Evaluation of Safety, Pharmacokinetics, and Clinical Effects of Intravenous Imifoplatin in Patients with Metastatic Castrate-Resistant Prostate Cancer

Trial ID: 2024-518506-41-00
Protocol: PT-112-101
Sponsor: Promontory Therapeutics Inc.

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Diseases & Conditions

Hormone-refractory prostate cancer

Objectives

The primary objective of this Phase 1, open-label study is to define the recommended dose and schedule for **PT-112**, a solution for infusion, in patients with advanced solid tumors, including metastatic castrate-resistant prostate cancer. The study aims to determine the optimal dosing regimen for pivotal studies by comparing two dose levels: 250 mg/m² and 360 mg/m², administered on Days 1 and 15 of each 28-day cycle. The primary endpoint is the disease control rate at 4 months (DCR4), which is crucial for assessing the risk/benefit ratio of the treatment.

Secondary objectives include assessing the treatment effects on individual disease manifestations, evaluated both overall and for each treatment arm. This evaluation is essential for understanding the broader clinical impact of PT-112 on specific symptoms and disease progression in the patient population.

Participants

The clinical trial involves a total of **69 participants** diagnosed with **metastatic castrate-resistant prostate cancer**. The study population is exclusively male, aged **18 years and older**, with an **ECOG performance status** of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants were selected based on their ability to provide informed consent and their willingness to comply with the study protocol, including treatment and follow-up visits. All participants have a documented history of metastatic disease, confirmed through imaging, and are undergoing ongoing androgen deprivation therapy. They must have recovered from prior cancer therapy-related toxicities to a manageable level and possess adequate bone marrow, liver, and renal function. Lifestyle considerations include the requirement for participants to use condoms during the study and for six months after the last dose of PT-112 to prevent potential drug-related risks to partners. The trial does not include any vulnerable populations, and female subjects are not part of this study. Participants have previously received at least three life-prolonging therapies for metastatic disease, including anti-androgen therapies and taxane-containing regimens. The trial aims to define the recommended dose and schedule for PT-112 based on the disease control rate at four months.

Plans and Procedures

The clinical trial is designed to evaluate the safety, pharmacokinetics, and clinical effects of **PT-112**, a **solution for infusion** containing the active substance **imifoplatin**, in patients with advanced solid tumors, specifically focusing on metastatic castrate-resistant prostate cancer. This is a Phase 1, open-label study with subsequent expansion cohorts. The trial employs a randomized, controlled design to determine the recommended dose and schedule for PT-112, administered intravenously on Days 1 and 15 of each 28-day cycle. The primary endpoint is the disease control rate at four months (DCR4), with secondary endpoints including objective response rate, median duration of response, and safety measures.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as an ECOG performance status of 0-1, adequate organ function, and a confirmed diagnosis of metastatic castration-resistant prostate cancer. Following successful screening, participants will receive PT-112 infusions according to the assigned dose schedule. Follow-up visits will occur every two cycles (8±1 weeks) for the first six months, then every three cycles (12±1 weeks) to monitor treatment response and safety. The end-of-study visit will conclude the participant's involvement, which is expected to last until the estimated trial end date in July 2025.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they are unable to comply with the study protocol. The trial's estimated recruitment start date was May 2023, and it is anticipated to continue until the completion of data collection and analysis. The study aims to provide critical data to inform future pivotal studies and optimize the therapeutic use of PT-112 in this patient population.

Treatment

The clinical trial involves the administration of the experimental medication **PT-112**, which is a **solution for infusion**. The active substance in PT-112 is **imifoplatin**, a chemical compound also known by its synonyms: (R,R)-1,2-cyclohexanediamine pyrophosphatoplatinum(II) and cyclohexane-(1R,2R)-diamineplatinum(II) diphosphate. PT-112 is manufactured by Promontory Therapeutics Inc. and is administered via **intravenous infusion**. The dosing schedule for PT-112 involves administration on Days 1 and 15 of each 28-day cycle. Two dosing regimens are being evaluated: 360 mg/m² for Arm 1 and 250 mg/m² for Arm 2. A modified design includes a third arm (Arm 3), where PT-112 is administered at 360 mg/m² on Days 1 and 15 of Cycle 1, followed by 250 mg/m² on Day 15 of each subsequent cycle.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The primary endpoint of the trial is the disease control rate at 4 months (DCR4), which will help define the recommended dose and schedule for PT-112 in pivotal studies. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial is designed to evaluate the safety, pharmacokinetics, and clinical effects of PT-112 in patients with advanced solid tumors.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the **disease control rate (DCR)** at 4 months (DCR4), which serves as the primary endpoint. This trial involves patients with metastatic castration-resistant prostate cancer (mCRPC) and aims to define the recommended dose and schedule for PT-112. The trial will compare two dosing regimens: 250 mg/m² on Days 1 and 15 of each 28-day cycle (Arm 2) and 360 mg/m² on Days 1 and 15 of Cycle 1, followed by 250 mg/m² on Day 15 of each subsequent 28-day cycle (Arm 3).

Secondary endpoints include a variety of measures to further evaluate efficacy. These include the **objective response rate (ORR)** in patients with RECIST-measurable disease, assessed through CT scans with contrast at baseline and after every 2 cycles (8±1 weeks) for the first 6 months, then every 3 cycles (12±1 weeks). The **median duration of response (DOR)** for soft tissue lesions will be calculated from the first observation of response to the first observation of disease progression. Additional secondary endpoints include the percentage of patients achieving **PSA50**, defined as a ≥50% reduction in serum PSA, and the **median radiographic progression-free survival (rPFS)**. The trial will also measure the **median overall survival (OS)**, time to PSA progression, and changes in disease-related pain using the American Cancer Society Daily Pain Diary. Safety and tolerability will be assessed by the number of treatment-related adverse events (TRAEs), and pharmacokinetics of PT-112 will be determined following dosing on Days 1 and 15 of Cycle 1. The trial will also explore exposure-response and exposure-safety relationships for PT-112.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Signed informed consent before initiation of any study-specific procedures and treatment;
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.
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.

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Exclusion Criteria

Intolerance to CT, or FDG-PET contrast agents, as applicable.
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;
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.
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;
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;
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;
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;
Known hypersensitivity to platinum-containing therapies, PT-112, or any of PT-112 Injection excipients;
Patients on therapeutic doses of anti-coagulants.