A Study of AZD2936 Anti-TIGIT/Anti-PD-1 Bispecific Antibody in Participants With Advanced or Metastatic NSCLC

Study Overview
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Brief Summary
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This is a Phase I/II study designed to evaluate if experimental anti-TIGIT/anti-PD-1 bispecific antibody rilvegostomig (AZD2936) is safe, tolerable and efficacious in participants with Advanced or Metastatic Non-small Cell Lung Cancer.

Detailed Description
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This is a first-time-in-human (FTIH), open-label, multicenter, multi-part, dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of rilvegostomig (AZD2936) in adult participants with stage III unresectable or stage IV NSCLC. The study includes 4 parts: Part A (dose escalation) and Parts B-D (dose expansion).

Official Title
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Phase I/II, Open-label, Dose Escalation and Dose Expansion Study to Evaluate Safety, Pharmacokinetics, Pharmacodynamics and Efficacy of AZD2936 Anti-TIGIT/Anti-PD-1 Bispecific Antibody in Participants With Advanced or Metastatic NSCLC

Conditions
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Non-Small-Cell Lung Carcinoma

Intervention / Treatment
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* Drug: AZD2936


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Aged 18 or above Part A and Part B: Unresectable stage III or stage IV squamous or non-squamous NSCLC not amenable to curative surgery or radiation. Part C and Part D: Stage IV squamous or non-squamous NSCLC not amenable to curative surgery or radiation. Documented PD-L1 expression by PD-L1 IHC per local report. Part A and Part B: Confirmed progression during treatment with a CPI-including regimen. Part C and Part D: No prior I/O treatment for metastatic NSCLC. ECOG performance status of 0 or 1 at enrolment. Life expectancy of ≥ 12 weeks at enrolment. Have at least 1 measurable lesion per RECIST v1.1. Adequate bone marrow, liver and kidney function Exclusion Criteria: Sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusion Documented test result for any other known genomic alteration for which a targeted therapy is approved in first line per local standard of care (e.g. ROS1, NTRK fusions, BRAF, V600E mutation) Previous treatment with an anti-TIGIT therapy Any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal therapy for cancer treatment. Part A and Part B: Primary or secondary resistance after treatment with 2 or more regiments including a CPI. Part C and Part D: Any prior systemic treatment with an immune oncology agent (prior administration of immune-oncology agent for curative intent to treat other invasive malignancy is permitted). Treatment with one previous systemic chemotherapy will be allowed. Primary or secondary resistance after treatment with 2 or more regimens including a CPI. Symptomatic central nervous system (CNS) metastasis. Thromboembolic event within 3 months prior to enrolment. Other invasive malignancy within 2 years prior to screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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: The study includes 4 parts: Part A: Dose escalation; B & C: Dose expansion non-randomized; D: Randomized RP2D & alternative dose.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Part A: Checkpoint inhibitor (CPI) experienced Non-small Cell Lung Cancer (NSCLC)<br>Rilvegostomig Intravenous (IV) monotherapy | Drug: AZD2936<br>* Anti-TIGIT/Anti-PD-1 Bispecific Antibody<br>* Other names: Rilvegostomig;|
| Experimental: Dose Expansion Part B: CPI experienced NSCLC<br>Rilvegostomig IV monotherapy | Drug: AZD2936<br>* Anti-TIGIT/Anti-PD-1 Bispecific Antibody<br>* Other names: Rilvegostomig;|
| Experimental: Dose Expansion Part C: CPI Naive NSCLC<br>Rilvegostomig IV monotherapy | Drug: AZD2936<br>* Anti-TIGIT/Anti-PD-1 Bispecific Antibody<br>* Other names: Rilvegostomig;|
| Experimental: Dose Expansion Part D: CPI Naive NSCLC<br>Rilvegostomig IV monotherapy | Drug: AZD2936<br>* Anti-TIGIT/Anti-PD-1 Bispecific Antibody<br>* Other names: Rilvegostomig;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with adverse events (AEs) and immune mediated AEs (imAEs), serious AEs (SAEs), dose limiting toxicities (DLTs), vital signs, and abnormal laboratory parameters | A DLT is a toxicity defined by the study protocol that occurs from the first dose of study intervention up to the end of the DLT evaluation period that is assessed as clearly unrelated to the primary disease or intercurrent illness. | Part A, B, C and D: From the time of informed consent until 90 days after the last dose of rilvegostomig | 
| Rate of rilvegostomig discontinuation due to toxicity | Percentage of participants with AEs leading to discontinuation of rilvegostomig | Part A, B, C and D: From first dose to the last dose of rilvegostomig (an average of 6 months) | 
| Objective Response Rate (ORR) | Percentage of participants with a confirmed Complete Response (CR) or Partial Response (PR) according to RECIST v1.1 | Part B, C and D: From first dose of rilvegostomig to progressive disease (PD) or death in the absence of disease progression (approximately 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ORR | Percentage of participants with a confirmed CR or PR according to RECIST v1.1 | Part A: From first dose of rilvegostomig to PD or death in the absence of disease progression (approximately 2 years). | 
| Disease control rate (DCR) | Percentage of participants who have a best objective response of confirmed CR or PR or who have SD lasting for at least a certain time of period after start of treatment | Part A, B, C: From first dose of rilvegostomig to PD or death in the absence of disease progression (approximately 2 years). Part D: From randomization to PD or death in the absence of disease progression (approximately 2 years). | 
| Duration of response (DoR) | The time from first response according to RECIST v1.1 until progression or death in the absence of disease progression | Part A, B, C and D: From first dose of rilvegostomig to PD or death in the absence of disease progression (approximately 2 years). | 
| Durable response rate (DRR) | The percentage of participants according to RECIST v1.1 with a confirmed CR or PR lasting 6 months or more | Part A, B, C and D: From first dose of rilvegostomig to PD or death in the absence of disease progression (approximately 2 years). | 
| Progression-free survival (PFS) | The time from first dose of study intervention until the date of objective disease progression or death in the absence of disease progression | Part B, C: From first dose of rilvegostomig to PD or death in the absence of disease progression (approximately 2 years). Part D: From randomization to PD or death in the absence of disease progression (approximately 2 years). | 
| Measure the receptor occupancy (RO) of TIGIT and PD-1 on peripheral blood | Evaluation of the target engagement of rilvegostomig in peripheral blood | Part A, B: From first dose of study intervention, at predefined intervals throughout the administration of rilvegostomig (approximately 2 years). The predefined intervals for Part A will be different from Part B. | 
| PK of rilvegostomig: Maximum plasma concentration of the study drug (Cmax) | Maximum observed plasma concentration of rilvegostomig | From first dose of study intervention, at predefined intervals throughout the administration of rilvegostomig (approximately 2 years). The predefined intervals for Part A will be different from Part B, C and D. | 
| PK of rilvegostomig: Area under the concentration-time curve (AUC) | Area under the plasma concentration-time curve | From first dose of study intervention, at predefined intervals throughout the administration of rilvegostomig (approximately 2 years). The predefined intervals for Part A will be different from Part B, C and D. | 
| PK of rilvegostomig: Clearance | A pharmacokinetic measurement of the volume of plasma from which the study intervention is completely removed per unit time. | From first dose of study intervention, at predefined intervals throughout the administration of rilvegostomig (approximately 2 years). The predefined intervals for Part A will be different from Part B, C and D. | 
| PK of rilvegostomig: Terminal elimination half-life (t 1/2) | Terminal elimination half life | From first dose of study intervention, at predefined intervals throughout the administration of rilvegostomig (approximately 2 years). The predefined intervals for Part A will be different from Part B, C and D. | 
| Incidence of anti-drug antibodies (ADA) against rilvegostomig in serum | Immunogenicity of rilvegostomig | From first dose of study intervention, at predefined intervals throughout the administration of rilvegostomig (approximately 2 years). The predefined intervals for Part A will be different from Part B, C and D. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TIGIT, Anti-TIGIT, PD-1, Anti-PD-1, NSCLC, Non-small Cell Lung Cancer, Advanced, Metastatic, Solid Tumor, Solid Tumour, Stage 3 NSCLC, Stage III NSCLC, Stage 4 NSCLC, Stage IV NSCLC, PD L1+ tumors