Purpose

Patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) have limited treatment options. AKT and PI3K pathway activation is common in EOC/PPC, resulting in constitutive activation of downstream mTOR. The GOG conducted a phase II evaluation of efficacy and safety for the mTOR inhibitor, temsirolimus in EOC/PPC and explored circulating tumor cells (CTC) and AKT/mTOR/downstream tumor markers.

Methods

Eligible women with measurable, persistent/recurrent EOC/PPC who had received 1–3 prior regimens were treated with 25 mg weekly IV temsirolimus until progression or intolerable toxicity. Primary endpoints were progression-free survival (PFS) ≥6-months, tumor response, and toxicity. CellSearch® system was used to examine CTC, and AKT/mTOR/downstream markers were evaluated by archival tumor immunohistochemistry. Kendall’s tau-b correlation coefficient (r) and Cox regression modeling were used to explore marker associations with baseline characteristics and outcome.

Results

Sixty patients were enrolled in a two-stage sequential design. Of 54 eligible and evaluable patients, 24.1% (90%CI 14.9%–38.6%) had PFS ≥6 months (median 3.1 months), 9.3% (90%CI 3.7%–23.4%) experienced a partial response. Grade 3/4 adverse events included metabolic(8), gastrointestinal(8), pain(6), constitutional(5) and pulmonary(4). Suggested associations were between cyclin D1 and PFS ≥6 months, PFS or survival; positive CTC pre-treatment and lack of response; and high CTC expression of M30 and PFS ≥6 months/longer PFS.

Conclusions

Temsirolimus appears to have modest activity in persistent/recurrent EOC/PPC; however, PFS is just below that required to warrant inclusion in phase III studies in unselected patients. Cyclin D1 as a selection marker and CTC measures merit further study.

Background

The purpose of this study was to evaluate the safety and efficacy of cetuximab (C225), an antibody that inhibits epidermal growth factor receptor (EGFR) activity, with cisplatin and to explore associations between EGFR protein expression with patient demographics or clinical outcome.

Methods

Women with advanced, persistent, or recurrent carcinoma of the cervix were eligible. The women received cisplatin at 30 mg/m2 days 1 and 8 with a loading dose of cetuximab at 400 mg/m2 followed by 250 mg/m2 days 1, 8, and 15 in a 21 day cycle. Adverse events were assessed with CTCAE v 3.0. Primary measure of efficacy was tumor response by RECIST. The study was stratified by prior chemotherapy (CT). EGFR protein expression in pre-treatment tumor was analyzed by immunohistochemistry.

Results

Between September 2004 and March 2008, 76 patients were enrolled. Of these, 69 were eligible and evaluable; 44 (64%) received prior chemotherapy. There were 4 responses in each group, prior chemotherapy and no chemotherapy, 9% and 16%, respectively. Grade 4 toxicities included anemia (1), allergy (1), metabolic (1), and vascular (1). The most common grade 3 toxicities were metabolic (15), dermatologic (8), fatigue (6), and gastrointestinal (6). EGFR protein was expressed in 47/48 (98%) of tumors analyzed with a median cellular expression of 81%. Exploratory analyses revealed a trend between the percentage of cells expressing EGFR protein and PFS (hazard ratio =1.76, 95% confidence interval=0.96–3.21).

Conclusions

The combination of cetuximab with cisplatin was adequately tolerated but did not indicate additional benefit beyond cisplatin therapy.

This multi-center phase II trial was conducted by the Gynecologic Oncology Group to evaluate the activity and safety of irofulven in patients with recurrent epithelial ovarian cancer.

Eligible patients had documented recurrent ovarian cancer 6-12 months after receiving a front-line platinum-based regimen and no other chemotherapy. Patients were required to have measurable disease, performance status of 0-2, and adequate bone marrow, hepatic, and renal function prior to study entry. The dose of irofulven was 0.45 mg/kg IV on days 1 and 8 every 21 days. Responses were defined by RECIST.

Fifty-five of 61 enrolled patients were evaluable for response and toxicity. There were seven partial responses (12.7%) and 30 patients (54.6%) had stable disease. Median progression-free and overall survival were 6.4 mo (1.3-37.5) and 22.1+ mo (2.8-57.8+), respectively. Patients received a median of three cycles (range 1-21) of protocol therapy. Grade 4 hematologic toxicity was limited to reversible neutropenia and thrombocytopenia. Grade 4 non-hematologic toxicity was limited to one patient with anorexia and another with hypomagnesemia.

Irofulven administered at this dose and schedule was well tolerated but had modest activity as a single agent.

Translational Relevance

Clear cell carcinoma (CCC) of the ovary is a distinctive subtype of epithelial ovarian cancer associated with a poorer sensitivity to platinum-based chemotherapy and a worse prognosis than the more common serous adenocarcinoma (SAC). To improve survival, the development of new treatment strategies that target CCC more effectively is necessary. Our results show that mTOR is more frequently activated in CCCs than in SACs. Our data have relevance for the design of future clinical studies of first-line treatment for patients with CCC of the ovary. Moreover, the finding of increased expression of phospho-mTOR and greater sensitivity to RAD001 in cisplatin-resistant CCC cells than in cisplatin-sensitive cells suggests a novel treatment option for patients with recurrent disease after cisplatin-based first-line chemotherapy.

Purpose

mTOR (mammalian target of rapamycin) plays a central role in cell proliferation and is regarded as a promising target in cancer therapy including for ovarian cancer. This study aims to examine the role of mTOR as a therapeutic target in clear cell carcinoma (CCC) of the ovary which is regarded as aggressive, chemo-resistant histological subtype.

Experimental Design

Using tissue microarrays of 98 primary ovarian cancers (52 clear cell carcinomas and 46 serous adenocarcinomas), the expression of phospho-mTOR was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTOR inhibition by RAD001 (everolimus) was examined using 2 pairs of cisplatin-sensitive parental (RMG1 and KOC7C) and cisplatin-resistant human CCC cell lines (RMG1-CR and KOC7C-CR) both in vitro and in vivo.

Results

Immunohistochemical analysis demonstrated mTOR was more frequently activated in CCCs than in serous adenocarcinomas (86.6% vs 50%). Treatment with RAD001 markedly inhibited the growth of both RMG1 and KOC7C cells both in vitro and in vivo. Increased expression of phospho-mTOR was observed in cisplatin-resistant RMG1-CR and KOC7C-CR cells, compared to the respective parental cells. This increased expression of phospho-mTOR in cisplatin-resistant cells was associated with increased activation of AKT. RMG1-CR and KOC7C-CR cells showed greater sensitivity to RAD001 than parental RMG1 and KOC7C cells, respectively, in vitro and in vivo.

Conclusion

mTOR is frequently activated in CCC and can be a promising therapeutic target in the management of CCC. Moreover, mTOR inhibition by RAD001 may be efficacious as a second-line treatment of recurrent disease in patients previously treated with cisplatin.

Objectives

To determine the proportion of patients with tumor response, the proportion who survived progression-free for at least six months (PFS ≥ 6 months) and the frequency and severity of toxicities of patients with recurrent squamous cell carcinoma of the uterine cervix treated with erlotinib.

Methods

This was a multicenter, open-label single arm trial evaluating the toxicity and efficacy of oral erlotinib at an initial dose of 150 mg daily until progressive disease or adverse effects prohibited further therapy.

Results

Twenty-eight patients with squamous cell carcinoma were enrolled onto this trial. Twenty-five patients were evaluable. There were no objective responses with four (16%) achieving stable disease; only one patient had a PFS ≥ 6 months (4%). The one-sided 90% confidence interval (CI) for response was 0.0%–8.8%. The two-sided 90% CI for the proportion of patients surviving progression-free for at least 6 months is 0.2%–17.6%. Erlotinib was well tolerated with the most common drug-related adverse events being gastrointestinal toxicities, fatigue and rash.

Conclusion

Erlotinib is inactive as monotherapy in patients with recurrent squamous cell carcinoma of the uterine cervix.

Objectives

Determine if cetuximab dose escalation to induce grade 2 rash correlates with anti-tumor activity and if sera-based markers could predict likelihood of response.

Methods

Patients with persistent/recurrent ovarian or primary peritoneal carcinoma received an initial dose of cetuximab 400 mg/m2, then 250 mg/m2 weekly for two 3-week cycles. Patients who had stable disease (SD) and

Results

One of 25 patients achieved partial remission (PR) and 9 patients had SD. The median progression free survival was 2.1 months; the 1-year survival rate was 54.8%. Rash (96%) was the most common drugrelated adverse event. At first response assessment, 4 patients remained at 250 mg/m2; 8 patients were dose-escalated to 325 mg/m2; of these, 4 ultimately were increased to 400 mg/m2. Patients with progressive disease (PD) were removed from the study. Ninety-two serologic markers were analyzed from 20 patients to identify markers associated with clinical activity and/or predictive of outcome. Pretreatment levels of twelve markers were significantly elevated in patients exhibiting PD versus SD or PR; however, changes in marker levels during the course of treatment were not significant indicators of response.

Conclusions

Single-agent cetuximab showed minimal activity in patients with recurrent ovarian cancer. Patients with elevated levels of 12 serologic markers at baseline were more likely to have earlier disease progression.