Clinical trial NCT05278975: Study of RSO-021 in Patients With Malignant Pleural Effusion Due to Advanced/Metastatic Solid Tumors Including Mesothelioma
Official title: A Translational Phase 1/2 Dose-Escalation and Expansion Study to Determine Safety, Tolerability, and Recommended Phase 2 Dose of RSO-021 in Patients With Malignant Pleural Effusion Due to Advanced/Metastatic Solid Tumors Including Mesothelioma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Malignant Pleural Effusion
Malignant Pleural Mesothelioma
Mesothelioma
Mesotheliomas Pleural
Mesothelioma; Lung
Pleural Effusion, Malignant
Lead sponsor: RS Oncology LLC
Sponsor class: INDUSTRY
First posted: 2022-03-15
Enrollment: 186
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is an open-label, non-randomized, multicenter, translational Phase 1/2 dose-escalation and expansion study designed to determine the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity of RSO-021 after intrapleural (IP) administration in patients with malignant pleural effusion (MPE) (non-mesothelioma) and MPE from mesothelioma.

Detailed description: This is a Phase 1/2, open-label, multi-center study whose primary Phase 1 stage objective is to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of RSO-021 (thiostrepton), a naturally-occurring, sulfur-rich, cyclic oligopeptide antibiotic of the thiopeptide class, in patients with MPE from any solid tumor, including mesothelioma.

In the Phase 2 stage, once the RP2D has been identified, the antitumor activity of RSO-021 will be evaluated in four recruitment arms; (1) in patients with MPE (non-mesothelioma), (2) in patients with MPE (non-mesothelioma) in combination with paclitaxel, (3) in patients with MPE from mesothelioma after first-line SoC, and (4) in patients with MPE from mesothelioma who have a 'window of opportunity' for treatment prior to first-line systemic therapy.

Eligibility criteria: Inclusion Criteria:

1. Male or female ≥ 18 years old.
2. ECOG performance status 0-1.
3. Histological diagnosis of solid tumor/mesothelioma with MPE.

   Expansion Cohort 2:
   1. only patients with breast cancer, ovarian cancer or non-small cell lung cancer.
   2. patients for whom paclitaxel is a recommended SoC therapy.
   3. no contraindications to paclitaxel.
4. Patients with a disease burden that is predominantly pleural, and a pleural space that is accessible.

Expansion Cohorts 1 and 2: MPE (non-mesothelioma): patients must have received at least 1 prior standard of care treatment regimen for advanced, unresectable malignancy, with documented progression.

Expansion Cohort 3:

MPE mesothelioma: patients must have received at least 1 prior standard-of-care treatment regimen for advanced, unresectable malignancy, with documented progression and there is no approved life extending alternative available.

Expansion Cohort 4: MPE mesothelioma 'window of opportunity': patients should be treatment naïve, have refused or not be immediately requiring of systemic therapy and should be patients for whom drainage is planned immediately while further treatment options are arranged. It must be documented for each patient that protocol participation will not affect their subsequent ability to access standard systemic first line therapy due to RSO-021 being a local therapy.

6. Resolution of all acute reversible toxic effects of prior therapy or surgical procedure to Grade ≤1 (except alopecia).

7. For dose escalation: Archival paraffin block, ideally from the patient's most recent biopsy, should be provided prior to the first dose of study therapy, if sufficient tissue is available.

For dose expansion cohorts: fresh tumor biopsy must be obtained.

1. Patients enrolled in the mesothelioma expansion phase will be requested to undergo a tumor biopsy during the screening period and after the third dose.
2. Patients enrolled in the non-mesothelioma expansion phase will be requested to undergo a tumor biopsy during the screening period and after the third dose only if medically feasible.

   8. Patients must have adequate organ function.

Exclusion Criteria:

1. Last dose of prior anti-cancer therapies:

   1. Systemic anti-cancer therapy within 3 weeks or 5 half-lives prior to study entry, whichever is shorter.
   2. Thoracic radiation therapy or significant surgery within 3 weeks prior to study entry. Localized palliative radiotherapy for pain control in non-target lesions is allowed during the screening period.
   3. Received an investigational product or been treated with an investigational device within 30 days prior to first drug administration or plans to participate in any other clinical trial while on this study.
2. Previous or concurrent malignancy that would prevent evaluation of the primary endpoint (e.g. R/R hematological malignancy).
3. Patients whose extent of tumor or loculations would render intrapleural administration incomplete and/or ineffective.
4. Known hypersensitivity to the active ingredient or any excipient contained in the drug formulation.
5. History or clinical evidence of any surgical or medical condition which the investigator and/or medical monitor judges as likely to interfere with the results of the study or pose an additional risk in participating, e.g., rapidly progressive or uncontrolled disease involving a major organ system-vascular, cardiac, pulmonary, gastrointestinal, gynecologic, hematologic, neurologic, neoplastic, renal, endocrine, or an immunodeficiency, or clinically significant active psychiatric or abuse disorders.
6. Active infection with human immunodeficiency virus (HIV) and CD4+ T-cell count \< 350/μL. Patients not on established anti-retroviral therapy for at least four weeks prior to first dose of study drug and having a detectable HIV viral load. Testing is not required for eligibility.
7. Active infection with hepatitis B (surface antigen); or infection with hepatitis C in absence of sustained virologic response. Testing is not required for eligibility.
8. Pregnant or breast-feeding patients.
9. Patients with symptomatic or unstable CNS primary tumor or metastases and/or carcinomatous meningitis. Patients with documented treated CNS metastases stable off steroids may be enrolled at the discretion of the investigator.
10. Therapeutic oral anticoagulation for a thromboembolic event (prophylactic anticoagulation is allowed as long as patient can undergo catheter placement and biopsy). LMWH is allowed on condition that it is medically acceptable to interrupt LMWH therapy for all study procedures.
11. Use of systemic corticosteroids to treat inflammatory or autoimmune symptoms within 15 days or other immunosuppressive drugs within 3 weeks prior to start of the study. Inhaled and topical corticosteroids are permitted. Up to 10 mg/day prednisone or equivalent is permitted.

Primary outcomes:
measure: Dose-limiting Toxicity
timeFrame: First 21 days of treatment.
measure: Frequency and Severity of Adverse Events (AE)
timeFrame: Screening to 90 days from last dose.
measure: Dose Finding
timeFrame: Screening to 90 days from last dose.
Secondary outcomes:
measure: Pharmacokinetics of RSO-021
timeFrame: Day 1 of dosing through 21 days post last dose.
measure: Pharmacokinetics of RSO-021
timeFrame: Day 1 of dosing through 21 days post last dose.
measure: Objective Response Rate (ORR)
timeFrame: Day 1 of dosing through day 90 after the last dose.
measure: Disease Control Rate (DCR)
timeFrame: Day 1 of dosing through day 90 after the last dose.
measure: Progression Free Survival (PFS)
timeFrame: Day 1 of dosing through day 90 after the last dose.
Other outcomes:
Locations:
city: Bristol
country: United Kingdom
facility: South Mead North Bristol Hopsital
city: Glasgow
country: United Kingdom
facility: NHS Greater Glasgow & Clyde
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospital
city: Leicester
country: United Kingdom
facility: Facility: HOPE Clinical Trials Facility, Leicester Royal Infirmary
city: London
country: United Kingdom
facility: Barts Health NHS Cancer Institute
city: London
country: United Kingdom
facility: Guys and St Thomas NHS Foundation Trust
city: London
country: United Kingdom
facility: The Royal Marsden
city: Manchester
country: United Kingdom
facility: The Christie NHS
city: North Shields
country: United Kingdom
facility: Northumbria NorthTyne Side General Hospital
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Foundation
Study officials:
affiliation: Guys Hospital
name: James Spicer, MD
role: PRINCIPAL_INVESTIGATOR
References: