Phase 2 study of aldoxorubicin in relapsed glioblastoma.

Groves, Morris D.; Portnow, Jana; Boulmay, Brian C.; Chawla, Sant P.; Dinh, Hillary; Chawla, Shanta; Wieland, Scott; Levitt, Daniel

doi:10.1200/jco.2016.34.15_suppl.2027

Cited by 8 publications

(7 citation statements)

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“…The observation that DOX may possess anti-glioblastoma efficacy is in agreement with recent reports that showed an albumin-conjugated form of DOX (aldoxorubicin), which crosses the blood brain barrier better than DOX, was more effective than DOX in a nude mouse glioblastoma model and caused remissions of the glioblastoma in patients treated with this experimental therapy 39–41 . DOX has previously been shown to be effective at killing glioblastoma cells in a non-heterotypic glioblastoma model 42 .…”

Section: Discussionsupporting

confidence: 90%

A Human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine

Plummer¹,

Wallace²,

Ball

et al. 2019

Sci Rep

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A high throughput histology (microTMA) platform was applied for testing drugs against tumors in a novel 3D heterotypic glioblastoma brain sphere (gBS) model consisting of glioblastoma tumor cells, iPSC-derived neurons, glial cells and astrocytes grown in a spheroid. The differential responses of gBS tumors and normal neuronal cells to sustained treatments with anti-cancer drugs temozolomide (TMZ) and doxorubicin (DOX) were investigated. gBS were exposed to TMZ or DOX over a 7-day period. Untreated gBS tumors increased in size over a 4-week culture period, however, there was no increase in the number of normal neuronal cells. TMZ (100 uM) and DOX (0.3 uM) treatments caused ~30% (P~0.07) and ~80% (P < 0.001) decreases in the size of the tumors, respectively. Neither treatment altered the number of normal neuronal cells in the model. The anti-tumor effects of TMZ and DOX were mediated in part by selective induction of apoptosis. This platform provides a novel approach for screening new anti-glioblastoma agents and evaluating different treatment options for a given patient.

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Section: Discussionsupporting

confidence: 90%

A Human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine

Plummer¹,

Wallace²,

Ball

et al. 2019

Sci Rep

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“…Additional studies in other malignancies have been reported. In glioblastoma, a Phase II study of ALDOX in first relapse demonstrated that 3/21 (14%) patients with PR were evaluable 74. Pseudoprogression was documented surgically in two patients who showed radiological evidence of progression.…”

Section: Efficacy Studies Of Aldox In the Management Of Stssmentioning

confidence: 99%

“…In glioblastoma, a Phase II study of ALDOX in first relapse demonstrated that 3/21 (14%) patients with PR were evaluable. 74 Pseudoprogression was documented surgically in two patients who showed radiological evidence of progression. This suggests that ALDOX may penetrate the central nervous system in humans, as indicated preclinically.…”

Section: Efficacy Studies Of Aldox In the Management Of Stssmentioning

confidence: 99%

<p>Spotlight on aldoxorubicin (INNO-206) and its potential in the treatment of soft tissue sarcomas: evidence to date</p>

Cranmer¹

2019

OTT

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Anthracyclines, and doxorubicin in particular, remain a mainstay of sarcoma therapy. Despite modest activity and significant toxicities, no cytotoxic monotherapy has yet yielded superior overall survival over doxorubicin for therapy of advanced soft tissue sarcomas in a randomized trial. Similarly, combination regimens have also been unable to overcome doxorubicin in terms of overall survival. Strategies to ameliorate the most prominent side effect of doxorubicin, cardiotoxicity, are available, but their use in sarcoma patients has been limited. Aldoxorubicin is a prodrug consisting of doxorubicin with a covalent linker. It binds rapidly after intravenous infusion to cysteine-34 of human serum albumin. The drug–albumin conjugate is preferentially retained in tumor tissue, with uptake into tumoral cells. At physiologic pH, the complex is stable. Hydrolysis can occur under the acidic conditions of the endocytic lysosome, releasing doxorubicin. Doxorubicin then distributes to various cellular compartments, including Golgi, mitochondrion, and nucleus, with subsequent cytotoxic effects. Aldoxorubicin has demonstrated in vitro and in vivo activities in both cancer model systems and human xenografts. Preclinical models also support its decreased cardiac effects vs doxorubicin, although such promising results require formal comparison at efficacy equivalent doses of the two drugs. Phase I studies confirmed the tolerability of aldoxorubicin in humans. Clinical cardiotoxicity was not observed, but molecular and subclinical cardiac effects could be demonstrated. A Phase II study in treatment-naïve, advanced sarcoma patients demonstrated improved progression-free survival and response rate over doxorubicin, although no survival benefit was evident. A Phase III study of aldoxorubicin vs investigator’s choice from a panel of chemotherapy regimens in the salvage setting was unable to demonstrate a benefit in progression-free or overall survival in the entire population. Progression-free survival in L-sarcomas (leiomyosarcomas and liposarcomas) was documented. While evidence of subclinical cardiac effects was seen in a small proportion of aldoxorubicin-treated patients, data from both the Phase II and III studies indicated a favorable cardiotoxicity profile vs doxorubicin. Despite the negative results from this Phase III study, the importance of anthracycline therapy in sarcoma management merits further investigation of the potential role of aldoxorubicin in this indication. Other avenues for progress include identification of sensitive histologies and biomarkers of activity, exploration of clinical niches without proven standard therapies, and exploration of alternate dosing strategies.

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“…Groves presented a small (n = 21) Phase II study of the prodrug aldodoxorubicin in patients with first recurrent GBM [17]. Aldodoxorubicin is a prodrug of doxorubicin that is attached to a pH sensitive linker that binds covalently to albumin and is released preferentially within tumors.…”

Section: Salvage Trialsmentioning

confidence: 99%

Neuro-oncology: a selected review of ASCO 2016 abstracts

Chamberlain

2016

CNS Oncol.

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ASCO 2016, 29 May-2 June 2016, Chicago, IL, USA The largest annual clinical oncology conference the American Society of Clinical Oncology is held in the USA and gives researchers and other key opinion leaders the opportunity to present new cancer clinical trials and research data. The CNS tumors section of the American Society of Clinical Oncology 2016 covered various aspects of neuro-oncology including metastatic CNS diseases and primary brain tumors, presented via posters, oral talks and over 100 abstracts. This brief review selectively highlights presentations from this meeting in an organizational manner that reflects clinically relevant aspects of a large and multifaceted meeting.

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Phase 2 study of aldoxorubicin in relapsed glioblastoma.

Cited by 8 publications

References 0 publications

A Human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine

A Human iPSC-derived 3D platform using primary brain cancer cells to study drug development and personalized medicine

<p>Spotlight on aldoxorubicin (INNO-206) and its potential in the treatment of soft tissue sarcomas: evidence to date</p>

Neuro-oncology: a selected review of ASCO 2016 abstracts

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