Phase II Study of Carboplatin and Pemetrexed for the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer

Matulonis, Ursula A.; Horowitz, Neil S.; Campos, Susana M.; Lee, Hang; Lee, Julie; Krasner, Carolyn; Berlin, Suzanne; Roche, Maria; Duska, Linda R.; Pereira, Lauren; Kendall, Deborah; Penson, Richard T.

doi:10.1200/jco.2008.17.0282

Cited by 38 publications

(52 citation statements)

References 13 publications

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“…The rates of grade 3 or 4 toxicity seen in the ovarian cancer Phase II combination studies [44,46] are comparable to those in the pivotal Phase III mesothelioma study examining the combination of pemetrexed and cisplatin [23]. The grade 3/4 neutropenia (23.3%) and grade 3/4 leukopenia (14.9%) were the most common hematologic toxicities in the patient group supplemented with folic acid.…”

Section: Safety and Tolerabilitysupporting

confidence: 50%

“…Phase I and II studies indicate that the addition of pemetrexed to platinum, gemcitabine or PLD is associated with a high incidence of grade 3 and 4 toxicity [e.g., neutropenia (39 --86%), thrombocytopenia (5 --48%), febrile neutropenia (2 --24%)] [42][43][44]46]), and this level of toxicity will need to be balanced against promising initial response rates. The doses of individual agents in pemetrexed combination studies taken forward need to be chosen carefully.…”

Section: Expert Opinion and Conclusionmentioning

confidence: 98%

“…The combination of pemetrexed and carboplatin in platinum-sensitive recurrent ovarian cancer has been evaluated in two studies. In the first by Matulonis and colleagues [44], 44 patients were treated with carboplatin (AUC 5) and pemetrexed (500 mg/m 2 ) on day 1 of a 21-day cycle for between six and eight cycles. All patients received folic acid and vitamin B 12 supplementation.…”

Section: Phase IImentioning

confidence: 99%

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The current state of pemetrexed in ovarian cancer

Miller

Banerjee

2013

Expert Opinion on Investigational Drugs

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A number of Phase I and II clinical trials have evaluated the use of pemetrexed in patients with ovarian cancer. Thus far, there are no randomized studies that address the role of pemetrexed compared to current, standard treatments. The activity of single agent pemetrexed in platinum-resistant patients is worth exploring. Biomarker-driven randomized, clinical trials and patient selection are key for the future development of pemetrexed.

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Section: Safety and Tolerabilitysupporting

confidence: 50%

Section: Expert Opinion and Conclusionmentioning

confidence: 98%

Section: Phase IImentioning

confidence: 99%

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The current state of pemetrexed in ovarian cancer

Miller

Banerjee

2013

Expert Opinion on Investigational Drugs

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“…After we opened this trial, several reports appeared of IV pemetrexed, single agent and in combination, in ovarian cancer (10-15). In platinum sensitive recurrent ovarian cancer patients and in combination with carboplatin, IV pemetrexed doses up to 900 mg/m 2 were well tolerated and active (10,11).…”

Section: Discussionmentioning

confidence: 99%

Phase I Trial of Intraperitoneal Pemetrexed, Cisplatin, and Paclitaxel in Optimally Debulked Ovarian Cancer

Chambers

Chow

Janicek

et al. 2012

Clinical Cancer Research

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Purpose This phase I trial evaluated intraperitoneal (IP) pemetrexed, cisplatin, and paclitaxel in optimally debulked ovarian cancer. Experimental Design Dose escalation of d1 IP pemetrexed accrued 3 patients to each of 5 dose levels (60mg/m2 to 1000mg/m2), along with d2 IP cisplatin (75mg/m2), and d8 IP paclitaxel (60mg/m2). The goals were to determine maximum tolerated dose (MTD), 18-month progression-free survival (PFS), and pharmacokinetics (PK) of IP pemetrexed. Results Cycles, given every 21d, had an 80% 6-cycle completion rate. There was minimal grade 3 toxicity in the first 4 dose levels and remarkably an almost complete absence of peripheral neuropathy and alopecia. At the highest dose level, 2 of 3 patients experienced ≥grade 3 and dose-limiting toxicity (DLT) (hematologic, infection, gastrointestinal). There was a PK advantage for IP pemetrexed with a IP:plasma area under the concentration-time-curve ratio of 13-fold. Neither analysis of PK nor homocysteine levels explains the unexpected severity of toxicity in those 2 patients. Based on plasma C24 h levels, the 42 cycles at ≥500mg/m2 IP pemetrexed without DLT, the MTD appears to be 500 mg/m2. Median PFS is 30.1 months; 18-month PFS is 78.6% (median follow-up 22.4 months). Conclusions This IP only regimen in front-line ovarian cancer is feasible with PFS in line with recent literature. We suggest phase II trials of this regimen in this population with IP pemetrexed at 500mg/m2. The favorable toxicity profile at doses <1000mg/m2, which needs to be confirmed, appears to compare well with standard combination intravenous/IP platinum/taxane chemotherapy in this disease.

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“…We propose that, after surgical debulking and paclitaxel and platinum therapies (27,28), additional attack of the stem cell population should improve the outcomes for this disease. Although the markers reported here enrich for a progenitor population in ovarian cancers, others such as CD133 (29) and ALDH1 (30) can produce similar enrichments.…”

Section: Discussionmentioning

confidence: 99%

Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance

Meirelles¹,

Benedict²,

Dombkowski³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

114

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Women with late-stage ovarian cancer usually develop chemotherapeutic-resistant recurrence. It has been theorized that a rare cancer stem cell, which is responsible for the growth and maintenance of the tumor, is also resistant to conventional chemotherapeutics. We have isolated from multiple ovarian cancer cell lines an ovarian cancer stem cell-enriched population marked by CD44, CD24, and Epcam (3+) and by negative selection for Ecadherin (Ecad−) that comprises less than 1% of cancer cells and has increased colony formation and shorter tumor-free intervals in vivo after limiting dilution. Surprisingly, these cells are not only resistant to chemotherapeutics such as doxorubicin, but also are stimulated by it, as evidenced by the significantly increased number of colonies in treated 3+Ecad− cells. Similarly, proliferation of the 3+Ecad− cells in monolayer increased with treatment, by either doxorubicin or cisplatin, compared with the unseparated or cancer stem cell-depleted 3−Ecad+ cells. However, these cells are sensitive to Mullerian inhibiting substance (MIS), which decreased colony formation. MIS inhibits ovarian cancer cells by inducing G1 arrest of the 3+Ecad− subpopulation through the induction of cyclindependent kinase inhibitors. 3+Ecad− cells selectively expressed LIN28, which colocalized by immunofluorescence with the 3+ cancer stem cell markers in the human ovarian carcinoma cell line, OVCAR-5, and is also highly expressed in transgenic murine models of ovarian cancer and in other human ovarian cancer cell lines. These results suggest that chemotherapeutics may be stimulative to cancer stem cells and that selective inhibition of these cells by treating with MIS or targeting LIN28 should be considered in the development of therapeutics. chemotherapy with cisplatin | pluripotency factors

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Phase II Study of Carboplatin and Pemetrexed for the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer

Abstract: Carboplatin/pemetrexed is a well-tolerated regimen with activity in platinum-sensitive recurrent EOC; further testing of this regimen in platinum-sensitive EOC patients is warranted.

Cited by 38 publications

References 13 publications

The current state of pemetrexed in ovarian cancer

The current state of pemetrexed in ovarian cancer

Phase I Trial of Intraperitoneal Pemetrexed, Cisplatin, and Paclitaxel in Optimally Debulked Ovarian Cancer

Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance

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