Phase 1 Trial of ZM008 as Single Agent and in Combination With Pembrolizumab in Patients With Advanced Solid Tumors

Inclusion Criteria

• Age greater than 18 years at the time of signing the informed consent form.
• Patients with histologically confirmed diagnosis of locally advanced, locoregionally recurrent, not amenable to curative therapy, or metastatic solid tumors that have no standard therapeutic option or are intolerant to the therapies. Tumor types to be included are Non Small Cell Lung Cancer, Triple Negative Breast Cancer, Head & Neck Squamous Cell Cancer, Prostate Cancer, Colorectal cancer, pancreatic ductal adenocarcinoma, biliary tract cancer, high grade serous ovarian cancer, diffuse large B-cell lymphoma or Urothelial Cancer.
• Patients with tumors with actionable mutations should have progressed on all approved targeted therapies or have them contraindicated.
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 on computed tomography (CT), positron emission tomography (PET)/CT or magnetic resonance imaging (MRI) scan.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
• The patient has adequate hematologic function as defined by:
• Hemoglobin ≥9 g/dL (whole or partial blood transfusions not allowed in the weeks).
• Absolute neutrophil count ≥1.0 × 109/L (growth factors like granulocyte colony- stimulating factors are not allowed in the two previous weeks).
• Platelet count ≥75 × 109/L (platelet transfusions are not allowed in the 2 previous weeks).
• The patient has adequate hepatic function as defined by:
• Total bilirubin ≤1.5 times upper limit of normal (ULN).
• AST and 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. Patients with calculated CrCL <30 mL/minute can be enrolled if measured CrCL is ≥30 mL/minute.
• Women of childbearing potential (WOCBP) and men with sexual partners who are WOCBP must consent to adhere to contraceptive requirements 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.
• Access to archival biopsy if available. If no archival tissue is available, the patient can still be enrolled in the escalation phase but not in the subsequent cohort expansion study. Part 2.

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 stable replacement treatment.
• 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.
• 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 adverse effects of such therapy (except for alopecia).
• An active infection requiring parenteral or oral antibiotics at the time of the first dose. Oral antibiotics may be allowed if patient stable.
• 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.
• The patient has history of autoimmune disease requiring systemic immunosuppressive therapy (daily prednisone equivalent doses >10 mg/day) excluding vitiligo, type I diabetes, Grave's disease, or Hashimoto thyroiditis.
• 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.
• Patients has history of pneumonitis/interstitial lung disease due to any cause (infection, secondary to other treatments or idiopathic).
• 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 the Part 2 of the trial, 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.
• Has known or suspected allergy to trial treatment, excipients, or related products. -