MK-3475 Immunotherapy in Endometrial Carcinoma

Immunotherapy With MK-3475 in Surgically Resectable Endometrial Carcinoma

Due to the high expression of PD-L1 in endometrial cancers as well as in ovarian cancers which are molecularly similar to uterine serous cancers, using pembrolizumab should be beneficial in this patient population. Since the investigators are able to get a pre-treatment research- related endometrial biopsy as well as the surgical specimen post two cycles of pembrolizumab, the investigators will be able to evaluate the mechanism of action of this drug on the endometrial cancer tumor environment.

Study Overview

• Status: Completed
• Conditions: Endometrial Cancer; Endometrial Carcinoma; Neoplasms, Endometrial
• Intervention / Treatment: Procedure: Endometrial biopsy; Procedure: Peripheral blood draw; Procedure: Surgical resection (standard of care); Drug: MK-3475; Drug: Paclitaxel (standard of care); Drug: Carboplatin (standard of care); Radiation: Radiation (standard of care)

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Diagnosis of FIGO grade 3 endometrioid cancer, serous, clear cell, or mixed high grade endometrial cancer with confirmation on research-related endometrial biopsy.
• Radiographically confirmed endometrial adenocarcinoma of stages III-IV requiring adjuvant therapy. If stage III disease is suspected, there should be multiple pelvic and/or lymph nodes involved.
• Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >10 mm with CT scan, as >20 mm by chest x-ray, or >10 mm with calipers by clinical exam by RECIST 1.1.
• Treatment plan must include primary site biopsy followed by resection of the primary tumor site and any metastatic sites at time of surgery.
• At least 18 years of age.
• GOG performance status ≤ 2

• Normal bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1,500/mcl
  • Platelets ≥ 100,000/mcl
  • Hemoglobin ≥ 9 g/dL
  • Total bilirubin ≤ 1.5 x IULN OR direct bilirubin ≤ IULN for patients with total bilirubin > 1.5 x IULN
  • AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN (or ≤ 5 x IULN for patients with liver metastases)
  • Serum creatinine ≤ 1.5 x IULN OR creatinine clearance by Cockcroft-Gault ≥ 60 mL/min/1.73 m2 for patients with creatinine levels > 1.5 x IULN
  • INR or PT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants
  • aPTT ≤ 1.5 x IULN unless patient is receiving anticoagulant therapy as long as INR or PTT is within therapeutic range of intended use of anticoagulants
• Sexually active women of childbearing potential must agree to contraceptive methods as described by the protocol prior to study entry, for the duration of pre-operative study participation and until definitive hysterectomy/bilateral salpingo-oophorectomy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
• Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• FIGO grade 1 or 2 endometrioid cancer.
• Radiographic imaging demonstrating uterine cancer that is probably stage I or II.
• Prior treatment for endometrial cancer.
• Prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to first dose of MK-3475 or has not recovered (i.e., to ≤ grade 1 or baseline) from adverse events due to agents administered more than 4 weeks earlier.
• Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to the first dose of MK-3475 or has not recovered (i.e., to ≤ grade 1 or baseline) from adverse events due to a previously administered agent. Note, subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study. Note, if a subject received major surgery, she must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Received a live vaccine within 30 days prior to the first dose of MK-3475. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. FluMist) are live attenuated vaccines and are not allowed.
• A history of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only.
• Known active central nervous system metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of MK-3475 and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of MK-3475.
• Currently receiving any other investigational agents or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of MK-3475.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-3475 or other agents used in the study.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring systemic therapy, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, immunosuppression, autoimmune conditions, underlying pulmonary disease, or psychiatric illness/social situations that would limit compliance with study requirements.
• Has an 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
• Pregnant and/or breastfeeding. Patient must have a negative serum or urine pregnancy test within 72 hours of study entry.
• 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).
• Known history of HIV (HIV 1/2 antibodies).
• Known history of active TB.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm 1: MK-3475; Patients will undergo endometrial biopsy followed by 2 doses of MK-3475 3 weeks apart. 3-4 weeks after the second dose of MK-3475, the standard of care surgical resection will take place, followed by standard of care adjuvant therapy. Tissue and blood will be collected at the time of surgical resection for immune analysis. For patients whose pathology confirms high-risk features and advanced stage, MK-3475 will be given every 3 weeks starting 4 -6 weeks after completion of adjuvant therapy for a maximum of 4 doses post-surgery.; MK-3475 will be given intravenously at a dose of 200 mg over the course of 30 minutes.; The standard of care chemotherapy will consist of 6 cycles of paclitaxel and carboplatin AUC 5 every 3 weeks for 6 cycles.; The decision to administer radiation therapy will be per the treating physician. If the patient does not receive radiation therapy, then the patient will start MK-3475 every 3 weeks x 4 doses after the completion of chemotherapy.

Procedure: Endometrial biopsy; Procedure: Peripheral blood draw; Procedure: Surgical resection (standard of care); Drug: MK-3475; Other Names: Keytruda; pembrolizumab; Drug: Paclitaxel (standard of care); Other Names: Taxol; Drug: Carboplatin (standard of care); Other Names: Paraplatin; Paraplat; Radiation: Radiation (standard of care)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety as measured by treatment related adverse events	-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all adverse event reporting	90 days following last dose of MK-3475 (approximately 56 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.; Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).	Up to 2 years following completion of therapy

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Premal Thaker, M.D., MSc., Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2016
• Primary Completion (Actual): January 1, 2019
• Study Completion (Actual): October 3, 2020

Study Registration Dates

• First Submitted: December 10, 2015
• First Submitted That Met QC Criteria: December 10, 2015
• First Posted (Estimate): December 15, 2015

Study Record Updates

• Last Update Posted (Actual): November 9, 2020
• Last Update Submitted That Met QC Criteria: November 6, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Carcinoma; Endometrial Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Carboplatin; Paclitaxel; Pembrolizumab
• Other Study ID Numbers: 201601062

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No