Frontline Immunotherapy Combined With Radiation and Chemotherapy in High Risk Endometrial Cancer (FIERCE)

• ClinicalTrials.gov Identifier: NCT03932409
• Recruitment Status: Recruiting
• First Posted: April 30, 2019
• Last Update Posted: February 8, 2023
• Sponsor: University of Oklahoma
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): University of Oklahoma

Tracking Information

• First Submitted Date: April 26, 2019
• First Posted Date: April 30, 2019
• Last Update Posted Date: February 8, 2023
• Actual Study Start Date: February 19, 2020
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 11, 2020)

Proportion of patients completing three cycles [ Time Frame: 4 months ]

defined as completion of 3 cycles of pembrolizumab combined with dose dense paclitaxel and carboplatin chemotherapy

Original Primary Outcome Measures (submitted: April 29, 2019)

Proportion of patients completing three cycles [ Time Frame: 36 months ]

defined as completion of 3 cycles of pembrolizumab combined with dose dense paclitaxel and carboplatin chemotherapy

Current Secondary Outcome Measures (submitted: December 11, 2020)

• progression free survival [ Time Frame: up to 2 years ]
  time from study entry to the first tumor progression
• progression free survival [ Time Frame: 6 months ]
  progression free survival rate at 6 months
• Overall survival [ Time Frame: up to 2 years ]
  time from study entry to death
• Frequency of adverse events [ Time Frame: 5 months ]
  frequency and severity of adverse events as assessed by the CTCAE v5

Original Secondary Outcome Measures (submitted: April 29, 2019)

• progression free survival [ Time Frame: up to 3 years ]
  time from study entry to the first tumor progression
• progression free survival [ Time Frame: 6 months ]
  progression free survival rate at 6 months
• Overall survival [ Time Frame: up to 3 years ]
  time from study entry to death
• Frequency of adverse events [ Time Frame: up to 3 years ]
  frequency and severity of adverse events as assessed by the CTCAE v5

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Frontline Immunotherapy Combined With Radiation and Chemotherapy in High Risk Endometrial Cancer
• Official Title: A Phase Ib Trial of Vaginal Cuff Brachytherapy + Pembrolizumab (MK3475) Followed by 3 Cycles of Dose Dense Paclitaxel/q 21 Day Carboplatin + Pembrolizumab (MK3475) in High Intermediate Risk Endometrial Cancer
• Brief Summary: The purpose of this single arm, open label study is to evaluate the feasibility of pembrolizumab combined with radiation administered to the upper part of the vagina (vaginal cuff brachytherapy) followed by three cycles of pembrolizumab and chemotherapy in patients with endometrial cancer.

Detailed Description

Before the patient begins the study:

Endometrial cancer is commonly treated with surgery. The patient must have already had surgery including hysterectomy (removal of the uterus) prior to being considered eligible for this study. The surgery may also include removal of the ovaries, and removal of pelvic and para-aortic lymph nodes. Following the surgery, the doctor will identify if the patient has factors related to the cancer which places the patient at a greater risk for the cancer returning.

Prior to participating in this study there are exams, tests or procedures to find out if the patient can be treated in the study. Most are part of regular cancer care. Tumor tissue will need to be collected for study tests to see if the patient is eligible for to take part on the study.

TREATMENT If the patient is eligible, pembrolizumab will be given 7 days before radiation therapy. After radiation therapy, three cycles of pembrolizumab and chemotherapy will be given.

Study participation will be up to two years.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Endometrial Cancer

Intervention

• Drug: Pembrolizumab

  prior to VCB: 200mg IV given one week (7 days) before radiation

  after VCB: 200mg IV on day 1 of a 21 day cycle prior to chemotherapy

  Other Name: MK3475
• Radiation: Vaginal cuff brachytherapy (VCB)
  Treatment should commence within 12 weeks of the surgery/hysterectomy
• Drug: Paclitaxel
  after VCB, Paclitaxel IV on days 1,8 and 15 of a 21 day cycle for 3 cycles
• Drug: Carboplatin
  after VCB, Carboplatin IV on day 1 of a 21 day cycle for 3 cycles

Study Arms

Experimental: Pembrolizumab + Radiation Therapy + Pembrolizumab/Chemotherapy

Pembrolizumab given 7 days prior to radiation therapy (e.g., vaginal cuff brachytherapy) followed by three cycles pembrolizumab combined with Carboplatin/Paclitaxel chemotherapy

Interventions:

• Drug: Pembrolizumab
• Radiation: Vaginal cuff brachytherapy (VCB)
• Drug: Paclitaxel
• Drug: Carboplatin

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 8, 2021): 40
• Original Estimated Enrollment (submitted: April 29, 2019): 20
• Estimated Study Completion Date: June 2025
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. All patients must have undergone hysterectomy. Bilateral salpingooophorectomy is strongly encouraged but not mandatory.
2. Pelvic and para-aortic lymphadenectomy are optional, but strongly encouraged.
3. If either a bilateral salpingo-oophorectomy (BSO) or nodal sampling was not performed, post-operative pre-treatment CT/MRI is required and must not demonstrate evidence suggestive of metastatic disease (adnexa, nodes, intraperitoneal disease). Post-operative, pre-treatment CT/MRI must be performed if a BSO and/or lymphnode sampling was not performed.
4. Tissue from an archival sample or newly obtained core or excisional biopsy of a tumor lesion within 10 weeks confirming diagnosis.

5. All patients will be staged according to the FIGO 2009 staging system and with endometrial carcinoma (endometrioid types) confined to the corpus uteri or with endocervical glandular involvement fitting one of the following high-intermediate risk factor categories:

   • age ≥18 years with 3 risk factors

   • Risk factors:

     1. Grade 2 or 3 tumor, (+) lymphovascular space invasion, outer ½ myometrial invasion. Patients with these risk criteria may be enrolled with either positive or negative cytology.
     2. Patients with Stage II endometrial carcinoma (any histology) with cervical stromal invasion (occult or gross involvement), with or without high-intermediate risk factors.
     3. Patients with serous or clear cell histology (with or without other high-intermediate risk factors) are eligible provided the disease is Stage I or II (with or without cervical stromal invasion or endocervical glandular involvement). Eligibility for clear cell and serous histology is not based on presence of lymphovascular space invasion or depth of invasion.
6. Patients must have ECOG performance status 0 or 1.
7. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial and authorization permitting release of personal health information.
8. Neuropathy (sensory and motor) ≤ Grade 1.
9. Have adequate organ function as defined per Protocol.

Exclusion Criteria:

1. Patients with recurrent disease.
2. Greater than 12 weeks elapsed from surgery to enrollment
3. Patients have prior pelvic or abdominal radiation therapy
4. Known hypersensitivity to any component of study treatments that resulted in drug discontinuation
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor
6. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks [could consider shorter interval for kinase inhibitors or other short half-life drugs] prior to allocation.
7. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
8. Has received a live vaccine within 30 days prior to the first dose of study drug.
9. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
11. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
12. Has known active CNS metastases and/or carcinomatous meningitis.
13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
14. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
16. Has an active infection requiring systemic therapy. This excludes grade 2 urinary tract infections or grade 1-2 skin infections.
17. Has a known history of Human Immunodeficiency Virus (HIV).
18. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
19. Has a known history of active TB (Bacillus Tuberculosis).
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
21. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
22. Is pregnant or breastfeeding

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Lead Gyn Nurse; 1-405-271-8777; SCC-IIT-Office@ouhsc.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03932409
• Other Study ID Numbers: OUSCC-FIERCE
• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: University of Oklahoma
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Oklahoma
• Original Study Sponsor: Same as current
• Collaborators: Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Christina Washington, MD; Stephenson Cancer Center

• PRS Account: University of Oklahoma
• Verification Date: February 2023