Trial Information

A Phase II Study of Combination Therapy With Paclitaxel, Carboplatin and Megesterol Acetate for the Management of Advanced Stage or Recurrent Carcinoma of the Endometrium

Endometrial cancer is the most common gynecologic malignancy with 40,100 new cases diagnosed
and 6,800 deaths attributable to this malignancy in 2003. Most patients diagnosed with
endometrial cancer have early stage disease that is amenable to treatment with hysterectomy
and bilateral salpingo-oophorectomy with excellent clinical outcomes. Surgical staging has
improved accuracy over clinical staging for defining a low risk population of patients who
have favorable long-term outcomes with surgery alone. However, approximately 15% of
patients will have evidence of Stage III or IV disease at the time of initial diagnosis and
15% of surgical Stage I/II patients will have recurrent disease. Radiation therapy will be
effective in patients with disease confined to the pelvis; however, patients with metastatic
disease will require more systemic therapy in order to control disease.

Multiple chemotherapeutic agents including cisplatin, doxorubicin HCL, paclitaxel,
carboplatin, and oral etoposide, alone and in combination, have been studied for persistent,
advanced or recurrent endometrial cancer. A phase III study by the Gynecologic Oncology
Group (GOG) compared doxorubicin with and without cisplatin (GOG 107) for patients with
advanced or recurrent endometrial cancer. A higher response rate (45% vs. 27%) was noted
for combination therapy and has been considered by many to be the standard chemotherapy
regimen for treatment of patients with advanced endometrial cancer. However, clinical
trials have continued to define the optimal chemotherapy regimen for this disease.
Recently, the use of whole abdominal radiation therapy in the adjuvant setting for advanced
endometrial cancer was demonstrated to be inferior to the combination of cisplatin and
doxorubicin. The predicted 2-year survival of 70% for patients receiving the
chemotherapeutic regimen was superior to patients that received radiation therapy
(59%)(p<0.01).

Hormonal and cytotoxic chemotherapy agents are utilized in patients with metastatic or
recurrent disease not amenable to radiation therapy. Hormonal agents have been used in this
disease process since it has been demonstrated to be a hormonal responsive tumor. Notably, a
correlation between histologic grade and the presence or absence of hormonal receptors has
been noted, with well differentiated tumors more likely to express hormone receptors than
those with poor histology. Furthermore, the presence of estrogen receptors (ER) and
progesterone receptors (PR) varies with tumor histology. ER has been reported to be present
between 70% and 87% of endometrioid adenocarcinoma and 0 and 24% in UPSC; while, PR has
ranged from 67% to 91% in endometrioid tumors and 0 and 19% in UPSC.

Various progestins have been investigated including Megace (megesterol acetate) and Provera
(medroxyprogesterone acetate) for the treatment of endometrial cancer. These agents are
generally well tolerated and have been reported to have response rates of 15-30% with
long-term complete responses not uncommonly experienced. Furthermore, median survival in
patients treated with progestins ranges from 9 to 20 months.

As paclitaxel has been noted to be active in ovarian cancer and other malignancies, it seems
reasonable to evaluate its utility for endometrial cancer. Accordingly, single agent
paclitaxel was administered to 30 chemotherapy naïve patients with advanced or recurrent
endometrial cancer. The overall response rate was 36% when patients received a 24-hour
infusion of paclitaxel. Furthermore, paclitaxel given as a 3-hour infusion demonstrated a
response between 27 to 37% in patients that had failed prior chemotherapy.

Paclitaxel has been combined with platinum compounds, primarily cisplatin in several
studies. A phase II study that combined paclitaxel 175 mg/m2 as a 3-hour infusion with
cisplatin 75 mg/m2 reported a 67% response rate. There were seven complete responses and
nine partial responses with an 18 month median overall survival. An additional phase II
study evaluated the efficacy of combining paclitaxel and carboplatin in both primary
advanced and recurrent non-papillary and papillary tumors following radiation. The response
rate was 78% in patients with primary advanced non-papillary tumors with a median
disease-free survival of 23 months, with the median overall survival not being reached at
the time of publication. Furthermore, patients with recurrent endometrial cancer had a
response rate of 56%, with a median overall survival of 15 months.

A phase I study by the GOG combined paclitaxel, cisplatin, and doxorubicin with or without
granulocyte colony-stimulating factor. A 46% response rate with this regimen determined the
optimal dosing of the agents and led to a phase III GOG study (GOG 177). GOG 177
demonstrated the combination of paclitaxel, doxorubicin and cisplatin to have higher
response rates (57% vs. 33%) over the combination of doxorubicin and cisplatin, but the
three drug combination was associated with more toxicity and 12-month overall survival (58%
vs. 50%) was similar. Furthermore, more Grade 3 and 4 toxicity was experienced by patients
that received the three drug combination, although this was not statistically significant.
Accordingly, a phase III trial comparing the paclitaxel, doxorubicin, and cisplatin regimen
to a more tolerable regimen of paclitaxel and carboplatin is planned by the GOG, based on
equivalency studies in ovarian cancer patients where carboplatin was substituted for
cisplatin and demonstrated easier administration with equal efficacy and less toxicity.

The combination of hormonal agents with cytotoxic chemotherapy has also been investigated.
These studies utilized various combinations of non-taxane based cytotoxic chemotherapy in
addition to megesterol or medroxyprogesterone acetate. Patients had response rates that
varied from 33% to 60%, with the combination cyclophosphamide, doxorubicin, cisplatin and
megesterol producing the greatest response rate. Additionally, Pinelli et al. reported a
56% complete or partial response rate in a group of patients treated with carboplatin and
sequential hormonal therapy with megesterol and tamoxifen. These studies suggest that
sequential administration of hormonal therapy with chemotherapy has no detrimental effects
on patients, and may be beneficial as hormonal therapy is generally less toxic than
chemotherapy. Based on known tolerability and efficacy, investigating the combination of
megesterol acetate with paclitaxel and carboplatin chemotherapy appears to be a reasonable
option in the setting of advanced or recurrent endometrial cancer.

Accordingly, this phase II study will evaluate the combination of paclitaxel, carboplatin
and megesterol acetate for the treatment of advanced or recurrent adenocarcinoma of the
endometrium.