Phase 1/2 Open-Label Study of PRS-344/S095012 and Obinutuzumab in Patients with Solid Tumors
- Trial ID
- 2023-510046-25-00
- Protocol
- CL1-95012-001
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** profile of the single-agent PRS-344/S095012 in patients with solid tumors. This includes determining the maximum tolerated dose (MTD) or maximum administered dose (MAD) and establishing the recommended phase 2 dose (RP2D). In Phase 2, the study aims to assess the potential anti-tumor activity and efficacy of PRS-344/S095012, as per central assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. These objectives are clinically relevant as they provide critical information on the safety and potential therapeutic efficacy of PRS-344/S095012, which is essential for advancing treatment options for patients with solid tumors.
Secondary objectives include: - Phase 1: Characterizing the pharmacokinetics (PK) of PRS-344/S095012, evaluating its immunogenicity, and assessing preliminary anti-tumor activity according to RECIST v1.1. - Phase 2: Further describing the efficacy, characterizing the safety and tolerability, and further characterizing the PK profile and immunogenicity of PRS-344/S095012. These secondary objectives aim to provide a comprehensive understanding of the drug's behavior in the body, its immune response, and its preliminary effectiveness against tumors, which are crucial for optimizing its clinical application.
Participants
The clinical trial involves a total of **175 participants** diagnosed with **solid tumors**. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, including a histological diagnosis of unresectable, locally advanced, or metastatic solid tumors for which standard treatment options are unavailable, ineffective, or not tolerated. The trial also includes patients with recurrent, persistent, and/or metastatic cervical cancer and locally advanced or metastatic cutaneous squamous cell carcinoma. Participants are required to have a measurable disease as per RECIST 1.1 criteria and a life expectancy of at least three months. The trial population is characterized by an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a Royal Marsden Prognosis score of 0 to 1. Adequate organ function is mandatory, as assessed by laboratory tests. Lifestyle considerations such as the use of effective birth control methods for female participants and condom use for male participants with childbearing potential partners are required during the study and for a specified period after the last dose of the study treatment. The trial includes a vulnerable population, and participants must test negative for infections such as cytomegalovirus, Epstein-Barr virus, Hepatitis B, and Hepatitis C according to local standards.
Plans and Procedures
The clinical trial is a **Phase 1/2** open-label, multicenter study designed to evaluate the safety, tolerability, and efficacy of **PRS-344/S095012** in patients with **solid tumors**. The trial employs a dose escalation and expansion approach to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) and the recommended phase 2 dose (RP2D) of the investigational product. The study is not categorized as low intervention and involves the administration of the investigational product via **intravenous use**. The trial is expected to run from September 30, 2021, to December 31, 2027, with participant involvement varying based on individual response and progression.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, disease status, and prior treatment history. The screening process will include laboratory tests to ensure adequate organ function and the absence of specific viral infections. Following successful screening, participants will enter the dose escalation phase, where they will receive the investigational product and be monitored for dose-limiting toxicities (DLTs) and adverse events (AEs). The primary endpoints for Phase 1 include the incidence of DLTs and AEs, while secondary endpoints involve pharmacokinetic parameters and the detection of antidrug antibodies (ADA).
In the dose expansion phase, participants will be grouped based on specific tumor types, such as cervical cancer and cutaneous squamous cell carcinoma, to further evaluate the anti-tumor activity of PRS-344/S095012. Follow-up visits will be scheduled to assess treatment efficacy using criteria such as the Objective Response (OR) and Progression-free Survival (PFS). The end-of-study visit will conclude the participant's involvement, with assessments to document the overall survival (OS) and any long-term effects of the treatment.
Participant involvement is expected to last until disease progression, unacceptable toxicity, or withdrawal of consent. Conditions that may lead to early termination from the study include significant adverse reactions or the availability of alternative treatment options. The trial's design ensures rigorous monitoring and data collection to support the evaluation of PRS-344/S095012's safety and efficacy in treating solid tumors.
Treatment
The clinical trial involves the administration of **S95012**, a **concentrate for solution for infusion** containing the active substance **PRS-344**. This investigational medicinal product is of biological/biotechnological origin and is not classified as an Advanced Therapy Investigational Medicinal Product (ATIMP). The pharmaceutical form is a concentrate for solution for infusion, with a concentration of 400 mg in 16 ml. The route of administration is **intravenous use**. The dosing schedule and frequency of administration are determined based on the phase of the trial, with the primary objective in Phase 1 being the evaluation of safety and tolerability, and in Phase 2, the assessment of anti-tumor activity and efficacy. Participant compliance is monitored through regular assessments and adherence to the dosing regimen.
In addition to the experimental treatment, the trial also includes the administration of **Gazyvaro**, a **1,000 mg concentrate for solution for infusion**. The active substance in Gazyvaro is **obinutuzumab**, which is also of biological/biotechnological origin. This product is authorized for use in the European Union and is administered intravenously. The role of Gazyvaro in the trial is to serve as a comparator treatment, providing a standard against which the effects of S95012 can be measured. The administration schedule for Gazyvaro is aligned with its approved usage guidelines, and participant adherence is closely monitored to ensure accurate assessment of treatment outcomes.
Efficacy
The efficacy of the investigational product PRS-344/S095012 in the clinical trial will be assessed through a series of primary and secondary endpoints. In Phase 1, the primary endpoints include the incidence of dose-limiting toxicities (DLTs), the incidence and severity of adverse events (AEs), discontinuation of study treatment due to an AE, and laboratory, electrocardiogram (ECG), and vital sign measurements. In Phase 2, the primary endpoints focus on the objective response (OR) as per central assessment according to RECIST v1.1 criteria for Arms 1 and 2, and a composite response criteria for Arm 3, which includes digital medical photography and/or imaging as per RECIST v1.1.
Secondary endpoints in Phase 1 include serum pharmacokinetic (PK) parameters of PRS-344/S095012, detection of antidrug antibodies (ADA) against PRS-344/S095012, and their titration when applicable. Additionally, objective response (OR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS) will be evaluated. In Phase 2, secondary endpoints encompass OR as per investigator assessment, disease control (DC), DoR, PFS, OS, and time to response (TTR). Furthermore, adverse events (AEs), serious adverse events (SAEs), laboratory, ECG, and vital signs will be monitored, along with serum concentrations of PRS-344/S095012 and detection of ADA against PRS-344/S095012.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥18 years on the day the consent is signed.
- Patient must have a life expectancy of at least 3 months.
- Patient should have a documented disease progression on prior therapy before entry into this study
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
- Royal Marsden Prognosis score of 0 to 1 (score based on lactate dehydrogenase (LDH) value, albumin value and number of sites of metastasis).
- Adequate organ function as assessed by laboratory tests within 7 days prior to pretreatment with obinutuzumab: -Lymphocyte count ≥ 800/μ -Gamma-globulin level > 6g/L (by serum protein electrophoresis) or IgG level > 4g/L (by measurement of quantitative immunoglobulins)
- A female patient must use a highly effective method of birth control during study treatment and until, for 120 days after the last dose of the study treatment. PRS-344/S095012, or 18 months after the last obinutuzumab infusion, whichever comes the latest.
- A male patient with childbearing potential partners must use a condom during the study and for at least 4 months after the last dose of the study treatment, or 6 months after the last Obinutuzumab infusion, whichever comes the latest. Sperm donation will not be allowed during the study and for 4 months after the last dose of study treatment, or 6 months after the last obinutuzumab infusion, whichever comes the latest.
- Test should be negative for cytomegalovirus (CMV), Epstein-Barr virus (EBV), Hepatitis B virus (HBV), and Hepatitis C virus (HCV) infection, according to local standards: - Negative CMV DNA testing in serum or plasma by a sensitive quantitative molecular method. - Absence of immunoglobulin (Ig)M antibodies against EBV-VCA (Viral Capside Antigen) - Negative serologic testing for hepatitis B surface antigen (HbsAg) or a negative result by a sensitive quantitative molecular method for HBVDNA in serum or plasma -Negative HCV RNA testing in serum or plasma by a sensitive quantitative molecular method.
- Negative test results for human T-lymphotropic virus 1 (HTLV 1). HTLV testing is only required for participants from countries in which HTLV 1 infection is endemic (Japan, countries in the Caribbean basin,South America, Central America, sub-Saharan Africa, and Melanesia).
- Dose Escalation: Patients with a histological diagnosis of an unresectable, locally advanced or metastatic solid tumor for which standard treatment options are not available, no longer effective, or not tolerated.
- Dose Escalation: Patients must have measurable disease per RECIST 1.1 as assessed by the local site investigator/imaging. Lesions situated in a previously irradiated area are considered measurable only if progression has been demonstrated in such lesions.
- Dose Escalation:Patients with no available archived material must have one or more tumor lesions amenable to biopsy
- Dose Expansion: Patients with histologically diagnosed Arm 1 and 2: recurrent, persistent, and/or metastatic cervical cancer. Acceptable histologies are squamous carcinoma, adenocarcinoma, and adenosquamous carcinoma. Arm 3: locally advanced or metastatic cutaneous squamous cell carcinoma.
- Dose Expansion: Patients must have received : Arm 1 (cervical , CPI-naïve): at least 1 prior line of platinum-based combination therapy. Patients must not have received any prior treatment with an immune checkpoint inhibitor (anti-PD-1, PD-L1 or anti-CTLA-4 [cytotoxic T lymphocyte-associated protein 4]) and do not have access to an approved immune checkpoint inhibitor. Surgery, radiation therapy, and additional chemotherapy must not be considered appropriate alternative treatment options for these patients. Arm 2 (cervical cancer, CPI-relapsed/refractory): at least 1 prior line of systemic therapy with an immune checkpoint inhibitor as monotherapy or in combination with chemotherapy and/or any other systemic therapies. Surgery, radiation therapy, and additional chemotherapy must not be considered appropriate lternative treatment options for these patients. Arm 3 (CSCC, CPI-relapsed/refractory): at least 1 prior line of systemic therapy with an immune checkpoint inhibitor as monotherapy or in combination with chemotherapy and/or any other systemic therapies. Surgery, radiation therapy, and additional chemotherapy must not be considered appropriate alternative treatment options for these patients.
- Dose Expansion: Biopsy requirements Arms 1 and 2 (cervical cancer): fresh baseline biopsies are mandatory, on-treatment biopsies are optional. Arm 3 (skin cancer): fresh baseline biopsies are mandatory, on-treatment biopsies are mandatory unless medically contra-indicated.
- Dose Expansion: Patients must have at least one measurable target lesion as per RECIST 1.1 and/or World Health Organization (WHO) criteria for only externally visible skin tumors confirmed by central review. Lesions situated in a previously irradiated area are considered measurable only if progression has been demonstrated in such lesions
Exclusion Criteria
- Patients with previously treated brain metastases may participate provided they are radiologically stable, clinically asymptomatic and are off immunosuppressive therapies for at least 4 weeks. Low dose of steroid (≤ 10 mg/day prednisone or equivalent) is allowed
- Patients who have received prior: a. Chemotherapy, small molecule inhibitors, monoclonal antibodies, antibody-drug conjugates, and/or other similar investigational agent: at least 3 weeks or 5 half-lives prior to first IMP administration, whichever is shorter. b. Radioimmunoconjugates or other similar experimental therapies at least 6 weeks or 5 half-lives prior to first IMP administration, whichever is shorter.
- Patients who have received a 4-1BB agonist in the past.
- Patients who had a major surgery within 4 weeks prior to first administration of IMP.
- Patients who have received either systemic corticosteroids (> 10 mg per day or equivalent) or other immunosuppressive medications during the 2 months prior to the first dose of the study drug. Higher single doses of corticosteroids given as premedication against infusion-related reactions are allowed. Treatment with local steroids (inhaled, intranasal, injected are allowed.
- Patients with an active infection with a viral, bacterial, or fungal pathogen requiring systemic treatment within seven days before first IMP administration.
- Patients with a history of an opportunistic infection within a year prior to first IMP administration
- History of progressive multifocal leukoencephalopathy.
- Active tuberculosis requiring treatment within 3 years prior to the start of treatment or a suspicion of latent tuberculosis by the investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 30 Sept 2021 | 35 |
 France | Not Recruiting | 30 Sept 2021 | 18 |
 Spain | Not Recruiting | 30 Sept 2021 | 49 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
S95012 concentrate solution for infusion 400mg/ 16 ml | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD7929664 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | — | — | PRD1753415 |