (unconjugated) hyperbilirubinemia may occur in patients with Gilbert’s syndrome. 2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3×ULN, (if liver metastases are present, then ≤5×ULN is allowed). 3. Serum creatinine ≤1.5×ULN or creatinine clearance ≥40 mL/min (measured or calculated using the Cockroft-Gault formula) 4. Hemoglobin ≥9.0 g/dL (whole or partial blood transfusions not allowed in the 2 previous weeks). 5. Absolute neutrophil count (ANC) ≥1.0×109/L (growth factors like G-CSF are not allowed in the 2 previous weeks). 6. Platelet count ≥75×109/L (platelet transfusions within the previous 2 weeks are not allowed). 7. INR/partial thromboplastin time (PTT) ≤1.5×ULN. Note: Patients who being treated chronically with warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists; close monitoring of at least weekly evaluations will be performed until INR/PTT ratio is stable based on a measurement that is pre-dose as defined by the local SoC.