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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 70
- 试验地点
- 12
- 主要终点
- Objective response rate (ORR)
研究概览
简要总结
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.
详细描述
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.
Those patients with PROC who have received prior bevacizumab, either in the platinum-resistant or in the platinum-sensitive setting, have few options. They typically receive subsequent single-agent chemotherapy. Unfortunately, response rates to single-agent chemotherapy are modest (~10 to 15%) and DOR is typically 4 to 8 months. Similarly, OS is poor (median ~11 to 14 months). Because PROC remains a significant unmet medical need, the National Comprehensive Cancer Network (NCCN) guidelines recommend that platinum-resistant patients participate in clinical trials.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Patients must have biopsy-confirmed high grade serous epithelial ovarian cancer.
- •Patients must present with stage III or IV disease and be appropriate to receive neoadjuvant chemotherapy
- •Patients must be willing to provide an archival tumor tissue block or slides, or undergo procedure to obtain a new biopsy using a low-risk, medically routine procedure for immunohistochemistry (IHC) confirmation of FRα positivity
- •Patients must have a performance status of 0 or
- •Patient's tumor must be positive for FRα expression as defined by a score of PS2+ intensity in >75% of cells
- •Patients must have adequate hematologic, liver and kidney functions defined as:
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1,500/μL)
- •Platelet count ≥ 100 x 109/L (100,000/μL) without platelet transfusion in the prior 10 days
- •Hemoglobin ≥ 9.0 g/dL
- •Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN
- •Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 x ULN)
- •Serum albumin ≥ 2 g/dL
- •Patients must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements
- •Women of childbearing potential (WCBP) must agree to use highly effective contraceptive method(s) (as defined in Section 5.8.6 while on MIRV and for at least 4 months after the last dose
- •WCBP must have a negative pregnancy test within the 4 days prior to the first dose of MIRV
排除标准
- •Patients who have previously been treated with a systemic anti-cancer therapy
- •Patients with low-grade serous, endometrioid, clear cell, or mucinous histology
- •Patients with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring, such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and /or monocular vision
- •Patients with serious concurrent illness or clinically relevant active infection, including, but not limited to the following:
- •History of hepatitis B or C infection (whether or not on active antiviral therapy)
- •History of human immunodeficiency virus (HIV) infection
- •Any other concurrent infectious disease requiring IV antibiotics within 2 weeks prior to the first dose of MIRV
- •Patients with a history of multiple sclerosis (MS) or other demyelinating disease and/or Lambert-Eaton syndrome (paraneoplastic syndrome)
- •Patients with clinically significant cardiac disease including, but not limited to, any of the following:
- •Myocardial infarction ≤ 6 months prior to first dose
- •Unstable angina pectoris
- •Uncontrolled congestive heart failure (New York Heart Association > class II)
- •Uncontrolled ≥ Grade 3 hypertension (per CTCAE)
- •Uncontrolled cardiac arrhythmias
- •Patients with a history of hemorrhagic or ischemic stroke within 6 months prior to 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 (ILD), including noninfectious pneumonitis
- •Patients requiring use of folate-containing supplements (eg, folate deficiency)
- •Patients with prior hypersensitivity to monoclonal antibodies (mAb)
- •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 (CNS) metastases
- •Patients with a history of other malignancy within 3 years prior to enrollment Note: patients with tumors with a negligible risk for metastasis or death (eg, adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix or breast) are eligible
研究组 & 干预措施
Arm A: alpha receptor positive_neoadjuvant chemotherapy regimen
- IV Carboplatin AUC 5 (Q21 days) 7 cycles (first cycle is Carbo alone, dosing for C1D1 will be provider's choice)
- IV Mirvetuximab 6 mg/kg (adjusted ideal body weight) day 1 (Q21 days) 6 cycles (starting with cycle #2)
干预措施: mirvetuximab soravtansine (MIRV; IMGN853) (Drug)
Arm B: alpha receptor negative
If a patient is found to be negative for FRα expression, they will be ineligible to receive the study treatment under the main study (Arm A). FRα negative patients will be enrolled under the biomarker-only arm (Arm B), and their treating physician can select the treatment they deem appropriate.
结局指标
主要结局
Objective response rate (ORR)
时间窗: Baseline through 2 years
To assess ORR per iRECIST 1.1 and GCIG CA-125 criteria
progression free survival (PFS)
时间窗: Baseline through 2 years
To assess percentage of patients with advanced-stage ovarian, fallopian tube, and peritoneal cancers per Response Evaluation Criteria in Solid Tumors (RECIST)1.1 and Gynecological Cancer Intergroup Cancer antigen 125 (GCIG CA-125) criteria.
Radiographic tumor assessment per RECIST v1.1 criteria
时间窗: Baseline through 2 years
Radiographic tumor response by CT or MRI of chest, abdomen, and pelvis using RECIST v1.1
次要结局
- Serum Cancer Antigen 125 (CA-125) assessments(Baseline through 2 years)
- Safety profile of treatment with carboplatin-mirvetuximab soravtansine according to CTCAE v4.03(Baseline through 2 years)
研究者
Rebecca Arend
Assistant Professor
University of Alabama at Birmingham