A Phase II Evaluation of Docetaxel and Carboplatin Followed by Tumor Volume Directed Pelvic Irradiation

Endometrial carcinoma is the most common malignancy in the female reproductive tract. For
the percentage of patients with advanced stage (III - IV) optimum adjuvant therapy
status-post surgical staging and/or optimal cytoreductive surgery is not well defined and
limited in the rates of response. Survival rates range from 18 - 49% with high levels of
toxicity with the current treatment regimens.(1)

The Gynecologic Oncology Group (GOG) explored the use of chemotherapy in protocol #107
comparing adriamycin with a combination of adriamycin and cisplatin.(2) This trial boasted
a 45% response rate for the combination arm compared to a 27% response rate in the
adriamycin only arm. Although no difference was seen in overall survival, the combination
arm showed an improvement in progression free survival from 3.8 to 5.7 months.
Subsequently, GOG protocol #122 randomized patients to this chemotherapeutic regimen versus
whole abdominal radiation therapy. This trial is now closed to accrual and results are
pending.

Ball et. al. reported on a phase II trial of paclitaxel in advanced or recurrent endometrial
cancer done through the GOG.(3) At 250 mg/m2 (200mg/m2 for patients with previous radiation
therapy) over 24 hours, every 21 days, 10/28 patients responded. There were 4 complete
responders and 6 partial responders with an overall response rate of 35.7%. Toxicity was
remarkably high with grade 3 and 4 neutropenia and neurotoxicity seen in 62% and 10.7%,
respectively.

Dimpoulos et. al. reported the use of paclitaxel 175 mg/m2 over 3 hours and cisplatin
75mg/m2 every 21 days in advanced or recurrent endometrial carcinoma.(4) A 67% objective
response rate was seen with 29% showing a complete response and 38% partial response.
Toxicities included a 9%

grade 3 and 4 peripheral neuropathy rate. These response rates changed the standard of
care in the community setting from the more toxic regimen of adriamycin and cisplatin to
paclitaxel and carboplatin.

Hoskins et. al. substituted carboplatin for cisplatin in an effort to reduce the peripheral
neuropathy seen in the Dimpoulos trial. This phase II combination of paclitaxel and
carboplatin with radiation therapy in advanced endometrial cancer resulted in a 75% response
rate. The median failure-free survival time was 23 months, with a 62% 3-year overall
survival rate. Toxicities were primarily hematologic and reversible.(5)

The ongoing GOG protocol, #184, is exploring the combination of tumor directed radiation
followed by a randomization to adriamycin and cisplatin versus adriamycin, cisplatin and
paclitaxel with G-CSF support. Increased toxicity will be expected in the three-drug
regimen. With a significant response rates to a combination of paclitaxel and carboplatin
along with radiation therapy in the phase II setting it is hard to justify the added
toxicity of this three-drug regimen.

The SCOTROC phase III trial comparing docetaxel (75 mg/m2) over 1 hour plus carboplatin (AUC
6) vs. paclitaxel (175 mg/m2) over 3 hours plus carboplatin (AUC 6) yielded equivalent
overall response rates in 1,077 patients with ovarian cancer.(6) The docetaxel arm resulted
in significantly less overall grade 2 and 3 sensory and motor neurotoxicity. Only 4
patients withdrew from the trial due to neurotoxicity on the docetaxel arm vs. 32 patients
on the paclitaxel arm. However, the docetaxel arm resulted in a higher incidence of
neutropenia and associated complications without compromising treatment delivery of overall
safety.

Based on the information to date, it seems prudent to explore a phase II trial of docetaxel
plus carboplatin every 3 weeks for 6 cycles followed by radiation therapy in the management
of patients with advanced endometrial cancer. The proposed protocol design requires that
chemotherapy be administered prior to radiation therapy in order to control distant
metastatic disease before attempting to control for local-regional recurrences with
radiation.

Inclusion Criteria:

- All patients with advanced endometrial adenocarcinoma, stage III A, B, C and Stage IV
confined to the pelvis, and recurrent disease limited to the pelvis.

Surgical stage III and limited stage IV disease, including those patients with positive
adnexa, tumor invading the serosa, positive and/or para-aortic nodes, pelvic metastases,
positive pelvic washings or vaginal involvement.

Histology must be adenocarcinoma, adenosquamous cell, squamous cell, clear cell or serous
papillary carcinoma

Status post surgical resection, including a hysterectomy and bilateral
salpingo-oophorectomy within the past 6 weeks (Pelvic lymph node and para-aortic lymph
node sampling are optional)

Patients may be sub-optimally or optimally debulked (disease < 2 cm). Patients are
eligible with measurable disease or evaluable disease. All positive para-aortic node
patients must be further staged by chest CT scan. If chest CT scan is negative, patients
are eligible.

Patients who have met the pre-entry criteria including following lab findings:

ANC > 1500, Platelet count > 100,000/mm3, Hemoglobin ≥ 8 mg/dl, Creatinine < 2.0 mg/dl.

Total Bilirubin must be within normal limits. (WNL)

AST or ALT and Alkaline Phosphatase must be within the range allowing for eligibility

Patients who have signed an approved informed consent.

GOG Performance Grade 0, 1, or 2.

Women ≥ 18 years of age

Exclusion Criteria:

- Patients with Stage IV or recurrent disease outside of the pelvis.

Patients who have had prior pelvic or abdominal radiation therapy.

Patients with concomitant malignancy other than non-melanoma skin cancer.

Patient with a prior malignancy who have been disease-free for < 5 years or who received
prior chemotherapy or radiation therapy for that malignancy.

Patients with a history of serious co-morbid illness that would preclude protocol therapy.

Patients with an estimated survival of less than three months.

Patients with parenchymal liver metastases.

Patients who received prior chemotherapy excluding low-dose methotrexate for rheumatologic
reasons.

Histology consistent with uterine sarcomas, carcinosarcoma or leiomyosarcoma.

Women with baseline peripheral neuropathy Grade ≥ 2.

Women with a history of severe hypersensitivity reaction to drugs formulated with
polysorbate 80.