Study of INCA32459 a LAG-3 and PD-1 Bispecific Antibody in Participants With Select Advanced Malignancies

Study Overview
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Brief Summary
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This is a multicenter, open-label, single-arm study to investigate the safety, tolerability, PK, pharmacodynamics and preliminary activity of INCA32459 in participants with selected advanced malignancies. Part 1 (dose escalation) will determine the recommended dose of INCA 32459 for expansion (RDE) and the maximum tolerated dose (MTD). Part 2 (dose expansion) will further evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary antitumor activity of INCA 32459 at the recommended dose(s) for expansion in 2 tumor-specific cohorts.

Official Title
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A Phase 1, Open-Label, Multicenter Study of INCA32459 in Participants With Select Advanced Malignancies

Conditions
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Advanced Malignancies

Intervention / Treatment
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* Drug: INCA32459-101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced malignancies as follows: Part 1 only: Participants with the select advanced malignancies as specified in the protocol. Part 2 only: Cohort 1 only: Participants with Stage III (unresectable) or Stage IV (metastatic) melanoma that is considered nonamenable to curative treatments or procedures. Cohort 2 only: Participants with histologically or cytologically confirmed recurrent/metastatic SCCHN that is PD-L1 positive (CPS ≥ 1) which is not amenable to local therapy with curative intent. Participants must have experienced disease progression after treatment with standard therapies, or are intolerant to or ineligible for standard treatment: Part 1: All available standard therapies, including anti-PD-(L)1 and platinum-based therapy, if applicable, that are known to confer clinical benefit. Prior anti-PD-(L)1 therapy should not have been discontinued because of intolerance. Part 2: Available standard therapies, including anti-PD-(L)1 and platinum-based therapy, if applicable, that are known to confer clinical benefit. Prior anti-PD-(L)1 therapy should not have been discontinued because of intolerance. Part 2 participants may have received up to 2 prior systemic therapies in the a advanced/metastatic setting. ECOG performance status of 0 or 1 Part 2 only: Measurable disease according to RECIST v1.1. Part 2 only: Willingness to undergo a fresh tumor biopsy at screening (core or excisional). Part 2 only: Willingness to undergo a fresh tumor biopsy at screening and on-treatment in selected participant. Willingness to avoid pregnancy or fathering children Exclusion Criteria: Prior treatment with any LAG-3- or MHC Class II-directed therapy for current malignancy, or any prior malignancy. Treatment with anticancer therapies or participation in another interventional clinical study within 28 days before the first administration of study treatment (this includes curative radiation to the thorax or systemic anticancer therapies). Not recovered to ≤ Grade 1 or baseline from residual toxicities of prior therapy (with exceptions specified in the protocol). Not recovered adequately from toxicities and/or complications from surgical intervention before starting study treatment. Palliative radiation therapy administered within 1 week of first dose of study treatment or radiation therapy in the thoracic region that is > 30 Gy within 6 months of the first dose of study treatment. Any known additional malignancy that is progressing or requires active treatment; history of other malignancy within 3 years of the first dose of study treatment (with exceptions specified in the protocol). Evidence of interstitial lung disease or history of interstitial lung disease, or active, noninfectious pneumonitis. Active autoimmune disease requiring systemic immunosuppression with corticosteroids (> 10 mg/day of prednisone or equivalent) or immunosuppressive drugs within 2 years before the first dose of study treatment. Untreated brain or CNS metastases or brain or CNS metastases that have progressed (eg, evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). Chronic treatment with systemic steroids (> 10 mg/day of prednisone or equivalent).

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: Part 1 will be dose escalation using a statistical hybrid design to identify the RDE(s). Part 2 will be dose expansion portion which will administer the RDE(s) defined in Part 1 to participants in 2 tumor-specific cohorts.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Escalation<br>INCA32459 will be administered at a protocol defined starting regimen intravenously. Subsequent dose regimens will be determined during study conduct. | Drug: INCA32459-101<br>* solution for infusion<br>|
| Experimental: Part 2: Dose Expansion Cohort Disease Group 1<br>INCA32459 will be administered at the recommended dose or doses for expansion (RDE[s]) for unresectable or metastatic melanoma. | Drug: INCA32459-101<br>* solution for infusion<br>|
| Experimental: Part 2: Dose Expansion Cohort Disease Group 2<br>INCA32459 will be administered at the recommended dose or doses for expansion (RDE[s]) for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) that is PD-L1 positive. | Drug: INCA32459-101<br>* solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Occurrence of Dose Limiting Toxicities (DLTs) | Toxicities occurring during Part 1 will define tolerability. DLTs will be assessed for severity by the investigator using CTCAE v5.0 criteria. | Up to approximately 12 months | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE is any Adverse Event (AE) either reported for the first time or worsening of a pre-existing event after first dose of study drug. | Up to approximately 12 months | 
| Number of Participants with Dose Interruptions due to TEAE | Dose interruptions will occur according to protocol guidelines. | Up to approximately 12 months | 
| Number of Participants discontinue study due to TEAE | TEAE is defined as any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. | Up to approximately 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Defined as having Complete Response (CR) or Partial Response (PR), as determined by the investigator by radiographic disease assessment according to RECIST v1.1 or Lugano criteria (B-cell lymphomas only). | Up to 12 months | 
| Disease Control Response (DCR) | Defined as having CR, PR, or Stable Disease (SD) as determined by the investigator by radiographic disease assessment according to RECIST v1.1. or Lugano criteria (B-cell lymphomas only). | Up to 12 months | 
| Duration of Response (DOR) | Defined as the time from earliest date of disease response (Completed Response or Partial Response) until earliest date of disease progression as determined by the investigator by radiographic disease assessment according to RECIST v1.1 or Lugano criteria (B-cell lymphomas only) or death due to any cause if occurring sooner than progression. | Up to 12 months | 
| PK parameters: Cmax | Defined as the maximum (peak) plasma drug concentration | Up to 24 months | 
| PK parameters: tmax | Defined as the time to reach maximum (peak) plasma concentration following drug administration | Up to 24 months | 
| PK parameters: Cmin | Defined as concentration at the end of the dosing interval | Up to 24 months | 
| PK Parameters: AUC | Defined as the area under the plasma concentration-time curve | Up to 24 months | 
| PK Parameters: CL | Defined as the apparent total body clearance of the drug from plasma | Up to 24 months | 
| PK Parameters: Vz | Defined as apparent volume of distribution during terminal phase | Up to 24 months | 
| PK Parameters: t1/2 | Defined as Elimination half-life (to be used in one-or noncompartmental model) | Up to 24 months | 
| Receptor Occupancy | Defined as PD-1 receptor occupancy in peripheral blood samples. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LAG-3, bispecific antibody, melanoma, squamous cell carcinoma of the head and neck (SCCHN)