Evaluation of Ocular Toxicity Mitigation with Mirvetuximab Soravtansine, Brimonidine Tartrate, and Prednisolone Acetate in Recurrent Ovarian Cancer Patients
- Trial ID
- 2023-505617-24-00
- Protocol
- IMGN853-0424
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **incidence rate** and severity of MIRV-related corneal adverse events (AEs) of grade 2 or higher in asymptomatic patients with recurrent ovarian cancer with high folate receptor-alpha (FRα) expression receiving Mirvetuximab Soravtansine (MIRV). This evaluation is clinically relevant as it aims to understand the ocular toxicity associated with MIRV, which is crucial for optimizing patient safety and treatment efficacy in this population.
Secondary objectives include:
- Assessing the incidence rate and severity of all ocular treatment-emergent adverse events (TEAEs) in patients receiving MIRV.
- Comparing the incidence rate and severity of MIRV-related corneal AEs and all ocular TEAEs in asymptomatic versus symptomatic patients.
- Comparing the incidence rate and severity of MIRV-related corneal AEs (≥ Grade 2) and all ocular TEAEs in patients using corticosteroid versus vasoconstricting eye drop primary prophylaxis.
- Evaluating and describing ocular health-related quality of life (HRQoL) using the composite score of the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25).
- Evaluating the pharmacokinetics (PK) of MIRV to assess exposure in symptomatic versus asymptomatic patients in both prophylaxis groups.
Participants
The clinical trial involves a total of **41 participants** who are exclusively female, as the study focuses on patients with **recurrent ovarian cancer** exhibiting high folate receptor-alpha expression. The age range of the participants is 18 years and older, ensuring that all individuals are adults. Participants were selected based on specific health criteria, including adequate hematologic, liver, and kidney functions, and a confirmed diagnosis of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with high folate receptor-alpha expression. The trial population is characterized by a history of prior anticancer therapy, with requirements for previous platinum-based treatments and specific conditions regarding platinum sensitivity or resistance. Lifestyle considerations such as diet and physical activity are not specified, but participants must have stabilized or recovered from prior therapy-related toxicities. The study does not include male subjects, and the population is considered vulnerable due to the nature of the disease and treatment. The sponsor has not provided additional information regarding other lifestyle factors or health status beyond the inclusion criteria.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the ocular toxicity and mitigation strategies during treatment with **Mirvetuximab Soravtansine** in patients with recurrent ovarian cancer characterized by high folate receptor-alpha expression. The trial is set to commence on April 1, 2024, and is expected to conclude by May 25, 2027. The study involves a series of structured visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, including age, prior treatment history, and health status. Participants will be randomly assigned to receive either the investigational drug or a control, with neither the participants nor the investigators aware of the group assignments, ensuring the study's double-blind nature.
The trial will span multiple cycles, each lasting 21 days, with the primary endpoint being the incidence and severity of **MIRV-related corneal adverse events**. Participants will undergo regular follow-up visits throughout the trial to monitor for any adverse events and to assess the effectiveness of the prophylactic strategies using corticosteroid versus vasoconstricting eye drops. These visits will include comprehensive ophthalmic assessments to detect any ocular toxicities. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination, which may be necessitated by severe adverse events, non-compliance with the study protocol, or withdrawal of consent by the participant.
Participant involvement is expected to last up to 18 weeks from the first cycle day 1 or until the 30-day follow-up visit, whichever is earlier. Conditions that may lead to early termination from the study include the development of severe adverse events, failure to adhere to the study protocol, or voluntary withdrawal by the participant. The study aims to provide valuable insights into the management of ocular toxicities associated with **Mirvetuximab Soravtansine** treatment, potentially improving therapeutic outcomes for patients with recurrent ovarian cancer.
Treatment
**Mirvetuximab Soravtansine** is an experimental medication used in this clinical trial. It is formulated as a **concentrate for solution for infusion** and is administered via **intravenous infusion**. The dosage is calculated based on the patient's body weight, with a maximum daily dose of 6 mg/kg. The treatment period is set for a maximum of 21 days. This medication is developed by ImmunoGen Inc. and is designated as an orphan drug for the treatment of recurrent ovarian cancer with high folate receptor-alpha expression. Participant compliance with the dosing schedule is monitored throughout the trial.
**Alphagan 2 mg/ml colirio en solución** is a non-experimental treatment used in the study. It is an **eye drops solution** containing **brimonidine tartrate** as the active substance. The medication is administered via **conjunctival use**, with a maximum daily dose of 0.3 ml and a total maximum dose of 6.3 ml over the treatment period. This product is manufactured by AbbVie Spain S.L.U. and is used to mitigate ocular toxicity associated with the experimental treatment.
**Pred Forte 10 mg/ml colirio en suspensión** is another non-experimental treatment included in the study. It is an **eye drops suspension** containing **prednisolone acetate**. The administration route is **conjunctival use**, with a maximum daily dose of 0.6 ml and a total maximum dose of 4.6 ml over the 21-day treatment period. This medication is also produced by AbbVie Spain S.L.U. and serves as a standard-of-care therapy to manage potential ocular adverse events during the trial.
Efficacy
Efficacy in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the incidence rate and severity of **MIRV-related corneal adverse events (AEs)**, specifically those of Grade 2 or higher, in asymptomatic patients with recurrent ovarian cancer exhibiting high folate receptor-alpha expression. This assessment will be conducted up to 18 weeks from Cycle 1 Day 1 (C1D1) or at the 30-Day Follow-up visit, whichever occurs earlier.
Secondary endpoints include evaluating the incidence rate and severity of all ocular treatment-emergent adverse events (TEAEs) in patients using corticosteroid versus vasoconstricting eye drop primary prophylaxis, assessed over the same timeframe. Additionally, the study will compare the incidence and severity of MIRV-related corneal AEs and all ocular TEAEs in asymptomatic versus symptomatic patients identified through ophthalmic assessments. The composite score of the NEI VFQ-25 will be utilized to evaluate ocular health-related quality of life (HRQoL) and patient-reported outcomes at Cycle 5 Day 1 (C5D1) or at the 30-Day Follow-up visit, whichever is earlier. Pharmacokinetic parameters, including area under the curve, maximum serum concentration, and trough concentration, will also be measured in both asymptomatic and symptomatic patients across the prophylaxis groups.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients ≥ 18 years of age or age of maturity as per local law
- Patients must have an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of 0 or 1
- Patients must have a confirmed diagnosis of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (collectively referred to as EOC hereafter) with high FRα expression
- Patient's tumor must be FRα positive (FRα high) as defined by either the VENTANA FOLR1 (FOLR-2.1) IUO Assay or VENTANA FOLR1 (FOLR1-2.1) RxDx Assay (hereafter collectively termed Ventana FOLR1 Assay) (≥75% cells exhibit 2 or 3+ membrane staining intensity)
- Patients must have recurrent ovarian cancer that may be platinum-resistant or platinum-sensitive as defined below). - Platinum-resistant disease: a. Patients who have only had 1 line of platinum-based therapy must have received ≥ 4 cycles of platinum, must have had a disease response (complete response [CR], partial response [PR], or no evaluable disease after surgery with neoadjuvant/adjuvant therapy), and then had disease progression > 3 months and < 6 months after the date of the last dose of platinum; b. Patients who have received 2 to 4 lines of platinum therapy must have progressed during or < 6 months after the date of the last dose of platinum; c. Patients with primary platinum-refractory disease (disease progression ≤ 3 months from last dose of platinum of first line of treatment) will not be eligible. - Platinum-sensitive disease: d. Patients with platinum-sensitive disease are defined as radiographic progression ≥ 6 months from the last dose of the most recent platinum therapy; e. Patients’ disease must have progressed radiographically on (non-platinum only) or after their most recent line of anticancer therapy.
- Patients with known breast cancer susceptibility gene mutations (tumor or germline) must have received poly adenosine diphosphate ribose polymerase inhibitors (PARPi).
- With regard to prior anticancer therapy: a. Neoadjuvant ± adjuvant therapies are considered 1 line of therapy; b. Maintenance therapy (eg, bevacizumab, PARPi) will be considered part of the preceding line of therapy (ie, not counted independently); c. Therapy changed due to toxicity in the absence of progression will be considered part of the same line (ie, not counted independently); d. Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance. 7.1 Requirements for prior anticancer therapy (PSOC patients ONLY): a. Patients must have received ≥ 2 prior systemic lines of platinum therapy and be considered by the investigator as appropriate for single-agent, non-platinum therapy (documentation required – eg, high risk of hypersensitivity reaction; risk of further cumulative toxicity with additional platinum, including but not limited to myelosuppression, neuropathy, renal insufficiency, or other). 7.2 Requirements for prior anticancer therapy (PROC patients ONLY): a. Patients must have received ≥1 line but no more than 4 prior systemic lines of anticancer therapy and must be considered by the investigator as appropriate for single-agent therapy as the next line of treatment.
- Patients must have completed prior therapy within the specified times below: a. Systemic antineoplastic therapy ≥ 5 half-lives or 4 weeks (whichever is shorter) before the first dose of MIRV; b. Focal radiation completed ≥ 2 weeks before the the first dose of MIRV.
- Patients must have stabilized or recovered (Grade 1 or baseline) from all prior therapy-related toxicities (except alopecia).
- Patients must have completed any major surgery ≥ 4 weeks before the first dose of MIRV and have recovered or stabilized from the side effects of prior surgery before the first dose of MIRV.
- Patients must have adequate hematologic, liver, and kidney functions, defined as: a. Absolute neutrophil count ≥ 1.5 × 109/L (1500 cells/μL) without granulocyte colony-stimulating factor in the previous 10 days or long-acting white blood cell growth factors in the previous 20 days; b. Platelet count ≥ 100 × 109/L (100,000 cells/μL) without platelet transfusion in the previous 10 days; c. Hemoglobin ≥ 8.0 g/dL without packed red blood cell transfusion in the previous 7 days; Note: Erythropoietin is allowed. d. Creatinine clearance ≥ 30 mL/min per the Cockcroft-Gault formula; e. Aspartate aminotransferase and alanine aminotransferase ≤ 3.0× ULN (upper limit of normal); f. Serum bilirubin ≤ 1.5 × ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 × ULN); g. Serum albumin ≥ 2 g/dL.
- Patients must be willing and able to sign the informed consent form (ICF) and adhere to the protocol requirements
- Women of childbearing potential (WOCBP) must agree to use highly effective contraceptive method(s) while on MIRV and for ≥ 7 months after the last dose.
- WOCBP must have a negative pregnancy test ≤ 4 days before the first dose of MIRV
- The following requirements are for patients who are HIV seropositive: a. On established highly active antiretroviral therapy (HAART) for ≥ 12 weeks with an HIV viral load of less than 200 copies/mL, HAART is a requirement for the duration of the study. The specific agents are at the discretion of the investigator; b. Cluster of differentiation 4 (CD4+) T cell counts ≥ 400 cell/μL; c. No AIDS-defining opportunistic infection within the past 12 months
Exclusion Criteria
- Patients with borderline ovarian tumor or non-epithelial histology or mixed histology, including borderline or non-epithelial histology will be excluded
- Patients with clinically significant comorbid conditions, including but not limited to any of the following: a. Myocardial infarction ≤ 6 months before first dose; b. Unstable angina pectoris; c. Uncontrolled congestive heart failure (New York Heart Association > Class II); d. Uncontrolled ≥ Grade 3 hypertension (per NCI-CTCAE v5.0); e. Uncontrolled cardiac arrhythmias; f. Patients with a history of hemorrhagic or ischemic stroke ≤ 6 months before enrollment; g. Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C); h. Patients with a previous clinical diagnosis of noninfectious interstitial lung disease (ILD), including noninfectious pneumonitis or evidence of ILD/pneumonitis on baseline chest CT; i. Patients with medical conditions requiring use of folate-containing supplements (eg, folate deficiency).
- Patients with prior hypersensitivity to monoclonal antibodies (mAbs)
- Patients who are pregnant or breastfeeding
- Patients who received prior treatment with MIRV or other FRα-targeting agents
- Patients with untreated or symptomatic central nervous system metastases
- Patients with a history of other malignancy ≤ 2 years before enrollment
- Patients with a prior known hypersensitivity reaction to study drugs or any of their excipients
- PROC patients with primary platinum-refractory disease, defined as disease that did not respond to (CR or PR), or progressed within ≤ 3 months of the last dose of first line platinum-containing chemotherapy
- Patients with prior wide-field radiotherapy (RT) affecting ≥ 20% of the bone marrow
- Patients with > Grade 1 peripheral neuropathy per National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0)
- Patients with significant active or chronic corneal disorders (eg, corneal dystrophies, degenerations, limbal stem cell deficiency), history of corneal transplantation, significant ocular inflammatory conditions (eg, active or recurrent uveitis), or other active ocular conditions requiring ongoing treatment/monitoring, such as uncontrolled glaucoma, active diabetic retinopathy with macular edema, macular degeneration requiring treatment ≤ 90 days before the first dose, presence of papilledema, BCVA worse than 20/70 in either eye, or monocular vision.
- Patients receiving corticosteroid or vasoconstricting eye drops at baseline or within 5 weeks of C1D1
- Patients who are ineligible to receive either brimonidine or corticosteroid eye drop
- Patients with serious concurrent illness or clinically relevant active infection, including, but not limited to the following: a. Active hepatitis B or C infection (whether or not on active antiviral therapy); b. HIV infection (if inclusion criteria #15 is not met) c. Active cytomegalovirus infection; d. Any other concurrent infectious disease requiring intravenous (IV) antibiotics ≤ 2 weeks before the first dose of MIRV
- Patients with a history of multiple sclerosis or other demyelinating disease or Lambert-Eaton syndrome (paraneoplastic syndrome).
- Patients with medical conditions requiring chronic systemic corticosteroids, including those requiring low physiologic doses. Patients requiring topical, inhaled, and/or intranasal corticosteroid therapy are eligible.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 01 Apr 2024 | 10 |
 France | Not Recruiting | 01 Apr 2024 | 13 |
 Ireland | Not Recruiting | 01 Apr 2024 | 10 |
 Spain | Not Recruiting | 01 Apr 2024 | 13 |
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 |
|---|---|---|---|---|---|---|
Mirvetuximab Soravtansine | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 6 | 21 | PRD3448766 |
Pred Forte 10 mg/ml colirio en suspensión | Test | COLIRIO EN SUSPENSIÓN | CONJUNCTIVAL USE | 0.6 | 21 | PRD9902305 |
Brimonidine Tartrate 0.2% w/v Eye Drops. | Test | EYE DROPS | CONJUNCTIVAL USE | 0.3 | 21 | PRD377824 |
Pred Forte 1% w/v, Eye Drops Suspension | Test | EYE DROPS SUSPENSION | CONJUNCTIVAL USE | 0.6 | 21 | PRD9616688 |
Alphagan 2 mg/ml colirio en solución | Test | COLIRIO EN SOLUCIÓN | CONJUNCTIVAL USE | 0.3 | 21 | PRD9910803 |