Maintenance therapy of patients with recurrent epithelial ovarian carcinoma with the anti-tumor-associated-mucin-1 antibody gatipotuzumab: results from a double-blind, placebo-controlled, randomized, phase II study

Abstract

Background Gatipotuzumab is a humanized monoclonal antibody recognizing the carbohydrate-induced epitope of the tumor-associated mucin-1 (TA-MUC1). This study aimed to evaluate the efficacy and safety of switch maintenance therapy with gatipotuzumab in patients with TA-MUC1-positive recurrent ovarian, fallopian tube, or primary high-grade serous peritoneal cancer. Patients and methods In this double-blind, randomized, placebo-controlled, phase II trial, patients with at least stable disease (SD) following chemotherapy were randomized 2:1 to receive intravenous gatipotuzumab (500 mg followed by 1700 mg 1 week later) or placebo every 3 weeks until tumor progression or unacceptable toxicity occurred. Stratification factors were the number of prior chemotherapy lines (2 versus 3-5), response versus SD after the most recent chemotherapy, and progression-free survival (PFS) <6 versus 6-12 months following the prior therapy. Primary endpoint was PFS according to modified immune-related RECIST 1.1 response criteria. Secondary endpoints were PFS at 6 months, safety, overall response rate, CA-125 progression, overall survival, quality of life, and pharmacokinetics. Results Overall, 216 patients were randomized to gatipotuzumab ( n = 151) or placebo ( n = 65). Median PFS with gatipotuzumab was 3.5 months as compared with 3.5 months with placebo (hazard ratio 0.96, 95% confidence interval 0.69-1.33, P = 0.80). No advantage for gatipotuzumab over placebo was seen in the secondary efficacy endpoints or in any stratified subgroups. Gatipotuzumab was well tolerated, with mild to moderate infusion-related reactions being the most common adverse events. Conclusions Gatipotuzumab switch maintenance therapy does not improve outcome in TA-MUC1-positive ovarian cancer patients. Trial registration ClinicalTrials.gov NCT01899599 ; https://clinicaltrials.gov/ct2/show/NCT01899599

Mucins and mucinous ovarian carcinoma: Development, differential diagnosis, and treatment

“…Gatipotuzumab, a humanized monoclonal antibody, recognizes the tumor-associated mucin-1 (TA-MUC1) carbohydrate-induced epitope and binds TA-MUC1 selectively with high affinity. Gatipotuzumab was found to be effective in clinical trials for the treatment of advanced ovarian cancer but not for the maintenance treatment of recurrent ovarian cancer [ [66] , [67] , [68] ]. CVac is a dendritic cell vaccine that targets the MUC-1 glycoprotein.…”

Antibody-Drug Conjugates Targeting Tumor-Specific Mucin Glycoepitopes

“…While still imperfect, here we report antibody-antigen affinity values (K D -dissociation constant) when the assessment was performed on epitope-expressing live cells (Scatchard analysis or KinExA methods unless otherwise indicated). In vivo mouse models [74] PankoMab (m) β-amanitin-conjugated PankoMab Cervical, ovarian, lung, breast, gastric, colorectal, liver, kidney, and thyroid tumors [75][76][77][78] β-amanitin-PankoMab in vitro [79] Gatipotuzumab/PankoMab-GEX (hu) gatipotuzumab /PankoMab-GEX humanize unconjugated form Phase I (NCT0122624) [80,81] Phase II (NCT01899599) [82,83] (m)DS6 huDS6-SPDB-DM4 (SAR566658)…”

“…Due to its antibody dependent cellular cytotoxicity (ADCC) activity [79], Gatipotuzumab (unconjugated form) was tested in Phase I clinical trials (NCT01222624) in patients with advanced TA-MUC1-positive carcinomas and Phase II trial (NCT01899599) in patients with TA-MUC1-positive ovarian tumors. While the mAb was well tolerated in ovarian cancer patients, unfortunately, gatipotuzumab did not improve disease outcomes compared to the placebo [81,83]. The potential of gatipotuzumab to function as an ADC, however, has not been fully explored.…”

GT-00AxIL15, a Novel Tumor-Targeted IL-15-Based Immunocytokine for the Treatment of TA-MUC1-Positive Solid Tumors: Preclinical In Vitro and In Vivo Pharmacodynamics and Biodistribution Studies

“…We developed GT-00AxIL15 as first-in-class IL-15-based immunocytokine targeting a tumor-associated, glycosylated epitope of MUC1 (TA-MUC1) to optimize tumor accumulation, efficacy, safety and half-life of IL-15 compared to untargeted therapeutics. The antibody-targeting moiety of GT-00AxIL15 is based on GT-00A (gatipotuzumab, historically PankoMab), a humanized IgG1 mAb designed for exclusive binding to TA-MUC1 and clinically developed for treatment of solid tumors [29][30][31]. TA-MUC1 is a combined carbohydrate-protein epitope which is expressed on a variety of carcinomas, their respective metastases as well as on cancer stem cells and is virtually absent on normal cells [32][33][34][35][36][37][38][39].…”