Multicenter Phase Ib/II Trial of the Radiation Enhancer Motexafin Gadolinium in Patients With Brain Metastases

Carde, Patrice; Timmerman, Robert; Mehta, Minesh P.; Koprowski, Christopher; Ford, Judith M.; Tishler, Roy B.; Miles, Dale; Miller, Richard A.; Renschler, Markus F.

doi:10.1200/jco.2001.19.7.2074

Cited by 121 publications

(88 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…MGd could therefore modulate a variety of downstream processes by mobilizing zinc. The importance of this would likely depend on the particular system under study but would be most likely to occur in tumors, where the drug seems to localize selectively (15)(16)(17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

“…For example, motexafin gadolinium (MGd, Xcytrin, Fig. 1A), an expanded porphyrin containing the lanthanide cation gadolinium, is currently in clinical trials for the treatment of several forms of cancer (15)(16)(17)(18)(19)(20)(21)(22)(23). MGd is an electron-affinic compound that mediates electron transfer from a variety of intracellular reducing species, such as ascorbate, NADPH, and thiols, to oxygen to form superoxide and hydrogen peroxide (20)(21)(22)(23).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

et al. 2005

Self Cite

View full text Add to dashboard Cite

To gain a better understanding of the mechanism of action of the metal cation-containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling analyses were conducted on plateau phase human lung cancer (A549) cell cultures treated with MGd. Drug treatment elicited a highly specific response that manifested in elevated levels of metallothionein isoform and zinc transporter 1 (ZnT1) transcripts. A549 cultures incubated with MGd in the presence of exogenous zinc acetate displayed synergistic increases in the levels of intracellular free zinc, metallothionein transcripts, inhibition of thioredoxin reductase activity, and cell death. Similar effects were observed in PC3 prostate cancer and Ramos B-cell lymphoma cell lines. Intracellular free zinc levels increased in response to treatment with MGd in the absence of exogenous zinc, indicating that MGd can mobilize bound intracellular zinc. These findings lead us to suggest that an important component of the anticancer activity of MGd is related to its ability to disrupt zinc metabolism and alter cellular availability of zinc. This class of compounds may provide insight into the development of novel cancer drugs targeting control of intracellular free zinc and the roles that zinc and other metal cations play in biochemical pathways relevant to cancer. (Cancer Res 2005; 65(9): 3837-45)

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…Preliminary studies in patients with brain metastases treated with motexafin gadolinium and WBRT showed radiologic responses in 68% to 72% of patients (40,68). A large randomized phase III study of motexafin gadolinium in 401 patients did not show a significant increase in median survival (5.2 versus 4.9 months; P = 0.48) or median time to neurologic progression (9.5 versus 8.3 months; P = 0.95).…”

Section: Prevention Of Neurocognitive Impairment: Enhancing Radiationmentioning

confidence: 96%

“…Motexafin gadolinium is a metalloporphyrin redox modulator that shows selective tumor localization and catalyzes the oxidation of a number of intracellular reducing metabolites, such as ascorbate, glutathione, and NADP + , thereby generating reactive oxygen species and depleting the pools of reducing agents necessary to repair cytotoxic damage (67). Selective uptake of motexafin gadolinium in tumors, but not in normal tissues, has been shown in patients by magnetic resonance imaging because of its paramagnetic characteristics (34,39,68,69).…”

Section: Prevention Of Neurocognitive Impairment: Enhancing Radiationmentioning

confidence: 99%

Targeted Therapy for Brain Metastases: Improving the Therapeutic Ratio

Patel

Mehta²

2007

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Brain metastasis is the most common intracranial malignancy in adults. Improvements in modern imaging techniques are detecting previously occult brain metastases, and more effective therapies are extending the survival of patients with invasive cancer who have historically died from extracranial disease before developing brain metastasis. This combination of factors along with increased life expectancy has led to the increased diagnosis of brain metastases. Conventional treatment has been whole brain radiotherapy, which can improve symptoms, but potentially results in neurocognitive deficits. Several strategies to improve the therapeutic ratio are currently under investigation to either enhance the radiation effect, thereby preventing tumor recurrence or progression as well as reducing collateral treatment-related brain injury. In this review article, we discuss new directions in the management of brain metastases, including the role of chemical modifiers, novel systemic agents, and the management and prevention of neurocognitive deficits.

show abstract

“…The company filed an investigational new drug (IND) application with the FDA to begin clinical testing of the drug in human patients. After a successful Phase I/II study, 62 the company began a Phase III study (called trial 9801) that enrolled patients with any type of cancerous tumor who developed brain metastases. Subjects were randomized to either whole brain radiation therapy (WBRT) alone (the control arm) or MGd and WBRT (treatment arm).…”

Section: A Background On Mgdmentioning

confidence: 99%

Accounting for Differences Among Patients in the FDA Approval Process

Laan¹,

Malani²,

Bembom³

2009

SSRN Journal

View full text Add to dashboard Cite

Abstract. The FDA employs an average-patient standard when reviewing drugs: it approves a drug only if the average patient (in clinical trials) does better on the drug than on control. It is common, however, for different patients to respond differently to a drug. Therefore, the average-patient standard can result in approval of a drug with significant negative effects for certain patient subgroups (false positives) and disapproval of drugs with significant positive effects for other patient subgroups (false negatives). Drug companies have a financial incentive to avoid false negatives. After their clinical trials reveal that their drug does not benefit the average patient, they conduct what is called post hoc subgroup analysis to highlight patients that benefit from the drug. The FDA rejects such analysis due to the risk of spurious results. With enough data dredging, a drug company can always find some patients that benefit from their drug. This paper asks whether there workable compromise between the FDA and drug companies. Specifically, we seek a drug approval process that can use post hoc subgroup analysis to eliminate false negatives but does not risk opportunistic behavior and spurious correlation. We recommend that the FDA or some other independent agent conduct subgroup analysis to identify patient subgroups that may benefit from a drug. Moreover, we suggest a number of statistical algorithms that operate as veil of ignorance rules to ensure that the independent agent is not indirectly captured by drug companies. We illustrate our proposal by applying it to the results of a recent clinical trial of a cancer drug (motexafin gadolinium) that was recently rejected by the FDA.

show abstract

Multicenter Phase Ib/II Trial of the Radiation Enhancer Motexafin Gadolinium in Patients With Brain Metastases

Abstract: Motexafin gadolinium was well tolerated at doses up to 6.3 mg/kg, was selectively accumulated in tumors, and, when combined with WBRT of 30 Gy in 10 fractions, was associated with a high radiologic response rate.

Cited by 121 publications

References 0 publications

Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

Motexafin Gadolinium Disrupts Zinc Metabolism in Human Cancer Cell Lines

Targeted Therapy for Brain Metastases: Improving the Therapeutic Ratio

Accounting for Differences Among Patients in the FDA Approval Process

Contact Info

Product

Resources

About