IRB Study Number 25-169
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
● To compare progression-free-survival (PFS) in patients with platinum-resistant ovarian cancer (PROC) receiving rinatabart sesutecan (Rina-S) versus investigator’s choice of therapy (IC)
Secondary Objectives
● To assess additional measures of efficacy of Rina-S compared to IC in patients with PROC.
● To assess the safety of Rina-S compared to IC in patients with PROC
● To assess potential changes in QTc associated with Rina-S
● To assess patient reported outcomes in patients receiving Rina-S and IC
Inclusion Criteria
The patient must provide written informed consent.
Be at least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place).
Patients must have histologically or cytologically confirmed high grade serous or endometrioid epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.
Patients must have received 1 to 4 prior lines of therapy.
Patients must have received prior treatment with the following therapies:
a) Platinum chemotherapy
b) Prior bevacizumab treatment is required, if labeled and available as standard of care per institutional guidelines, unless the patient has a documented contraindication or due to precautions/intolerance
c) Patients with known or suspected deleterious germline or somatic BRCA mutations and who achieved a complete or partial response to platinum-based chemotherapy must have been treated with a poly ADP-ribose polymerase (PARP) inhibitor as maintenance treatment unless the patient is not eligible for treatment with PARP inhibitor
d) Mirvetuximab soravtansine, if:
• Mirvetuximab soravtansine is available in the enrollment region, and
• The patient is eligible based on positive FRα expression per an FDA-approved (or local equivalent) test, and
• The patient does not have a documented medical exception, including 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
Notes:
All patients in countries where mirvetuximab soravtansine is available must have a documented result of an FDA-approved (or local equivalent) test for tumor FRα expression. Mirvetuximab soravtansine is considered available when it has regulatory approval in the participating country, is covered by national healthcare or private insurance in countries without national healthcare, and there is an approved and covered FRα diagnostic test.
Diagnostic testing (e.g., for FRα and BRCA) should be performed in a laboratory certified by Clinical Laboratory Improvement Amendments (CLIA; or local equivalent) using a test approved by the relevant regulatory body (FDA or local equivalent).
Adjuvant ± neoadjuvant therapy is considered 1 line of therapy. Maintenance therapy (e.g., bevacizumab, PARP inhibitors) will be considered part of the preceding line of therapy (i.e., not counted independently).
Therapy changed due to toxicity in the absence of progression will be considered part of the same line (i.e., not counted independently).
Hormonal therapy alone (i.e., without chemotherapy) will not be counted as a separate line of therapy.
- Patients must have platinum-resistant disease:
a) Patients who have only had 1 line of platinum-based therapy must have received at least 4 cycles of platinum, and must have either had a response (CR or PR) or had non-measurable disease at the start of platinum-based therapy, and then progressed between > 91 days and ≤ 183 days after the date of the last dose of platinum.
b) Patients who have received 2 to 4 lines of platinum-based therapy must have progressed on or within 183 days after the date of the last dose of platinum.
Note: Progression should be calculated from the date of the last administered dose of platinum therapy irrespective of maintenance therapy with, for example, bevacizumab or PARP inhibitor, to the date of the radiographic imaging showing progression.
Patients must have a tumor FRα (ie, FOLR1) expression result available prior to randomization per local site assessment with the Ventana FOLR1 (FOLR1-2.1) RxDx Assay adhering to the manufacturer’s instructions or as assessed by a sponsor designated central laboratory using the Ventana FOLR1 (FOLR1-2.1) RxDx Assay. Note: All patients must have FRα expression status testing results available prior to randomization. If the local laboratory testing result is not available in a patient who has previously been treated with mirvetuximab soravtansine, a tumor biopsy must be submitted for central laboratory testing.
All patients must be willing to provide a pre-treatment tumor specimen (archival or fresh biopsy samples). If a fresh biopsy is required, procedures more invasive than a core biopsy or significant risk procedures for which the procedure-associated absolute risk of mortality or major morbidity in the patient’s clinical setting and specific institution is 2% or higher, should not be utilized.
An ECOG performance status of 0 or 1.
Measurable disease per RECIST v1.1 at baseline.
The following baseline laboratory data is required:
● Absolute neutrophil count (ANC) ≥1500/μL
● Hemoglobin (Hgb) ≥9 g/dL
● Platelet count ≥100,000/μL
● Serum total bilirubin ≤1.5 × upper limit of normal (ULN) or ≤3 × ULN for patients with Gilbert’s disease
● Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN (≤5 × ULN if there is evidence of hepatic involvement by malignant disease)
● Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2, as calculated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 method
● Serum albumin ≥3 g/dL
Patients cannot receive supportive care (including transfusions, granulocyte colony stimulating factor [G-CSF], or pegylated G-CSF) for low platelets, neutrophils, or hemoglobin within 2 weeks prior to collection of baseline laboratory data.
- All toxicities related to prior anti-cancer radiotherapy, systemic therapy or surgical procedure must have recovered to baseline or Grade ≤ 1 based on the NCI CTCAE v5.0 except alopecia, Grade 2 peripheral neuropathy, stable Grade 2 hypertension due to prior bevacizumab and that is controlled with 1 or 2 antihypertensive medications, stable chronic changes due to radiation or surgery, endocrine-related toxicities due to checkpoint inhibitor treatment that can be corrected through hormone replacement therapy, and Grade 2 laboratory abnormalities that meet eligibility requirements.
Exclusion Criteria
Prior therapy with an antibody-drug conjugate containing a topoisomerase 1 inhibitor.
Have primary platinum-refractory disease, defined as ovarian cancer that did not respond (CR or PR) to or progressed ≤ 91 days after the last dose of a first-line platinum-containing regimen.
History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS ≥90%), including, but not limited to, adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, ductal carcinoma in situ, or Stage I uterine cancer.
Known active central nervous system metastases or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry after brain metastasis treatment, they have no new or enlarging brain metastases, and are off corticosteroids and anticonvulsants prescribed for symptoms associated with brain metastases for at least 7 days prior to the first dose of study drug. Patients with suspected brain metastases at screening should undergo a CT/magnetic resonance imaging (MRI) of the brain prior to study entry.
Hospitalization or clinical symptoms due to gastrointestinal obstruction within the past 91 days or radiographic evidence of gastrointestinal obstruction at the time of screening. Enrollment of patients who currently require parenteral nutrition must be discussed with the study medical monitor to determine eligibility.
Ascites requiring frequent paracentesis (more often than approximately every 4 weeks) for symptomatic management. Enrollment of patients with an indwelling peritoneal catheter must be discussed with the medical monitor to determine eligibility.
Any uncontrolled Grade ≥ 3 (per NCI CTCAE v5.0) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of study drug. Routine antimicrobial prophylaxis is permitted.
Uncontrolled diabetes mellitus, defined as glycated hemoglobin (HbA1c) ≥8% or HbA1c between 7% and <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
Patient is known to be hepatitis B positive (defined by a positive test for hepatitis B surface antigen [HBsAg] or antibodies to hepatitis B surface [anti-HBs] or core antigens [anti-HBc]). Patients immune due to vaccination or passive immunization due to immunoglobulin therapy can be included [ie, positive HBsAb and negative to both HBsAg and HBcAb]. Patient is known to be hepatitis C positive (defined by polymerase chain reaction [PCR] or on antiviral therapy for hepatitis C within the last 183 days). Patients who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks.
Positive for human immunodeficiency virus (HIV).
Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, serious cardiac arrhythmia, or congestive heart failure with symptoms consistent with New York Heart Association Class III-IV (Appendix I) within 183 days prior to their first dose of study drug. For patients assigned to PLD only, LVEF must be within institutional normal/acceptable limits by MUGA or echocardiography at screening.
History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids within the past 2 years, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
Clinically significant autoimmune disease, either currently present or present within the previous 2 years, including a current requirement for systemic immunosuppressive therapy equivalent to >10 mg/prednisone daily (local immunosuppressive therapy such as inhaled or topical corticosteroids is allowed).
Prior anti-tumor treatments must have a washout period of 2 weeks for small molecules and 4 weeks for antibody-based therapeutics prior to the first dose of study drug. If the underlying disease has progressed on treatment with antibody-based therapeutics, a washout period of 2 weeks prior to the first dose of study drug is acceptable.
Concurrent participation in another clinical study of an investigational therapy. Participation in long-term survival follow-up from a prior study that does not require ongoing laboratory or imaging assessments is allowed.
Radiotherapy or major surgery that is not completed 2 weeks prior to the first dose of study drug.
Patients of childbearing potential, unless under the following conditions:
a) Must have a negative serum pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to the first dose of study drug. Patients with false positive results and documented verification that the patient is not pregnant are eligible for participation.
b) Must agree not to try to become pregnant during the study, starting at time of informed consent and for at least 7 months after the final dose of study drug.
c) Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 7 months after the final dose of study drug.
d) If sexually active in a way that could lead to pregnancy, must consistently use a highly effective method of birth control (as described in Appendix H) starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of study drug.
Known hypersensitivity to any excipient contained in the drug formulation of Rina-S or in the formulation of the assigned treatment in the IC arm.
Other serious underlying medical condition that, in the opinion of the investigator, would impair the patient’s ability to receive or tolerate the planned treatment and follow-up, including estimated life expectancy <12 weeks.
The following exclusion criteria apply only to patients participating in the QTc substudy:
a) A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms)
b) QRS duration of >120 ms
c) Clinically significant abnormal rhythm at screening
d) Clinically significant cardiac valve abnormality (e.g., stenosis, regurgitation)
e) History of left ventricular ejection fraction (LVEF) <0.30
f) A history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome)
g) Use of concomitant medications that prolong the QT/QTc interval
- Radiotherapy treatment to more than 25% of the bone marrow or with a wide field of radiation within 12 weeks of the first dose of study drug.
