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出境医 / 临床实验 / Adjuvant Sequential & Concurrent CarboTaxol + Radiotherapy for High Risk Endometrial Cancer

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

Study Description
Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Endometrial Cancer Drug: Carboplatin and Paclitaxel Radiation: Radiation Therapy Phase 2

Detailed Description:

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

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Study of Concurrent and Sequential Carboplatin and Paclitaxel With Adjuvant Radiotherapy for High Risk Endometrial Cancer
Actual Study Start Date : March 5, 2019
Estimated Primary Completion Date : March 31, 2021
Estimated Study Completion Date : March 31, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: Full Dose Chemo, Reduced Dose Chemo + RT, Full Dose Chemo
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
 Drug: 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
Other Names:
  • Paraplatin
  • Taxol

Radiation: Radiation Therapy

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.
Outcome Measures
Primary Outcome Measures :
  1. Acute Toxicities (CTCAE v5.0) [ Time Frame: 24 weeks ]
    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.


Secondary Outcome Measures :
  1. Treatment Delays [ Time Frame: 24 weeks ]
    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.

  2. Chronic Toxicities (CTCAE v5.0) [ Time Frame: 52 weeks ]
    To assess chronic toxicities associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients.

  3. local control [ Time Frame: 52 weeks ]
    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.

  4. pelvic failure-free survival [ Time Frame: 52 weeks ]
    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.

  5. distant metastasis-free survival [ Time Frame: 52 weeks ]
    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.

  6. disease-free survival [ Time Frame: 52 weeks ]
    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.

  7. cause-specific survival [ Time Frame: 52 weeks ]
    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.

  8. overall survival [ Time Frame: 52 weeks ]
    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.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Beth Chiappetta, BSN 708-216-2568 bchiappetta@lumc.edu
Contact: Matthew Harkenrider, MD 708-216-2592 mharkenrider@lumc.edu

Locations
Layout table for location information
United States, Illinois
Loyola University Medical Center Recruiting
Marywood, Illinois, United States, 60153
Contact: Beth Chiappetta, BSN    708-216-2568    bchiappetta@lumc.edu   
Contact: Matthew Harkenrider, MD    7082162592    mharkenrider@lumc.edu   
Sponsors and Collaborators
Loyola University
Investigators
Layout table for investigator information
Principal Investigator: Matthew Harkenrider, MD Loyola University Chicago
Tracking Information
First Submitted Date  ICMJE April 24, 2019
First Posted Date  ICMJE May 2, 2019
Last Update Posted Date May 21, 2020
Actual Study Start Date  ICMJE March 5, 2019
Estimated Primary Completion Date March 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 30, 2019) 		Acute Toxicities (CTCAE v5.0) [ Time Frame: 24 weeks ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 30, 2019)
  • Treatment Delays [ Time Frame: 24 weeks ]
    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.
  • Chronic Toxicities (CTCAE v5.0) [ Time Frame: 52 weeks ]
    To assess chronic toxicities associated with sequential and concurrent carboplatin and paclitaxel with EBRT in the adjuvant management of endometrial cancer patients.
  • local control [ Time Frame: 52 weeks ]
    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.
  • pelvic failure-free survival [ Time Frame: 52 weeks ]
    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.
  • distant metastasis-free survival [ Time Frame: 52 weeks ]
    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.
  • disease-free survival [ Time Frame: 52 weeks ]
    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.
  • cause-specific survival [ Time Frame: 52 weeks ]
    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.
  • overall survival [ Time Frame: 52 weeks ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Adjuvant Sequential & Concurrent CarboTaxol + Radiotherapy for High Risk Endometrial Cancer
Official Title  ICMJE Phase II Study of Concurrent and Sequential Carboplatin and Paclitaxel With Adjuvant Radiotherapy for High Risk Endometrial Cancer
Brief Summary 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.
Detailed Description

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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Endometrial Cancer
Intervention  ICMJE
  • Drug: 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
    Other Names:
    • Paraplatin
    • Taxol
  • Radiation: Radiation Therapy

    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.
Study Arms  ICMJE Experimental: Full Dose Chemo, Reduced Dose Chemo + RT, Full Dose Chemo
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
Interventions:
  • Drug: Carboplatin and Paclitaxel
  • Radiation: Radiation Therapy
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  • Mell LK, Sirák I, Wei L, Tarnawski R, Mahantshetty U, Yashar CM, McHale MT, Xu R, Honerkamp-Smith G, Carmona R, Wright M, Williamson CW, Kasaová L, Li N, Kry S, Michalski J, Bosch W, Straube W, Schwarz J, Lowenstein J, Jiang SB, Saenz CC, Plaxe S, Einck J, Khorprasert C, Koonings P, Harrison T, Shi M, Mundt AJ; INTERTECC Study Group. Bone Marrow-sparing Intensity Modulated Radiation Therapy With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2). Int J Radiat Oncol Biol Phys. 2017 Mar 1;97(3):536-545. doi: 10.1016/j.ijrobp.2016.11.027. Epub 2016 Nov 23.
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  • Murakami N, Norihisa Y, Isohashi F, Murofushi K, Ariga T, Kato T, Inaba K, Okamoto H, Ito Y, Toita T, Itami J. Proposed definition of the vaginal cuff and paracolpium clinical target volume in postoperative uterine cervical cancer. Pract Radiat Oncol. 2016 Jan-Feb;6(1):5-11. doi: 10.1016/j.prro.2015.04.008.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 30, 2019) 		24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 31, 2022
Estimated Primary Completion Date March 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Beth Chiappetta, BSN 708-216-2568 bchiappetta@lumc.edu
Contact: Matthew Harkenrider, MD 708-216-2592 mharkenrider@lumc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03935256
Other Study ID Numbers  ICMJE 211704
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Matthew Harkenrider, Loyola University
Study Sponsor  ICMJE Loyola University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Matthew Harkenrider, MD Loyola University Chicago
PRS Account Loyola University
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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