IMMU-132 in TROP-2 Overexpressed Advanced and Relapsed Ovarian Cancer

IMMU-132 in TROP-2 Overexpressed Advanced and Relapsed Ovarian Cancer: A Phases Ib, Single Arm Study

To observe the efficacy and safety of IMMU-132 in patients with advanced or recurrent ovarian cancer with high TROP-2 expression in tumor tissue, who have failed standard therapy or are unable to receive standard treatment.

Trophoblast cell surface antigen-2 (TROP-2) is overexpressed in a variety of epithelial-derived tumor tissues and represents a promising antitumor therapeutic target. Novel antibody-drug conjugates (ADCs) targeting TROP-2, such as IMMU-132 (SG), Datopotamab Deruxtecan (Dato-DXd), and Sacituzumab Tirumotecan (MK-2870), are under active development. In ovarian cancer, efficacy data for TROP-2 ADCs mainly derive from pan-solid tumor clinical studies. TROP-2 expression exhibits intratumoral heterogeneity. Currently, there is no standardized or internationally accepted guideline for evaluating TROP-2 expression. TROP-2 expression status can be assessed using the H-score scoring system: 0-100 as low expression, 100-200 as moderate expression, and >200 as high expression. An exploratory analysis of the ASCENT study in triple-negative breast cancer, which categorized TROP-2 expression as high, moderate, or low based on H-score, found that patients with high expression had double the efficacy compared to those with moderate expression (44% vs 22%). Therefore, subsequent studies are warranted to explore effective screening criteria for TROP-2 ADC drugs to achieve more precise diagnosis and treatment. Our center has observed that among 3 patients with heavily pretreated recurrent ovarian cancer and high TROP-2 expression in tumor tissue, 1 achieved a complete response (CR) and 2 achieved partial responses (PR) following SG monotherapy. Safety was favorable, with main side effects being grade 1-2 gastrointestinal reactions and no grade 3-5 adverse reactions. Accordingly, this study will prospectively observe the efficacy of IMMU-132 monotherapy in patients with advanced or recurrent ovarian cancer characterized by high TROP-2 expression in tumor tissue.

Inclusion Criteria:

• Age ≥ 18 years and ≤ 80 years;
• Histologically confirmed advanced or recurrent high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer;
• Recurrent patients meeting one of the following two conditions:

Disease recurrence or progression after at least one prior platinum-based chemotherapy regimen, with disease progression occurring less than 6 months from the last dose of platinum-based chemotherapy;

• Disease recurrence or progression after at least three prior platinum-based chemotherapy regimens, with disease progression occurring ≥ 6 months from the last dose of platinum-based chemotherapy, and who are unable to receive standard platinum-based chemotherapy;
• Patients with advanced epithelial ovarian cancer presenting with hematogenous metastasis, who are unable to receive standard treatment, with an estimated life expectancy of more than 3 months but approximately not exceeding 12 months with current therapy;
• Have measurable disease per RECIST 1.1 criteria (Appendix A) or diagnosis of recurrence/disease progression per GCIG criteria;
• Known BRCA (Breast Cancer Gene) and HRD (Homologous Recombination Deficiency) status;
• Have available paraffin-embedded or fresh tumor tissue for TROP-2 testing;
• Tumor tissue TROP-2 H-score > 200;
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2;
• Adequate bone marrow hematopoietic function and organ function, allowing the patient to receive treatment;
• Patients must have had at least a 2-week interval from prior therapy (chemotherapy, investigational agents including small molecule inhibitors, endocrine therapy, immunotherapy, and/or radiotherapy) or major surgery;
• Patients must have had at least a 2-week interval from high-dose systemic corticosteroids (however, low-dose corticosteroids < 20 mg prednisone or its equivalent are permitted);
• Patients must have recovered from acute toxicity due to prior therapy to Grade 1 or below;
• Signed informed consent.

Exclusion Criteria:

• Patients who have previously received topoisomerase I inhibitor therapy;
• Patients with known hypersensitivity to the study drug, its metabolites, or formulation excipients;
• Patients requiring ongoing treatment or prior use of any prohibited medications (e.g., UGT1A1 inhibitors);
• Patients with Gilbert's syndrome;
• Patients with other uncontrolled malignancies concurrently or within 5 years, whose treatment would interfere with the current therapy for recurrent ovarian cancer or affect the prognosis of this treatment. Carcinoma in situ and breast cancer (without active disease or signs of recurrence) are excluded;
• Patients with a history of clinically significant hemorrhage, bowel obstruction, or gastrointestinal perforation within 6 months prior to the start of study treatment, with an estimated life expectancy of less than 3 months;
• Patients with a history of significant cardiac disease within 6 months, such as uncontrolled hypertension, unstable angina, uncontrolled congestive heart failure (NYHA Class III-IV), or clinically significant arrhythmias requiring antiarrhythmic therapy (except stable atrial fibrillation);
• Patients with known clinically significant active chronic obstructive pulmonary disease (COPD) or other moderate-to-severe chronic respiratory disease within 6 months;
• Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with treated brain metastases may participate provided they have stable CNS disease for at least 4 weeks prior to the first dose, have all neurological symptoms returned to baseline, have no evidence of new or enlarging brain metastases, and are on a daily dose of ≤ 20 mg prednisone or its equivalent. All patients with carcinomatous meningitis are excluded regardless of clinical stability;
• Patients with uncontrolled seizure history or active neurologic disorders; Patients with known HIV-1 or HIV-2 (or HIV-1/2 antibody positive) with detectable viral load, or those taking medications that may interfere with SN-38 metabolism;
• Patients with active HBV or HCV. For patients with a history of HBV or HCV, those with detectable viral load will be excluded;
• Patients with known bleeding diathesis or active bleeding disorders;
• Patients with active ≥ Grade 2 anorexia, nausea, or vomiting, and/or signs of bowel obstruction;
• Patients with other concurrent medical or psychiatric conditions that, in the investigator's opinion, may confound study interpretation or prevent completion of study procedures and follow-up examinations;
• Patients with any unstable medical problems (including the cardiac issues mentioned above, active treatment for symptomatic pulmonary embolism, stroke, renal or hepatic insufficiency, active infection/sepsis requiring intravenous antibiotics);
• Any medical condition that, in the investigator's opinion, poses an undue risk to the patient's participation in the study.