GB-5267 for the Treatment Platinum-Resistant Ovarian, Peritoneal, or Fallopian Tube Cancer

PRIMARY OBJECTIVE:

• To evaluate the safety and tolerability of GB-5267 in patient with platinum resistant ovarian cancer
• To determine the maximum tolerated dose (MTD).

SECONDARY OBJECTIVE:

• To assess the anti-tumor activity of GB-5267

This is a dose escalation study of GB-5267 In Cohort 1 Patients receive IV only infusion. Dose escalation continues until Maximum tolerated dose (MTD) is established. Once the MTD has been established Cohort B (Dose expansion with Combined IV and IP Infusion) is intended to assess whether this approach enhances local antitumor effects in the peritoneal cavity.

Inclusion criteria

• At least 18 years of age
• Patients must have epithelial ovarian, peritoneal, or fallopian tube cancer that is confirmed by histology or cytology, with a histopathological diagnosis of serous, clear cell, endometrioid, mucinous carcinoma, or carcinosarcoma.
• Must have platinum-resistant disease, defined as:

• Progression of disease within 6 months of last platinum-based chemotherapy, OR
• Patients who have an intolerance for further platinum-based therapy.
• CA125 > 2 x ULN as assessed at the local lab by a 501(k) cleared test at Screening.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Must have evaluable disease or measurable disease defined as:

a. Measurable lesion as per RECIST v1.1 criteria

• Adequate hematological function, including:

• Absolute neutrophil count (ANC) > 1,000/mm3
• Platelet count > 50,000/mm3
• Hemoglobin > 8.5 g/dL
• Adequate renal function, including estimated creatinine clearance > 60 mL/min (Cockcroft-Gault) or directly measured with a 24-hour urine collection test.
• Adequate liver function, including:

• Total bilirubin < 1.5 x ULN, except in subjects with Gilbert's Syndrome who must have a total bilirubin < 3 x ULN
• Aspartate and alanine aminotransferase (AST and ALT) < 3 x ULN; < 5 x ULN if there is liver involvement by the tumor.
• Life expectancy of at least 3 months without treatment.
• Participant must be willing to undergo core or excisional biopsy of a tumor lesion

• A pretreatment biopsy must be obtained following completion of screening procedures and at least 7 days prior to the cell infusion.
• An on-treatment biopsy must be performed on Day 28 (±5 days) after infusion.
• An end-of-treatment biopsy must be performed within 10 days of disease progression or any other reason for discontinuation.
• Individuals of child-bearing potential (ICBP), defined as a sexually mature individual who has not undergone a hysterectomy, bilateral oophorectomy, or tubal ligation, or who has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months,

• Must have a negative serum beta human chorionic gonadotropin (β-hCG) pregnancy test, as verified by the Investigator, at Screening and Baseline.
• Must agree to abstain from breastfeeding during study participation and for at least 1 year post-GB-5267 infusion.
• Must agree to use effective methods of contraception during sexual contact that has the possibility of resulting in pregnancy without interruption from the time of infusion until at least 1 year post GB-5267 infusion.
• Ability and willingness to adhere to the study visit schedule and all protocol requirements.
• Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion criteria

• Coagulation Abnormalities and Hemorrhage:

• Recent significant bleeding, defined as a history of Grade ≥2 hemorrhage within 30 days before Screening.
• Coagulation parameters (assessed at Screening):

• Activated partial thromboplastin time (aPTT) >1.5 × ULN. Exception: Participants on therapeutic heparin may be allowed if aPTT is between 1.5 and 2.5 × ULN.
• International Normalized Ratio (INR) >1.5. Exception: Participants on warfarin are allowed if INR is between 2.0 and 3.0 on two consecutive measurements taken 1-4 days apart.
• Anticoagulant use: Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes is excluded. Prophylactic anticoagulation (e.g., low-molecular-weight heparin [LMWH] 40 mg/day) or use of anticoagulants for venous access device patency is permitted if the participant has been on a stable dose for ≥4 weeks without bleeding complications.

• History or evidence of thrombotic or hemorrhagic disorders within 3 months prior to Screening, including cerebrovascular accident (CVA) / stroke, transient ischemic attack (TIA), or subarachnoid hemorrhage.
• Known history or presence of clinically relevant CNS pathology (e.g., untreated or active brain metastases, epilepsy requiring ongoing treatment, stroke or subarachnoid hemorrhage within 3 months, severe neurodegenerative disorders, or psychosis).
• Active or clinically significant autoimmune disease requiring systemic immunosuppression (e.g., >10 mg/day prednisone equivalent or other immunosuppressants) within the past 6 months.

Exception: Patients with stable, well-controlled autoimmune conditions, including but not limited to:

• Type 1 Diabetes Mellitus on stable insulin therapy
• Hypothyroidism managed with hormone replacement
• Vitiligo
• Resolved childhood asthma
• Patients on low-dose immunosuppressants (≤10 mg/day prednisone equivalent) without recent exacerbations
• Other non-systemic autoimmune conditions deemed low risk at the Principal Investigator's (PI) discretion

• Any treatment-related immune-mediated AEs from previous immunotherapy that have not resolved to baseline or Grade ≤1 at least 3 months prior to enrollment.
• Ongoing systemic bacterial, viral, or fungal infection not improving despite appropriate antimicrobial therapy, or requiring intravenous (IV) antimicrobials at Screening. Participants receiving prophylactic antimicrobials are eligible if there is no active infection.
• Any other active malignancy within 2 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ (e.g., cervix, breast).
• Need for urgent intervention due to tumor mass effects (e.g., bowel obstruction or major vascular compression) that would preclude protocol compliance.
• Cardiac-Related Exclusions:

• History of Class III or IV congestive heart failure, non-ischemic cardiomyopathy, unstable or poorly controlled angina, or peripheral arterial disease event within 6 months prior to enrollment.
• Echocardiogram or multigated acquisition (MUGA) scan with left ventricular ejection fraction (LVEF) <40%.
• Previous myocardial infarction within 1 year prior to Screening.
• Clinically significant arrhythmia (e.g., second- or third-degree AV block, paroxysmal atrial fibrillation requiring active treatment, or prior pacemaker/defibrillator placement).
• Any history of myocarditis.
• Signs or symptoms of active angina, arrhythmia, or heart failure. Moderate-to-severe valvular disease not surgically corrected is also excluded.
• Baseline plasma troponin above institutional ULN. Exception: Minimally elevated troponin-T is permitted if cleared by a cardiologist.
• Inadequately controlled hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg).
• Known history of hypertensive crisis or hypertensive encephalopathy.
• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, recent peripheral arterial thrombosis) within 6 months prior to enrollment.
• Pericardial involvement in the primary ovarian malignancy.
• Pulmonary and Third-Space Fluid:

• Oxygen saturation <92% on room air.
• Known history or evidence of interstitial lung disease (ILD) or active, non-infectious pneumonitis within the past 5 years.
• Clinically significant third-space fluid (pericardial, pleural, or peritoneal) requiring recurrent drainage, or fluid drained for symptom management within 28 days prior to Screening.
• Any serious, uncontrolled medical condition (e.g., cirrhotic liver disease, recent significant trauma, or severe psychiatric illness) that, in the opinion of the Investigator, could compromise participant safety or the interpretation of study data.
• Prior or Concurrent Therapies:

• Treatment with any previous anti-MUC16 therapy.
• Prior allogenic stem cell transplant.
• Receipt of any cellular or gene therapy.
• Prohibited medications relative to leukapheresis or study treatment:

• Steroids: Therapeutic doses (>10 mg/day prednisone equivalent) within 72 hours prior to leukapheresis/GB-5267 infusion; physiologic replacement doses and topical/inhaled steroids are allowed.
• Immunosuppressants: Any non-steroidal immunosuppressive medications (e.g., cyclosporine, biologic TNF inhibitors) within 2 weeks prior to leukapheresis.
• Antiproliferative therapies: Within 2 weeks prior to leukapheresis.
• Radiation therapy: Within 2 weeks prior to leukapheresis.
• Live Vaccine Administration:

• Receipt of a live vaccine within 30 days prior to enrollment.

• Infectious Disease (HIV, Hepatitis):
• Active or inadequately controlled hepatitis A, B, or C infection:

• Hepatitis A: Positive anti-HAV IgM excludes participation; positive anti-HAV IgG alone is allowed.
• Hepatitis B: Vaccinated individuals (positive HBsAb only) are eligible. Past exposure (HBcAb positive) is permitted if the participant has undetectable HBV DNA for ≥6 months and is on or has completed antiviral prophylaxis.
• Hepatitis C: Participants with positive anti-HCV antibody must have undetectable HCV RNA (PCR) for ≥6 months.
• Participants who are hepatitis antibody-positive but DNA/RNA-negative (e.g., due to recent IVIG) may be allowed at Investigator discretion