A Study to Evaluate Safety, Tolerability and Preliminary Activity of LB101 in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to assess safety, tolerability, and preliminary activity of LB101 monotherapy in participants with advanced solid tumors.

Detailed Description
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This study consists of 2 parts: First in Human (FIH) dose escalation and dose optimization (Part 1a and Part 1b, respectively) and dose expansion (Part 2). Part 1 will evaluate LB101 monotherapy in participants with selected, advanced solid tumors and determine the Recommended Dose(s) for Expansion (RDE(s)) for Part 2. The design of Part 2 depends on the results of Part 1 and will further evaluate the safety, efficacy, tolerability, pharmacokinetics, and immune response of LB101.

Official Title
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A Phase 1/2a, First in Human, Open-Label, Multicenter, Dose Escalation Study With Expansion Cohorts to Evaluate the Safety, Tolerability, and Preliminary Activity of LB101 in Subjects With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: LB101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals must meet all of the following inclusion criteria to be included in the study: Male or female subjects ≥ 18 years old at the time of informed consent Signed informed consent form (ICF) indicating that the subject understands the purpose and procedures required for the study and is willing and able to participate in the study prior to any study-related assessment or procedure For Part 1a (dose escalation) and Part 1b (dose optimization): subjects who i). have a histologically confirmed solid tumor that is listed below and is advanced, unresectable, and/or metastatic and ii). have no standard therapy, are not candidates for available standard therapy, or have failed systemic therapy due to lack of response, progression, or intolerance: a. Non-small cell lung cancer (NSCLC), which is known to be PD-L1 positive (combined positive score [CPS] ≥ 1 or tumor proportion score [TPS] ≥ 1%) after having received pembrolizumab or other analog immune checkpoint inhibitor at any stage of their prior therapy i. Subjects with PD-L1 positive NSCLC with known genomic alterations for which targeted therapy is approved are not required to have been treated with pembrolizumab, etc. but must have received such approved targeted therapy. Genomic alternations include, but are not limited to, epidermal growth factor receptor [EGFR] and anaplastic lymphoma kinase [ALK] b. Head and neck squamous cell carcinoma, which is known to be PD-L1 positive (CPS ≥ 1 or TPS ≥ 1%), after having received pembrolizumab or other analog immune checkpoint inhibitor at any stage of their prior therapy c. Cervical cancer, which is known to be PD-L1 positive (CPS ≥ 1 or TPS ≥ 1%), after having received pembrolizumab or other analog immune checkpoint inhibitor at any stage of their prior therapy d. Cutaneous squamous cell cancer after having received pembrolizumab or other analog immune checkpoint inhibitor at any stage of their prior therapy e. Colorectal cancer with low level microsatellite instability (MSI-low) and/or microsatellite stable (MSS) f. Ovarian cancer which is platinum resistant or platinum refractory, with platinum free interval of less than 6 months, and without rapidly progressing disease in the investigator's judgment; in France, subjects should have received at least 1 line but no more than 2 lines of systemic therapy in the platinum-resistant setting g. Gastric cancer which is known to be PD-L1 positive (CPS ≥ 1 or TPS ≥ 1%) after having received pembrolizumab or other analog immune checkpoint inhibitor at any stage of their prior therapy Subjects have measurable disease according to RECIST v1.1 Subjects agree to provide tumor tissue: In Part 1a tumor type specific backfill cohort(s), Part 1b, and Part 2, subjects must agree to undergo baseline tumor biopsy with the exception of subjects where biopsy is associated with high risk in accordance with American Society of Clinical Oncology (ASCO) guidelines, in which case the sponsor medical director's approval for biopsy waiver needs to be obtained All other subjects (Part 1a dose escalation cohorts and where biopsy is not feasible) must be able to provide archived tumor tissue from most recent biopsy performed prior to study entry Subjects have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Subjects have adequate hematological function defined as: Absolute neutrophil count ≥ 1.5 × 109/L Platelet ≥ 75 × 109/L without need for transfusions within 7 days prior to screening and during the screening period Hemoglobin ≥ 9.0 g/dL (≥ 5.6 mmol/L) without need for transfusions within 7 days prior to screening and during the screening period Subjects have adequate hepatic and renal function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN); for subjects with primary or secondary liver tumors: ALT and AST ≤ 5 × ULN Total bilirubin ≤ 1.5 x ULN (or ≤ 2 x ULN) for subjects with Gilbert's syndrome or known liver metastasis) Estimated creatinine clearance rate ≥ 50 mL/min Albumin ≥ 3.5 g/dL or ≥ lower limit of the institution's normal range Subjects have a baseline QT interval as corrected by Fridericia's formula ≤ 480 msec Subjects with life expectancy ≥ 12 weeks Subjects have a body weight ≥ 40 kg For female subjects of childbearing potential, subjects have a negative urine or serum pregnancy test within 72 hours prior to the start of LB101 dosing For female subjects of childbearing potential, subjects are willing to use 2 highly effective methods of contraception including 1 barrier method throughout the treatment period until 6 months after the treatment period. Note: A female subject is considered to be of childbearing potential unless she has had ahysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and follicle-stimulating hormone levels within the institutional laboratory postmenopausal range and a negative serum or urine beta human chorionic gonadotropin [βHCG]); or is menopausal (age ≥ 50 years with amenorrhea for ≥ 6 months) For male subjects who can father a child with a female partner of childbearing potential, subjects are willing to use 2 highly effective methods of contraception including 1 barrier method and refrain from sperm donation throughout the treatment period until 6 months after the treatment period. Note: A male subject is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy Exclusion Criteria: Individuals meeting any of the following exclusion criteria at screening or baseline are ineligible to participate in this study: PD-L1 Status Subjects with unknown PD-L1 status for the following tumor types: NSCLC, head and neck squamous cell carcinoma, cervical cancer, or gastric cancer a. In tumor type specific backfill cohort(s) in Part 1a, any subject with unknown PD-L1 status, including ovarian, colorectal, or cutaneous squamous cell cancer, ie, all subjects in Part 1a tumor type specific backfill cohort(s) must be PD-L1 positive (CPS ≥ 1 or TPS ≥ 1%) Subjects with known negative PD-L1 status Prior and Concomitant Therapies Subjects with NSCLC, head and neck squamous cell carcinoma, cervical cancer, cutaneous squamous cell cancer, or gastric cancer that have NOT received checkpoint inhibitor for advanced/metastatic disease, unless such therapy is not approved for treating a subject's specific condition. Subjects who receive adjuvant systemic therapy and progressed with advanced disease within 6 months of completing treatment - the adjuvant therapy will be considered a line of systemic therapy for advanced/metastatic disease Subjects with platinum sensitive ovarian cancer Subjects who have had previous exposure to CD47 or SIRPα targeting anticancer therapy Subjects have received prior anticancer therapy within the specified time frame prior to the start of LB101 including: Anticancer therapy (chemotherapy, endocrine therapy, targeted therapy, or tumor embolization) within 2 weeks of the start of LB101 or less than 5 times the half-life of the most recent therapy prior to the start of LB101, whichever is shorter; immunotherapy/monoclonal antibodies/antibody-drug conjugates within 4 weeks of the start of LB101; nitrosoureas, or radioactive isotopes within 6 weeks of the start of LB101 Prior radiotherapy within 2 weeks of the start of LB101 Major surgery within 4 weeksof the start of LB101 (tumor biopsy not considered major surgery) Chronic corticosteroid treatment at a dose higher than 10 mg prednisone (or equivalent). The maximal cumulative dose is 70 mg prednisone within 7 days of the start of LB101 Subjects participating in another interventional clinical study except for observational (non-interventional) clinical studies or survival follow-up phase of interventional studies, within the previous 30 days Subjects who have ongoing side effects to any prior therapy or procedure, which have not recovered to National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade ≤ 1 (with the exception of alopecia, fatigue, and peripheral neuropathy Grade ≤ 2) (see exclusion criterion number 19) Subjects who have received immunosuppressive drugs within 7 days prior to the start of LB101 (excluding topical, intra-nasal, or inhaled glucocorticoids) or systemic glucocorticoids equivalent to more than 10 mg prednisone/day Subjects who have received a live attenuated vaccine within 4 weeks prior to the start of LB101. Subjects with primary brain tumors and evidence of new or progressing cerebrospinal or leptomeningeal metastases during screening. Subjects with brain metastases may be eligible if they: Have stable brain metastases on imaging performed within 4 weeks of starting LB101 treatment in the study and have no neurological symptoms; and Have received therapy for brain metastases - surgery, radiotherapy, or stereotactic radiotherapy; and Are not receiving steroid or anticonvulsant therapy for brain metastases Concomitant Conditions Subjects who have a history of Grade ≥ 3 allergic reactions to monoclonal antibody therapy as well as known or suspected allergy or intolerance to any components of LB101 Subjects with active or suspected systemic inflammatory autoimmune diseases or with a history of documented autoimmune disease over the past 2 years (the following subjects can be included in the study: subjects with vitiligo, psoriasis, alopecia, or Grave's disease; subjects who have not required systemic treatment within 2 years; hypothyroidism subjects who require only thyroid hormone replacement therapy, or type I diabetes subjects requiring only insulin replacement therapy) Subjects with a known history of hemophagocytic lymphohistiocytosis Subjects who have ongoing or active infection requiring IV anti-infective medications or who have received systemic treatment for an infection within 2 weeks of the first dose of LB101 Subjects with known or suspected chronic active Epstein-Barr virus infection Subjects with a history of interstitial lung disease (ILD)/non-infectious pneumonitis that required ≥1 mg/kg steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis Subjects with a known history of: Seropositivity for human immunodeficiency virus (HIV) Positive serology for hepatitis B (unless immune due to vaccination, resolved natural infection, or passive immunization due to immunoglobulin therapy), known history/positive serology for hepatitis C virus (HCV) (subjects who have completed curative antiviral therapy are allowed provided HCV viral load is not detected) Allogenic organ transplantation (except for corneal transplant) and/or hematopoietic stem cell transplantation Subjects who have had a history of life-threatening treatment-related AEs with prior immunotherapy or who have not recovered from prior cancer therapy-induced AEs (ie, any AE that remains ≥ Grade 2, according to NCI CTCAE criteria; or that has not returned to baseline) with the exception of: Hypothyroidism or endocrine insufficiencies that are controlled with hormone replacement therapy Grade 3 rash that resolved with topical therapy Subjects with clinically significant ascites who are in need of treatment for ascites. Subjects who show only a small amount of ascites on imaging and who are asymptomatic are not considered to have clinically significant ascites and can be included in the study Subjects with moderate bilateral pleural effusion or massive bilateral pleural effusion or respiratory dysfunction requiring drainage Subjects with uncontrolled cardiovascular disease, in the opinion of the treating investigator, including but not limited to: Symptomatic congestive heart failure (New York Heart Association Class III-IV) Symptomatic or poorly controlled arrhythmias Any arterial thromboembolism including myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack that occurred within 6 months prior to enrollment Subjects with any other acute or chronic diseases, psychiatric disorders, or abnormal laboratory test values that, at the discretion of the investigators, are deemed ineligible to participate in this study based on the investigators' view that these conditions may interfere with planned staging, treatment, or the interpretation of research results or may place the subjects at high risk for treatment-related complications Subjects with a history of other advanced solid tumor malignancies except: Cured malignant tumors for > 2 years prior to enrollment and no known active disease Tumors with negligible risk of metastases or death including but not limited to localized basal or squamous cell skin cancer, localized prostate cancer, ductal carcinoma in situ, and adequately treated cervical carcinoma in situ Other Exclusion Criteria Pregnant or lactating female subjects Subjects with significant weight loss due to cancer related conditions within 6 months of first dose of study drug (eg, weight loss > 6% for subjects with BMI ≤ 20 kg/m2 or weight loss > 11% for subjects with BMI > 20 kg/m2) Subjects not eligible to participate in the study at the discretion of the investigator For France only: Vulnerable subjects indicated in Articles 1121-6 to 1121-8 of the French Public Health Code For France only: Subjects who are not affiliated with a social security scheme

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
Intervention Model: Sequential Assignment
Interventional Model Description: Part 1 of the study will be non-randomized and Part 2 design will depend on results of Part 1.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LB101<br>Part 1 Part 1a participants will receive LB101 once every 2 weeks (Q2W) (28-day cycle), with a preliminary plan for 6 sequential dose levels. Part 1b will be a dose optimization and will include >1 dose levels and/or dose schedules that have been deemed safe and tolerable in Part 1a. Part 2 Dose regimen(s) for participants in Part 2 will be based on the results of Part 1. | Drug: LB101<br>* Part 1: IV infusion of LB101 Q2W (28-day cycle) and Part 2: IV infusion of LB101<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants with Dose Limiting Toxicities (DLTs) as graded according to the NCI CTCAE v5.0 |  | 28 days following the first dose of LB101 (Days 1 to 28 of Cycle 1) | 
| Part 1 and 2: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) as defined as events that started or worsened after first dose of study intervention until 30 days after last dose |  | From start of study treatment up to 3 years | 
| Part 1: Number of Participants with Recommended Dose(s) for Expansion | Recommended Dose for expansion will be determined. | 28 days following the first dose of LB101 (Days 1 to 28 of Cycle 1) | 
| Part 2: Proportion of Participants with Confirmed Objective Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) Evaluated by the Blinded Independent Central Review (BICR) |  | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 and 2: Proportion of Participants with Objective Response Rate (ORR) According to RECIST v1.1 Evaluated by the Investigator |  | Up to 3 years | 
| Part 1 and 2: Duration of Response (DoR) According to RECIST v1.1 Evaluated by the Blinded Independent Central Review (BICR) |  | Time from first objective response to first occurrence of objective tumor progression or death from any cause (up to 3 years) | 
| Part 1 and 2: Proportion of Participants with Disease Control Rate (DCR) According to RECIST v1.1 Evaluated by the Blinded Independent Central Review (BICR) |  | Up to 3 years | 
| Part 1 and 2: Duration of Response (DoR) Assessed by Investigator |  | Time from first objective response to first occurrence of objective tumor progression or death from any cause (up to 3 years) | 
| Part 1 and 2: Disease Control Rate (DCR) Assessed by Investigator |  | Up to 3 years | 
| Part 1 and 2: Number of Participants with Antidrug Antibodies (ADA) and Neutralizing Antibodies (NAb) to LB101 |  | Up to 3 years | 
| Part 1: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 2, 3, 5, 8, 11, 15, 16, and 22), Cycle 2 (Day 1, 2, 8, and 15), Cycle 3 (Day 1, and 15), and Cycle 4 (Day 1, and 15) | 
| Part 2: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-inf) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 15, 16, and 22), Cycle 2 (Day 1, and 15), and Cycle 3 (Day 1, and 15) | 
| Part 1: Maximum (peak) Concentration (Cmax) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 2, 3, 5, 8, 11, 15, 16, and 22), Cycle 2 (Day 1, 2, 8, and 15), Cycle 3 (Day 1, and 15), and Cycle 4 (Day 1, and 15) | 
| Part 2: Maximum (peak) Concentration (Cmax) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 15, 16, and 22), Cycle 2 (Day 1, and 15), and Cycle 3 (Day 1, and 15) | 
| Part 1: Time to Maximum Observed Concentration (Tmax) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 2, 3, 5, 8, 11, 15, 16, and 22), Cycle 2 (Day 1, 2, 8, and 15), Cycle 3 (Day 1, and 15), and Cycle 4 (Day 1, and 15) | 
| Part 2: Time to Maximum Observed Concentration (Tmax) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 15, 16, and 22), Cycle 2 (Day 1, and 15), and Cycle 3 (Day 1, and 15) | 
| Part 1: Area Under the Concentration-time Curve at 14 days Post Drug Administration (AUC14days) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 2, 3, 5, 8, 11), Cycle 2 (Day 1, 2, and 8), Cycle 3 (Day 1), and Cycle 4 (Day 1) | 
| Part 2: Area Under the Concentration-time Curve at 14 days Post Drug Administration (AUC14days) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1), Cycle 2 (Day 1), and Cycle 3 (Day 1) | 
| Part 1: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-last) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 2, 3, 5, 8, 11, 15, 16, and 22), Cycle 2 (Day 1, 2, 8, and 15), Cycle 3 (Day 1, and 15), and Cycle 4 (Day 1, and 15) | 
| Part 2: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Concentration (AUC0-last) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 15, 16, and 22), Cycle 2 (Day 1, and 15), and Cycle 3 (Day 1, and 15) | 
| Part 1: Elimination Half-life (t1/2) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 2, 3, 5, 8, 11, 15, 16, and 22), Cycle 2 (Day 1, 2, 8, and 15), Cycle 3 (Day 1, and 15), and Cycle 4 (Day 1, and 15) | 
| Part 2: Elimination Half-life (t1/2) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 15, 16, and 22), Cycle 2 (Day 1, and 15), and Cycle 3 (Day 1, and 15) | 
| Part 1: Elimination Rate Constant (Kel) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 2, 3, 5, 8, 11, 15, 16, and 22), Cycle 2 (Day 1, 2, 8, and 15), Cycle 3 (Day 1, and 15), and Cycle 4 (Day 1, and 15) | 
| Part 2: Elimination Rate Constant (Kel) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 15, 16, and 22), Cycle 2 (Day 1, and 15), and Cycle 3 (Day 1, and 15) | 
| Part 1: Apparent Total Body Clearance (CL/F) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 2, 3, 5, 8, 11, 15, 16, and 22), Cycle 2 (Day 1, 2, 8, and 15), Cycle 3 (Day 1, and 15), and Cycle 4 (Day 1, and 15) | 
| Part 2: Apparent Total Body Clearance (CL/F) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 15, 16, and 22), Cycle 2 (Day 1, and 15), and Cycle 3 (Day 1, and 15) | 
| Part 1: Apparent Volume of Distribution (Vd/F) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 2, 3, 5, 8, 11, 15, 16, and 22), Cycle 2 (Day 1, 2, 8, and 15), Cycle 3 (Day 1, and 15), and Cycle 4 (Day 1, and 15) | 
| Part 2: Apparent Volume of Distribution (Vd/F) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 15, 16, and 22), Cycle 2 (Day 1, and 15), and Cycle 3 (Day 1, and 15) | 
| Part 1: Predose Trough Concentrations (CTrough) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 2, 3, 5, 8, 11, 15, 16, and 22), Cycle 2 (Day 1, 2, 8, and 15), Cycle 3 (Day 1, and 15), and Cycle 4 (Day 1, and 15) | 
| Part 2: Predose Trough Concentrations (CTrough) of LB101 |  | Day 0 (pre-dose) and at multiple time points (up to End of infusion) post-dose in Cycle 1 (Day 1, 15, 16, and 22), Cycle 2 (Day 1, and 15), and Cycle 3 (Day 1, and 15) |