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Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics.

ABSTRACT: This phase 1 study evaluated the safety and tolerability of antiangiogenic therapy using vandetanib and metronomic cyclophosphamide and methotrexate in metastatic breast cancer. Eligible patients had metastatic breast cancer with 0-4 prior chemotherapy regimens. All received cyclophosphamide 50 mg daily, methotrexate 2.5 mg days 1-2 weekly, and vandetanib daily in 3 dose-escalation cohorts: 100 mg (C1), 200 mg (C2), and 300 mg (C3). The primary endpoint was safety and tolerability; secondary endpoints included response rate and evaluation of platelet-associated proteins. Twenty three patients were treated and evaluable for toxicity. Common mild toxicities included nausea, vomiting, LFTs abnormalities, fatigue, and rash. Three episodes of dose-limiting toxicity occurred in C3. In all cohorts, 1/3 of patients required vandetanib dose reduction, and 22 % ended therapy for toxicity. Of the 20 response-evaluable patients, 10 % demonstrated partial response and 15 % stable disease ?24 weeks. Proteomic analyses demonstrated changes in platelet content of angiogenesis regulators, including vascular endothelial growth factor and platelet factor 4, with exposure to therapy. This regimen was tolerable at a maximum vandetanib dose of 200 mg; modest clinical activity was observed in this heavily pretreated population. Changes in the platelet proteome may serve as pharmacodynamic markers of angiogenesis inhibition. Metronomic chemotherapy is an attractive partner with biologics and deserves further study in metastatic breast cancer.

SUBMITTER: Mayer EL

PROVIDER: S-EPMC5472381 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics.

Mayer Erica L EL Isakoff Steven J SJ Klement Giannoula G Downing Sean R SR Chen Wendy Y WY Hannagan Keri K Gelman Rebecca R Winer Eric P EP Burstein Harold J HJ

Breast cancer research and treatment 20120923 1

This phase 1 study evaluated the safety and tolerability of antiangiogenic therapy using vandetanib and metronomic cyclophosphamide and methotrexate in metastatic breast cancer. Eligible patients had metastatic breast cancer with 0-4 prior chemotherapy regimens. All received cyclophosphamide 50 mg daily, methotrexate 2.5 mg days 1-2 weekly, and vandetanib daily in 3 dose-escalation cohorts: 100 mg (C1), 200 mg (C2), and 300 mg (C3). The primary endpoint was safety and tolerability; secondary end ...[more]

PMID: 23001754

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Project description:Abstract BACKGROUND: Prognosis of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor (ATRT) is dismal despite intensive therapy including high-dose chemotherapy with stem cell rescue. We report on 28 patients with recurrent medulloblastoma and ATRT treated with an alternative approach to conventional chemotherapy that targets neovascularisation by interfering with tumor angiogenesis at various levels. Patients and METHODS: From 11/2006 to 06/2016, 28 patients were diagnosed with recurrent embryonal tumors, 20 with a recurrent medulloblastoma (13 first, 7 multiple recurrences) and eight with recurrent ATRT (5 first, 3 multiple), three had germ line mutations. Treatment consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and liposomal cytarabine). Median age at start of antiangiogenic therapy was 10 (1–24) years for medulloblastoma and 1.5 (1–13) years for ATRT. Results: As of 11/2016, 12/20 patients with medulloblastoma are alive at a median of 25 (12–97) months after their last recurrence. 8/12 surviving patients are currently in CR for 97, 94, 93, 29, 27, 23, 19 and 18 months, five off therapy for 79, 62, 60, 22 and 18 months, three are in PR 23, 12 and 2 months after their last recurrence and one patient has stable disease 12 months after her last recurrence. 5-year-OS is 57.6?±?13.2%. One patient died of an accident in CR 23 months after initiation of antiangiogenic therapy and one patient with a very good PR died of a septicemia seven months after his last recurrence. Two patients had prior been treated with the same antiangiogenic approach and had recurred 67 and 40 months after their last recurrence while off therapy for 36 and 21 months and both patients are in remission again, one off therapy for 18 months. 3/8 patients with ATRT are alive. Follow-up since last recurrence is 72, 27 and 24 months and all patients are off therapy for 52, 14 and 13 months. One patient died of another cause without evidence of tumor at autopsy 54 months after recurrence and while off therapy for 46 months. One surviving patient with a germ line mutation and a fourth recurrence was prior treated with the same approach albeit without intrathecal therapy. He recurred 78 months after his last recurrence while off therapy for 36 months. He is again in CR and off therapy for 13 months. Therapy is primarily outpatient, was generally well tolerated, and toxicities were manageable. CONCLUSION: The proposed antiangiogenic regimen is currently being evaluated for medulloblastomas in an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290). The same approach seems to be also efficacious in recurrent ATRTs and warrants further evaluation.

Project description:Abstract BACKGROUND Prognosis of patients with recurrent medulloblastoma and atypical teratoid rhabdoid tumor (ATRT) is dismal despite intensive therapy including high-dose chemotherapy with stem cell rescue. An evolving alternative approach to conventional chemotherapy is to target neovascularisation by interfering with tumor angiogenesis at various levels. We report on 32 patients with recurrent medulloblastoma and ATRT treated with an antiangiogenic combination therapy. PATIENTS AND METHODS From 11/2006 to 02/2018, 32 patients were diagnosed with recurrent embryonal tumors, 20 with a recurrent medulloblastoma (14 first, 6 multiple recurrences) and 12 with recurrent ATRT (6 first, 6 multiple), three had germ line mutations. Treatment consisted of an antiangiogenic multidrug-regime including IV bevacizumab, oral thalidomide, celecoxib, fenofibrate, and etoposide alternating with cyclophosphamide, and augmented with intraventricular therapy (etoposide and aqueous or liposomal cytarabine). Median age at start of antiangiogenic therapy was 10 (1–24) years for medulloblastoma and 3 (1–12) years for ATRT. RESULTS As of 05/2018, 10/20 patients with medulloblastoma are alive, eight in CR, six off therapy for 96, 79, 77, 34, 12, and 4 months. 5-year-OS is 54.5 ± 11.2% and 5-year-EFS is 25.0 ± 9.7%. One patient died of an accident in CR 23 months after initiation of antiangiogenic therapy. 6/12 patients with ATRT are alive and in CR for 123, 90, 45, 9, 6 and 3 months after start of antiangiogenic therapy, the first three off therapy. OS for the whole cohort was 47.7 ± 16.6% at 3 years and 31.8 ± 17.1% at 5-years with a median OS of 22.8 months (KI 0.0–66.8). Therapy was generally well tolerated and toxicities were manageable. CONCLUSION The proposed antiangiogenic regimen is currently being evaluated for medulloblastomas in an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290). The same approach seems to be also efficacious in recurrent ATRTs and warrants further evaluation.

Dataset Information

Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics.

Publications

Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics.

Similar Datasets

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