Dataset Information

Ocular Side Effects of EGFR-Inhibitor ABT-414 in Recurrent Glioblastoma: A Long-Term Safety Study.

ABSTRACT: This study aimed to prospectively evaluate, on a long-term basis, corneal side effects secondary to compassionate administration of epidermal growth factor receptor (EGFR) inhibitor depatuxizumab mafodotin (ABT-414) in patients affected by EGFR-amplified recurrent glioblastoma. Fifteen patients with a median follow-up of 4.3 months after treatment discontinuation were enrolled. Each patient underwent full ophthalmologic examination including in vivo corneal confocal microscopy (CCM). No CTCAE grade 4 toxicity and four (27%) grade 3 toxicities were documented during treatment. Ocular symptoms (blurred vision, eye pain, photophobia) were experienced by all patients, reaching maximal severity after the second ABT-414 infusion, with persistence until treatment discontinuation. During treatment, CCM documented specific changes in the corneal epithelium and in the sub-basal nerve plexus layer fibers of all eyes. The median time of symptoms resolution after treatment discontinuation ranged from 38 days (eye pain) to 53 days (photophobia). The median time of signs resolution ranges from 14 days (corneal ulcer) to 38 days (superficial punctate epitheliopathy, corneal stroma edema and intraepithelial cysts). ABT-414 corneal side effects are detectable in all treated patients. Related symptoms are gradually experienced by all patients during treatment and although reversible, they are characterized by a relative prolonged persistence after treatment discontinuation.

SUBMITTER: Parrozzani R

PROVIDER: S-EPMC7591744 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Ocular Side Effects of EGFR-Inhibitor ABT-414 in Recurrent Glioblastoma: A Long-Term Safety Study.

Parrozzani Raffaele R Lombardi Giuseppe G Midena Edoardo E Londei Davide D Padovan Marta M Marchione Giulia G Caccese Mario M Midena Giulia G Zagonel Vittorina V Frizziero Luisa L

Frontiers in oncology 20201014

This study aimed to prospectively evaluate, on a long-term basis, corneal side effects secondary to compassionate administration of epidermal growth factor receptor (EGFR) inhibitor depatuxizumab mafodotin (ABT-414) in patients affected by EGFR-amplified recurrent glioblastoma. Fifteen patients with a median follow-up of 4.3 months after treatment discontinuation were enrolled. Each patient underwent full ophthalmologic examination including <i>in vivo</i> corneal confocal microscopy (CCM). No C ...[more]

PMID: 33154952

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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:BackgroundThe cytotoxicity of radiotherapy and chemotherapy can be enhanced by modulating DNA repair. PARP is a family of enzymes required for an efficient base-excision repair of DNA single-strand breaks and inhibition of PARP can prevent the repair of these lesions. The current study investigates the trimodal combination of ABT-888, a potent inhibitor of PARP1-2, ionizing radiation and temozolomide(TMZ)-based chemotherapy in glioblastoma (GBM) cells.MethodsFour human GBM cell lines were treated for 5 h with 5 ?M ABT-888 before being exposed to X-rays concurrently with TMZ at doses of 5 or 10 ?M for 2 h. ABT-888's PARP inhibition was measured using immunodetection of poly(ADP-ribose) (pADPr). Cell survival and the different cell death pathways were examined via clonogenic assay and morphological characterization of the cell and cell nucleus.ResultsCombining ABT-888 with radiation yielded enhanced cell killing in all four cell lines, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER50) ranging between 1.12 and 1.37. Radio- and chemo-sensitization was further enhanced when ABT-888 was combined with both X-rays and TMZ in the O6-methylguanine-DNA-methyltransferase (MGMT)-methylated cell lines with a SER50 up to 1.44. This effect was also measured in one of the MGMT-unmethylated cell lines with a SER50 value of 1.30. Apoptosis induction by ABT-888, TMZ and X-rays was also considered and the effect of ABT-888 on the number of apoptotic cells was noticeable at later time points. In addition, this work showed that ABT-888 mediated sensitization is replication dependent, thus demonstrating that this effect might be more pronounced in tumour cells in which endogenous replication lesions are present in a larger proportion than in normal cells.ConclusionsThis study suggests that ABT-888 has the clinical potential to enhance the current standard treatment for GBM, in combination with conventional chemo-radiotherapy. Interestingly, our results suggest that the use of PARP inhibitors might be clinically significant in those patients whose tumour is MGMT-unmethylated and currently derive less benefit from TMZ.

Dataset Information

Ocular Side Effects of EGFR-Inhibitor ABT-414 in Recurrent Glioblastoma: A Long-Term Safety Study.

Publications

Ocular Side Effects of EGFR-Inhibitor ABT-414 in Recurrent Glioblastoma: A Long-Term Safety Study.

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