A Phase 1 Study of HMBD-002-V4C26 (HMBD-002), a Monoclonal Antibody Targeting VISTA, as Monotherapy and Combined With Pembrolizumab, in Patients With Advanced Solid Malignancies

This is a phase 1/2, open-label, multi-center study whose principal phase 1 stage objective is to determine the recommended phase 2 dose (RP2D) of the anti-VISTA monoclonal antibody (mAb) as a single agent and combined with the anti-PD-1 mAb pembrolizumab in subjects with advanced solid malignancies.

In the phase 2 stage, the antitumor activity of HMBD-002 alone or combined with pembrolizumab will be evaluated in patients with triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC) and a wide range of other malignancies known or documented to express VISTA.

Inclusion Criteria (Phase 1 and 2 Stages)

1. Histologic or cytologic evidence of a malignant solid cancer (any histology) with advanced or metastatic disease and no available therapies known to confer clinical benefit.
2. Tumor tissue, or paraffin block, ideally from the patient's most recent biopsy. A fresh tumor biopsy will be obtained if archival samples are not available.
3. Measurable by Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
4. At least 18 years old.
5. An Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
6. Adequate hematopoietic, kidney, and liver functions.
7. A left ventricular ejection fraction (LVEF) ≥ 45%.
8. Women of childbearing potential (WOCBP) must not be pregnant or breastfeeding. A WOCBP must agree to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
9. Male subjects must agree to follow contraceptive guidance during the study period and for at least 120 days after the last dose of study treatment.
10. Patient must give informed written consent for the study.

Inclusion Criteria for HMBD-002 Phase 2 Stage

Triple Negative Breast Cancer (TNBC)

1. Histologic or cytologic evidence of TNBC that is advanced or metastatic.
2. Will be requested to undergo a tumor biopsy before treatment and after 6 weeks of treatment.
3. Must have received appropriate treatment with at least one prior regimen for TNBC and there are no available therapies known to confer clinical benefit.

Non-Small Cell Lung Cancer (Monotherapy and Combination)

1. Histologic or cytologic evidence of NSCLC that is advanced or metastatic.
2. Will be requested to undergo a tumor biopsy before treatment and after 6 weeks of treatment.
3. Absence of an activating mutation of the EGFR or ALK.
4. Must have received treatment with an approved therapy if there are other genomic aberrations for which targeted therapies are approved and available.
5. Must have had disease progression on at least one approved or comparable standard therapy for NSCLC.
6. Must have received appropriate prior treatment with a mAb to PD-1 or PD-L1.

Multiple Other Cancers (Combination Therapy Baskets)

1. Histologic or cytologic evidence of an advanced or metastatic cancer aside from TNBC and NSCLC with no available therapies known to confer clinical benefit.
2. Will be requested to undergo a tumor biopsy before treatment and after 6 weeks of treatment.
3. Must have had appropriate treatment for their specific cancer and there is an absence of available therapy with a reasonable likelihood of conferring clinical benefit.

Exclusion Criteria

1. If the patient received prior therapy with an anti-PD-1 or anti-PD-L1 mAb or with an agent targeting stimulatory or co-inhibitory T-cell receptor and was discontinued from that treatment due to a Grade 3 or higher immune related adverse event.
2. Received radiotherapy within 2 weeks of treatment.
3. Received radiotherapy exceeding 30 Gray (Gy) to the lung within 6 months of the first dose of study medication.
4. Received an allogeneic tissue/solid organ transplant.
5. Received a live or live-attenuated vaccine within 30 days prior to the first dose of study medication.
6. Received a VISTA targeting agent.
7. The patient must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline.
8. The patient has an active autoimmune disease that required systemic treatment in the past.
9. Presence of an uncontrolled endocrine disorder.
10. Presence of clinically significant cardiovascular disease.
11. History of (non-infectious) pneumonitis or interstitial pulmonary disease that required steroids or has current pneumonitis or interstitial pulmonary disease.
12. Presence of uncontrolled, clinically significant pulmonary disease.
13. A previous a severe hypersensitivity reaction (≥ Grade 3) to pembrolizumab and/or any of its excipients.
14. A diagnosis of immunodeficiency or is receiving chronic systemic corticosteroids at a dose that exceeds 10 mg daily of prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.
15. An uncontrolled intercurrent illness that would limit compliance with the study.
16. A positive status for human immunodeficiency virus (HIV).
17. A known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C viral (defined as HCV RNA detected) infection.
18. Oxygen-dependence.
19. A medical condition which, in the opinion of the Investigator, places the patient at an unacceptably high risk for toxicity.
20. A positive COVID test within one week of study treatment if not fully vaccinated.
21. Another active malignancy that is progressing or has required active treatment within the past 3 years.
22. Known active central nervous system metastases and/or carcinomatous meningitis.