XTX301 in Patients With Advanced Solid Tumors

This is a first-in-human, multicenter, Phase 1/2, open-label study designed to evaluate the safety, tolerability, PK, PD, immunogenicity, and antitumor activity/efficacy of XTX301, a tumor-activated interleukin-12, as monotherapy in patients with advanced solid tumors.

Phase 1. Part 1A will examine XTX301 monotherapy in a standard 3+3 dose escalation design. Based on the results of Part 1A, patients with select advanced solid tumors will be enrolled in Part 1B, which will evaluate XTX301 monotherapy in relation to specific PD biomarkers.

Phase 2 will further evaluate the safety and antitumor activity/efficacy of XTX301 monotherapy in disease-specific expansion cohorts of patients with select tumors, namely: head and neck squamous cell carcinoma (HNSCC), melanoma (patients with uveal melanoma are excluded), non-small cell lung cancer (NSCLC), ovarian cancer, castrate-resistant prostate cancer (CRPC)/androgen pathway modulation-resistant prostate cancer (APMR-PC), triple-negative breast cancer (TNBC)

Inclusion criteria

• Disease Criteria: Part 1A - Any histologically or cytologically confirmed solid tumor malignancy that is locally advanced or metastatic and has failed standard therapy, standard therapy does not confer survival benefit, or standard therapy is not available.

Part 1B- Any histologically or cytologically confirmed solid tumor malignancy among the tumor types outlined below, that is locally advanced or metastatic and has failed standard therapy, standard therapy does not confer survival benefit, or standard therapy is not available. Patients with the following tumor types are eligible for Part 1B: melanoma, NSCLC, HNSCC, TNBC, cervical cancer, microsatellite instability high/mismatch repair deficient (MSI-H/dMMR) colorectal cancer, or MSI-H/dMMR endometrial cancer. Note: Based on evolving internal and external data, the Sponsor may decide to open a "backfill cohort" in Part 1B for patients with any of the following solid tumors: prostate cancer, ovarian cancer, pancreatic cancer, microsatellite stable colorectal cancer, T-cell lymphoma.

Phase 2 - All patients must have measurable disease at baseline per RECIST 1.1, except patients with CPRC/APMR-PC. Additional disease-specific criteria per cohort are as follows:

i. Cohort 2A: head and neck squamous cell carcinoma (HNSCC). Must have histologically or cytologically confirmed locally recurrent or metastatic HNSCC previously treated with 1 to 2 lines of therapy (therapy given in the curative setting or radiotherapy alone would not be counted as a line of therapy). Unless contraindicated, prior therapy must have included PD-1/PD-L1 inhibitor and/or platinum-based chemotherapy per local and institutional standard of care. Patients who received prior PD-1/PD-L1 inhibitor must have derived clinical benefit, i.e. either achieved a partial response (PR) or CR or have remained stable on PD-1/PD-L1 therapy (alone or in combination) without progression for at least 6 months. Patients must have a known human papillomavirus (HPV) status (either HPV-positive or HPV-negative). Patients with known or suspected invasion or encasement of major vessel or with active or imminent airway obstruction are excluded.

ii. Cohort 2B: melanoma. Must have unresectable or metastatic melanoma previously treated with 1 to 2 lines of therapy in the recurrent or metastatic setting. Unless contraindicated, prior therapy must have included a PD-1/PD-L1 inhibitor alone or in combination. Patients with known BRAF V600-activating mutation must have previously received targeted therapy per local and institutional standard of care. Note: patients with uveal melanoma are excluded.

iii. Cohort 2C: non-small cell lung cancer (NSCLC). Must have histologically confirmed locally advanced or metastatic NSCLC previously treated with 1 to 2 lines of therapy. Unless contraindicated, prior therapy must have included a PD1/PD-L1 inhibitor and a platinum-based regimen, given either concurrently or separately per local and institutional standard of care. Patients with known genomic alteration for which a targeted therapy is approved (e.g. ROS1 fusion, NTRK fusion, BRAF V600E mutation, EGFR mutation, or ALK fusion) must have been previously treated with relevant targeted therapy per local and institutional standard of care.

iv. Cohort 2D: ovarian cancer. Must have histologically confirmed epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer with current platinum-resistant disease per investigator's assessment (e.g. patient is not eligible for further platinum-containing treatment). Patients must have previously experienced a response lasting at least 180 days to first-line platinum-based therapy. Patients who have been unable to tolerate platinum therapy are also eligible. Unless contraindicated, patients with known BRCA mutation must have received a poly(ADP-ribose) polymerase (PARP) inhibitor.

v. Cohort 2E: castrate-resistant prostate cancer (CRPC)/androgen pathway modulation-resistant prostate cancer (APMR-PC). Histopathologically or cytopathologically confirmed adenocarcinoma without neuroendocrine differentiation or small cell features. Must have metastatic disease either on bone scan and/or in soft tissue by CT or MRI. Patients without measurable extra-skeletal lesions must have prostate-specific antigen (PSA) levels ≥ 2 ng/mL at screening. Must have been previously treated with an androgen receptor pathway inhibitor (e.g. abiraterone, enzalutamide, darolutamide, or apalutamide) and/or chemotherapy per local and institutional standard of care. Baseline total testosterone must be ≤ 50 ng/dL (≤ 2.0 nM), and surgical or ongoing medical castration must be maintained throughout the duration of the study. Patients receiving anti-resorptive agent (e.g. bisphosphonate, denosumab) therapy must have been on stable regimen prior to study entry.

vi. Cohort 2F: triple-negative breast cancer (TNBC). Must have metastatic TNBC with disease relapse after 2 to 4 previous lines of therapy per local and institutional standard of care. Neoadjuvant and/or adjuvant chemotherapy will count as 1 prior line of therapy only if recurrence during or within 6 months of completing adjuvant systemic therapy. Unless contraindicated, patients with known actionable mutations (e.g. BRCA1 or BRCA2) must have received prior therapy with the corresponding targeted agent per local and institutional standard of care

• ECOG performance status of 0-2 for Phase 1
• ECOG performance status of 0 or 1 for Phase 2
• Adequate organ function
• Tumor tissue samples: Part 1B: patients must have lesions amenable to biopsy and be willing and able to provide fresh tumor biopsies before and after initiation of treatment
• Patients with recent major surgery must have adequately recovered with no ongoing complications from the surgery before receiving study drug

Exclusion criteria

• Prior treatment with IL-12 therapy (any form, e.g. recombinant human, prodrug, intratumoral, etc.)
• Known liver metastasis based on imaging
• Possible area of ongoing necrosis (non-disease-related), such as active ulcer, nonhealing wound, or intercurrent bone fracture
• Active primary central nervous system (CNS) malignancy, CNS metastases, and/or carcinomatous meningitis
• Active autoimmune disease
• History of Grade ≥ 3 immune-related adverse events associated with prior immunotherapy unless these were adequately resolved with therapy within 14 days
• A diagnosis of immunodeficiency; receiving chronic systemic therapy exceeding prednisone 10 mg daily or equivalent or any other form of immunosuppressive therapy within 7 days before the first dose of study drug
• Active hepatitis B or active hepatitis C infection
• Prior treatment with gene therapy, organ transplant, or hematopoietic stem-cell transplant
• Known malignancy (other than disease under study) that is progressing or has required active treatment within the past 3 years