Study of Carboplatin and Mirvetuximab Soravtansine in First-Line Treatment of Patients Receiving Neoadjuvant Chemotherapy With Advanced-Stage Ovarian, Fallopian Tube or Primary Peritoneal Cancer
brief summary
The proposed study design is a single arm Phase II trial to document the feasibility of carboplatin-mirvetuximab - in patients with advanced-stage EOC. Patients with biopsy confirmed, newly diagnosed, advanced-stage serous EOC deemed appropriate for NACT will have their tumors evaluated for FRα receptor over-expression via a centralized immunohistochemical assay (IHC) and identified as appropriate for study participation if IHC staining is PS2+ in \>75% of cells (40% of all serous patients). Eligible patients will receive NACT with one cycle of carboplatin, followed by mirvetuximab + carboplatin (if FRα +) every 21 days for three cycles prior to interval cytoreductive surgery (iCRS). A total of 70 will be included in the study. Following completion of 4 cycles total of NACT and after allowing for appropriate recovery of cycle # 4, patients eligible for surgery, will undergo an iCRS. Patients will then complete 3 more cycles of mirvetuximab + carboplatin for a total of 7 intended cycles of treatment. It is up to the treating physician if they want to add bevacizumab to the last 2 cycles or use any type of maintenance therapy. The decision to add bevacizumab or use maintenance therapy does not need to be made upfront. Patients will sign a screening consent form prior to tissue biopsy. If a patient is found to be FRα negative, their treating physician can select the treatment they deem appropriate and the patient will be declared a screen failure. Patients with BRCA mutations are not excluded from this trial and are allowed to receive standard of care maintenance therapy including bevacizumab and/or PARP inhibitors.
detailed description
Mirvetuximab soravtansine (also known as IMGN853 and MIRV) is an antibody-drug conjugate (ADC) that consists of a high affinity humanized monoclonal antibody against folate receptor α (FRα, the protein product of the folate receptor 1 \[FOLR1\] gene) that is conjugated to a cytotoxic maytansinoid by the hindered disulfide succinimidyl 4-(pyridin-2-yl)disulfanyl)-2-sulfo-butyrate linker (sulfo-SPDB) linker. FRα is a glycosyl-phosphatidylinositol (GPI)-linked protein, which shows limited normal tissue expression and high expression on the surface of solid tumors, particularly epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer (referenced herein collectively as EOC), endometrial cancer, non-small cell lung cancer (NSCLC), and renal cell cancer. The selective upregulation of FRα in solid tumors and the potent and selective cytotoxicity of MIRV against FRα-positive tumor cells demonstrated in nonclinical studies and clinical studies to date provide rationale for further investigation of MIRV in the treatment of FRα-positive tumors.
Ovarian cancer is a lethal disease with 22,530 new cases and 13,980 deaths expected in 2019 in the US. The estimated number of new EOC cases in the EU (EU27) in 2012 was 44,149 with 29,758 deaths. The overall 5-year survival for EOC patients is only 44%. Besides the incorporation of a platinum- and taxane-based chemotherapy regimen into the upfront treatment, no major strides have been made to improve overall survival (OS) following EOC diagnosis.
Standard of care chemotherapy includes every 21-day paclitaxel and carboplatin, weekly paclitaxel and every 21-day carboplatin. Recently, bevacizumab was approved to be given with and to follow intravenous chemotherapy in front line ovarian cancer based on the PFS advantage demonstrated in GOG 218 and ICON7. This study continued bevacizumab for 15 cycles post completion of 6 cycles of chemotherapy. In evaluating the morphology of the Kaplan Meier curves from both these trials, it is apparent that there is an inflexion in the curves at the point where the bevacizumab is discontinued. To evaluate whether further continuation of bevacizumab would improve PFS, AGO-OVAR17 (BOOST study) is evaluating 15 versus 30 cycles of bevacizumab following front line chemotherapy. These results are anticipated in 2021. Given the above data, this trial as designed, will not include a specific maintenance portion, but physicians can choice what type of maintenance therapy, if any, they give at the completion of at least 7 cycles of platinum +Mirvetuximab soravtansine.
Despite considerable improvements in primary therapy, 80% of the patients with advanced EOC are expected to relapse during or after treatment with platinum-containing regimens. Disease recurring within 6 months of platinum-based chemotherapy is classified as platinum resistant, whereas, disease recurring longer than 6 months after therapy is termed platinum sensitive.
official title
Single-Arm Phase II Study of Carboplatin and Mirvetuximab Soravtansine in First-Line Treatment of Patients Receiving Neoadjuvant Chemotherapy With Advanced-Stage Ovarian, Fallopian Tube or Primary Peritoneal Cancer Who Are Folate Receptor α Positive