Study in Patients With Advanced Cancers Associated With Expression of DLL3

Small-Cell Lung Cancer Clinical Trial

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04471727
• Other study ID #: HPN328-4001
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 29, 2020
• Est. completion date: December 2025

Study information

• Verified date: May 2024
• Source: Harpoon Therapeutics
• Contact: Harpoon ClinicalTrials.gov Contact
• Phone: (650) 452-7280
• Email: hpn328_4001ctgov[@]harpoontx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 162
• Est. completion date: December 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

Major Inclusion Criteria:

1. 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

2. Available archival tissue sample or fresh biopsy tissue sample

1. For SCLC and NEPC: must be available for shipment prior to enrollment but confirmation of DLL3 expression is not required prior to enrollment.

2. 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 treatment.

3. 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)

4. Adequate renal function, including:

• Calculated creatinine clearance =50 mL/min using the formula of Cockcroft and Gault

5. 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:

1. Untreated 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.

2. Patients with glioma or other primary CNS malignancy.

3. 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.

4. History of intracranial hemorrhage or spinal cord hemorrhage.

5. Active neurologic paraneoplastic syndrome.

6. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (e.g., biweekly or more frequently).

7. 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.

8. 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.

9. History of allogeneic stem cell transplant or solid-organ transplant.

10. 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.

11. History of interstitial lung disease, 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.

12. Treatment with other investigational drug within 3 weeks of scheduled dosing (or 5 half-lives of drug, whichever is shorter).

Related Conditions & MeSH terms

• Carcinoma, Neuroendocrine
• Lung Neoplasms
• Neuroendocrine Carcinoma
• Small Cell Lung Carcinoma
• Small-Cell Lung Cancer

Intervention

Drug:
• HPN328
HPN328 is a tri-specific recombinant protein construct (Tri-specific T Cell Activating Construct [TriTAC®]) containing 3 humanized antibody derived binding domains
• Atezolizumab
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

Locations

Country	Name	City	State
United States	University of Colorado	Aurora	Colorado
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Comprehensive Cancer Center	Buffalo	New York
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Karmanos Cancer Center	Detroit	Michigan
United States	Cedar-Sinai Medical Center, Samuel Oschin Comprehensive Cancer Institute	Los Angeles	California
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Tennessee Oncology	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Providence	Portland	Oregon
United States	University of California San Francisco	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Harpoon Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

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