Brief Title: Selective TrkA Inhibitor VMD-928 to Treat TrkA Overexpression Driven Solid Tumors or Lymphoma

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Number and severity of treatment-emergent Adverse Events (Phase 1)

Primary Outcome 1 - Timeframe: First cycle (21 days per cycle)

Primary Outcome 2 - Measure: To determine the recommended Phase 2 dose for VMD-928 (Phase 1)

Primary Outcome 2 - Timeframe: First cycle (21 days per cycle)

Primary Outcome 3 - Measure: To determine the RP2D of VMD-928 in combination with pembrolizumab (Phase 1)

Primary Outcome 3 - Timeframe: First cycle (21 days per cycle)

Primary Outcome 4 - Measure: Antitumor activity of VMD-928 in subjects with TrkA-driven tumors (Phase 2)

Primary Outcome 4 - Timeframe: Up to 18 months

Primary Outcome 5 - Measure: Antitumor activity of VMD-928 in combination with pembrolizumab in subjects with TrkA-driven tumors (Phase 2)

Primary Outcome 5 - Timeframe: Up to 18 months

CONDITION

• Head and Neck Carcinoma
• Adenoid Cystic Carcinoma
• Lung Cancer
• Non-Small Cell Lung Cancer
• Pancreatic Cancer
• Mesothelioma
• Esophageal Cancer
• Any Solid Tumors Progressed After a Prior Immunotherapy
• Head and Neck Squamous Cell Carcinoma
• Head and Neck Squamous Cell Carcinoma HNSCC
• Salivary Gland Carcinomas
• Head and Neck Cancers - Salivary Gland
• Head and Neck Cancers - Nasopharyngeal
• Head and Neck Cancers - Throat
• Small Cell Lung Cancer ( SCLC )
• Lung Cancer (Locally Advanced or Metastatic)
• Head and Neck Cancers - Tonsils
• Head and Neck Cancers Hypopharynx
• Head and Neck Cancers Larynx
• Head and Neck Cancers Lip
• Head and Neck Cancers Nasopharynx
• Head and Neck Cancers Oral Cavity
• Head and Neck Cancers
• Head and Neck Cancers Oropharynx
• Head and Neck Cancers Trachea

ELIGIBILITY

Key Inclusion Criteria:
#. Histologically or cytologically confirmed diagnosis of any type of solid tumor malignancy or lymphoma:
Phase 1 Dose Escalation only: Subjects with
(A) any advanced solid tumors of
1. Head and Neck Cancers ("HNC") (of any types),

- 2. Esophageal cancer,

- 3. Lung cancers (of any types),

- 4. Mesothelioma,

- 5. Pancreatic cancers,
Or,
(B) any NTRK1 gene fusion positive ("NTRK1+") solid tumors or lymphomas, that is relapsed, refractory or intolerant (R/R/I) to standard of care (SOC) and for which there is no approved or curative therapy. Additionally, patients must not be candidates for or have exhausted regimens known to provide clinical benefit, including hematopoietic stem cell transplantation in lymphoma patients if they are deemed transplant eligible.
Phase 2 Monotherapy and Combination with Pembrolizumab only:
Subjects must have
1. TrkA-driven HNC, Esophageal, Lung, Mesothelioma, Pancreatic cancers; or,

- 2. any NTRK1+ solid tumors or lymphoma*, that is R/R/I to SOC.
Key Inclusion Criteria:
* Eastern Cooperative Oncology Group (ECOG) Performance Status: 0 or 1.

- * Able to swallow and retain oral medication.

- * Subjects must either have available archival tumor tissue samples, or consent to tumor tissue sampling prior to the first dose.

- * Adequate organ system function as defined as follows:
1. Absolute neutrophil count ≥1.5x10^9/L

- 2. Hemoglobin ≥9g/dL

- 3. Platelets ≥100x10^9/L

- 4. PT/INR, PTT ≤1.5xULN

- 5. Total bilirubin ≤1.5x ULN

- 6. AST, ALT ≤2.5xULN

- 7. Creatinine ≤1.2xULN for age, weight

- 8. Calculated creatinine clearance or 24h urine creatinine clearance ≥60mL/min
Key Exclusion Criteria:
* Received chemotherapy having delayed toxicity within the last 14 days (six weeks for prior nitrosourea or mitomycin C).

- * Received anticancer therapy with radiation, immunotherapy, and a biologic, surgery and/or tumor embolization within the past 2 weeks.

- * Received an investigational anticancer drug within 14 days or 5 half-lives of the investigational agent, whichever is longer, prior to the first dose of VMD-928. Any exceptions to the above must be approved by the Sponsor Medical Monitor.

- * Unresolved toxicity from previous anticancer therapy > CTCAE Grade 1 (except alopecia or anemia) unless agreed to by both the Sponsor Medical Monitor and the Investigator.

- * Known active infections including HIV disease.

- * Currently pregnant, nursing, or planning to become pregnant during the course of the study.

- * QTcF interval ≥ 480 msec.

- * Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.

- * Acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks.

- * Unstable or uncompensated respiratory, hepatic, renal, or cardiac disease that would compromise the patient's safety or interfere with assessment of the drug.

- * Psychological, familial, sociological, geographical, or other concurrent conditions that would interfere with safety evaluation, limit the patient's ability to follow the procedures in the protocol or otherwise jeopardize compliance with the protocol. Patients with uncontrolled major depression, bipolar disorder, or severe anxiety disorder are excluded.

- * Patient has had or is currently having other malignant tumors within 3 years.

- * Patients have multiple factors that affect their oral medication.

- * Patients have long-term unhealed wounds or fractures.

- * Patients have uncontrolled pleural effusion, pericardial effusion, or ascites that still require repeated drainage.

- * Patients are taking the following drugs and can't stop them during the study:
* Tylenol or medicine containing acetaminophen (paracetamol).

- * Antacids (e.g. TUMS, calcium carbonate, or magnesium hydroxide), proton pump inhibitors (e.g. omeprazole), H2 blockers (e.g. famotidine), or buffered vitamins.

- * Epstein-Barr virus (EBV) negative nasopharyngeal carcinoma.
For Phase 2 only:
* Negative result on TrkA immunohistochemistry (IHC) assay.

- * Have visceral crisis, defined as severe organ dysfunction and rapid progression of the cancer. (It is not about presence of visceral metastasis.)
For combination therapy with Pembrolizumab only:
* Serious adverse immune related adverse events (grade 3 or 4) with previous PD-1(L1) inhibitor therapy, that were symptomatic and required prolong immunosuppression (>6 weeks).

- * Any grade Pneumonitis and Myocarditis related to prior PD-1(L1) inhibitor therapy.

- * For subjects that received PD-1(L1) inhibitors before, there should be a washout period of at least 21 days between the last day of PD-1(L1) inhibitor and first day of study medications.

- * Subjects who relapsed after prior treatment with PD-1(L1) inhibitors. Relapsed is defined as patients having best overall response of CR or PR after treatment with a PD-1(L1) inhibitor.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Clinical Development

Role: Study Chair

Affiliation: VM Oncology

Overall Contact

Name: Jay Wu, PhD

Phone: 1-510-270-2790

Email: [email protected]

LOCATION