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Cancer Chemother Pharmacol. 2017 Apr;79(4):673-680. doi: 10.1007/s00280-017-3245-5. Epub 2017 Mar 9.

A phase 1 study of anti-TGFβ receptor type-II monoclonal antibody LY3022859 in patients with advanced solid tumors.

Author information

1
South Texas Accelerated Research Therapeutics LLC, San Antonio, TX, 78229, USA. atolcher@start.stoh.com.
2
Vanderbilt-Ingram Cancer Center, Nashville, TN, 37232, USA.
3
Eli Lilly and Company, Indianapolis, IN, 46285, USA.
4
Merck KGaA, Darmstadt, Germany.
5
UT M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
6
South Texas Accelerated Research Therapeutics LLC, San Antonio, TX, 78229, USA.

Abstract

PURPOSE:

LY3022859 is an anti-TGFβRII IgG1 monoclonal antibody that inhibits receptor-mediated signaling activation. The primary objective of this phase I study was to determine a phase II dose in patients with advanced solid tumors. Secondary objectives were to assess safety and pharmacokinetics (PK).

METHODS:

LY3022859 was infused intravenously (IV) at 1.25 mg/kg over 1 h every 2 weeks (Q2W) (cohort 1A) and at flat doses of 12.5 mg (cohort 1B) and 25 mg (cohort 2) over 3 h Q2W.

RESULTS:

Fourteen patients were enrolled in cohorts 1A (n = 2), 1B (n = 5), and 2 (n = 7). DLTs were experienced by both patients in cohort 1A (infusion-related reaction) and 2 patients in cohort 2 (cytokine release syndrome and infusion-related reaction). No MTD was determined. At the 25 mg dose level (cohort 2), after fifth infusion, LY3022859 had a short t1/2 (4.37-7.80 h) and rapid clearance (CLss, 0.412 L/h). Exposure increased twofold (from 28.5 to 60.2 μg·h/mL) with increase in dose from 12.5 to 25 mg. No accumulation was observed after repeat administration.

CONCLUSIONS:

The MTD for LY3022859 was not determined. Dose escalation beyond 25 mg was considered unsafe due to worsening symptoms (uncontrolled cytokine release) despite prophylaxis (corticosteroids and antihistamines).

TRIAL REGISTRATION:

clinicaltrials.gov Identifier: NCT01646203.

KEYWORDS:

Monoclonal antibody; Solid tumors; TGFβ; TGFβ receptor; Therapy resistance

PMID:
28280971
PMCID:
PMC5893148
DOI:
10.1007/s00280-017-3245-5
[Indexed for MEDLINE]
Free PMC Article

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