This is a Phase 1 Trial of ZM008, an Anti-LLT1 Antibody, Used as Single Agent Followed by Combination Treatment With Toripalimab in Patients With Advanced Solid Tumors

Inclusion criteria

• Adult patients aged 18 years and older, at the time of signing the informed consent form.
• Part 1: Patients with histologically confirmed diagnosis of advanced (locoregionally recurrent, not amenable to curative therapy) or metastatic solid tumors that have no standard therapeutic option with a proven clinical benefit or are intolerant to these therapies with the following selected tumor histologies: NSCLC, triple-negative breast cancer, head and neck squamous cell carcinoma, prostate cancer, colorectal cancer, pancreatic ductal adenocarcinoma, biliary tract cancer, high grade serous ovarian cancer, diffuse large B cell lymphoma, kidney cancer, or urothelial cancer. This selection corresponds to tumor histologies known to express higher LLT1 levels. Other tumor histologies can be enrolled only if approved by the sponsor after discussion with the investigator. Tumors should be progressing or deserving another anticancer treatment in the opinion of the investigator. Part 2: The same patient population as Part 1 although it will be enriched or modified based on the observed antitumor activity observed in Part 1. In case the patient population is modified to include patients with standard therapeutic alternatives, a substantial amendment will be issued.
• Patients with tumors with actionable mutations should have progressed to all approved targeted therapies or have them contraindicated.
• The patient has measurable disease with RECIST 1. 1 on computed tomography (CT), positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI) scan. Imaging tests outside the screening period are valid if performed not more than 3 weeks before consent signature and otherwise fulfill protocol criteria. Patients with non-measurable disease may be allowed in Part 1 only with the explicit approval of the trial Medical Monitor.
• The patient has Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. Patients with renal cell carcinoma (RCC) to be allocated to a backfill cohort in Part 1 can have PS ≤2.
• The patient has adequate hematologic function as defined by:
• Hemoglobin ≥9 g/dL (whole or partial blood transfusions not allowed in the two previous weeks).
• Absolute neutrophil count (ANC) ≥1.0 × 109/L (growth factors like granulocyte colony-stimulating factor are not allowed in the two previous weeks).
• Platelet count ≥75 × 109/L (platelet transfusions are not allowed in the two previous weeks).
• The patient has adequate hepatic function as defined by:
• Total bilirubin ≤1.5 times upper limit of normal (ULN).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0 times ULN, (if liver metastases are present, then ≤5.0 times ULN is allowed).
• The patient has adequate renal function as defined by: estimated creatinine clearance (CrCL) using the Cockcroft- Gault formula ≥30 mL/minute.
• Women of childbearing potential (WOCBP) and men with sexual partners who are WOCBP must consent to adhere to contraceptive requirements as detailed in the protocol from the day of the signature of the informed consent to at least 4 months after the last dose of trial treatment.
• Suitable venous access for safe drug administration and the trial-required drug concentration and pharmacodynamic sampling.
• Permission to access archival biopsy located at the treating site or elsewhere. Note: Archival tissue does not need to be checked before Cycle 1 Day 1. The most modern archival biopsy is requested. If no archival tissue is available, the patient can still be enrolled in the escalation phase but not in Part 2.
• Pretreatment fresh biopsy is highly encouraged in Part 1 dose escalation once BED has been achieved. In Part 2, fresh pre-treatment and on-treatment biopsies should be obtained unless biopsy is associated with significant risk or declined by the patient and per discussion with the sponsor medical monitor (or designee).

Exclusion criteria

• Patients should have recovered from toxicity related to previous anticancer treatments (including surgery and radiation) to Grade 0/1 or baseline (except alopecia and peripheral neuropathy). Patients with endocrinopathies should have the replacement treatment in stable dosing.
• The patient has a 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 ZM008. For asymptomatic patients, screening brain imaging is not required.
• The patient has received extended field radiotherapy ≤4 weeks before the start of treatment (≤2 weeks for limited field radiation for palliation), and who has not recovered to Grade ≤1 or baseline from related side effects of such therapy (except for alopecia).
• The patient had an active infection requiring parenteral or oral antibiotics at the time of the first dose. Patients receiving oral antibiotics can be enrolled after discussion and approval of the trial Medical Monitor.
• The patient has 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 trial or that might jeopardize compliance with the protocol.
• The patient has a psychiatric illness/social circumstance that would limit compliance with trial requirements and substantially increase the risk of AEs or has compromised ability to provide written informed consent.
• The patient has clinical evidence of an active second invasive malignancy with the exception of stable prostate cancer on watchful waiting, in situ cervical cancer, in situ breast carcinoma or localized non-melanoma skin cancers.
• The patient has uncontrolled or significant cardiovascular disease defined as New York Heart Association classification III or IV.
• The patient has baseline QTc (using the Fridericia correction calculation) \>470 msec in patients without pacemaker. Active autoimmune disease that is requiring systemic treatment (i.e., with use of disease modifying agents, corticosteroids at \>10 mg/day of equivalent prednisone, or immunosuppressive drugs at any dose). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Participants with adrenal insufficiency on oral steroid replacement are allowed to participate in the study. Participants with controlled type I diabetes mellitus on stable insulin regimen are also eligible for the study. Participants with rheumatoid arthritis or psoriasis may be eligible if they have not experienced a flare in 2 years and do not require systemic therapy within the past year. Participants with vitiligo are also eligible.
• Use of therapeutic immunosuppressive medication (eg, prednisone dose of ≥ 10 mg/day or equivalent, tumor necrosis factor inhibitors at any dose) within 28 days prior to the first planned dose of study treatment. This does not include intranasal, intraocular, inhaled corticosteroids, topical and intra-articular joint injections, or physiologic replacement doses of systemic corticosteroids. Less than 10 mg prednisone per day or equivalent, short term, is allowed.
• For patients in the ZM008 monotherapy and combination arms: Patients who discontinued prior treatment with any immune checkpoint due to immune-related AEs, 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.
• History of interstitial lung disease/non-infectious pneumonitis, including immune-related pneumonitis of any Grade, radiation pneumonitis, active pulmonary tuberculosis, or evidence of active pneumonitis on screening chest CT scan. Participants with radiation therapy to the lung that is \>30 Gy within 6 months of the first dose of treatment are excluded. Participants with active lung infections requiring treatment are also excluded.
• The patient has live vaccines reception within 30 days of enrollment.
• Known active hepatitis B or C.
• Patients positive for human immunodeficiency virus (HIV) can be enrolled only in Part 2 of the trial, but HIV-positive patients must meet the following criteria: a. have CD4+ T cell (CD4+) counts ≥350 cells/μL. b. have not had an opportunistic infection within the past 12 months. Patients on prophylactic antimicrobials can be included in the trial. c. should be on established antiretroviral therapy for at least 4 weeks. d. have an HIV viral load of less than 400 copies/mL prior to enrollment. e. known history of any other relevant congenital or acquired immunodeficiency other than HIV infection.
• Has known or suspected allergy to trial treatment, excipients, or related products.
• Prior allogeneic bone marrow transplantation or solid organ transplantation.
• Toripalimab cohort only: Any contraindication present in the toripalimab prescribing information.