A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of KD033 (SAR445710) in Subjects With Metastatic or Locally Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a Phase1, open-label, sequential dose-escalation and dose-expansion study of KD033 (SAR445710) in adult participants with advanced or metastatic solid tumors. The main purpose of this study is to test KD033 (SAR445710) at different dose levels to see if it is safe and well tolerated when given once every 2 weeks and when given weekly. Additional purposes of the study are to find out whether the study drug has anti-cancer effects and how the study drug is processed by the body.

Detailed Description
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The foreseen treatment duration is until disease progression, unacceptable toxicity, criterion for withdrawal or for a maximum of 2 years.

Official Title
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A Phase 1, Open-label, Multiple-ascending Dose Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of KD033 (SAR445710) in Subjects With Metastatic or Locally Advanced Solid Tumors

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: KD033 (SAR445710)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed/documented advanced and/or metastatic solid tumor with at least one tumor lesion of location accessible to biopsy per clinical judgement of treating physician. Participants must be willing to provide a tumor biopsy at the following time points: Pre-treatment and at Cycle 4, Day 1. All other study eligibility criteria must be met before any biopsy sample is obtained. Measurable disease at baseline per RECIST v1.1 guidelines. Life expectancy of at least 3 months. Eastern Cooperative Oncology Group Performance Status (ECOG PS) score ≤ 1. Adequate organ and bone marrow functions. All toxicities related to prior radiotherapy, chemotherapy, or surgical procedure must have recovered to baseline or Grade ≤ 1 based on NCI-CTCAE v5.0 except alopecia (any grade), Grade 2 peripheral neuropathy and adverse events that are clinically non-significant or stable on supportive care. All participants, male and female, who are not surgically sterilized or postmenopausal must agree to use 'highly effective methods of contraception' during the study and for at least 60 days after the last dose of KD033 (SAR445710). Women of childbearing potential must have a negative pregnancy test within 7 days prior to KD033 (SAR445710) treatment. Ability to understand the purpose of the study, provide signed and dated informed consent from the participant/legal representative prior to performing any protocol-related procedures and able to comply with the study procedures and any locally required authorization. Exclusion Criteria: Use of immunotherapy, biological therapy, cytokine therapy < 21 days prior to the first dose of study drug. Use of immunomodulating agents < 21 days prior to the first dose of study drug. Use of chemotherapy and approved tyrosine kinase inhibitor (TKI) therapy < 14 days prior to the first dose of study drug. Anti PD-L1 or anti PD-1 therapy < 6 weeks prior to the first dose of study drug. Radiotherapy within 14 days before the start of trial treatment (prior diagnostic biopsy is permitted), with the exception of palliative radiation as described: patients assigned to radiotherapy require at least 1 additional lesion that can be safely irradiated while sparing the index lesion(s), and for which radiation at the limited, palliative doses contemplated would be considered medically appropriate; The lesion should be causing some signs or symptoms (e.g., tumor-related pain), for which radiation is indicated per the physician's standard clinical practice. Use of any investigational drug or have major surgery within 28 days before the start of trial treatment Ongoing or recent (within 2 years) evidence of significant autoimmune disease that required systemic immunosuppressive treatments. Systemic therapy with immunosuppressive agents including corticosteroids within 14 days before the start of trial treatment with the exception of corticosteroid replacement therapy for adrenal insufficiency Rapidly progressive disease which, in the opinion of Investigator, may predispose to inability to tolerate treatment or trial procedure. History or clinical evidence of central nervous system primary tumors or metastases including leptomeningeal metastases unless they have been previously treated, demonstrated no progression at least 1 months, are asymptomatic and have had no requirement for steroids or enzyme inducing anticonvulsants in the last 14 days before Screening - Participants with suspected brain metastases at Screening should undergo a CT/MRI of the brain prior to study entry. Receipt of any organ transplantation including hematopoietic cell transplantation. Has a paraneoplastic syndrome of autoimmune nature. History of interstitial lung disease or severe obstructive pulmonary disease. Clinically significant cardiovascular/cerebrovascular disease. QTc(F) interval > 450 ms for men or > 470 ms for women) Left ventricular ejection fraction (LVEF) < 50% as measured by an echocardiogram (ECHO). Active infection requiring therapy. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding. Pregnant or breast-feeding women Known severe hypersensitivity reactions to monoclonal antibodies, any history of or recent (within 6 months) of anaphylaxis Vaccine administration within 4 weeks of investigational drug administration. Vaccination with live vaccines while on trial is prohibited. Administration of inactivated vaccines like inactivated influenza vaccines is allowed. COVID-19 vaccines are approved to be administered prior to KD033 (SAR445710) administration and during the treatment phase, however, it is preferred to not vaccinate during the 28-day DLT period. Note: Other protocol-defined exclusion criteria could apply.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bi-weekly Monotherapy Dose Escalation (Q2W)<br>KD033 (SAR445710) will be administered in sequential ascending doses as a monotherapy via intravenous (IV) administration every 2 weeks (Q2W). | Drug: KD033 (SAR445710)<br>* Pharmaceutical form: Solution for infusion Route of administration: intravenous (IV)<br>|
| Experimental: Weekly Monotherapy Dose Escalation (Q1W)<br>KD033 (SAR445710) will be administered in sequential ascending doses as a monotherapy via intravenous (IV) administration once a week (QW) for 6 weeks and then every 2 week-dosing. | Drug: KD033 (SAR445710)<br>* Pharmaceutical form: Solution for infusion Route of administration: intravenous (IV)<br>|
| Experimental: Dose Expansion<br>KD033 (SAR445710) will be administered at recommended dose/schedule for expansion | Drug: KD033 (SAR445710)<br>* Pharmaceutical form: Solution for infusion Route of administration: intravenous (IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Dose Limiting Toxicities (DLTs) | To evaluate the number of participants who experienced DLTs during the dose escalation phase | Up to 28 days | 
| Treatment Emergent Adverse Events (TEAEs) and Treatment-related AEs by Severity | To evaluate the number of TEAEs and treatment-related AEs by severity for all dose groups/cohorts according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) | Up to 30 days after last treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response (BOR) | To evaluate the best overall response from study treatment according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and Immune Response Evaluation Criteria in Solid Tumors (iRECIST) criteria per Investigator assessment | Through study completion, an expected average of 1 year | 
| Duration Of Response (DOR) | To evaluate the duration of response from study treatment according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and Immune Response Evaluation Criteria in Solid Tumors (iRECIST) criteria per Investigator assessment | Through study completion, an expected average of 1 year | 
| Exploration of KD033 (SAR445710) Pharmacokinetic (PK) Profile - AUC | Area under the concentration versus time curve (AUC) | Through study completion, an expected average of 1 year | 
| Exploration of KD033 (SAR445710) Pharmacokinetic (PK) Profile - Cmax | Maximum plasma concentration observed (Cmax) | Through study completion, an expected average of 1 year | 
| Exploration of Anti-KD033 (SAR445710) Antibodies | To evaluate serum titers and assessment of neutralization of anti-KD033 (SAR445710) antibodies using blood samples collected during the dose escalation and dose expansion phases | Through study completion, an expected average of 1 year |