Phase 1b/2 Trial of OMTX705, an Anti-Fibroblast Activation Protein Antibody-Drug Conjugate, in Combination with Carboplatin, Pemetrexed and Tislelizumab in Patients with Advanced/Metastatic Non-squamous Non-Small Cell Lung Cancer

Prior treatment

• Previous or concurrent cancer that is distinct in primary site or histology from NSCLC within 3 years prior to randomization, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]).
• History of cerebrovascular stroke or myocardial infarction within the previous 3 months.
• The patient is under chronic systemic steroids. Patients with asthma requiring intermittent use of bronchodilators or inhaled steroids are eligible for the study.
• Is unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period (8-day period for long acting agents, such as piroxicam).
• Treatment with systemic anticancer treatments, investigational products, or major surgery within 4 weeks before the first dose of study drug or 5 half-lives elimination period for drug therapies, whichever is shorter. Patients treated with systemic anticancer therapies/investigational drugs should have recovered from previous treatment toxicity to Grade 1, baseline (except alopecia). Patients with endocrinopathies should have the replacement treatment in a stable dosing regimen.
• Patients 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.
• Patients who received live vaccines within 30 days of enrollment.
• 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.
• Known or suspected allergy to study treatment or related products, and specifically patients with a prior history of life-threatening reaction to polysorbate 20.
• Before the first dose of trial treatment: • Has received prior systemic cytotoxic chemotherapy or immunotherapy for metastatic disease • Has received antineoplastic biological therapy (e.g., erlotinib, osimertinib, crizotinib, cetuximab) NOTE: Patients with initial locoregional disease are eligible after progression to chemoradiation/surgery ± immune checkpoint therapies.
• Received radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of study treatment.
• Known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate, provided they are clinically stable for at least 2 weeks and have no evidence of new or enlarging brain metastases and are off steroids 3 days prior to dosing with study medication. Stable brain metastases by this definition should be established prior to the first dose of study medication. Patients with asymptomatic brain metastases (i.e., no neurological symptoms, no requirement for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of the brain as a site of disease. Patients without CNS symptoms are not required to have brain images to participate.
• Major surgical procedure, open biopsy, or significant traumatic injury ≤28 days prior to randomization.

Other illness

• Has symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions (including therapeutic thoracentesis, paracentesis, or pleurodesis) is eligible.
• 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.
• Uncontrolled or significant cardiovascular disease defined by the New York Hearth Association (NYHA) classification III or IV.
• History of autoimmune disease requiring systemic immunosuppressive therapy (daily prednisone equivalent doses >10 mg/day).
• Patients with interstitial lung disease or a history of pneumonitis requiring oral or IV glucocorticoids to assist with management. Lymphangitic spread of the NSCLC is not exclusionary.
• History of myocarditis.
• Cardiac arrhythmias requiring anti-arrhythmic therapy. NOTE: Pacemakers, beta blockers, or digoxin are permitted.
• Active infection requiring parenteral or oral antibiotics. Antibiotics given for prophylaxis are allowed. They are also allowed for minor localized infections like cystitis, tonsillitis, or localized skin infections.
• Evidence of a 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: • have CD4+ T-cell (CD4+) counts ≥350 cells/µL. • have not had an opportunistic infection within the past 12 months. Patients on prophylactic antimicrobials can be included in the trial. • should be on established antiretroviral therapy for at least 4 weeks. • have an HIV viral load of less than 400 copies/mL prior to enrollment. • known history of any other relevant congenital or acquired immunodeficiency other than HIV infection.

Other

• Has predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the predominant cell type; if small cell elements are present, the patient is ineligible.
• Grade ≥2 peripheral neuropathy.
• Is unable or unwilling to take folic acid or vitamin B12 supplementation.
• 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 a signed informed consent form (ICF) as described in Section 12.2 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. A signed ICF 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.
• Have provided tumor tissue from locations not radiated prior to biopsy; formalin-fixed specimens after the patient has been diagnosed with metastatic disease will be preferred for determination of PD-L1 status prior to randomization (not required for Part 1). Biopsies obtained prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if recent biopsy is not feasible.
• Male and female patients aged 18 years and older.
• Have a histologically or cytologically confirmed diagnosis of stage IV (M1a or M1b subcategory, based on the seventh edition of the American Joint Committee on Cancer Staging Manual) non-squamous NSCLC or stage III that has exhausted available locoregional therapies, or if they are contraindicated or locally unavailable
• PD-L1 TPS, ranging from 0 to 100%, in a tumor biopsy measured locally with an approved test. NOTE: In Part 2, the PD-L1 TPS result should be available for randomization
• Have confirmation that any targeted therapy (EGFR-, ALK-directed, or any other targeted therapy) is not indicated. Documentation of absence of tumor-activating EGFR mutations AND absence of ALK gene rearrangements OR presence of Rat sarcoma (RAS) mutations is required
• Measurable disease by RECIST 1.1 on computed tomography (CT) scan, PET/CT or magnetic resonance imaging (MRI) scan. Image tests outside the screening period are valid if performed no more than 3 weeks before consent signature and otherwise fulfil protocol criteria
• Have not received prior systemic treatment for their advanced/metastatic NSCLC. Patients who received adjuvant or neoadjuvant therapy for initial stages I to III are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the development of metastatic disease.
• Easter Cooperative Oncology Group Performance (ECOG) performance status 0-1.
• Adequate bone marrow, hepatic and renal function: • Total bilirubin ≤1.5 times the upper limit of normal (ULN) or total bilirubin <3.0×ULN with direct bilirubin within normal range in patients with documented Gilbert’s syndrome. • AST and ALT ≤3×ULN (if liver metastases are present, then ≤5×ULN is allowed). • Calculated creatinine clearance (CrCL) of ≥45 mL/minute using the Cockcroft Gault formula. • Hemoglobin ≥9.0 g/dL (whole or partial blood transfusions not allowed in the 2 previous weeks). • Absolute neutrophil count (ANC) ≥1.5×109/L (growth factors like granulocyte-colony stimulating factor [G-CSF] are not allowed in the 2 previous weeks). • Platelet count ≥100×109/L (platelet transfusions in the 2 previous weeks are not allowed).