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).

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)

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.