A Safety and Tolerability Study of NC318 in Subjects With Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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This research study is studying a new drug, NC318, as a possible treatment for advanced or metastatic solid tumors.

Official Title
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A Phase 1/2, Open-Label, Dose-Escalation, Safety and Tolerability Study of NC318 in Subjects With Advanced or Metastatic Solid Tumors

Conditions
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Lung Cancer, Advanced or Metastatic Solid Tumors, Breast Cancer, Head and Neck Squamous Cell Carcinoma, Endometrial Cancer, Melanoma, CRC, Urothelial Carcinoma, Cholangiocarcinoma

Intervention / Treatment
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* Drug: NC318


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women aged 18 or older. Willingness to provide written informed consent for the study. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1. Subjects with advanced unresectable and/or metastatic solid tumors. Subjects who have disease progression after treatment with available therapies that are known to confer clinical benefit, or who are intolerant to treatment, or who refuse standard treatment. Note: There is no limit to the number of prior treatment regimens. Presence of measurable disease based on RECIST v1.1. Tumor lesions situated in a previously irradiated area, or in an area subjected to other locoregional therapy, are not considered measurable unless there has been demonstrated progression in the lesion. Able to provide pretreatment tumor tissue sample at Screening. Subjects of childbearing potential (defined as female subjects who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy and are not postmenopausal, defined as ≥ 12 months of amenorrhea not caused by reversible conditions, diseases, or medications) and non-sterilized male subjects must agree to take appropriate precautions to avoid pregnancy or fathering children (with at least 99% certainty) from screening through 90 days after the last dose of study drug. Exclusion Criteria: Inability to comprehend or unwilling to sign the Informed Consent Form. Screening laboratory values of: Absolute neutrophil count < 1.5 × 10^9/L Platelets < 100 × 10^9/L Hemoglobin < 9 g/dL or < 5.6 mmol/L Serum creatinine > 1.5 × institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2.5 × ULN Total bilirubin > 1.5 × ULN. International normalized ratio (INR) or prothrombin time (PT) > 1.5 × ULN or activated partial thromboplastin time (aPTT) > 1.5 × ULN Transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (including granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 7 days before the first administration of study drug. Receipt of anticancer medications or investigational drugs within the following intervals before the first administration of study drug: ≤ 14 days for chemotherapy, targeted small molecule therapy, or radiation therapy. Subjects must also not require chronic use of corticosteroids and must not have had radiation pneumonitis because of a treatment. A 1-week washout is permitted for palliative radiation to non-central nervous system (CNS) disease with medical monitor approval. Note: Bisphosphonates and denosumab are permitted medications. ≤ 28 days for prior immunotherapy or persistence of active cellular therapy (e.g., chimeric antigen receptor T cell therapy; other cellular therapies must be discussed with the medical monitor to determine eligibility). ≤ 28 days for a prior monoclonal antibody used for anticancer therapy except for denosumab. ≤ 7 days for immune-suppressive-based treatment for any reason. Note: Use of inhaled or topical steroids or corticosteroid use for radiographic procedures is permitted. Note: The use of corticosteroids equivalent to prednisone </= 10mg/day is allowed. ≤ 28 days or 5 half-lives (whichever is longer) before the first dose for all other investigational study drugs or devices. ≤ 14 days for COVID-19 vaccine. Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior immunotherapy) and/or complications from prior surgical intervention before starting therapy. Receipt of a live vaccine within 30 days of planned start of study therapy. Active autoimmune disease that required systemic treatment in the past (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Known active CNS metastases and/or carcinomatous meningitis. Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry after treatment with curative intent. Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease. Documented known activating or driver mutations (i.e. EGFR mutations/amplification, BRAF mutations, ALK alterations, etc.) which have not been previously treated with a standard of care targeted therapy. Subjects with screening QTc interval >470 milliseconds are excluded. Uncontrolled systemic fungal, bacterial, viral, or other infection despite appropriate anti-infection treatment. Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV), unless the hepatitis is considered to be cured. Known history of HIV (HIV 1 or HIV 2 antibodies). Known allergy or reaction to any component of study drug or formulation components. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after the last dose of study treatment. Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the subject; or interfere with interpretation of study data.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1 will utilize a 3 + 3 design to explore escalating dose levels. Phase 2 Dose Expansion will further evaluate the safety, tolerability, preliminary efficacy, and PK/PD activity of NC318 at the RP2D utilizing a Simon 2-stage design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NC318 8mg<br>Phase 1 Dose Escalation (Cohort -1): Subjects received NC318 IV at 8mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). | Drug: NC318<br>* NC318 is an experimental antibody drug that may make the immune response more active against cancer.<br>|
| Experimental: NC318 24mg<br>Phase 1 Dose Escalation (Cohort 1): Subjects received NC318 IV at 24mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). | Drug: NC318<br>* NC318 is an experimental antibody drug that may make the immune response more active against cancer.<br>|
| Experimental: NC318 80mg<br>Phase 1 Dose Escalation/Safety Expansion (Cohort 2): Subjects received NC318 IV at 80mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). | Drug: NC318<br>* NC318 is an experimental antibody drug that may make the immune response more active against cancer.<br>|
| Experimental: NC318 240mg<br>Phase 1 Dose Escalation/Safety Expansion (Cohort 3): Subjects received NC318 IV at 240mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). | Drug: NC318<br>* NC318 is an experimental antibody drug that may make the immune response more active against cancer.<br>|
| Experimental: NC318 400mg<br>Phase 1 Dose Escalation/Safety Expansion (Cohort 4): Subjects received NC318 IV at 400mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). | Drug: NC318<br>* NC318 is an experimental antibody drug that may make the immune response more active against cancer.<br>|
| Experimental: NC318 800mg<br>Phase 1 Dose Escalation (Cohort 5): Subjects received NC318 IV at 800mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). | Drug: NC318<br>* NC318 is an experimental antibody drug that may make the immune response more active against cancer.<br>|
| Experimental: NC318 1600mg<br>Phase 1 Dose Escalation (Cohort 6): Subjects received NC318 IV at 1600mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). | Drug: NC318<br>* NC318 is an experimental antibody drug that may make the immune response more active against cancer.<br>|
| Experimental: Dose Expansion: 400mg Q2W<br>Phase 2 Dose Expansion (400mg): Subjects received NC318 IV at 400mg Q2W until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). | Drug: NC318<br>* NC318 is an experimental antibody drug that may make the immune response more active against cancer.<br>|
| Experimental: Dose Expansion: 800mg QW<br>Phase 2 Dose Expansion (800mg): Subjects received NC318 IV at 800mg QW for 8 weeks, then Q2W thereafter until disease progression, withdraw of consent, or intolerable toxicity (whichever comes first). | Drug: NC318<br>* NC318 is an experimental antibody drug that may make the immune response more active against cancer.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent Adverse Events as assessed by CTCAE v5.0 | Frequency, duration, and severity of treatment-emergent adverse events (AEs) per CTCAE v5.0 | From enrollment through up to 90 days after end of treatment, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | To assess antitumor activity/efficacy by evaluating objective response rate (ORR), defined as the percentage of participants who experienced a complete response (CR; disappearance of all target lesions) or a partial response (PR; at least a 30% decrease in the sum of diameters of target lesions) based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | Approximately 1 year | 
| Duration of response (DoR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | To assess antitumor activity/efficacy by evaluating duration of response (DoR), defined as the time from the first documented complete response or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 to the first documented progressive disease or death due to any cause, whichever occurs first. | Approximately 1 year | 
| Disease Control Rate (DCR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | To assess antitumor activity/efficacy by evaluating disease control rate (DCR), defined as the proportion of participants in whom a documented complete response, partial response, or stable disease is observed as the best overall response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | Approximately 1 year | 
| Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | To evaluate progression-free survival (PFS), defined as the time from the first dose of NC318 to the first occurrence of documented progressive disease or death due to any cause, whichever occurs first. | Approximately 1 year | 
| Overall survival (OS) as assessed by | To evaluate overall survival (OS), defined as the time from the first dose of NC318 to death due to any cause. | Approximately 1 year | 
| Maximum Plasma Concentration (Cmax) of NC318 | To evaluate the Maximum Plasma Concentration (Cmax) of NC318 | Days 1, 2, and 3 of Cycles 1 and 5 and Day 1 of Cycles 2, 3, 6, 9, 13, 17, and 21. Each cycle is 7 days during Cycles 1-8 and 14 days thereafter. | 
| Area Under the Curve (AUC) of NC318 | To evaluate the Area Under the Curve (AUC) of NC318 | Days 1, 2, and 3 of Cycles 1 and 5 and Day 1 of Cycles 2, 3, 6, 9, 13, 17, and 21. Each cycle is 7 days during Cycles 1-8 and 14 days thereafter. | 
| Half-life (t1/2) of NC318 | To evaluate the half-life (t1/2) of NC318 | Days 1, 2, and 3 of Cycles 1 and 5 and Day 1 of Cycles 2, 3, 6, 9, 13, 17, and 21. Each cycle is 7 days during Cycles 1-8 and 14 days thereafter. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Cancer, Metastatic Cancer, NC318, Immunotherapy, PD-L1, Dose Escalation, Biomarker, PK, Cohort Expansion, Solid Tumor