A Phase 1, Open-Label, Study Evaluating the Safety, Pharmacokinetics, and Clinical Effects of Intravenously Administered PT-112 Injection in Patients with Advanced Solid Tumors and Subsequent Expansion Cohorts

Prior treatment

• Target disease exceptions: a. Carcinomatous meningitis; b. Known brain metastases and/or active epidural disease, subject to the following exceptions: - Patients with a history of CNS metastases are eligible if they have received therapy if required (e.g., surgery, radiotherapy, gamma knife), are neurologically stable, asymptomatic, have no single lesion > 2 cm, and are not receiving corticosteroids to maintain neurologic integrity; - Patients with asymptomatic, previously treated CNS metastases are eligible provided they have been clinically stable (not requiring steroids for at least 28 days before the first dose of PT-112), and they have had appropriate scans at screening assessment. For patients with parenchymal and CNS metastasis or a history of CNS metastasis, baseline and subsequent radiologic imaging must include evaluation of the brain; - Patients with epidural disease, canal disease, and prior cord involvement are eligible if they are not neurologically impaired, those areas are stable, and symptoms are readily controlled. For these patients, baseline and subsequent radiologic imaging must include evaluation of the brain; c. Symptomatic or impending cord compression unless appropriately treated, clinically stable, and asymptomatic;
• Any minor surgical procedure within <5 days or any major surgical procedure within <28 days before the first dose of PT-112. In all cases, patients must be sufficiently recovered and stable before starting PT-112 treatment;
• Received treatment with chemotherapy, immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, radiation, experimental drug, or PARP inhibitors within < 14 days of receiving the first dose of PT-112. Treatment with hormonal therapies (except for LHRH analog) must be discontinued at least 14 days before the first dose of PT-112;
• Medical history and concurrent disease: a. Active infection requiring systemic therapy or significant acute or chronic infection including, among others: - Active hepatitis B virus (HBV) infection, defined by a positive HBV surface antigen (HBsAg) test at screening. Patients with a past or resolved HBV infection, defined as the presence of hepatitis B core antibody and absence of HBsAg, are eligible; - Active hepatitis C virus (HCV) infection, defined by HCV RNA positive PCR test at screening; - Known history or testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome;

Other illness

• Known hypersensitivity to platinum-containing therapies, PT-112, or any of PT-112 Injection excipients;
• Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. Patients with adequately treated non-melanoma skin cancer, superficial bladder cancer, and patients with a prior history of malignancy who have been disease-free for 3 years or more are eligible;
• Known psychiatric or substance abuse disorders that might interfere with cooperation with the requirements of the trial;

Lab values

• History or current evidence of any circumstance, condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient’s participation for the full duration of the trial, or is not in the best interest of the patient to participate in the opinion of the Investigator;
• Resting ECG indicating uncontrolled cardiac condition, including unstable ischemia, uncontrolled asymptomatic arrhythmia, congestive heart failure (New York Heart Association functional classification Grade II or higher), or QTcF prolongation >450 ms, or patients with congenital long QT syndrome;

Other

• Intolerance to CT, or FDG-PET contrast agents, as applicable.
• Patients on therapeutic doses of anti-coagulants.
• Patients non-evaluable for both bone and soft-tissue progression, as defined by meeting both of the following criteria:A bone scan that is referred to as a superscan showing an intense symmetric activity in the bones; ● No soft tissue lesion (measurable or non-measurable) can be assessed by RECIST v1.1.

• Signed informed consent before initiation of any study-specific procedures and treatment;
• ECOG performance status of 0-1;
• Estimated life expectancy of ≥16 weeks.
• Must have recovered to CTCAE grade ≤ 1 from all clinically significant toxicities related to prior cancer therapies, excluding alopecia or toxicities related to the use of LHRH agonist or antagonist, based on CTCAE v5.0;
• Adequate bone marrow, liver, and renal function.
• Must use a condom during study treatment and 6 months after the last dose of PT-112 when having intercourse with a pregnant woman or a woman of childbearing potential. Female partners of male patients also should use a highly effective form of contraception if they are of childbearing potential.
• The patient is willing and able to comply with the protocol for the study’s duration, including undergoing treatment and scheduled visits and examinations at the institution and completing required surveys, assessments, and follow-up visits.
• Male ≥18 years of age;
• Histologically or cytologically confirmed adenocarcinoma of the prostate, excluding pure neuroendocrine/small-cell features at original diagnosis;
• Documented current evidence of metastatic castration-resistant prostate cancer (mCRPC), where metastatic status is defined as having documented metastatic lesion(s) on either bone scan or CT scan. Patients whose disease spread is limited to regional pelvic lymph nodes or local recurrence (e.g., bladder, rectum) are not eligible.
• Ongoing androgen deprivation therapy with a GnRH analog or a bilateral orchiectomy (i.e., surgical or medical castration);
• Serum testosterone level ≤ 1.73 nmol/L (50 ng/dL) at screening;
• Patients receiving bisphosphonates or denosumab must have been on a stable dose for at least 4 weeks before starting the study. No bisphosphonate treatment was administered within 7 days before initiating study treatment. While on the study, denosumab may be administered on the same day as PT- 112. However, bisphosphonates can be administered only once a month on Day 21 (±2 days) of the 28-day treatment cycle or, in the event of dose holds, can be given only 7 (±2) days apart from any PT-112 infusions.
• Patients who have received at least three prior intended life-prolonging therapies for metastatic disease, as follows: a. At least one new-generation anti-androgen therapy (e.g. abiraterone, apalutamide, darolutamide, enzalutamide); b. At least one but no more than two taxane-containing regimens (e.g., docetaxel, cabazitaxel). Use of docetaxel in the mHSPC setting counts toward this number. Patients receiving the same taxane-containing regimen(s) at separate points in time during their course of therapy are considered to have received separate exposures; c. Other FDA approved therapy for mCRPC (e.g., including radium 223, sipuleucel-T, PARP inhibitors, 177Lutetium-PSMA-617) or other agents PT-112 Injection Protocol PT-112-101, Amendment 12 15 February 2023 CONFIDENTIAL 115 Promontory Therapeutics Inc. which may be approved during the conduct of this study based on a demonstrated treatment benefit on survival; d. Prior investigational regimens are allowed but do not count towards this number.
• Progressive disease at study entry, defined as either / both of the following criteria that occurred on or after the most recent therapy (Note: for the avoidance of doubt, PSA progression alone does not fulfill this criterion): ● Soft-tissue disease progression, defined by RECIST v1.1. (Patients whose disease spread is limited to regional pelvic lymph nodes are not eligible under this parameter); ● Bone disease progression, defined by PCWG3 as ≥ 2 new lesions confirmed on bone scan.