Dataset Information

Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study.

ABSTRACT: PURPOSE:Patients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~?50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody-drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monotherapy at the recommended Phase 2 dose (RPTD) in patients with EGFR-amplified, rGBM. METHODS:M12-356 (NCT01800695) is an open-label study with three escalation and expansion cohorts. Sixty-six patients with EGFR-amplified, rGBM were treated with depatux-m monotherapy at 1.25 mg/kg intravenously every 2 weeks. Adults with measurable rGBM, who were bevacizumab-naïve, with EGFR amplification were eligible. RESULTS:Among 66 patients, median age was 58 years (range 35-80). All patients were previously treated with radiotherapy/temozolomide. The most common adverse events (AEs) were eye related (91%), including blurred vision (65%), dry eye (29%), keratitis, and photophobia (27% each). Grade 3/4 AEs occurred in 42% of all patients, and ocular Grade 3/4 AEs occurred in 33% of patients overall. One patient (2%) had a Grade 4 ocular AE. Ocular AEs were manageable and usually resolved once treatment with depatux-m ceased. The objective response rate was 6.8%, the 6-month progression-free survival rate was 28.8%, and the 6-month overall survival rate was 72.5%. CONCLUSION:Depatux-m monotherapy displayed frequent but mostly Grade 1/2 ocular toxicities. A PFS6 of 28.8% was observed in this rGBM population, warranting further study.

SUBMITTER: van den Bent M

PROVIDER: S-EPMC5686264 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study.

van den Bent Martin M Gan Hui K HK Lassman Andrew B AB Kumthekar Priya P Merrell Ryan R Butowski Nicholas N Lwin Zarnie Z Mikkelsen Tom T Nabors Louis B LB Papadopoulos Kyriakos P KP Penas-Prado Marta M Simes John J Wheeler Helen H Walbert Tobias T Scott Andrew M AM Gomez Erica E Lee Ho-Jin HJ Roberts-Rapp Lisa L Xiong Hao H Bain Earle E Ansell Peter J PJ Holen Kyle D KD Maag David D Reardon David A DA

Cancer chemotherapy and pharmacology 20171026 6

<h4>Purpose</h4>Patients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~ 50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody-drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monothe ...[more]

PMID: 29075855

Similar Datasets

Project description:Abstract Background: Recurrent GBM (rGBM) has dismal prognosis. Almost 50% GBM tumors harbor amplified (amp) EGFR. ABT-414 is a tumor specific ADC combining an antibody targeting a unique conformation of EGFR (ABT-806) to a microtubule cytotoxin, monomethyl auristatin F (MMAF). Here we report the safety and efficacy of ABT-414 monotherapy at recommended phase 2 dose (RPTD) in EGFR amp, rGBM. Methods: M12-356 (NCT01800695) is an open-label, phase 1, 3-arm study: Arm A (ABT-414+radiation/temozolomide (TMZ) in newly diagnosed GBM (nGBM)), Arm B (ABT-414+TMZ in nGBM as adjuvant therapy, or in rGBM) and Arm C (ABT-414 monotherapy in rGBM). Each arm had an escalation cohort to determine the RPTD and an expansion cohort to establish the safety and preliminary efficacy at RPTD. Results of Arm C expansion cohort at 1.25?mg/kg RPTD (IV infusion) are shown here. Eligible patients (pts) were adults with KPS score ?70, EGFR amp (confirmed centrally), rGBM, normal end-organ function and no prior bevacizumab. Results: As of January 7, 2016, 48 EGFR amp, rGBM pts were treated in this cohort. The median age was 59 years (range, 35–80). Most pts had prior therapies: 40% had 1, 48% had 2, 10% had ?3 prior therapies. Most common treatment emergent adverse events (TEAEs) (?25% pts) were blurred vision (60%), headache, photophobia (29% each), dry eye, eye pain, fatigue (27% each). The most common serious AE (>1 pt) was seizure (8%). Grade 3/4 TEAEs (>1 pt) were keratitis (15%), corneal epithelial microcysts (8%), hemiparesis, hyperglycemia, muscular weakness, seizure (6% each), blurred vision, ulcerative keratitis (4% each). No dose-limiting toxicities were reported. Best RANO responses of 44 pts with complete data were: 2 partial responses, 18 stable disease, 24 progressive disease. The 6-month progression-free survival (PFS6) estimate was 30% [95% CI=17, 44]. Conclusions: ABT-414 monotherapy, at 1.25?mg/kg RPTD, displayed frequent yet reversible ocular toxicities. An encouraging tumor stability/response and PFS6 were observed in this highly refractory EGFR amp, rGBM. A global randomized trial of ABT-414, alone or with TMZ, vs. TMZ or lomustine, is underway in EGFR amp, rGBM (NCT02343406).

Project description:Abstract BACKGROUND Depatuxizumab mafodotin (depatux-m, formerly ABT-414), is an antibody-drug conjugate comprised of an EGFR-targeted antibody, a non-cleavable linker maleimidocaproyl, and the microtubule inhibitor monomethylauristatin F. Promising antitumor activity of depatux-m was observed in patients with glioblastoma (GBM) in Phase 12 studies. Dosage of depatux-m is limited by ocular side effects (OSE), such as blurred vision, dry eye, and photophobia from corneal epitheliopathy, which are generally reversible after dose reduction or drug discontinuation. This Phase 3b study evaluates depatux-m-related OSE management strategies used in depatux-m clinical trials. METHODS This open-label study will enroll approximately 90 patients with newly diagnosed, histologically confirmed, grade IV GBM that is epidermal growth factor receptor (EGFR)-amplified. Patients will receive depatux-m during the chemoradiation phase (radiation and temozolomide [TMZ]), and during adjuvant therapy with TMZ. Patients are randomized to one of three prophylactic ocular treatments: standard steroids (SS), SS with vasoconstrictors and cold compress (VC), or enhanced steroids (ES) with VC. Primary objective is to evaluate these prophylactic strategies for their effect on the proportion of patients requiring a change in OSE management due to inadequate control of OSEs, defined as either a 3-line decline in visual acuity from baseline or Grade 3 OSE severity on the Corneal Epithelial Adverse Event (CEAE) activities of daily living-based scale. Inadequate control with initial prophylactic regimen will trigger a switch to the addition of bandage contact lenses (BCL). Secondary objective assesses change in OSE management due to inadequate control of OSEs by BCL, defined as percentage of patients with Grade 3 CEAE that will trigger transition of patient to investigator discretion regimen (depatux-m interruption/dose reduction, VC prophylaxis, or ES prophylaxis). ClinicalTrials.gov: NCT03419403.

Project description:Abstract BACKGROUND Depatuxizumab-mafodotin is an EGFR-directed monoclonal antibody that targets activated EGFR (wild type or EGFRvIII) conjugated to a microtubule inhibitor. EGFRamp correlated with recurrent GBM response in a phase I trial (M12-356, NCT01800695), thus becoming a centrally determined inclusion criterion in an ensuing phase II/III randomized study for newly diagnosed disease now accruing (RTOG 3508, M13-813, NCT02573324). Centrally detected EGFRvIII mutation and MGMT promoter methylation are also stratification factors in RTOG 3508 to balance randomization for biomarkers of potential predictive or prognostic significance. Allowing use of locally determined molecular profiling may reduce accrual barriers by avoiding added time of tissue shipping and repeat central testing. However, discordant results between local and central tests could confound interpretation of clinical trial results. Therefore, we compared local vs. central biomarker results among patients screened for M12-356 or RTOG 3508 at Columbia University Medical Center (CUMC). METHODS We retrospectively tabulated local and central EGFRamp, EGFRvIII, and MGMT results. EGFRamp was analyzed by FISH/CISH and EGFRvIII and MGMT by PCR, although the assays for each differed slightly between laboratories. RESULTS 109 GBMs were molecularly profiled from 73 patients who underwent 1–4 resection(s) and screened for M12-356 (n=44) or RTOG 3508 (n=29) at CUMC. EGFRamp, EGFRvIII, and MGMT promoter methylation each was observed in 54, 36, and 27% of tumors tested locally vs. 68, 33, and 43% centrally, respectively. Concordance between laboratories was observed 88%, 86%, and 61%. CONCLUSIONS EGFRamp and EGFRvIII results were mainly concordant (over 85%) between local and central laboratories. EGFRamp frequency was higher centrally, likely biased by investigators who preferentially sent cases known to harbor EGFRamp locally for central testing. Of concern, MGMT results were discordant in 39%. Allowing local MGMT testing for stratification could unacceptably imbalance randomization if confirmed in a larger dataset.

Project description:BACKGROUND:Epidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR-directed therapies have led to increased efficacy but are associated with specific side effects. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor-specific. METHODS:This phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux-m in patients who had advanced solid tumors with known wild-type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux-m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux-m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD. RESULTS:Fifty-six patients were treated. The MTD and the recommended phase 2 dose for depatux-m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR-amplified, triple-negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux-m exposures were approximately dose-proportional. CONCLUSIONS:Depatux-m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow-up confirmed that ocular AEs were reversible. Lowering the drug-antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR-amplified disease provides the opportunity to study depatux-m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174-83. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Project description:IntroductionThe Understanding New Interventions with GBM ThErapy (UNITE) study was designed to assess the effect of prophylaxis for ocular side effects (OSEs) in patients with glioblastoma receiving the antibody-drug conjugate (ADC) depatuxizumab mafodotin. UNITE (NCT03419403) was a phase 3b, open-label, randomized, exploratory study performed at 18 research sites in 5 countries.MethodsThe study enrolled adult patients with epidermal growth factor receptor-amplified, histologically confirmed, newly diagnosed supratentorial glioblastoma or grade IV gliosarcoma, and a Karnofsky Performance Status ≥70, receiving depatuxizumab mafodotin. All patients were administered depatuxizumab mafodotin during concurrent radiotherapy and temozolomide and with adjuvant temozolomide. Ninety patients were to be randomized (1:1:1) to OSE prophylactic treatments with each depatuxizumab mafodotin infusion: (a) standard steroid eye drops, (b) standard steroid eye drops plus vasoconstrictor eye drops and cold compress, or (c) enhanced steroids plus vasoconstrictor eye drops and cold compress. A Corneal Epitheliopathy Adverse Event (CEAE) scale was devised to capture symptoms, grade OSEs (scale of 0-5), and inform ADC dose modifications. The primary endpoint was the frequency of a required change in OSE management due to inadequate control of OSEs, defined as decline from baseline in visual acuity (using logarithm of the minimum angle of resolution [LogMAR] scale) or a Grade ≥3 CEAE event, in the worst eye in the first 8 weeks of treatment; unless otherwise specified, the treatment period refers to both the chemoradiation and adjuvant phases.ResultsThe UNITE study was stopped early after interim analysis of separate phase III trial showed no difference in survival from depatuxizumab mafodotin. Forty patients were randomized (38 received depatuxizumab mafodotin). Overall, 23 patients experienced inadequate control of OSEs that required change in OSE management within 8 weeks of treatment, with 21 (70.0%) experiencing ≥+0.3 change on LogMAR scale in baseline-adjusted visual acuity and 12 reporting a grade ≥3 CEAE. There were no definitive differences among prophylactic treatments.ConclusionsThe premature cessation of the study precludes definitive conclusions regarding the OSE prophylaxis strategies. No new clinically significant safety findings were noted. Despite these limitations, this study highlights the need for novel assessment tools to better understand and mitigate OSEs associated with ADCs.

Dataset Information

Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study.

Publications

Efficacy of depatuxizumab mafodotin (ABT-414) monotherapy in patients with EGFR-amplified, recurrent glioblastoma: results from a multi-center, international study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets