title: 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.
abstract: 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 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia.
authors.forename: S M
authors.initials: SM
authors.lastname: Keefe
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University Hospital, Philadelphia.
authors.forename: J
authors.initials: J
authors.lastname: Hoffman-Censits
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia.
authors.forename: R B
authors.initials: RB
authors.lastname: Cohen
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia.
authors.forename: R
authors.initials: R
authors.lastname: Mamtani
authors.affiliation: Southern Methodist University, Dallas.
authors.forename: D
authors.initials: D
authors.lastname: Heitjan
authors.affiliation: Cerulean Pharma Inc., Waltham.
authors.forename: S
authors.initials: S
authors.lastname: Eliasof
authors.affiliation: Duke University School of Medicine, Durham.
authors.forename: A
authors.initials: A
authors.lastname: Nixon
authors.affiliation: BioBridges LLC, Boston, USA.
authors.forename: B
authors.initials: B
authors.lastname: Turnbull
authors.affiliation: Cerulean Pharma Inc., Waltham.
authors.forename: E G
authors.initials: EG
authors.lastname: Garmey
authors.affiliation: Landspitali University Hospital, Reykjavik, Iceland.
authors.forename: O
authors.initials: O
authors.lastname: Gunnarsson
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia.
authors.forename: M
authors.initials: M
authors.lastname: Waliki
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia.
authors.forename: J
authors.initials: J
authors.lastname: Ciconte
authors.affiliation: Cerulean Pharma Inc., Waltham.
authors.forename: L
authors.initials: L
authors.lastname: Jayaraman
authors.affiliation: Cerulean Pharma Inc., Waltham.
authors.forename: A
authors.initials: A
authors.lastname: Senderowicz
authors.affiliation: Cerulean Pharma Inc., Waltham.
authors.forename: A B
authors.initials: AB
authors.lastname: Tellez
authors.affiliation: Cerulean Pharma Inc., Waltham.
authors.forename: M
authors.initials: M
authors.lastname: Hennessy
authors.affiliation: Cerulean Pharma Inc., Waltham.
authors.forename: A
authors.initials: A
authors.lastname: Piscitelli
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia.
authors.forename: D
authors.initials: D
authors.lastname: Vaughn
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia.
authors.forename: A
authors.initials: A
authors.lastname: Smith
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia naomi.haas@uphs.upenn.edu.
authors.forename: N B
authors.initials: NB
authors.lastname: Haas
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D003505:Cyclodextrins / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D003505:Cyclodextrins; C542292:IT-101; D047428:Protein Kinase Inhibitors; D000068258:Bevacizumab; D002166:Camptothecin
keywords: CRLX101; angiogenesis; hypoxia-inducible factor; nanoparticle–drug conjugate; recommended phase II dose; renal cell carcinoma