PBI-MST-01 (NCT04541108) Substudy MSD-03: Intratumoral Microdosing of Pembrolizumab Alone and With MK-0482 or MK-4830 in HNSCC or STS

Pembrolizumab Alone and in Combination(s) With MK-0482 and MK-4830 Via Intratumoral Injection in Patients With Head and Neck Squamous Cell Carcinoma or Soft Tissue Sarcoma Prior to Planned Surgical Intervention

This is a multi-center, open-label, Phase 0 substudy designed to evaluate the ability of pembrolizumab, alone and in combination with MK-0482 or MK-4830, to elicit pharmacodynamic changes suggestive of antitumor immune activation within the native tumor microenvironment (TME) following intratumoral microdosing via the CIVO device in patients with surface accessible Head and Neck Squamous Cell Carcinoma (HNSCC) or Soft Tissue Sarcoma (STS) lesion(s) who are scheduled for tumor and/or regional node dissection as part of their standard treatment.

The CIVO Microdose Injection Device (MID) simultaneously delivers multiple drugs and drug combinations (up to 8), each in microdose amounts, into a single patient tumor and enables comparisons of the resulting biomarker responses that occurred while that tumor was still in the native microenvironment. The microdose injection procedure is conducted ahead of the patient's scheduled surgical intervention and localized biomarker responses are then evaluated in the injected tumor tissue following surgery. This enables assessments of drug-induced changes to the tumor, stroma, and local immune cells within the unique landscape of each individual patient and their respective tumor genomic profile and immune system functional status. CIVO is a research tool used only to assess the responses of tumor cells and other cell populations with the TME following intratumoral administration of drug microdoses; it is not a therapeutic device.

MK-0482, MK-4830, and pembrolizumab have distinct mechanisms of action (MOAs) that affect the TME, including relief of immune suppression and enhanced T-cell activation. Surgery is the standard primary treatment for most patients with STS, and surgical intervention of the primary tumor and cervical lymph node dissection may be recommended for patients with HNSCC. Dysfunction of the immune system (e.g., immune evasion, expression of suppressive immune checkpoint receptors, etc.) plays a major role in the development and progression of HNSCC and STS. Therefore, in this Phase 0 study, the ability of pembrolizumab, alone and in combination with MK-0482 or MK-4830, to elicit pharmacodynamic changes suggestive of antitumor immune activation within the native TME in patients with HNSCC or STS will be assessed. Pembrolizumab, alone and in combination with MK-0482 or MK-4830, will be injected in microdose quantities at tumor sites in HNSCC or STS patients with a surface accessible lesion who are scheduled for tumor and/or regional node dissection as part of their standard treatment. Injected tumors will be resected as per surgical standard of care following 2 to 4 days in situ exposure. Thereafter, the CIVO-injected portion of the tissue will be analyzed for localized response at sites of drug exposure in the TME.

Inclusion Criteria:

1. Ability and willingness to comply with the study's visit and assessment schedule.

2. Male or female ≥18 years of age at Visit 1 (Screening).

3. Pathologic diagnosis of HNSCC or STS.

4. Ability and willingness to provide written informed consent. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

5. At least one lesion (primary tumor, recurrent tumor, or metastatic lymph node) of at least approximately 2.5 cm in the shortest diameter that is surface accessible for CIVO injection that contains viable minimum tissue volume and characteristics (e.g., based on clinical evaluation, available pre-operative imaging, pre-injection ultrasound imaging, or pathology reports indication lesion with appropriate viable tumor volume, without excessive cysts or necrosis) and for which there is a planned surgical intervention.

6. Female patients who:

   • Are postmenopausal for at least one year before the screening visit, OR
   • Are surgically sterile, OR
   • Are of childbearing potential who agree to practice a highly effective method of contraception from the time of signing the Informed Consent Form (ICF) through up to 120 days after the tumor injection procedure OR agree to completely abstain from heterosexual intercourse.
   • Agree to refrain from donating ova during study participation.

   Male patients, even if surgically sterile (i.e., status post-vasectomy), who:

   • Agree to practice effective barrier contraception from the time of signing the ICF and during study participation OR agree to completely abstain from heterosexual intercourse.
   • Agree to refrain from donating sperm during study participation.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

Exclusion Criteria:

1. Patients who have received neoadjuvant therapy associated with the surgical intervention described in Inclusion Criterion #5 within 6 months of the CIVO injection procedure.

2. Tumors near or involving critical structures for which, in the opinion of the treating clinician, injection would pose undue risk to the patient.

3. Female patients who are:

   • Both lactating and breastfeeding, OR
   • Have a positive beta human chorionic gonadotropin (beta-hCG) pregnancy test at screening verified by the Investigator.

4. Any uncontrolled intercurrent illness, condition, serious medical or psychiatric illness, or circumstance that, in the opinion of the Investigator, could interfere with adherence to the study's procedures or requirements, or otherwise compromise the study's objectives.

5. Patients with a history of concurrent second cancers requiring active, ongoing systemic treatment. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

6. Patients with a diagnosis of immunodeficiency.

7. Patients with known HIV/AIDS with uncontrolled viral load and CD4 less than 200, or those with concurrent active hepatitis B (defined as HBsAg positive or detectable HBV DNA) or hepatitis C (defined as anti-HCV Ab positive and detectable HCV RNA) infection. Note: HIV infected participants with a history of Kaposi's sarcoma or Multicentric Castleman's Disease are excluded. Hepatitis B and C screening tests are not required unless:

   • Patient has a known history of hepatitis B/C infection
   • Mandated by local health authority

8. Patients that have received a live or live-attenuated vaccine within 4 weeks of the baseline/screening visit.

9. Use of any of the following ≤ 2 weeks prior to CIVO injection:

   1. Chronic systemic immunosuppressive therapy or corticosteroids (in dosing exceeding 10 mg daily of prednisone equivalent). Intranasal, inhaled, topical, or local corticosteroid injections (e.g., intra-articular injection), or steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication) are exceptions to this criterion.
   2. Biological response modifiers for treatment of active autoimmune disease.
   3. Hematopoietic growth factors.

10. Patients who have received prior treatment with radiation or systemic therapy (e.g., cytotoxic chemotherapy, targeted agents, or checkpoint inhibitor immunotherapy, etc.), or have participated in a study of an investigational device within 6 months of the CIVO injection procedure. Note: Participants must have recovered from all radiation-related toxicities, must not require corticosteroids, and must not have had radiation pneumonitis.

11. Patients who have a history of (noninfectious) pneumonitis that required steroids or have current pneumonitis.

12. Patients who have had allogenic tissue/solid organ transplant.

13. Patients who have had severe hypersensitivity (≥Grade 3) to pembrolizumab, MK-4830, MK-0482, or any of their excipients.

14. Patients with an active infection requiring systemic therapy.