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Ann Oncol ; 27(8): 1579-85, 2016 08.
Article in English | MEDLINE | ID: mdl-27457310

ABSTRACT

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/m(2)) 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.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Bevacizumab/administration & dosage , Camptothecin/administration & dosage , Carcinoma, Renal Cell/drug therapy , Cyclodextrins/administration & dosage , Adult , Aged , Angiogenesis Inhibitors/administration & dosage , Angiogenesis Inhibitors/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/chemistry , Bevacizumab/adverse effects , Camptothecin/adverse effects , Carcinoma, Renal Cell/pathology , Cyclodextrins/adverse effects , Disease-Free Survival , Drug-Related Side Effects and Adverse Reactions/classification , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Male , Middle Aged , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects
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