Endometrial Cancer, Endometrial Carcinoma, Neoplasms, Endometrial
Conditions
Brief summary
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.
Interventions
DRUGCarboplatin (standard of care)
RADIATIONRadiation (standard of care)
PROCEDUREEndometrial biopsy
PROCEDUREPeripheral blood draw
DRUGMK-3475
DRUGPaclitaxel (standard of care)
Sponsors
Merck Sharp & Dohme LLC
Washington University School of Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Through 90 days following last dose of MK-3475 (approximately 56 weeks) | -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 |
| Safety as Measured by Any Grade 3 or Higher Treatment Related Adverse Events | Through 90 days following last dose of MK-3475 (approximately 56 weeks) | -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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 2 years following completion of therapy (median follow-up of 35 months (full range 11.3-46 months) | * 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Did not undergo cytoreductive surgery due to pre-operative disease progression | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Arm 1: MK-3475 |
|---|---|
| Age, Continuous | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 1 / 10 |
Outcome results
Primary
Safety as Measured by Any Grade 3 or Higher 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
Time frame: Through 90 days following last dose of MK-3475 (approximately 56 weeks)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: MK-3475 | Safety as Measured by Any Grade 3 or Higher Treatment Related Adverse Events | Bone infection | 1 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade 3 or Higher Treatment Related Adverse Events | Anemia | 4 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade 3 or Higher Treatment Related Adverse Events | Neutropenia | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade 3 or Higher Treatment Related Adverse Events | Hyperglycemia | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade 3 or Higher Treatment Related Adverse Events | Decreased white blood cells | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade 3 or Higher Treatment Related Adverse Events | Menorrhagia | 1 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade 3 or Higher Treatment Related Adverse Events | Heart failure | 1 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade 3 or Higher Treatment Related Adverse Events | Hypophosphatemia | 1 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade 3 or Higher Treatment Related Adverse Events | Pulmonary edema | 1 Participants |
Primary
Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients
-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
Time frame: Through 90 days following last dose of MK-3475 (approximately 56 weeks)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Abdominal pain | 10 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Nausea | 9 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Constipation | 8 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Cough | 8 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Dyspnea | 8 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Peripheral neuropathy | 8 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Alopecia | 7 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Fatigue | 7 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Anemia | 6 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Blurred vision | 6 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Depression | 6 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Bloating | 5 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Bruising | 5 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Headache | 5 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Hyperglycemia | 5 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Vaginal hemorrhage | 5 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Vomiting | 5 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Leukocytosis | 5 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Increased ALT | 4 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Anorexia | 4 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Back pain | 4 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Hot flashes | 4 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Hypoalbuminemia | 4 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Myalgia | 4 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Pain in extremity | 4 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Rash acneiform | 4 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Increased alkaline phosphatase | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Chest pain | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Dizziness | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Hypocalcemia | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Hyponatremia | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Neutropenia | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Palpitations | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Rash maculo-papular | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Urinary incontinence | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Limb edema | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Infusion related reaction | 3 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Abdominal distension | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Anxiety | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Increased AST | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Chills | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Dysmenorrhea | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Hearing impaired | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Hematuria | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Hyperkalemia | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Hypokalemia | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Hypothyroid | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Malaise | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Menorrhagia | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Mucositis | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Pain | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Decreased platelets | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Pruritus | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Respiratory, thoracic and mediastinal disorders | 2 Participants |
| Arm 1: MK-3475 | Safety as Measured by Any Grade Treatment Related Adverse Events Experienced by ≥ 2 Patients | Urinary urgency | 2 Participants |
Secondary
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).
Time frame: Up to 2 years following completion of therapy (median follow-up of 35 months (full range 11.3-46 months)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: MK-3475 | Progression-free Survival (PFS) | 201.3 weeks | Standard Deviation 160.4 |