Lisa Fichtel

Efficacy and safety results of ABT-414 in combination with radiation and temozolomide in newly diagnosed glioblastoma

Background The purpose of this study was to determine the maximum tolerated dose (MTD), recommended phase II dose (RPTD), safety, and pharmacokinetics of ABT-414 plus radiation and temozolomide in newly diagnosed glioblastoma. ABT-414 is a first-in-class, tumor-specific antibody-drug conjugate that preferentially targets tumors expressing overactive epidermal growth factor receptor (EGFR). Methods In this multicenter phase I study, patients received 0.5-3.2 mg/kg ABT-414 every 2 weeks by intravenous infusion. EGFR alterations, O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, and isocitrate dehydrogenase (IDH1) gene mutations were assessed in patient tumors. Distinct prognostic classes were assigned to patients based on a Molecular Classification Predictor model. Results As of January 7, 2016, forty-five patients were enrolled to receive ABT-414 plus radiation and temozolomide. The most common treatment emergent adverse events were ocular: blurred vision, dry eye, keratitis, photophobia, and eye pain. Ocular toxicity at any grade occurred in 40 patients and at grades 3/4 in 12 patients. RPTD and MTD were set at 2 mg/kg and 2.4 mg/kg, respectively. Among 38 patients with pretreatment tumor tested centrally, 39% harbored EGFR amplification, of which 73% had EGFRvIII mutation. Among patients with available tumor tissue (n = 30), 30% showed MGMT promoter methylation and none had IDH1 mutations. ABT-414 demonstrated an approximately dose proportional pharmacokinetic profile. The median duration of progression-free survival was 6.1 months; median overall survival has not been reached. Conclusion ABT-414 plus chemoradiation demonstrated an acceptable safety and pharmacokinetic profile in newly diagnosed glioblastoma. Randomized studies are ongoing to determine efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

Safety, Pharmacokinetics and Antitumor Response of Depatuxizumab Mafodotin as Monotherapy or in Combination with Temozolomide in Patients with Glioblastoma

Background We recently reported an acceptable safety and pharmacokinetic profile of depatuxizumab mafodotin (depatux-m), formerly called ABT-414, plus radiation and temozolomide in newly diagnosed glioblastoma (arm A). The purpose of this study was to evaluate the safety and pharmacokinetics of depatux-m, either in combination with temozolomide in newly diagnosed or recurrent glioblastoma (arm B) or as monotherapy in recurrent glioblastoma (arm C). Methods In this multicenter phase I dose escalation study, patients received depatux-m (0.5-1.5 mg/kg in arm B, 1.25 mg/kg in arm C) every 2 weeks by intravenous infusion. Maximum tolerated dose (MTD), recommended phase II dose (RP2D), and preliminary efficacy were also determined. Results Thirty-eight patients were enrolled as of March 1, 2016. The most frequent toxicities were ocular, occurring in 35/38 (92%) patients. Keratitis was the most common grade 3 adverse event observed in 6/38 (16%) patients; thrombocytopenia was the most common grade 4 event seen in 5/38 (13%) patients. The MTD was set at 1.5 mg/kg in arm B and was not reached in arm C. RP2D was declared as 1.25 mg/kg for both arms. Depatux-m demonstrated a linear pharmacokinetic profile. In recurrent glioblastoma patients, the progression-free survival (PFS) rate at 6 months was 30.8% and the median overall survival was 10.7 months. Best Response Assessment in Neuro-Oncology responses were 1 complete and 2 partial responses. Conclusion Depatux-m alone or in combination with temozolomide demonstrated an acceptable safety and pharmacokinetic profile in glioblastoma. Further studies are currently under way to evaluate its efficacy in newly diagnosed (NCT02573324) and recurrent glioblastoma (NCT02343406).

Hypoxia-activated evofosfamide for treatment of recurrent bevacizumab-refractory glioblastoma: a phase I surgical study

Background Anti-angiogenic therapy is known to induce a greater degree of hypoxia, including in glioblastoma (GBM). Evofosfamide (Evo) is a hypoxia-activated prodrug which is reduced, leading to the release of the alkylating agent bromo-isophosphoramide mustard. We assessed the safety, tolerability, preliminary efficacy, and biomarkers of Evo plus bevacizumab (Bev) in Bev-refractory GBM. Methods Twenty-eight patients with Bev-refractory GBM were enrolled in a dose escalation study receiving from 240 mg/m2 (cohort 1) to 670 mg/m2 (cohort 4) of Evo every 2 weeks in combination with Bev. Patients deemed surgical candidates underwent a single dose of Evo or placebo with pimonidazole immediately prior to surgery for biomarker evaluation, followed by dose escalation upon recovery. Assessments included adverse events, response, and survival. Results Evo plus Bev was well tolerated up to and including the maximum dose of 670 mg/m2, which was determined to be the recommended phase II dose. Overall response rate was 17.4%, with disease control (complete response, partial response, and stable disease) observed in 14 (60.9%) of the 23 patients. The ratio of enhancement to non-enhancement was significant on log-rank analysis with time to progression (P = 0.023), with patients having a ratio of less than 0.37 showing a median progression-free survival of 98 days versus 56 days for those with more enhancement. Conclusions Evo plus Bev was well tolerated in patients with Bev-refractory GBM, with preliminary evidence of activity that merits further investigation.

416OA PHASE 1 STUDY EVALUATING ABT-414 WITH CONCURRENT RADIOTHERAPY (RT) AND TEMOZOLOMIDE (TMZ) IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM)

ABSTRACT Aim: Despite standard therapy for GBM, median survival is 1-2 years. Abnormal epidermal growth factor receptor (EGFR) expression and signaling are common in GBM. ABT-414 is a unique antibody-drug conjugate, with a toxic payload (monomethylauristatin F) targeted to active EGFR or mutant EGFRvIII, that has demonstrated high antitumor activity in preclinical GBM tumor models. Methods: Objectives were to evaluate the safety, pharmacokinetics (PK), and the maximum tolerated dose (MTD) of ABT-414 when administered every 14 days with concurrent RT and TMZ in newly diagnosed GBM. Adverse events, PK parameters, objective response (RANO), and tumor tissue EGFR biomarkers were assessed. Dose escalation was determined by the exposure-adjusted continual reassessment method (EACRM). Results: As of April 9, 2014, 22 pts were treated (13/9 Male/Female, median age 58 years, range 34-79). Common treatment-emergent adverse events (TEAEs, ≥ 5 pts) included fatigue (n= 11); blurred vision (n = 10); thrombocytopenia (n = 8); AST increase (n = 9); ALT increase (n = 8); nausea (n = 7); eye pain (n = 6); lacrimation increase (n = 6); dry eye, headache, and constipation (n = 5 each). Grade 3/4 TEAEs (≥ 2 pts) included lymphopenia (n = 3); eye toxicity (n = 3); brain edema, ALT, AST (n = 2 each). Doses from 0.5 - 3.2 mg/kg have been explored. Dose limiting toxicities primarily affecting the eye (keratitis) and liver occurred at the 2, 2.6, 3.0, and 3.2 mg/kg doses. The EACRM has predicted 2.4 mg/kg as the MTD. Confirmatory safety data are being collected. PK data from 9 subjects in the dose range of 0.5 - 3 mg/kg indicate that exposure (Cmax and AUC) of ABT‐414 appeared to be dose proportional with a half‐life of approximately 11 days. Efficacy endpoints are not yet mature. Patient samples are being evaluated for EGFR expression, amplification and EGFRvIII status to determine which marker best associates with clinical benefit. Conclusions: PK and safety data support a dose of 2.4 mg/kg as the predicted MTD. Preliminary safety data demonstrate increased liver and eye toxicities in addition to common RT + TMZ toxicities. Further follow-up may demonstrate whether ABT-414 improves outcome. Disclosure: H.K. Gan: employee of Ludwig Institute for Cancer Research, which has licensed ABT-806; A. Lassman: Consultancy: Amgen, Celgene, Genentech, Sigma-Tau, Agenus, Roche, Stemline, Synapse, RadMD, Venture Inflections, Novartis, Kyowa Hakko Kirin, Abbott, Scientia Advisors, MSD, GSK, Able Assoc, Defined Health, Easton Assoc.; M.J. van den Bent: Consultancy: Roche, ABBVIE, Actelion, Celldex, AMGEN. Research support: Roche, ABBVIE. Speakers bureau: MSD; A. Scott: employee of Ludwig Institute for Cancer Research, which has licensed ABT-806; Consultancy and stock ownership - Life Science Pharmaceuticals; M. Pedersen, E. Gomez, J. Fischer, W. Ames, H. Xiong, M. Dudley, L. Roberts-Rapp, P.J. Ansell and K. Holen: is an AbbVie employee and may own stock; D.A. Reardon: Speakers Bureau – Merck/Schering and Genentech/Roche; Advisory Board – Novartis; Amgen; Roche/Genentech; EMD Serono; Stemline Therapeutics; Momenta Pharmaceuticals. All other authors have declared no conflicts of interest.