2022-501606-35-00 – Randomized, multicenter, open-label, Phase 3 study of mirvetuximab soravtansine in combination with bevacizumab versus bevacizumab alone as maintenance therapy for patients with FRα-high recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancers who have not progressed after second-line platinum-based chemotherapy plus bevacizumab (GLORIOSA).
- Trial ID
- 2022-501606-35-01
- Protocol
- IMGN853-0421
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare **progression-free survival (PFS)**, as assessed by the investigator using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), in patients with FRα-high recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancers. These patients have not progressed after second-line platinum-based chemotherapy plus bevacizumab and are randomized to receive maintenance therapy with mirvetuximab soravtansine (MIRV) plus bevacizumab (Arm 1) versus bevacizumab alone (Arm 2). PFS is a critical endpoint in oncology trials as it provides an indication of how effectively a treatment can delay disease progression, which is particularly relevant for patients with recurrent cancers.
Secondary objectives include:
- Comparing overall survival (OS) between patients randomized to maintenance MIRV plus bevacizumab versus bevacizumab alone.
- Evaluating the safety and tolerability of MIRV in combination with bevacizumab.
- Assessing the time to second disease progression (PFS2).
- Determining the objective response rate (ORR) as assessed by the investigator and by blinded independent central review (BICR) in patients with measurable disease per RECIST v1.1 at randomization.
- Measuring the duration of response (DOR) in patients who achieved a confirmed best overall response of complete response (CR) or partial response (PR) upon completion of platinum-based combination chemotherapy with bevacizumab.
- Evaluating disease-free survival (DFS) in patients who have no measurable disease per RECIST v1.1 at randomization.
- Assessing the CA-125 response rate per Gynecologic Cancer Intergroup (GCIG) criteria.
- Evaluating patient-reported outcome health-related quality of life (HRQoL) of disease-related symptoms using the NCCN-FACT Ovarian Symptom Index (NFOSI-18) DRS-P (disease-related symptom subscale – physical).
Participants
The clinical trial involves a total of **255 participants** who are exclusively **female** and aged **18 years and older**. The study population consists of individuals diagnosed with **platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancers**. Participants were selected based on their completion of platinum-based triplet therapy and achieving a complete response (CR), partial response (PR), or stable disease (SD) before randomization. The trial does not include male subjects, and the population is considered vulnerable. Participants must have adequate hematologic, liver, and kidney functions and have stabilized or recovered from prior therapy-related toxicities. Lifestyle considerations such as diet and physical activity are not specified. The trial requires participants to have a confirmed diagnosis of high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer, and they must be willing to provide tumor tissue for immunohistochemistry confirmation of high FRα expression. Prior BRCA testing is required, and participants must have relapsed after one line of platinum-based chemotherapy, demonstrating platinum sensitivity. The sponsor has not provided additional information regarding lifestyle factors or other demographic details.
Plans and Procedures
The clinical trial is designed as a **randomized**, open-label, Phase 3 study to evaluate the efficacy of **mirvetuximab soravtansine** in combination with **bevacizumab** versus bevacizumab alone as maintenance therapy for patients with FRα-high recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancers. The primary objective is to compare progression-free survival (PFS) as assessed by the investigator using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The trial will also conduct a sensitivity analysis of PFS by a blinded independent central review (BICR). The estimated duration of the trial is from August 31, 2023, to August 30, 2030.
Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, prior treatment history, and current health status. Following successful screening, participants will be randomized into one of two arms: Arm 1 receiving mirvetuximab soravtansine plus bevacizumab, or Arm 2 receiving bevacizumab alone. The trial includes regular follow-up visits to monitor treatment response and adverse events, with assessments including CT/MRI scans and CA-125 measurements. The end-of-study visit will occur after the completion of the treatment period or upon early termination.
The expected length of participant involvement is determined by the treatment period, which may vary based on individual response and tolerance to the therapy. Conditions that may lead to early termination from the study include disease progression, unacceptable toxicity, or withdrawal of consent. Participants are required to adhere to the protocol requirements, including the use of effective contraception for females of childbearing potential and compliance with scheduled visits and assessments.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments. **Mirvetuximab Soravtansine** is an experimental medication used in this study. It is a concentrate for solution for infusion, administered via **intravenous infusion**. The maximum daily dose is 6 mg/kg, with a total treatment period of 21 days. This medication is an antibody-drug conjugate that binds with high specificity and affinity to folate receptor α. Participant compliance is monitored through regular assessments and adherence checks.
**Bevacizumab** is used both as an experimental and comparator treatment in this trial. It is available in several formulations, including MVASI, Zirabev, and Alymsys, all as concentrates for solution for infusion. The administration route is intravenous, with a maximum daily dose of 15 mg/kg and a treatment period of up to 180 days. Bevacizumab is a monoclonal antibody that inhibits angiogenesis, and its administration is monitored for compliance and adverse effects.
**Gemcitabine** is another experimental medication used in the trial, available as a concentrate for solution for infusion. The maximum daily dose is 1000 mg/m², with a treatment period of 24 days. It is administered intravenously, and participant adherence is ensured through scheduled dosing and monitoring.
**Paclitaxel** is administered as a concentrate for solution for infusion, with a maximum daily dose of 175 mg/m² and a treatment period of 24 days. It is used in combination with other treatments, and compliance is monitored through infusion records and patient logs.
**Carboplatin** is used in the trial as a concentrate for solution for infusion, with a maximum daily dose of 400 mg/m² and a treatment period of 32 days. It is administered intravenously, and adherence is tracked through infusion schedules and patient follow-ups.
**Doxorubicin Hydrochloride** is provided as a pegylated liposomal concentrate for solution for infusion, with a maximum daily dose of 50 mg/m² and a treatment period of 32 days. It is administered intravenously, and compliance is monitored through infusion records and patient assessments.
**Propylene Glycol** is used as a non-experimental treatment in the form of eye drops, with a maximum daily dose of 0.3 ml and a treatment period of 156 days. It is administered for ocular use, and adherence is monitored through patient diaries and follow-up visits.
**Prednisolone Acetate** is provided as an eye drops suspension, with a maximum daily dose of 0.3 ml and a treatment period of 156 days. It is administered for conjunctival use, and compliance is ensured through patient logs and regular check-ups.
Efficacy
The efficacy of the clinical trial will be assessed primarily through **progression-free survival (PFS)**, as evaluated by the investigator using the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). PFS is defined as the time from the date of randomization until the occurrence of investigator-assessed progressive disease (PD) or death, whichever occurs first. Additionally, PFS will be assessed as a sensitivity analysis by a blinded independent central review (BICR) in the same patient population.
Secondary endpoints for efficacy evaluation include overall survival (OS), defined as the time from randomization to death, with patients alive at the time of analysis being censored at the last date known to be alive. Other secondary endpoints include treatment-emergent adverse events (TEAEs), PFS2, overall response rate (ORR), duration of response (DOR), disease-free survival (DFS), CA-125 response rate per GCIG criteria, and patient-reported outcomes/health-related quality of life (PRO/HRQoL) measured by NFOSI-18 DRS-P.
The schedule for measuring and collecting these efficacy parameters involves CT/MRI scans and CA-125 measurements conducted at least 3 weeks but no more than 8 weeks after the last planned dose of triplet therapy and before randomization. The analysis of these parameters will be conducted at various timepoints throughout the trial, including at the end of treatment and during follow-up assessments.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must be ≥ 18 years of age and ≥ age of majority per local country legal status.
- Patients must have received paclitaxel, gemcitabine, or pegylated liposomal doxorubicin as the partner drug to platinum-based triplet therapy in the second-line.
- All patients must have CT/MRI scans and CA 125 measurement within 3 to 8 weeks after last dose of triplet therapy and within 21 days prior to randomization. The last dose of triplet therapy is defined as Day 1 of last cycle of platinum-based triplet therapy in second-line.
- Patients must receive the first dose of maintenance therapy within 10 weeks from the last dose of platinum-based triplet therapy in the second-line (defined as Day 1 of last cycle of platinum-based triplet therapy).
- After completion of triplet therapy and before randomization, patients must meet one of the following criteria: a. Have at least 1 lesion that meets RECIST v1.1 (radiologically measured by the investigator) and determined by the investigator to have either SD or a PR to their treatment; or b. Have persistently elevated CA-125 without measurable disease and determined by the investigator to have either SD or a PR to their treatment; or c. Have no evidence of disease by both radiographic interpretation by the investigator and normalization of their CA-125, determined to be a CR. Note: For patients entering on Run-In, inclusion criteria 14 through 20 must be satisfied at time of Run-In enrollment (prior to first dose of Run-In therapy on study).
- Patients must have stabilized or recovered (to Grade 1 or baseline) from all prior therapyrelated toxicities (excluding alopecia).
- Patients must have completed any major surgery at least 4 weeks before the first dose of study treatment (either Run-In or maintenance therapy) and have recovered or stabilized from the side effects of prior surgery before the first dose of treatment on study.Targeted radiation is allowed with a washout period of 2 weeks.
- Patients must have adequate hematologic, liver, and kidney functions at the time of randomization and before first dose defined as follows: a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor in the prior 10 days or long-acting white blood cell (WBC) growth factors in the prior 10 days of C1D1 of maintenance treatment; b. Platelet count ≥ 100 × 109/L (100,000/μL) without platelet transfusion in the prior 10 days of C1D1 of maintenance treatment; c. Hemoglobin ≥ 9.0 g/dL without packed red blood cell (PRBC) transfusion in the prior 10 days of C1D1 of maintenance treatment; Note: Patients with Grade 2 anemia are permitted to enroll. d. Estimated glomerular filtration rate via the Chronic Kidney Disease Epidemiology Collaboration equation, (eGFRCKD-EPI) ≥ 30 mL/min/1.73 m2; 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 Note: For any patients who have received a transfusion to correct a laboratory abnormality during the timeframe defined above, they should have repeat laboratory assessments to confirm that they meet the criteria no sooner than 4 days prior to dosing.
- Patients or their legally authorized representative(s) must be willing and able to sign the informed consent form (ICF), adhere to the protocol requirements, and are able to complete the scheduled assessments. Note: If ICF is signed by a legally authorized representative, certain study assessments, including ocular symptom assessments, adverse event (AE) reporting, and patient-reported outcome (PRO), must be completed by the patient.
- Females of childbearing potential (FCBP) must agree to use highly effective contraceptive method(s) while on study medication during the study and for at least 7 months after the last dose of MIRV and 6 months after the last dose of bevacizumab.
- FCBP must have a negative pregnancy test within 4 days before the first dose of therapy.
- Patients must have an Eastern Cooperative Oncology Group performance status of 0 or 1.
- Patients must have a confirmed diagnosis of high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer.
- Patients must be confirmed high FRα expression as defined by FRα positivity of ≥ 75% of tumor membrane staining at ≥ 2+ intensity (PS2+) based on the regulatory agency-approved Ventana FOLR1 (FOLR1-2.1) Assay for entry into the study. Patients must be willing to either provide documentation of Ventana FOLR1 (FOLR1-2.1) Assay results from prior testing or provide tissue for central testing in the study tissue testing laboratory using the Ventana FOLR1 (FOLR1-2.1) Assay. Patients undergoing Pre-screening must provide an archival tumor tissue block or slides or must undergo a procedure to obtain a new biopsy using a low-risk, medically routine procedure for IHC confirmation of high FRα expression (reported as “positive”) as defined by the Ventana FOLR1 (FOLR1-2.1) Assay in a tissue testing laboratory. Note: Samples may be submitted for central testing as soon as patients pass the 6-month time point for platinum sensitivity (ie, sites do not have to wait for recurrence to determine FRα expression status).
- Testing on the tumor or prior germline testing of both BRCA1 and BRCA2 is required for eligibility before study entry where available as standard of care. Patients with somatic or germline BRCA mutations must have received prior treatment with a PARPi in maintenance following first-line treatment unless documented as clinically contraindicated. If BRCA1 and BRCA2 tests are not available as standard of care, test results and prior PARPi therapy are not required.
- Patients’ disease must have relapsed after frontline (first-line) platinum-based chemotherapy and must be platinum-sensitive defined as progression greater than 6 months from last dose of primary platinum therapy. Note: Bevacizumab treatment is allowed, but not required, in frontline regimen. HIPEC is allowed if given prior to initiating second-line triplet therapy.
- Patients must be appropriate for platinum-based triplet therapy for treatment of their first recurrence of PSOC (entering at Run-In phase) or undergoing or have completed triplet therapy for treatment of their first recurrence of PSOC (entering at maintenance phase).
- Patients must have received 4 to 8 cycles of second-line platinum-based triplet therapy, to include at least 3 cycles of bevacizumab in combination with platinum-based chemotherapy. Note: A minimum of 4 cycles of combination chemotherapy is required. If carboplatin, paclitaxel, gemcitabine, or pegylated liposomal doxorubicin (PLD) is stopped due to toxicity before 4 cycles of combination chemotherapy are given, the chemotherapy agent must be replaced by one of the other chemotherapies allowed by the study to complete at least 4 cycles. Up to 4 additional cycles of single agent in combination with bevacizumab is acceptable if appropriately documented. Documented toxicity must have been clinically evaluated as unlikely to be related to bevacizumab.
- In the case of interval secondary cytoreductive surgery, patients are permitted to have received only 2 cycles of bevacizumab if given in combination with the last 3 cycles of platinum-based triplet therapy in the second-line. In the case of cytoreductive surgery before second-line platinum-based triplet therapy, patients must have received at least 3 cycles of bevacizumab in combination with platinum-based chemotherapy after their surgery and before randomization.
- The following requirements are for patients who are HIV positive: 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 but should be checked for interaction with study agents before enrollment; b. Cluster of differentiation 4 (CD4+) T cell counts ≥ 350 cell/μL; c. No AIDS-defining opportunistic infection within the past 12 months; d. No history of other AIDS-defining illness besides opportunistic infection > 12 months before randomization. Note: Use of experimental antiretroviral agents are not allowed, HIV-positive patients must be managed in conjunction with an HIV specialist and managed according to the current local guidelines for the prevention of opportunistic infections in HIV infected adults. HIV testing is not required for study enrollment in patients not known to be HIV positive.
Exclusion Criteria
- Patients with endometrioid, clear cell, mucinous, or sarcomatous histology; mixed tumors containing any of the above histologies; or low-grade/borderline ovarian tumor
- More than one line of prior chemotherapy before current/planned triplet therapy. Lines of prior anticancer therapy are counted with the following considerations: a. Neoadjuvant ± adjuvant therapies are considered 1 line of therapy if the neoadjuvant and adjuvant correspond to 1 fully predefined regimen; otherwise, they are counted as 2 prior regimens. b. Maintenance therapy (eg, bevacizumab, PARPi) will be considered part of the preceding line of therapy (ie, not counted independently). c. Change due to toxicity will be considered part of the proceeding line of therapy.d.Use of hormonal therapy in the first-line therapy setting of a CA-125 elevation without evidence of disease on imaging is allowed and will not be counted as a line of therapy for recurrent disease.
- Patients with PD while on or following platinum-based triplet therapy
- After completion of triplet therapy and prior to randomization: Patients who receive an intervening dose of bevacizumab after completing the planned second-line triplet therapy (before randomization). (Note: The Day 15 dose of bevacizumab in the last prior cycle of triplet therapy including pegylated liposomal doxorubicin is not considered as an intervening dose).
- Patients with prior whole-pelvic or other wide-field radiotherapy affecting at least 20% of the bone marrow.Note: For patients entering on Run-In, exclusion criterion 5 must be satisfied at time of enrollment. All criteria will need to be met prior to randomization.
- Patients with > Grade 1 peripheral neuropathy per Common Terminology Criteria for Adverse Events (CTCAE).
- Patients with the following ocular history and/or concurrent disorders: b.Active or chronic corneal epithelial disorders other than non-confluent superficial keratopathy/keratitis, including confluent superficial punctate keratopathy/keratitis (SPK) not expected to resolve to non-confluence or better within the screening window with standard-of-care intervention c. History of corneal transplantation d.Undergoing active postoperative management for refractive surgery, cataract surgery, corneal cross-linking, or corneal complications of surgery e.Active or chronic clinically significant (≥ Grade 3) corneal disorders (eg, Fuch’s dystrophy or neurotrophic keratitis) f.Active ocular conditions requiring ongoing treatment/monitoring, such as glaucoma, which is not adequately controlled with medication or surgery, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, presence of papilledema or an ocular condition with high risk of retinal detachment g.Monocular vision with visual acuity in the worse-seeing eye worse than 20/200 or visual fields less than 20 degrees.
- Patients with serious concurrent illness or clinically relevant active infection, including but not limited to, the following:a.Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection Patients with HBV positivity must not meet criteria for anti-HBV therapy and must be HBsAg-negative. Patients with HCV positivity must have completed curative antiviral treatment and have either a negative HCV RNA or an undetectable viral load. b. HIV infection (if inclusion criterion #20 is not met).c.Active cytomegalovirus infection. d.Any other concurrent infectious disease requiring intravenous (IV) antibiotics within 2 weeks before the first dose of maintenance therapy. Note: Testing at screening is not required for the above infections unless clinically indicated.
- Patients with a history of multiple sclerosis or other demyelinating diseases and/or Lambert-Eaton syndrome (paraneoplastic syndrome)
- Patients with clinically significant cardiac disease including, but not limited to, any of the following: a. Myocardial infarction ≤ 6 months prior to C1D1 of maintenance treatment b. Unstable angina pectoris c. Uncontrolled congestive heart failure (New York Heart Association > class II) d. Uncontrolled ≥ Grade 3 hypertension (per CTCAE) e. Uncontrolled cardiac arrhythmias
- Patients with a history of hemorrhagic or ischemic stroke within 6 months before enrollment
- Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C)
- Patients with a previous clinical diagnosis of noninfectious interstitial lung disease, including noninfectious pneumonitis (exception: Grade 1 noninfectious pneumonitis diagnosed on or within 6 weeks after treatment with an immunotherapeutic agent used in the treatment of their malignancy that has resolved per investigator or resolution of the radiologic findings)
- History of bowel obstruction (including sub-occlusive disease) related to underlying disease within 6 months before the start of maintenance study treatment (triplet therapy for Run-In patients)
- History of abdominal fistula or gastrointestinal perforation
- Intra-abdominal abscess, evidence of rectosigmoid involvement by pelvic examination, bowel involvement on CT scan, or clinical symptoms of bowel obstruction within 4 weeks prior to randomization (or within 4 weeks prior to starting triplet therapy for Run- In patients)
- Clinically significant proteinuria: urine-protein to creatinine (UPC) ratio ≥ 1.0 or urine dipstick result ≥ 2+; patients with UPC ratio ≥ 1.0 or ≥ 2+ proteinuria should undergo 24- hour urine collection and must show result ≤ 2 g of protein in a 24-hour period
- History of Grade 4 thromboembolic events
- Patients not appropriate for bevacizumab 15 mg/kg dosing at the start of maintenance therapy as per the treating physician
- Patients requiring use of folate-containing supplements (eg, folate deficiency)
- Patients with prior hypersensitivity to monoclonal antibodies (mAbs)
- Women 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 within 3 years prior to signing study consent Note: Patients with tumors with a negligible risk for metastasis or death (eg, controlled basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast) are eligible.
- Prior known hypersensitivity reactions to study drugs or any of their excipients
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 31 Aug 2023 | 7 |
 Bulgaria | Not Recruiting | 31 Aug 2023 | 2 |
 Czechia | Not Recruiting | 31 Aug 2023 | 2 |
 France | Not Recruiting | 31 Aug 2023 | 12 |
 Germany | Not Recruiting | 31 Aug 2023 | 14 |
 Greece | Not Recruiting | 31 Aug 2023 | 2 |
 Hungary | Not Yet Recruiting | 31 Aug 2023 | 5 |
 Ireland | Not Recruiting | 31 Aug 2023 | 9 |
 Italy | Not Recruiting | 31 Aug 2023 | 28 |
 Poland | Not Recruiting | 31 Aug 2023 | 6 |
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 |
|---|---|---|---|---|---|---|
MVASI 25 mg/mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | CONCENTRATE FOR SOLUTION FOR INFUSION | 15 | 180 | PRD5803005 |
Carboplatin Accord, 10 mg/ml, koncentrat do sporządzania roztworu do infuzji | Other | KONCENTRAT DO SPORZĄDZANIA ROZTWORU DO INFUZJI | CONCENTRATE FOR SOLUTION FOR INFUSION | 400 | 32 | PRD2005421 |
Bendacitabin 38 mg/ml Pulver zur Herstellung einer Infusionslösung | Other | PULVER ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | CONCENTRATE FOR SOLUTION FOR INFUSION | 1000 | 24 | PRD4731079 |
Alymsys 25mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | CONCENTRATE FOR SOLUTION FOR INFUSION | 15 | 180 | PRD8838614 |
Pred Forte 1% w/v, Eye Drops Suspension | Other | EYE DROPS SUSPENSION | CONJUNCTIVAL USE | 0.3 | 156 | PRD9616688 |
Carboplatin Accord 10 mg/ml koncentratas infuziniam tirpalui | Other | KONCENTRATAS INFUZINIAM TIRPALUI | INTRAVENOUS INFUSION | 150 | 32 | PRD415301 |
Zirabev 25 mg/ml concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | CONCENTRATE FOR SOLUTION FOR INFUSION | 15 | 180 | PRD7082677 |
PROPYLENE GLYCOL | Other | — | OCULAR USE | 0.3 | 156 | SUB12566MIG |
Paclitaxel Bendalis 6 mg/ml Konzentrat zur Herstellung einer Infusionslösung | Other | KONZENTRAT ZUR HERSTELLUNG EINER INFUSIONSLÖSUNG | CONCENTRATE FOR SOLUTION FOR INFUSION | 175 | 24 | PRD8983541 |
Caelyx pegylated liposomal 2 mg/ml concentrate for solution for infusion | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | CONCENTRATE FOR SOLUTION FOR INFUSION | 30 | 32 | PRD9163065 |