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Investigational New Drugs

, Volume 32, Issue 4, pp 653–660 | Cite as

A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors

  • Colin D. WeekesEmail author
  • Muralidhar Beeram
  • Anthony W. Tolcher
  • Kyriakos P. Papadopoulos
  • Lia Gore
  • Priti Hegde
  • Yan Xin
  • Ron Yu
  • L. Mason Shih
  • Hong Xiang
  • Rainer K. Brachmann
  • Amita Patnaik
PHASE I STUDIES

Summary

The human monoclonal antibody MNRP1685A targets the VEGF binding domain of neuropilin-1 (NRP1), a multi-domain receptor necessary for neural development and blood vessel maturation. In nonclinical studies, MNRP1685A prevents vascular maturation by keeping blood vessels in an immature, highly VEGF-dependent state. We explored the safety and tolerability of MNRP1685A in patients with advanced solid tumors. Patients were treated with MNRP1685A given intravenously every 3 weeks using a 3 + 3 dose-escalation design with 7 dose-escalation cohorts. Twenty-four of 35 patients (69 %) experienced drug-related adverse events (AEs) of infusion-related reaction on the day of MNRP1685A administration. With premedication including dexamethasone, infusions were well-tolerated with main symptoms of pruritus and rash. Outside the day of infusion, most common (≥ 2 patients) related AEs were fatigue (17 %), pruritus (9 %), myalgia and thrombocytopenia (both 6 %) (all were Grade 1–2). MNRP1685A-related Grade ≥ 3 AEs consisted of one dose-limiting toxicity of Grade 3 upper gastrointestinal bleeding and one related Grade 3 thrombocytopenia, coinciding with unrelated Grade 3 fungemia and duodenal obstruction. MNRP1685A showed nonlinear PK with more-than-dose proportional increases in exposure, consistent with broad target expression. Transient platelet count reductions (≥ 30 % from predose) were observed in 56 % of evaluable patients. Nine patients were on study for ≥ 4 cycles, one colorectal cancer patient for one year. MNRP1685A was generally well-tolerated. The primary MNRP1685A-related AE was infusion-related reaction, which were attenuated by premedication including dexamethasone. Transient platelet count reductions were frequent but did not impact MNRP1685A dosing.

Keywords

Neuropilin-1 MNRP1685A VEGF Clinical trial 

Notes

Acknowledgement

We thank the patients who participated in the study and their families. Medical writing assistance provided by Genentech, Inc.

Research support

This study was sponsored by Genentech, Inc.

Disclosure information

CDW: advisor to and research support from Genentech, Inc.

MB: research support from Genentech, Inc.

AWT: advisor to and research support from Genentech, Inc.

KP: nothing to disclose

LG: nothing to disclose

PH, YX, RY, LMS, HX, and RKB: employees of Genentech, Inc., and shareholders of F. Hoffmann La Roche, Ltd.

AP: advisor to and research support from Genentech, Inc.

Author contributions

CDW: conception and design, collection and assembly of data, data analysis and interpretation, provision of study patients

MB: collection and assembly of data

AWT: collection and assembly of data, provision of study patients

KP: collection and assembly of data

LG: data analysis and provision of study patients

PH: conception and design, data analysis and interpretation

YX: data analysis and interpretation

RY: data analysis and interpretation

LMS: data analysis and interpretation

HX: conception and design, data analysis and interpretation

RKB: conception and design, collection and assembly of data, data analysis and interpretation

AP: conception and design, collection and assembly of data, data analysis and interpretation, provision of study patients

All authors participated in manuscript writing, and approved the final version of the manuscript.

Supplementary material

10637_2014_71_MOESM1_ESM.pdf (501 kb)
Supplementary Figure 1 (PDF 500 kb)
10637_2014_71_MOESM2_ESM.doc (38 kb)
Supplementary Table 1 (DOC 38 kb)
10637_2014_71_MOESM3_ESM.doc (59 kb)
Supplementary Table 2 (DOC 59 kb)
10637_2014_71_MOESM4_ESM.doc (34 kb)
Supplemental Table 3 (DOC 34 kb)
10637_2014_71_MOESM5_ESM.doc (36 kb)
Supplemental Table 4 (DOC 36 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Colin D. Weekes
    • 1
    Email author
  • Muralidhar Beeram
    • 2
  • Anthony W. Tolcher
    • 2
  • Kyriakos P. Papadopoulos
    • 2
  • Lia Gore
    • 1
  • Priti Hegde
    • 3
  • Yan Xin
    • 3
  • Ron Yu
    • 3
  • L. Mason Shih
    • 3
  • Hong Xiang
    • 3
  • Rainer K. Brachmann
    • 3
  • Amita Patnaik
    • 2
  1. 1.University of Colorado School of Medicine and Developmental Therapeutics Program, University of Colorado Cancer CenterAuroraUSA
  2. 2.South Texas Accelerated Research TherapeuticsSan AntonioUSA
  3. 3.Genentech Research and Early DevelopmentSouth San FranciscoUSA

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