IRB Study Number 25-701
Status Recruiting
Phase Phase 2
Locations Fairview Hospital, Hillcrest Hospital, Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objective
To evaluate the anti-tumor activity of carboplatin + MIRV in newly diagnosed subjects with advanced-stage FRα-expressing (≥ 75%, ≥ 2+) serous EOC as measured by RECIST v1.1 imaging response.
Secondary Objectives
• To evaluate change in CA-125 measurements from baseline in newly diagnosed subjects with advanced-stage FRα-expressing (≥ 75%, ≥ 2+) serous EOC receiving carboplatin + MIRV
• To assess the proportion of newly diagnosed subjects with advanced-stage FRα-expressing (≥ 75%, ≥ 2+) serous EOC for whom IDS is feasible after 3–6 cycles of carboplatin + MIRV, and to define the proportion of these subjects with a favorable surgical outcome, as defined by complete (R0) and near-complete (≤ 1 cm residual) resection
• To evaluate the safety and tolerability of neoadjuvant carboplatin + MIRV in newly diagnosed subjects with advanced-stage FRα-expressing (≥ 75%, ≥ 2+) serous EOC
• To assess PFS in newly diagnosed subjects with advanced-stage FRα- expressing (≥ 75%, ≥ 2+) serous EOC treated with neoadjuvant carboplatin + MIRV, IDS if feasible, ± postoperative bevacizumab, ± optional standard-of-care maintenance therapy
• To evaluate PROs including time to deterioration in disease-related symptoms in newly diagnosed subjects with advanced-stage FRα-expressing (≥ 75%, ≥ 2+) serous EOC treated with neoadjuvant carboplatin + MIRV, IDS if feasible, ± postoperative bevacizumab, ± optional standard-of-care maintenance therapy
Inclusion Criteria
Subjects must voluntarily sign and date an informed consent, approved by an IEC/IRB, prior to the initiation of any screening or study-specific procedures.
Age ≥ 18 years.
ECOG performance status of 0 or 1.
Laboratory values meeting the following criteria within the screening period prior to the first dose of study treatment:
• AST and ALT ≤ 3 × ULN;
• Estimated GFR ≥ 45 mL/min/1.73m2 by the 2009 CKD-EPI creatinine equation33,34 (see Section 15 Appendix C);
• Serum bilirubin ≤ 1.5 × ULN (subjects with a documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 × ULN);
• Serum albumin ≥ 2 g/dL;
• Absolute neutrophil count > 1,500/μL;
• Platelet count > 100,000/μL, without platelet transfusion in the prior 10 days;
• Hemoglobin > 9 g/dL, without red blood cell transfusion in the prior 10 days.
Are willing and able to comply with procedures required in this protocol.
Be judged by the investigator and/or treating physician to be an appropriate candidate to receive neoadjuvant chemotherapy.
Diagnosis of biopsy-confirmed high-grade, serous epithelial ovarian, fallopian tube or primary peritoneal cancer. Note: Core-biopsy results showing mullerian malignancy will be permitted if high-grade serous and no alternative primary malignancy suspected or confirmed such as endometrial carcinoma
Subject meets the following disease criteria: (See protocol)
Subjects who are HIV positive must meet the following requirements to be eligible:
• On established 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.
• CD4+ T cell counts ≥ 400 cell/μL;
• No AIDS-defining opportunistic infection within the past 12 months. Note: Use of experimental antiretroviral agents is not allowed. HIV-positive subjects must be managed in conjunction with an HIV specialist and according to the current local guidelines for the prevention of opportunistic infections in HIV-infected adults. Note: HIV testing is not required for study enrollment in subjects not known to be HIV positive.
Subject must have completed any major surgery at least 3 weeks before the first dose of study treatment and have recovered or stabilized from the side effects of prior surgery before the first dose of treatment on study.
Pregnancy testing in female subjects of childbearing potential:
• Subjects must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at baseline within 4 days prior to the first dose of the study treatment.
• Subjects with a borderline serum pregnancy test at Screening must have absence of clinical suspicion of pregnancy or other pathological causes of borderline results and a serum pregnancy test ≥ 3 days later to document continued lack of a positive result (unless prohibited by local requirements).
• Subjects with a urine pregnancy test at Baseline that is borderline or ambiguous must have a serum pregnancy test. In such cases, the subject must be excluded from participation if the serum pregnancy result is positive.
Female subjects of childbearing potential must practice at least 1 protocol-specified method of birth control, from Study Day 1 through at least 7 months after the last dose of study treatment. Female subjects of nonchildbearing potential do not need to use birth control.
Female subject who is not pregnant or breastfeeding, and is not considering becoming pregnant or donating eggs during the study or for at least 7 months after the last dose of study treatment.
Exclusion Criteria
Endometrioid, clear cell, mucinous, or sarcomatous tumor histology; mixed tumors containing any of the above histologies; or low-grade/borderline ovarian tumor.
> Grade 1 peripheral neuropathy per CTCAE v5.0.
Prior wide-field radiotherapy affecting more than 20% of the bone marrow.
Subjects with the following ocular history and/or concurrent disorders:
• History of corneal transplantation;
• Undergoing active postoperative management for refractive surgery, cataract surgery, corneal cross-linking, or corneal complications of surgery;
• Confluent SPK not expected to resolve to non-confluence or better within the screening window with SOC intervention;
• Active or chronic clinically significant (≥ Grade 3) corneal dystrophy (e.g., Fuchs dystrophy);
• 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, macular degeneration, presence of papilledema or an ocular condition with high risk of retinal detachment;
• Monocular vision with visual acuity in the worse eye, worse than 20/200 or visual fields less than 20 degrees (i.e., functional blindness in at least one eye).
History of multiple sclerosis or other demyelinating disease and/or Lambert-Eaton syndrome (paraneoplastic syndrome).
Clinically significant cardiac disease including, but not limited to, any of the following:
• Myocardial infarction ≤ 6 months prior to C1D1;
• Unstable angina pectoris;
• Uncontrolled congestive heart failure (New York Heart Association > Class II);
• Uncontrolled ≥ Grade 3 hypertension (per CTCAE v5.0);
• Uncontrolled cardiac arrhythmias;
• Significant ECG abnormalities, including ECG with QTcF > 470 msec (females).
History of hemorrhagic or ischemic stroke within 6 months prior to enrollment.
History of cirrhotic liver disease (Child-Pugh Class B or C).
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 that has resolved per investigator or resolution of the radiologic findings).
Prior treatment with MIRV or other FRα-targeting agents.
Spinal cord compression or clinically active CNS metastases.
History of other malignancy within 3 years prior to signing study consent. Note: Subjects with tumors with a negligible risk for metastasis or death (e.g., adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix or breast) are eligible.
Serious concurrent illness or clinically relevant active infection, including, but not limited to the following:
• Active hepatitis B or C infection (whether or not on active antiviral therapy);
• HIV infection (unless subject meets inclusion criterion #9);
• Active cytomegalovirus infection;
• Any other concurrent infectious disease requiring IV treatment within 14 days prior to the first dose of study treatment. Note: Testing at screening is not required for the above infections unless clinically indicated.
Clinically significant (per investigator's judgment) drug or alcohol abuse within the last 6 months.
History of clinically significant medical conditions, rapidly progressive disease, or any other reason that the investigator determines would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study treatment.
History of an allergic reaction or significant sensitivity to constituents of the study treatment (and its excipients) or other products in the same class.
Previously treated with any investigational treatment within 28 days or 5 half-lives of the treatment (whichever is longer) prior to the first dose of study treatment or is currently enrolled in another clinical study.
Previously treated with anticancer therapy including chemotherapy, radiation therapy, immunotherapy, or biologic agent for current cancer, with the exception of one cycle of singleagent carboplatin.
Requiring use of folate-containing supplements (e.g., folate deficiency).
