Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study

Kantarjian, Hagop M.; DeAngelo, Daniel J.; Advani, Anjali S.; Stelljes, Matthias; Kebriaei, Partow; Cassaday, Ryan D.; Merchant, Akil; Fujishima, Naohito; Uchida, Toshiki; Calbacho, M.; Ejduk, Anna; O’Brien, Susan; Jabbour, Elias; Zhang, Hui; Sleight, Barbara; Vandendries, Erik; Marks, David I.

doi:10.1016/s2352-3026(17)30103-5

Cited by 178 publications

(176 citation statements)

References 23 publications

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“…75 Risk factors for post-HSCT VOD/SOS may be patient related (eg, age, history of liver diseases, active hepatitis, prior treatment, primary disease) or transplant related (eg, type of transplant, conditioning regimen intensity, GVHD prophylaxis). 86 Specific chemotherapies observed to increase risk of VOD/SOS include inotuzumab ozogamicin 87 and gemtuzumab ozogamicin in patients with and without HSCT. 88,89 Reduced intensity conditioning may decrease the risk of VOD/SOS post-HSCT, although VOD/SOS has still been reported in ;2% to 9% of allogeneic-transplant patients who received reduced intensity conditioning.…”

Section: Key Development Milestones and Approvals Grantedmentioning

confidence: 99%

The use of defibrotide in blood and marrow transplantation

et al. 2018

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propensity analysis-estimated between-group difference: 23%; P 5 .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graftversus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.

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Section: Key Development Milestones and Approvals Grantedmentioning

confidence: 99%

The use of defibrotide in blood and marrow transplantation

et al. 2018

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“…Treatment with chemotherapeutic agents (i.e., azathioprine, cyclophosphamide, oxaliplatin, and irinotecan) or ADCs may be associated with the development of VOD/SOS . In addition, vascular lesions consistent with hepatic VOD/SOS have been reported in patients with hematologic malignancies treated with other calicheamicin immunoconjugates, targeted to CD22 and CD33 . The relative contribution to the development of these abnormalities by a potential ADC uptake in hepatic sinusoidal cells through mannose receptors or on‐target effects in normal tissues remains to be defined …”

Section: Discussionmentioning

confidence: 99%

First‐in‐human, phase I study of PF‐06647263, an anti‐EFNA4 calicheamicin antibody–drug conjugate, in patients with advanced solid tumors

Krop

Burris

Hamilton

et al. 2019

Intl Journal of Cancer

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PF‐06647263, a novel antibody–drug conjugate consisting of an anti‐EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple‐negative breast cancer (TNBC). In the dose‐escalation part 1 of this multicenter, open‐label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF‐06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose‐expansion cohort), 12 patients with pretreated, metastatic TNBC received PF‐06647263 at the RP2D to further evaluate tumor response and overall safety. PF‐06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thrombocytopenia). The most common AEs with the QW regimen (fatigue, nausea, vomiting, mucosal inflammation, thrombocytopenia, and diarrhea) were mostly mild to moderate in severity. The MTD was not estimated. PF‐06647263 exposures increased in a dose‐related manner across the doses evaluated. The RP2D was determined to be 0.015 mg/kg QW. Six (10%) patients achieved a confirmed partial response and 22 (36.7%) patients had stable disease. No correlations were observed between tumor responses and EFNA4 expression levels. Study findings showed manageable safety and favorable PK for PF‐06647263 administered QW at the RP2D, with preliminary evidence of limited antitumor activity in patients with TNBC and ovarian cancer.

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“…Our exploratory analysis of risk factors for SOS in study patients with ALL who subsequently underwent HCT found that previous InO exposure was one of several risk factors, but not the dominant factor in an exploratory multivariable analysis. InO exposure had not been examined as a potential risk factor for posttransplant SOS in the study‐site analysis …”

Section: Discussionmentioning

confidence: 99%

Liver Complications Following Treatment of Hematologic Malignancy With Anti‐CD22‐Calicheamicin (Inotuzumab Ozogamicin)

et al. 2019

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The frequencies of SOS and DILI after inotuzumab ozogamicin treatment were 1.5% and 7.9%, respectively, compared to none and 1% among controls who received standard chemotherapy. These data suggest that ADCs that do not target antigens present in the normal liver have a relatively low frequency of SOS but a relatively high frequency of DILI. This article is protected by copyright. All rights reserved.

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Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study

Cited by 178 publications

References 23 publications

The use of defibrotide in blood and marrow transplantation

The use of defibrotide in blood and marrow transplantation

First‐in‐human, phase I study of PF‐06647263, an anti‐EFNA4 calicheamicin antibody–drug conjugate, in patients with advanced solid tumors

Liver Complications Following Treatment of Hematologic Malignancy With Anti‐CD22‐Calicheamicin (Inotuzumab Ozogamicin)

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