A Study to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-tumor Activity of RO7616789 in Advanced Small Cell Lung Cancer and Other Neuroendocrine Carcinomas

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of RO7616789. The study will have 3 parts: Dose Escalation (Parts 1 and 2) and Dose Expansion (Part 3). Participants with advanced stage small cell lung cancer (SCLC) and neuroendocrine carcinoma (NEC) will be enrolled in the study.

Official Title
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An Open-Label, Multicenter Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Anti-Tumor Activity of RO7616789 in Participants With Advanced Small Cell Lung Cancer and Other Neuroendocrine Carcinomas

Conditions
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Small Cell Lung Cancer, Neuroendocrine Carcinoma

Intervention / Treatment
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* Drug: RO7616789
* Drug: Tocilizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Life expectancy at least 12 weeks Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Adequate hematologic and end organ function Negative serum pregnancy test. Adequate contraception and no or interruption of breastfeeding Histologically confirmed extensive SCLC or poorly differentiated NEC of any other origin, relapsed after at least 1 systemic therapy Measurable disease according to Response Evaluation criteria in Solid Tumors (RECIST) Version 1.1 Confirmed availability of representative archival tumor specimens in formalin-fixed, paraffin-embedded (FFPE) blocks or unstained slides Exclusion Criteria: Pregnant or breastfeeding, or intending to become pregnant during the study or within 40 days after the final dose of study treatment Poorly controlled Type 2 diabetes mellitus defined as a screening hemoglobin A1c ≥ 8% or a fasting plasma glucose ≥ 160 mg/dL (or 8.8 mmol/L) QT interval corrected using Fridericia's formula (QTcF) > 470 ms. Abnormal electrocardiograms (ECGs) (triplicate) should be performed > 30 minutes apart Current treatment with medications that are well known to prolong the QT interval Prior treatment with anti-cluster of differentiation (CD)137 agents, anti-CD3 agents and/or delta-like ligand 3 (DLL3) targeted therapies Any anti-cancer therapy, whether investigational or approved, including chemotherapy, hormonal therapy, or radiotherapy, within 21 days prior to initiation of study treatment Any history of an immune-related Grade 4 adverse event (AE) attributed to prior anti-programmed death ligand-1 (PD-L1) /PD-1 or anti-cytotoxic T-lymphocyte-associated protein (CTLA-4) therapy (other than asymptomatic elevation of serum amylase or lipase) Any history of an immune-related Grade 3 adverse event attributed to prior anti-PD-L1 /PD-1 or anti-CTLA-4 therapy (other than asymptomatic elevation of serum amylase or lipase) that resulted in permanent discontinuation of the prior immunotherapeutic agent History or clinical evidence of primary central nervous system (CNS) malignancy, symptomatic CNS metastases, CNS metastases requiring any anti-tumor treatment, or leptomeningeal disease and current or history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease Spinal cord compression that has not been definitively treated with surgery and/or radiation Active or history of clinically significant autoimmune disease Positive test for human immunodeficiency virus (HIV) infection Positive hepatitis B surface antigen (HbsAg) test, and/or positive total hepatitis B core antibody (HbcAb) test at screening Prior allogeneic hematopoietic stem cell transplantation or prior solid organ transplantation Administration of a live, attenuated vaccine within 4 weeks before first RO7616789 infusion Known allergy or hypersensitivity to any component of the RO7616789 formulation

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: Part 1: RO7616789 QW: Dose Escalation<br>Participants will receive a fixed dose of RO7616789 intravenously once weekly (QW) per dose level on Day 1, 8, and 15 of each 21-day cycle. In case of toxicity, step-up (single or double) dosing may be explored. | Drug: RO7616789<br>* RO7616789 solution for infusion will be administered intravenously at a dose and per schedule as specified for the respective part.<br>Drug: Tocilizumab<br>* Tocilizumab will be used as rescue therapy, in case of clinical presentation of cytokine release syndrome (CRS). Tocilizumab solution for infusion will be administered intravenously at 8 mg/kg for participants >/= 30 kg or at 12 mg/kg for participants < 30 kg.<br>* Other names: Actemra, RoActemra;|
| Experimental: Part 2: RO7616789 Q3W: Dose Escalation<br>Participants will receive a fixed dose of RO7616789, at a dose determined in Part 1, intravenously once every 3 weeks (Q3W) on Day 1 of each 21-day cycle. In case of toxicity, step-up (single or double) dosing may be explored. | Drug: RO7616789<br>* RO7616789 solution for infusion will be administered intravenously at a dose and per schedule as specified for the respective part.<br>Drug: Tocilizumab<br>* Tocilizumab will be used as rescue therapy, in case of clinical presentation of cytokine release syndrome (CRS). Tocilizumab solution for infusion will be administered intravenously at 8 mg/kg for participants >/= 30 kg or at 12 mg/kg for participants < 30 kg.<br>* Other names: Actemra, RoActemra;|
| Experimental: Part 3: Dose Expansion<br>Based on emerging data from Part 1 and 2, one or more dosing regimens will be further investigated in Part 3. | Drug: RO7616789<br>* RO7616789 solution for infusion will be administered intravenously at a dose and per schedule as specified for the respective part.<br>Drug: Tocilizumab<br>* Tocilizumab will be used as rescue therapy, in case of clinical presentation of cytokine release syndrome (CRS). Tocilizumab solution for infusion will be administered intravenously at 8 mg/kg for participants >/= 30 kg or at 12 mg/kg for participants < 30 kg.<br>* Other names: Actemra, RoActemra;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1, 2 and 3: Number of Participants with Adverse Events and Serious Adverse Events | Adverse events were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0), and Cytokine release syndrome (CRS), will be graded based on the American Society for Transplantation and Cell Therapy (ASTCT) criteria. | Up to approximately 26 months | 
| Part 1 and 2: Number of Participants with Dose Limiting Toxicities (DLTs) |  | Day 1 through Day 21 in cycle 1 (Cycle is 21 days) | 
| Part 3: Objective Response Rate (ORR) as determined by Investigator |  | Up to approximately 26 months | 
| Part 3: Disease Control Rates as Determined by the Investigator |  | Up to approximately 26 months | 
| Part 3: Duration of Response (DOR) as Determined by the Investigator |  | Up to approximately 26 months | 
| Part 3: Progression Free Survival (PFS) as Determined by the Investigator |  | Up to approximately 26 months | 
| Part 3: Overall Survival (OS) |  | Up to approximately 26 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1, 2 and 3: Serum Concentration of RO7616789 |  | Up to approximately 26 months | 
| Part 1, 2 and 3: Maximum Serum Concentration (Cmax) of RO7616789 |  | Up to approximately 26 months | 
| Part 1, 2 and 3: Area Under the Concentration-Time Curve (AUC) of RO7616789 |  | Up to approximately 26 months | 
| Part 1, 2 and 3: Total Clearance of RO7616789 |  | Up to approximately 26 months | 
| Part 1, 2 and 3: Terminal Half-Life of RO7616789 |  | Up to approximately 26 months | 
| Part 1, 2 and 3: Volume of Distribution of RO7616789 |  | Up to approximately 26 months | 
| Part 1, 2 and 3: Time to Reach Steady State Concentration of RO7616789 |  | Up to approximately 26 months | 
| Part 1, 2 and 3: Accumulation Ratio of RO7616789 |  | Up to approximately 26 months | 
| Part 1 and 2: ORR as Determined by the Investigators |  | Up to approximately 26 months | 
| Part 1 and 2: Disease Control Rates as Determined by the Investigator |  | Up to approximately 26 months | 
| Part 1 and 2: DOR as Determined by the Investigators |  | Up to approximately 26 months | 
| Part 1 and 2: PFS as Determined by the Investigators |  | Up to approximately 26 months | 
| Part 1 and 2: OS as Determined by the Investigators |  | Up to approximately 26 months | 
| Part 1, 2 and 3: Percentage of Participants With Anti-Drug Antibody (ADA) to RO7616789 |  | Up to approximately 26 months |