A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma

Brian Slomovitz, Karen H. Lu, Taren Johnston, Robert L. Coleman, Mark Munsell, Russell R. Broaddus, Cheryl Walker, Lois M. Ramondetta, Thomas W. Burke, David M. Gershenson, Judith Wolf

Research output: Contribution to journalArticle

158 Citations (Scopus)

Abstract

Background: Dysregulation of phosphatase and tensin homolog (PTEN) and the gene that encodes the p110α catalytic subunit of phosphatidylinositol-3- kinase (PI3K), PIK3CA, are the most common mutations in endometrial carcinoma (EC). Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT, which leads to up-regulation of mammalian target of rapamycin (mTOR). Everolimus is an oral rapamycin analog that acts by selectively inhibiting mTOR. Methods: A single-institution, open-labeled, phase 2 study of everolimus in patients with measurable recurrent EC who had failed at least 1 and no more than 2 prior chemotherapeutic regimens was performed. Everolimus was administered at a dose of 10 mg orally daily for 28-day cycles. Patients were treated until disease progression or toxicity. The primary endpoint was clinical benefit response (CBR), defined as a confirmed complete or partial response or prolonged stable disease (SD) (≥8 weeks). Inclusion was limited to patients with endometrioid histology. Results: A total of 35 patients were enrolled (median age, 58 years; range, 38-81 years). A total of 81 cycles were administered. Twelve of 28 (43%) evaluable patients had not developed disease progression at the time of the first objective evaluation (8 weeks). All these patients had SD (median, 4.5 cycles; range, 2-10 cycles). Six of the 28 (21%) patients had a confirmed CBR at 20 weeks of therapy. Patients with CBR discontinued treatment because of toxicity (6 patients), disease progression (5 patients), and noncompliance (1 patient). Seven patients were unevaluable after receiving ≤1 cycle because of toxicity (5 patients) or noncompliance (2 patients). The most common drug-related toxicities were fatigue, anemia, pain, lymphopenia, and nausea. Conclusions: Everolimus demonstrated encouraging single-agent CBR in pretreated patients with recurrent endometrioid EC. Future studies will evaluate this agent in combination with hormonal and/or cytotoxic therapy. Cancer 2010. 2010 American Cancer Society. Everolimus is an oral rapamycin analog that acts by selectively inhibiting mammalian target of rapamycin, an intracellular protein downstream to phosphatase and tensin homolog (PTEN) that helps to regulate cell growth and proliferation. Everolimus demonstrated an encouraging single-agent clinical benefit response rate in pretreated patients with recurrent endometrioid endometrial cancer.

Original languageEnglish (US)
Pages (from-to)5415-5419
Number of pages5
JournalCancer
Volume116
Issue number23
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

Fingerprint

Sirolimus
Endometrial Neoplasms
Phosphoric Monoester Hydrolases
Disease Progression
Patient Compliance
Everolimus
TOR Serine-Threonine Kinases
Phosphatidylinositol 3-Kinase
Endometrioid Carcinoma
Lymphopenia
Drug-Related Side Effects and Adverse Reactions
Nausea
Fatigue
Anemia
Catalytic Domain
Histology
Up-Regulation
Therapeutics

Keywords

  • clinical trial
  • endometrial carcinoma
  • mammalian target of rapamycin (mTOR) inhibitor
  • phase 2 study
  • phosphatase and tensin homolog (PTEN)

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. / Slomovitz, Brian; Lu, Karen H.; Johnston, Taren; Coleman, Robert L.; Munsell, Mark; Broaddus, Russell R.; Walker, Cheryl; Ramondetta, Lois M.; Burke, Thomas W.; Gershenson, David M.; Wolf, Judith.

In: Cancer, Vol. 116, No. 23, 01.12.2010, p. 5415-5419.

Research output: Contribution to journalArticle

Slomovitz, B, Lu, KH, Johnston, T, Coleman, RL, Munsell, M, Broaddus, RR, Walker, C, Ramondetta, LM, Burke, TW, Gershenson, DM & Wolf, J 2010, 'A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma', Cancer, vol. 116, no. 23, pp. 5415-5419. https://doi.org/10.1002/cncr.25515
Slomovitz, Brian ; Lu, Karen H. ; Johnston, Taren ; Coleman, Robert L. ; Munsell, Mark ; Broaddus, Russell R. ; Walker, Cheryl ; Ramondetta, Lois M. ; Burke, Thomas W. ; Gershenson, David M. ; Wolf, Judith. / A phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. In: Cancer. 2010 ; Vol. 116, No. 23. pp. 5415-5419.
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AU - Coleman, Robert L.

AU - Munsell, Mark

AU - Broaddus, Russell R.

AU - Walker, Cheryl

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AU - Wolf, Judith

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N2 - Background: Dysregulation of phosphatase and tensin homolog (PTEN) and the gene that encodes the p110α catalytic subunit of phosphatidylinositol-3- kinase (PI3K), PIK3CA, are the most common mutations in endometrial carcinoma (EC). Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT, which leads to up-regulation of mammalian target of rapamycin (mTOR). Everolimus is an oral rapamycin analog that acts by selectively inhibiting mTOR. Methods: A single-institution, open-labeled, phase 2 study of everolimus in patients with measurable recurrent EC who had failed at least 1 and no more than 2 prior chemotherapeutic regimens was performed. Everolimus was administered at a dose of 10 mg orally daily for 28-day cycles. Patients were treated until disease progression or toxicity. The primary endpoint was clinical benefit response (CBR), defined as a confirmed complete or partial response or prolonged stable disease (SD) (≥8 weeks). Inclusion was limited to patients with endometrioid histology. Results: A total of 35 patients were enrolled (median age, 58 years; range, 38-81 years). A total of 81 cycles were administered. Twelve of 28 (43%) evaluable patients had not developed disease progression at the time of the first objective evaluation (8 weeks). All these patients had SD (median, 4.5 cycles; range, 2-10 cycles). Six of the 28 (21%) patients had a confirmed CBR at 20 weeks of therapy. Patients with CBR discontinued treatment because of toxicity (6 patients), disease progression (5 patients), and noncompliance (1 patient). Seven patients were unevaluable after receiving ≤1 cycle because of toxicity (5 patients) or noncompliance (2 patients). The most common drug-related toxicities were fatigue, anemia, pain, lymphopenia, and nausea. Conclusions: Everolimus demonstrated encouraging single-agent CBR in pretreated patients with recurrent endometrioid EC. Future studies will evaluate this agent in combination with hormonal and/or cytotoxic therapy. Cancer 2010. 2010 American Cancer Society. Everolimus is an oral rapamycin analog that acts by selectively inhibiting mammalian target of rapamycin, an intracellular protein downstream to phosphatase and tensin homolog (PTEN) that helps to regulate cell growth and proliferation. Everolimus demonstrated an encouraging single-agent clinical benefit response rate in pretreated patients with recurrent endometrioid endometrial cancer.

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