Adjuvant Sequential & Concurrent CarboTaxol + Radiotherapy for High Risk Endometrial Cancer

Phase II Study of Concurrent and Sequential Carboplatin and Paclitaxel With Adjuvant Radiotherapy for High Risk Endometrial Cancer

The purpose of this trial is to evaluate the safety of sequential and concurrent carboplatin and paclitaxel with adjuvant external beam radiotherapy for locally advanced endometrial cancer. The primary objective is to assess the acute toxicities namely grade 3-4 non hematologic and grade 4 hematologic toxicities associated with the above regimen. The null hypothesis is that the unacceptable toxic response rate is ≥40%. This will be tested against a one-sided alternative that the toxicity rate is 20% or less. Simon's two-stage design was used to power this aim. In the first stage, 11 patients will be accrued. If there are 5 or more toxic responses in these 11 patients, the study will be stopped for safety reasons. Otherwise, 13 additional patients will be accrued for a total of 24 patients. Under these conditions, the probability of stopping early is 47% if the toxic response rate is truly higher than 20.0%. If this regimen is safe then its efficacy can be studied in a Phase III study.

Endometrial cancer is the most common gynecologic malignancy in the United States. Risk factors for development of endometrial cancer include increasing age, early menarche, late menopause, nulliparity, obesity, use of unopposed estrogen, and Lynch syndrome. The most common histology is endometrioid type adenocarcinoma, but less common, high-risk histologies include serous carcinoma, clear cell carcinoma, and carcinosarcoma. High risk stage I-II disease includes those with high risk histologies or any histology with multiple high risk features including deep myometrial invasion, high grade, and presence of extensive lymphovascular invasion. Locally advanced risk disease is routinely classified as Stage III-IVA. Despite treatment with adjuvant radiotherapy, chemotherapy, or combination radiotherapy and chemotherapy, relapse-free survival rates are 58-75% in modern series of GOG 258 and PORTEC-3. Therefore, there is significant need for improved therapies and optimization of combination therapy to improve these outcomes. Standard initial management of endometrial cancer is total hysterectomy, bilateral salpingo-oophorectomy, and peritoneal washings with or without pelvic and paraaortic lymph node dissection. Endometrial cancer is surgically staged according the International Federation of Gynecologic Oncology (FIGO). Endometrioid type carcinomas most commonly present in an early stage, and several studies have established risk factors for recurrence including increasing depth of myometrial invasion, high grade, lymphovascular space invasion (LVSI), older age, greater tumor size, and increasing stage. Historically, the rationale behind including adjuvant chemotherapy, either simultaneously with radiation therapy or sequentially, was the high rate of distant metastases despite lower pelvic failure rates with adjuvant radiation. The combination of chemotherapy and radiation therapy has additionally been shown to have greater survival compared either modality as monotherapy. This study is designed to test the safety of adjuvant chemotherapy and radiotherapy with a novel regimen that addresses several of the hypotheses regarding the differing rate of distant metastases in GOG 258 while still using radiotherapy due to the locoregional control benefit from PORTEC-3. To the knowledge of the investigators, no prospective study has reported on sequential and concurrent carboplatin and paclitaxel with EBRT for surgically managed endometrial cancer patients. With expeditious initiation of high dose systemic therapy and use of platinum/taxane combination chemotherapy concurrent with radiotherapy, we can address several potential hypotheses regarding the role that chemotherapy has to decrease the risk of distant metastases. Our primary objective is to assess the acute toxicities associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients. If this regimen is safe, then its efficacy can be studied in a Phase III study. This study will include high risk early stage and locally advanced endometrial cancer patients who are surgically managed with total or radical hysterectomy. Patients will be included if combination radiation therapy and chemotherapy is recommended. The most common patients to be enrolled Endometrioid type FIGO Stage I-II with high risk features, IIIC1 & IVA OR Serous Carcinoma, Clear Cell Carcinoma, Carcinosarcoma Stage I-IIIC1 & IVA

Week 1 : Cycle 1: Full Dose Carboplatin and Paclitaxel Week 4: Pelvic Radiotherapy Begins Cycle 2: Dose reduced Carboplatin and Paclitaxel Week 7 : Cycle 3: Dose reduced Carboplatin and Paclitaxel Weeks 10,13,16: Cycle 4-6: Full Dose Carboplatin and Paclitaxel

Regimen I: Carboplatin AUC 6 & Paclitaxel 175mg/m2 given intravenously for 4 cycles during weeks 1, 10, 13, 16 Regimen II: Carboplatin AUC 2 & Paclitaxel 45mg/m2 given intravenously for 2 cycles during weeks 4 & 7 concurrent with radiotherapy

An external beam radiation dose of 45 Gy in 25 fractions is routinely prescribed to the Planning Target Volume (PTV) for postoperative radiotherapy. The Vaginal Brachytherapy (VBT) Boost will be delivered after the external beam radiation. Doses of 12-18 Gy in 2-3 fractions are often prescribed to the surface of the vagina to a treatment length of 3-5 cm. There is no standard dose or fractionation schedule, so this dose, fractionation, location of dose specification , and length of vagina treated will be individualized for the patient and will be at the discretion of the treating radiation oncologist.

The primary outcome will be the number of Grade 3-4 acute non-hematologic and grade 4 hematologic toxicities associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients as described in CTCAE version 5.0. These toxicities will be assess during the on treatment visits by the radiation and medical oncologist. If there are 5 or more toxic responses in the first 11 patients the study will be stopped for safety reasons.

To assess the number treatment delays in scheduled therapy > 3 weeks associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients.

To assess chronic toxicities associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients.

To evaluate the disease specific outcome of local control associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients. These endpoints will be assessed clinically and radiographically.

To evaluate the disease specific outcome of pelvic failure-free survival associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients. These endpoints will be assessed clinically and radiographically.

To evaluate the disease specific outcome of distant metastasis-free survival associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients. These endpoints will be assessed clinically and radiographically.

To evaluate the disease specific outcome of disease-free survival associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients. These endpoints will be assessed clinically and radiographically.

To evaluate the disease specific outcome of cause-specific survival associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients. These endpoints will be assessed clinically and radiographically.

To evaluate the outcome of overall survival associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients. These endpoints will be assessed clinically and radiographically.

Inclusion Criteria: Surgically managed endometrial cancer with total or radical hysterectomy with pathology of endometrioid, serous, clear cell or carcinosarcoma histologies Any patient for whom combination of adjuvant radiotherapy and chemotherapy is recommended following pathology review Endometrioid type FIGO Stage I-II with high risk features AND IIIC1, IVA Serous Carcinoma, Clear Cell Carcinoma, Carcinosarcoma Stage I-IIIC1, IVA ECOG Performance Status 0-2 No prior history of pelvic radiotherapy No clinical or radiographic evidence of nodal disease or distant metastases Ability to understand and willingness to sign a written informed consent. Exclusion Criteria: Patients undergoing irradiation of the para-aortic node chain Prior history of endometrial cancer Prior local radiotherapy for a pelvic malignancy Prior platinum or taxane based chemotherapy for any malignancy Patients receiving any other investigational agents Patients with a known malignancy with a disease free interval < 6 months prior to enrollment Uncontrolled intercurrent illness including but not limited to ongoing or active infection, severely symptomatic congestive heart failure, cardiac arrhythmia, or psychiatric illness/social situations that could limit compliance with study requirements Patients enrolled on a competing investigational study.

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