Study in Patients With Advanced Cancers Associated With Expression of DLL3

Study Overview
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Brief Summary
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A Phase 1/2 Open-label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and Pharmacokinetics of HPN328 Monotherapy and HPN328 With Atezolizumab in Patients With Advanced Cancers Associated With Expression of Delta-like Canonical Notch Ligand 3 (DLL3)

Official Title
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A Phase 1/2 Open-label, Multicenter, Dose Escalation and Dose Expansion Study of the Safety, Tolerability, and Pharmacokinetics of HPN328 Monotherapy and HPN328 With Atezolizumab in Patients With Advanced Cancers Associated With Expression of Delta-like Canonical Notch Ligand 3 (DLL3)

Conditions
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Small-cell Lung Cancer

Intervention / Treatment
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* Drug: HPN328
* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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Major Inclusion Criteria: Histologically or cytologically confirmed malignancy associated with expression of DLL3: SCLC which is relapsed/refractory following at least 1 prior line of systemic therapy that included platinum-based chemotherapy Neuroendocrine Prostate Cancer (NEPC; de novo or treatment-emergent) which is relapsed/refractory to standard systemic therapy High-grade neuroendocrine tumor types other than SCLC and NEPC has at least of the following: Disease that is relapsed/refractory to standard systemic therapy, Disease for which standard therapy does not exist, or Disease for which standard therapy is not considered appropriate by the Investigator Available archival tissue sample or fresh biopsy tissue sample For SCLC and NEPC: must be available for shipment prior to enrollment but confirmation of DLL3 expression is not required prior to enrollment. For high-grade neuroendocrine tumor types other than SCLC and NEPC: demonstration of DLL3 expression in a tumor sample is required and must be confirmed prior to screening. Adequate hematologic status, including: Absolute neutrophil count (ANC) ≥1500 cells/μL Platelet count ≥100,000/μL Hemoglobin ≥9 g/dL (no transfusions allowed within 2 weeks prior to screening) Adequate renal function, including: • Calculated creatinine clearance ≥50 mL/min using the formula of Cockcroft and Gault Adequate liver function, including Total bilirubin ≤1.5 x upper limit of normal (ULN), regardless of direct bilirubin, unless the patient has documented Gilbert syndrome in which case the maximum total serum bilirubin should be 5 mg/dL Aspartate and alanine transaminase (AST and ALT) ≤3 x ULN Major Exclusion Criteria: Untreated central nervous system (CNS) metastases. Patients with history of CNS metastases can participate provided they are pretreated and radiologically stable (i.e., without evidence of progression) for at least 2 weeks by repeated imaging (note: repeated imaging should be performed during study screening), asymptomatic, and without requirement of steroid treatment for at least 7 days before the first dose of study treatment. Patients with glioma or other primary CNS malignancy. Patients with spinal cord compression or symptomatic/uncontrolled epidural disease. Patients with previously treated spinal cord compression or epidural disease may be eligible if stable for at least 1 week prior to first dose of study drug. History of intracranial hemorrhage or spinal cord hemorrhage. Active neurologic paraneoplastic syndrome. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (e.g., biweekly or more frequently). Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, or multiple sclerosis. Exceptions apply. Ongoing treatment with immunosuppressive medications (including, but not limited to, systemic corticosteroids [prednisone dose >10mg per day or equivalent], cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] alpha agents) within 2 weeks prior to initiation of treatment, or anticipation of need for systemic immunosuppressive medication during study treatment (except protocol-required pre-medications). Exceptions apply. History of allogeneic stem cell transplant or solid-organ transplant. For patients enrolled in the HPN328/Atezolizumab combination cohorts: Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation, or other anti-PD-(L)1 agents. Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment. History of severe anaphylactic reactions to chimeric or humanized antibodies or fusion proteins. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT). History of radiation pneumonitis in the radiation field is permitted.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HPN328 monotherapy dose escalation<br>HPN328 will be administered as a single agent once weekly via IV infusion during each 21 day cycle. | Drug: HPN328<br>* HPN328 is a tri-specific recombinant protein construct (Tri-specific T Cell Activating Construct [TriTAC®]) containing 3 humanized antibody derived binding domains<br>|
| Experimental: HPN328 monotherapy dose escalation with extended dosing intervals<br>HPN328 will be administered as a single agent, via IV infusion either once every 2 weeks (28-day cycle), or once every 3 weeks (21-day cycle). | Drug: HPN328<br>* HPN328 is a tri-specific recombinant protein construct (Tri-specific T Cell Activating Construct [TriTAC®]) containing 3 humanized antibody derived binding domains<br>|
| Experimental: HPN328 dose escalation in combination with atezolizumab<br>SCLC patients will be treated with a combination regimen of HPN328 and atezolizumab. HPN328 will be administered once every 2 weeks via IV infusion during each 28-day cycle. Atezolizumab will be administered once every 4 weeks via IV infusion on Day 1 of each 28-day cycle. | Drug: HPN328<br>* HPN328 is a tri-specific recombinant protein construct (Tri-specific T Cell Activating Construct [TriTAC®]) containing 3 humanized antibody derived binding domains<br>Drug: Atezolizumab<br>* Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody which potently and selectively inhibits binding of programmed death receptor 1 ligand (PD-L1) on tumor cells and tumor infiltrating immune cells in the tumor microenvironment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of treatment-emergent AEs (TEAEs) graded according to NCI CTACAE version 5.0 (ASTCT grading criteria for CRS and ICANS). |  | Up to 4 years | 
| Number and severity of DLTs following treatment with HPN328 as monotherapy or in combination with atezolizumab. |  | Up to 4 years | 
| PK parameters of HPN328 as monotherapy or in combination with atezolizumab. | Single dose - maximum concentration, time to maximum concentration, area under the single dose concentration-time curve over the dosing interval, area under the concentration-time curve extrapolated to infinity, terminal elimination half-life, and clearance as data permit Multiple dose (assuming stead state is achieved) - maximum concentration at steady state, time to maximum concentration, area under the steady state concentration-time curve over dosing interval, terminal elimination half-life, minimum concentration, clearance, volume of distribution, and accumulation ratio as data permit. | Up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in selected clinical laboratory parameters, vital signs, and ECGs. |  | Up to 4 years | 
| Objective response rate (ORR) based on RECIST v1.1 (PCWG3 for patients with NEPC) |  | Up to 4 years | 
| Extra-cranial objective response rate (EC-ORR) based on modified RECIST v1.1 |  | Up to 4 years | 
| Best Overall Response (BOR) |  | Up to 4 years | 
| Progression-free survival (PFS) |  | Up to 4 years | 
| Extra-cranial progression free survival (EC-PFS) |  | Up to 4 years | 
| Overall survival (OS) |  | Up to 4 years | 
| Duration of response (DOR) |  | Up to 4 years | 
| Duration of extra-cranial response (EC-DOR) |  | Up to 4 years | 
| Incidence and titers of ADAs against HPN328 and atezolizumab (for combination-treatment patients) |  | Up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lung Cancer, Small-Cell Lung Cancer, DLL3, Harpoon, TriTAC, Prostate Cancer, Neuroendocrine Tumors, High Grade Neuroendrocrine Features, Delta Like Canonical Notch Ligand 3