Efficacy of the nanoparticle-drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I-IIa clinical trial
| Autor: | Andrew B. Nixon, Ronac Mamtani, Daniel F. Heitjan, Jean H. Hoffman-Censits, B. Turnbull, Lata Jayaraman, Naomi B. Haas, Stephen M. Keefe, Meliessa Hennessy, David J. Vaughn, Amanda M. Smith, Roger B. Cohen, M. Waliki, Anthony Piscitelli, Scott Eliasof, Edward Graeme Garmey, J. Ciconte, A. Senderowicz, Orvar Gunnarsson, A. B. Tellez |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Adult Male medicine.medical_specialty Bevacizumab Drug-Related Side Effects and Adverse Reactions Population Angiogenesis Inhibitors Antibodies Monoclonal Humanized Disease-Free Survival 03 medical and health sciences 0302 clinical medicine Renal cell carcinoma Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans education Adverse effect Carcinoma Renal Cell Protein Kinase Inhibitors Aged education.field_of_study Cyclodextrins business.industry Cancer Hematology Original Articles Middle Aged medicine.disease Clinical trial 030104 developmental biology Response Evaluation Criteria in Solid Tumors 030220 oncology & carcinogenesis Nanoparticles Camptothecin Female business Progressive disease medicine.drug |
| Zdroj: | Annals of oncology : official journal of the European Society for Medical Oncology. 27(8) |
| ISSN: | 1569-8041 |
| Popis: | Background Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle–drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. Patients and methods Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m2) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. Results Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. Conclusions CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing. |
| Databáze: | OpenAIRE |
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