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Item Augmenting Experimental Gastric Cancer Activity of Irinotecan through Liposomal Formulation and Antiangiogenic Combination Therapy(American Association for Cancer Research, 2022) Awasthi, Niranjan; Schwarz, Margaret A.; Zhang, Changhua; Klinz, Stephan G.; Meyer-Losic, Florence; Beaufils, Benjamin; Thiagalingam, Arunthathi; Schwarz, Roderich E.; Surgery, School of MedicineGastric adenocarcinoma (GAC) is the third most common cause of cancer-related deaths worldwide. Combination chemotherapy remains the standard treatment for advanced GAC. Liposomal irinotecan (nal-IRI) has improved pharmacokinetics (PK) and drug biodistribution compared with irinotecan (IRI, CPT-11). Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated the antitumor efficacy of nal-IRI in combination with novel antiangiogenic agents in GAC mouse models. Animal survival studies were performed in peritoneal dissemination xenografts. Tumor growth and PK studies were performed in subcutaneous xenografts. Compared with controls, extension in animal survival by nal-IRI and IRI was >156% and >94%, respectively. The addition of nintedanib or DC101 extended nal-IRI response by 13% and 15%, and IRI response by 37% and 31% (MKN-45 xenografts); nal-IRI response by 11% and 3%, and IRI response by 16% and 40% (KATO-III xenografts). Retardation of tumor growth was greater with nal-IRI (92%) than IRI (71%). Nintedanib and DC101 addition tend to augment nal-IRI or IRI response in this model. The addition of antiangiogenic agents enhanced tumor cell proliferation inhibition effects of nal-IRI or IRI. The tumor vasculature was decreased by nintedanib (65%) and DC101 (58%), while nal-IRI and IRI alone showed no effect. PK characterization in GAC xenografts demonstrated that compared with IRI, nal-IRI treatment groups had higher retention, circulation time, and tumor levels of CPT-11 and its active metabolite SN-38. These findings indicate that nal-IRI, alone and in combination with antiangiogenic agents, has the potential for improving clinical GAC therapy.Item First-in-Human, Phase 1 Dose-Escalation Study of Biparatopic Anti-HER2 Antibody-Drug Conjugate MEDI4276 in Patients with HER2-positive Advanced Breast or Gastric Cancer(American Association for Cancer Research, 2021) Pegram, Mark D.; Hamilton, Erika P.; Tan, Antoinette R.; Storniolo, Anna Maria; Balic, Kemal; Rosenbaum, Anton I.; Liang, Meina; He, Peng; Marshall, Shannon; Scheuber, Anita; Das, Mayukh; Patel, Manish R.; Medicine, School of MedicineMEDI4276 is a biparatopic tetravalent antibody targeting two nonoverlapping epitopes in subdomains 2 and 4 of the HER2 ecto-domain, with site-specific conjugation to a tubulysin-based microtubule inhibitor payload. MEDI4276 demonstrates enhanced cellular internalization and cytolysis of HER2-positive tumor cells in vitro This was a first-in-human, dose-escalation clinical trial in patients with HER2-positive advanced or metastatic breast cancer or gastric cancer. MEDI4276 doses escalated from 0.05 to 0.9 mg/kg (60- to 90-minute intravenous infusion every 3 weeks). Primary endpoints were safety and tolerability; secondary endpoints included antitumor activity (objective response, progression-free survival, and overall survival), pharmacokinetics, and immunogenicity. Forty-seven patients (median age 59 years; median of seven prior treatment regimens) were treated. The maximum tolerated dose was exceeded at 0.9 mg/kg with two patients experiencing dose-limiting toxicities (DLTs) of grade 3 liver function test (LFT) increases, one of whom also had grade 3 diarrhea, which resolved. Two additional patients reported DLTs of grade 3 LFT increases at lower doses (0.4 and 0.6 mg/kg). The most common (all grade) drug-related adverse events (AEs) were nausea (59.6%), fatigue (44.7%), aspartate aminotransferase (AST) increased (42.6%), and vomiting (38.3%). The most common grade 3/4 drug-related AE was AST increased (21.3%). Five patients had drug-related AEs leading to treatment discontinuation. In the as-treated population, there was one complete response (0.5 mg/kg; breast cancer), and two partial responses (0.6 and 0.75 mg/kg; breast cancer)-all had prior trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1). MEDI4276 has demonstrable clinical activity but displays intolerable toxicity at doses >0.3 mg/kg.