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

S. M. Keefe, Jean Hoffman-Censits, R. B. Cohen, R. Mamtani, D. Heitjan, S. Eliasof, A. Nixon, B. Turnbull, E. G. Garmey, O. Gunnarsson, M. Waliki, J. Ciconte, L. Jayaraman, A. Senderowicz, A. B. Tellez, M. Hennessy, A. Piscitelli, D. Vaughn, A. Smith, Naomi B. Haas

Research output: Contribution to journalArticle

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/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.

Original languageEnglish (US)
Pages (from-to)1579-1585
Number of pages7
JournalAnnals of Oncology
Volume27
Issue number8
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

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Clinical Trials, Phase I
Renal Cell Carcinoma
Nanoparticles
Research Personnel
Pharmaceutical Preparations
Histology
Disease-Free Survival
IT-101
Bevacizumab
Camptothecin
Phase II Clinical Trials
Angiogenesis Inhibitors
Cystitis
Dizziness
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor A
Stomach Neoplasms
Fatigue
Blood Vessels
Anemia

Keywords

  • Angiogenesis
  • CRLX101
  • Hypoxia-inducible factor
  • Nanoparticle-drug conjugate
  • Recommended phase II dose
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

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. / Keefe, S. M.; Hoffman-Censits, Jean; Cohen, R. B.; Mamtani, R.; Heitjan, D.; Eliasof, S.; Nixon, A.; Turnbull, B.; Garmey, E. G.; Gunnarsson, O.; Waliki, M.; Ciconte, J.; Jayaraman, L.; Senderowicz, A.; Tellez, A. B.; Hennessy, M.; Piscitelli, A.; Vaughn, D.; Smith, A.; Haas, Naomi B.

In: Annals of Oncology, Vol. 27, No. 8, 01.08.2016, p. 1579-1585.

Research output: Contribution to journalArticle

Keefe, SM, Hoffman-Censits, J, Cohen, RB, Mamtani, R, Heitjan, D, Eliasof, S, Nixon, A, Turnbull, B, Garmey, EG, Gunnarsson, O, Waliki, M, Ciconte, J, Jayaraman, L, Senderowicz, A, Tellez, AB, Hennessy, M, Piscitelli, A, Vaughn, D, Smith, A & Haas, NB 2016, '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', Annals of Oncology, vol. 27, no. 8, pp. 1579-1585. https://doi.org/10.1093/annonc/mdw188
Keefe, S. M. ; Hoffman-Censits, Jean ; Cohen, R. B. ; Mamtani, R. ; Heitjan, D. ; Eliasof, S. ; Nixon, A. ; Turnbull, B. ; Garmey, E. G. ; Gunnarsson, O. ; Waliki, M. ; Ciconte, J. ; Jayaraman, L. ; Senderowicz, A. ; Tellez, A. B. ; Hennessy, M. ; Piscitelli, A. ; Vaughn, D. ; Smith, A. ; Haas, Naomi B. / 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. In: Annals of Oncology. 2016 ; Vol. 27, No. 8. pp. 1579-1585.
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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/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.",
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TY - JOUR

T1 - Efficacy of the nanoparticle-drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma

T2 - Results of an investigator-initiated phase I-IIa clinical trial

AU - Keefe, S. M.

AU - Hoffman-Censits, Jean

AU - Cohen, R. B.

AU - Mamtani, R.

AU - Heitjan, D.

AU - Eliasof, S.

AU - Nixon, A.

AU - Turnbull, B.

AU - Garmey, E. G.

AU - Gunnarsson, O.

AU - Waliki, M.

AU - Ciconte, J.

AU - Jayaraman, L.

AU - Senderowicz, A.

AU - Tellez, A. B.

AU - Hennessy, M.

AU - Piscitelli, A.

AU - Vaughn, D.

AU - Smith, A.

AU - Haas, Naomi B.

PY - 2016/8/1

Y1 - 2016/8/1

N2 - 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.

AB - 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.

KW - Angiogenesis

KW - CRLX101

KW - Hypoxia-inducible factor

KW - Nanoparticle-drug conjugate

KW - Recommended phase II dose

KW - Renal cell carcinoma

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