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.
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.
The proposed neoadjuvant chemotherapy regimen is as follows:
IV Carboplatin AUC 5 day 1 (Q21 days) 7 cycles (first cycle is Carbo alone) IV Mirvetuximab 6
mg/kg (adjusted ideal body weight) day 1 (Q21 days) 6 cycles (starting with cycle #2)
Patients will continue to receive MIRV until they present with PD per RECIST 1.1, as assessed
by study Investigator, unacceptable toxicity, withdraw consent, or death, whichever comes
first, or until the Sponsor terminates the study. Study treatment and/or participation in the
study may be discontinued at any time at the discretion of the Investigator. The following
may be reasons for the Investigator to remove a patient from the study drug:
The patient suffers an intolerable Adverse Event (AE). Noncompliance, including failure to
appear at one or more study visits Study treatment and/or participation in the study may be
discontinued at any time at the discretion of the Investigator.
The reason for treatment discontinuation must be captured in the clinical trial database. Any
AEs experienced up to the point of discontinuation and 30 days thereafter must be documented.
All serious adverse events (SAEs), and those AEs assessed by the Investigator as at least
possibly related to study drug should continue to be followed until they resolve or
stabilize, whichever comes first. Patients will continue to be followed for OS, after
discontinuing study drug.
For purposes of this study, the period of safety observation extends from the time of
informed consent until the 30-Day Follow-up visit unless additional follow-up safety
information is requested as described in Section 9.3. Short-term follow-up for patients who
discontinue study drug without documented PD will be followed per RECIST 1.1 every 12±1 weeks
until PD, until the patient starts new anticancer treatment, the patient dies, or the patient
withdraws consent, whichever comes first. All patients will be followed every 3±1 months for
survival until death, lost to follow-up, withdrawal of consent for survival or until EOS,
whichever comes first.
Radiographic tumor evaluation by CT or MRI of chest, abdomen, and pelvis will be performed
within 28 days before first dose of study drug, before IDS within 21 days after C4D1, and a
minimum of 21 days following C7D1. The same method of radiologic assessment used at Screening
must be used at all subsequent radiographic evaluations.
Tumor response will be assessed by the Investigator using RECIST v1.1. Response as determined
by the Investigator will be recorded in the clinical trial database.
The sample size will comprise of approximately 70 patients from the University of Alabama at
Birmingham.
The primary objective will be feasibility (the proportion of consented patients who
successfully obtain biopsy confirmation of disease status and IHC analysis of FRα receptor
status prior to starting treatment with mirv). The primary analysis will include all
consenting patients. Patients who obtain both the biopsy confirm and are FRα positive will be
considered feasibility successes. The remainder of the consenting sample will be considered
feasibility failures, regardless of the reason for failure.
Key Secondary Objective will be progression free survival (PFS), percentage disease free at 2
years, ORR prior to interval debulking surgery (IDS) per iRECIST 1.1 and GCIG CA-125
criteria, and percentage of optimal cytoreduction and pathological complete response (PCR) at
IDS.
Inclusion Criteria:
- 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 1.
- 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
Exclusion Criteria:
- 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
