Safety and Pharmacokinetics of Escalated Doses of Weekly Intravenous Infusion of CCI-779, a Novel mTOR Inhibitor, in Patients With Cancer

Raymond, Éric; Alexandre, Jérôme; Faivre, Sandrine; Vera, Karina; Materman, Eric; Boni, Joseph; Leister, Cathie; Korth‐Bradley, Joan M.; Hanauske, Axel R.; Armand, Jean‐Pierre

doi:10.1200/jco.2004.08.116

Cited by 473 publications

(304 citation statements)

References 29 publications

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“…In the second study, patients received temsirolimus weekly as a 30 minute infusion over a dose range of 7.5 to 220 mg/m 2 /week. 72 At 220 mg/m 2 /week, dose-limiting manic-depressive syndrome, stomatitis, and asthenia seen in two of nine patients limiting further dose escalation. The pharmacokinetic profile and the MTD of temsirolimus weekly intravenously in patients with recurrent malignant gliomas taking enzyme-inducing anti-epileptic drugs (EIAEDs) has also been evaluated.…”

Section: Temsirolimus (Cci-779)mentioning

confidence: 97%

Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

184

134

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The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.

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Section: Temsirolimus (Cci-779)mentioning

confidence: 97%

Therapeutic targets: MTOR and related pathways

Dancey¹

2006

Cancer Biology & Therapy

184

134

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“…A case report of a patient with mIAS for whom treatment included topical dexamethasone, intralesional injections of the corticosteroid triamcinolone, and magic mouthwash oral rinse demonstrated significant improvement in the signs and symptoms of mIAS lesions 47. However, the collective studies report an overall lack of effectiveness for managing mIAS with the prophylactic use of other oral rinses, such as antiseptic‐based 51 or sodium bicarbonate‐based mouthwashes 52.…”

Section: Preventing and Treating Mtor Inhibitor–associated Stomatitismentioning

confidence: 99%

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice

et al. 2016

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In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state‐of‐the‐science regarding mTOR inhibitor‐associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2–78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR‐associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high‐dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.

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“…[8][9][10] We have previously shown that rapamycin induces apoptosis in precursor B ALL lines in vitro and has in vivo activity in transgenic mice with pre-B leukemia/lymphoma. 11 Second generation MTIs, CCI-779 and RAD-001, are currently in phase 1 to phase 3 clinical trials in patients with various cancers, [12][13][14][15] but preclinical studies have not previously been performed in primary human ALL.…”

Section: Introductionmentioning

confidence: 99%

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

Teachey

Obzut

Cooperman

et al. 2006

Blood

158

128

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Acute lymphoblastic leukemia (ALL) in adult patients is often resistant to current therapy, making the development of novel therapeutic agents paramount. We investigated whether mTOR inhibitors (MTIs), a class of signal transduction inhibitors, would be effective in primary human ALL. Lymphoblasts from adult patients with precursor B ALL were cultured on bone marrow stroma and were treated with CCI-779, a second generation MTI. Treated cells showed a dramatic decrease in cell proliferation and an increase in apoptotic cells, compared to untreated cells. We also assessed the effect of CCI-779 in a NOD/SCID xenograft model. We treated a total of 68 mice generated from the same patient samples with CCI-779 after establishment of disease. Animals treated with CCI-779 showed a decrease in peripheralblood blasts and in splenomegaly. In dramatic contrast, untreated animals continued to show expansion of human ALL. We performed immunoblots to validate the inhibition of the mTOR signaling intermediate phospho-S6 in human ALL, finding down-regulation of this target in xenografted human ALL exposed to CCI-779. We conclude that MTIs can inhibit the growth of adult human ALL and deserve close examination as therapeutic agents against a disease that is often not curable with current therapy. IntroductionWhile children with precursor B-cell acute lymphoblastic leukemia (ALL) are often cured, children with relapsed ALL and adults with ALL usually succumb to their disease with current therapy. Even with aggressive therapy, these patient groups have 5-year diseasefree survival rates of only 28% to 39%. 1 Thus, the development of novel therapeutic agents is crucial.One potential class of novel therapeutics is mTOR inhibitors (MTIs). MTIs are a class of signal transduction inhibitors with anticancer activity that were initially developed as immunosuppressive agents. [2][3][4][5] Rapamycin, a macrocyclic lactone produced by Streptomyces hydroscopicus, 6 was the first MTI to be used in a clinical setting. Rapamycin is well tolerated in humans. 7 MTIs also have been shown to be active against a wide variety of tumor types. [8][9][10] We have previously shown that rapamycin induces apoptosis in precursor B ALL lines in vitro and has in vivo activity in transgenic mice with pre-B leukemia/lymphoma. 11 Second generation MTIs, CCI-779 and RAD-001, are currently in phase 1 to phase 3 clinical trials in patients with various cancers, 12-15 but preclinical studies have not previously been performed in primary human ALL.Preclinical testing of chemotherapeutic agents often involves using transformed tumor lines and transgenic mouse models. While these are valuable tools, they may not be representative of human disease. More clinically relevant data may be obtained from systems using primary human ALL cells. Two of these systems, bone marrow stroma-supported culture 16 and xenografting human ALL in nonobese diabetic/severe combined immunodeficient (NOD/ SCID) mice, have recently been developed. 17 Both of these systems allow for direct testing...

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Safety and Pharmacokinetics of Escalated Doses of Weekly Intravenous Infusion of CCI-779, a Novel mTOR Inhibitor, in Patients With Cancer

Cited by 473 publications

References 29 publications

Therapeutic targets: MTOR and related pathways

Therapeutic targets: MTOR and related pathways

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice

The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL

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