P856 AVID200, first-in-class TGF-beta1 and beta3 selective inhibitor: results of a phase 1 monotherapy dose escalation study in solid tumors and evidence of target engagement in patients. (15th April 2020)

• Record Type: Journal Article
• Authors: Yap, Timothy; Araujo, Daniel; Wood, Debra; Denis, Jean-François; Gruosso, Tina; Tremblay, Gilles; O'Connor-McCourt, Maureen; Ghosh, Ria; Sinclair, Sandra; Nadler, Paul; Siu, Lilian; Lakhani, Nehal
• Is Part Of: Journal for immunotherapy of cancer. Volume 8(2020)Supplement 1
• Page Start: A6
• Page End: A7
• Publication Date: 2020-04-15
• Subjects: Cancer -- Immunotherapy -- Periodicals; Cancer -- Immunological aspects -- Periodicals; Tumors -- Immunological aspects -- Periodicals; Immunotherapy -- Periodicals; 616.99406105
• DOI: 10.1136/LBA2019.10
• Languages: English
• ISSNs: 2051-1426

Abstract

Abstract : Background: AVID200 is a rationally designed first-in-class receptor ectodomain trap that inhibits transforming growth factor-beta (TGF-beta) isoforms -beta1 and -beta3 with pM potency. TGF-beta signaling is highly immunosuppressive in the tumor microenvironment and has been associated with immune checkpoint inhibitor resistance. 1-4 TGF-beta1 and -beta3 are most closely associated with cancer progression whereas TGF-beta2 is required for normal cardiac function and hematopoiesis. Accordingly, selective targeting of TGF-beta1 and -beta3 by AVID200 may improve the efficacy of immunotherapy while avoiding toxicities associated with earlier generations of non-selective TGF-beta inhibitors. Methods: This open-label, multicenter Phase 1 study (NCT03834662 ) evaluated safety, tolerability and dose-limiting toxicities (DLTs) of sequential escalating doses of AVID200 (Q3W IV) to establish the recommended Phase 2 dose. Patients with documented, locally advanced or metastatic solid tumors without other treatment options were eligible. The primary objective was safety and tolerability; secondary objectives included preliminary anti-tumor activity, pharmacokinetics (PK), and assessment of pharmacodynamic biomarkers indicative of target modulation. PK was assessed by enzyme immunoassay. Ability of AVID200 to selectively sequester and neutralize its target was assessed by TGF-beta quantification per ELISA, as well as cell-based IL-11 release functional evaluation of TGF-beta signal inhibition. In addition, phosphorylation of SMAD2, a downstream target of TGF-beta, was assessed by immunohistochemistry in skin biopsies at screening and Cycle 1, Day 4 (C1D4). Results: Enrollment to all planned cohorts is complete: A total of 13 patients with ECOG 0-1 received AVID200 across the three planned dose levels of 180 (N=7), 550 (N=3), and 1100 mg/m2 (N=3) (~5, 15, and 30 mg/kg). The MTD was not reached. Grade 3 study drug-related AEs were reported in two patients (diarrhea, lipase elevation); no related Grade 4 or 5 AEs were observed. Serum exposure was dose-proportional. AVID200 sequestered circulating endogenous active TGF-beta at all dose levels. Moreover, AVID200 in patient plasma potently neutralized TGF-beta1- and -3 – but not -beta2 – mediated signaling. SMAD2 phosphorylation in skin biopsies was detectably reduced at C1D4 across all dose levels. Three of nine patients evaluated for response had a best response of stable disease (SD), including one prolonged SD which was ongoing at six months at time of writing. Conclusions: AVID200 has been well tolerated as monotherapy and engaged its target in patients providing proof-of-principle that selective and potent inhibition of TGF-beta1 and -beta3 is feasible in the clinic. The results warrant evaluation of AVID200 in combination with anti-PD(L)1 and other anti-cancer therapies. Acknowledgements: We would like to thank all participating patients, their families and caretakers as well as staff members at the clinical sites. Trial Registration: Clinicaltrials.gov NCT03834662 Ethics Approval: The study was approved by START-Midwest's IRB (approval number STMW2018.19), University Health Network's Research Ethics Board (approval number 18-6104), and The University of Texas MD Anderson Cancer Center's IRB (approval number 2018-1079). References: Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 2018; 554:544–548. Chakravarthy A, Khan L, Bensler NP, Bose P, De Carvalho DD. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun 2018; 9:4692. Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature . 2018; 554:538–543. Zhao F, Evans K, Xiao C, et al. Stromal Fibroblasts Mediate Anti–PD-1 Resistance via MMP-9 and Dictate TGFβ Inhibitor Sequencing in Melanoma. Cancer Immunol Res 2018; 6:1459–1471.