Study in Patients With Advanced Cancers Associated With Expression of DLL3

• ClinicalTrials.gov Identifier: NCT04471727
• Recruitment Status: Recruiting
• First Posted: July 15, 2020
• Last Update Posted: December 12, 2023
• Sponsor: Harpoon Therapeutics
• Information provided by (Responsible Party): Harpoon Therapeutics

Tracking Information

• First Submitted Date: July 6, 2020
• First Posted Date: July 15, 2020
• Last Update Posted Date: December 12, 2023
• Actual Study Start Date: December 29, 2020
• Estimated Primary Completion Date: January 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 22, 2023)

• Frequency and severity of treatment-emergent AEs (TEAEs) graded according to NCI CTACAE version 5.0 (ASTCT grading criteria for CRS and ICANS). [ Time Frame: Up to 4 years ]
• Number and severity of DLTs following treatment with HPN328 as monotherapy or in combination with atezolizumab. [ Time Frame: Up to 4 years ]
• PK parameters of HPN328 as monotherapy or in combination with atezolizumab. [ Time Frame: Up to 4 years ]
  • 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.

Original Primary Outcome Measures (submitted: July 13, 2020)

• Assessment of Adverse Events by CTCAE 5.0 of HPN 328 [ Time Frame: 3 years ]
  Assess safety and tolerability at increasing dose levels of HPN328 in successive cohorts of patients with solid tumors associated with DLL3 expression by adverse events (CTCAE v5.0)
• Determine MTD/RP2D [ Time Frame: 2 years ]
  Estimate the maximum tolerated dose (MTD) or select the recommended Phase 2 dose (RP2D)
• Characterize the pharmacokinetics (PK) of HPN328 [ Time Frame: 2 years ]
  Evaluate of levels of HPN328 in blood serum

Current Secondary Outcome Measures (submitted: March 22, 2023)

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

Original Secondary Outcome Measures (submitted: July 13, 2020)

• Determine preliminary activity of HPN328 [ Time Frame: 3 years ]
  Evaluate preliminary efficacy of HPN328 based on disease assessment using RECISTv1.1
• Determine the immunogenicity [ Time Frame: 3 years ]
  Evaluate the immunogenicity of HPN328 assessing Anti-drug Antibodies in blood serum

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study in Patients With Advanced Cancers Associated With Expression of DLL3
• 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)
• Brief 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)
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: Single (Participant); Primary Purpose: Treatment
• Condition: 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
• Drug: 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

Study Arms

• Experimental: HPN328 monotherapy dose escalation
  HPN328 will be administered as a single agent once weekly via IV infusion during each 21 day cycle.
  Intervention: Drug: HPN328
• Experimental: HPN328 monotherapy dose escalation with extended dosing intervals
  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).
  Intervention: Drug: HPN328
• Experimental: HPN328 dose escalation in combination with atezolizumab
  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.
  Interventions:

  • Drug: HPN328
  • Drug: Atezolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 22, 2023): 162
• Original Estimated Enrollment (submitted: July 13, 2020): 52
• Estimated Study Completion Date: June 2024
• Estimated Primary Completion Date: January 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 screening.

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 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.
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.
    • 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 100 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Harpoon ClinicalTrials.gov Contact; (650) 452-7280; hpn328_4001ctgov@harpoontx.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04471727
• Other Study ID Numbers: HPN328-4001
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Harpoon Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Harpoon Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Harpoon Therapeutics
• Verification Date: December 2023