Pembro/Carbo/Taxol in Endometrial Cancer

Study Overview
=================
Brief Summary
-----------------
This is a single-arm, open-label, multi-center phase II study for subjects with measurable advanced or recurrent endometrial cancer using pembrolizumab in combination with carboplatin and paclitaxel chemotherapy. As this combination of agents has not been tested in this subject population, the first six subjects enrolled will constitute a safety run-in cohort.

Detailed Description
-----------------
OUTLINE: This is a multi-center study. INVESTIGATIONAL TREATMENT: To ensure the safety of this combination treatment, an initial safety run-in will be conducted for the first 6 subjects. This initial cohort of 6 subjects will be enrolled and treated with standard doses as described below. Based on toxicity analysis of the initial 6 subjects following completion of 18 weeks of treatment, it will be determined if an extended safety run-in period would be beneficial. In the absence of receiving any prior therapy, eligible subjects will be treated as follows on D1 of cycles lasting 21 days (3 weeks) for a maximum of 6 cycles: Pembrolizumab 200mg will be administered as a 30-minute intravenous (IV) infusion every 3 weeks. Paclitaxel will be dosed at 175mg/m2 and be administered as a 3-hour continuous IV infusion. Carboplatin will be dosed at area under the curve (AUC) of 6 and given as an IV infusion in 250ml of D5W over 30 minutes. Subjects who have had prior radiotherapy/platinum-based chemotherapy must initiate paclitaxel and carboplatin at the following reduced dose levels if they have had prior external radiotherapy involving the whole pelvis or abdomen or over 50% of their spine, and/or prior platinum-based chemotherapy for this, or any other cancer. Eligible subjects will be treated as follows on Day 1 (D1) of cycles lasting 21 days (3 weeks) for a maximum of 6 cycles: Pembrolizumab 200mg administered as a 30-minute intravenous (IV) infusion every 3 weeks. Paclitaxel will be dosed at 135mg/m2 and be administered as a 3-hour continuous IV infusion. Carboplatin will be dosed at an AUC of 5 and given as an IV infusion in 250ml of D5W over 30 minutes. Subsequent doses of paclitaxel and carboplatin may be escalated to the higher doses as indicated above, provided these subjects do not exhibit hematologic or nonhematologic toxicity > Grade 1, except alopecia. The following laboratory values must be obtained within 14 days prior to registration for protocol therapy: Hematopoietic: Hemoglobin (Hgb) > 9 g/dL (without transfusion or erythropoietin (EPO) dependency within 7 days of assessment) Platelets > 100 K/mm3 Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 Renal: Creatinine or measured/calculated creatinine clearance (as calculated by institutional standard) ≤ 1.5 X institutional upper limits of normal (ULN) OR ≥60mL/min for subjects with creatinine levels > 1.5 x institutional ULN Hepatic: Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN Aspartate aminotransferase (AST), alanine transaminase (ALT) or alkaline phosphatase (ALP) < 2.5 x ULN OR ≤ 5 x ULN for subjects with liver metastases Albumin ≥ 2.5 mg/dL Coagulation (Blood Clotting) Tests: International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless subject is receiving anti-coagulant therapy as long as partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless subject is receiving anti-coagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants

Official Title
-----------------
Phase II Study of Pembrolizumab in Combination With Carboplatin and Paclitaxel for Advanced or Recurrent Endometrial Adenocarcinoma

Conditions
-----------------
Endometrial Cancer, Endometrial Adenocarcinoma

Intervention / Treatment
-----------------
* Drug: Pembrolizumab
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent and HIPAA authorization for release of personal health information prior to registration for protocol therapy. o NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Age ≥ 18 years at the time of consent. ECOG Performance Status of 0 or 1 within 28 days prior to registration for protocol therapy. Histological evidence of newly diagnosed Stage III or IV or recurrent endometrial carcinoma who have had definitive surgery for endometrial cancer (at least hysterectomy and bilateral salpingo-oophorectomy). Pathologic documentation of the recurrence (i.e., biopsy) will be performed per standard of care, at the treating physician's discretion. If a subject with recurrence is undergoing a biopsy for clinical indications and is willing and able, an optional collection of 3 frozen tissue cores of the recurrence site is requested for correlative analysis. Measurable disease according to RECIST v1.1 and obtained by imaging within 28 days prior to registration for protocol therapy. Disease in an irradiated field as the only site of measurable disease is acceptable only if there has been clear progression since completion of radiation treatment. The subject must have recovered (≤ grade 1) from the acute toxic effects of prior therapy. Prior treatment: Subjects may have received none or one platinum-based chemotherapy regimen and none or one non-platinum regimen. Subjects having received prior platinum-based chemotherapy must have a disease-free interval > 6 months (be platinum sensitive). Prior therapy with hormones or biologic agents is allowed. These treatments must be discontinued at least 28 days prior to registration for protocol therapy. The subject must have completed radiation therapy at least 28 days prior to registration for protocol therapy, provided that toxicity has resolved to ≤ grade 1. NOTES: Subjects may have received prior radiation therapy for treatment of endometrial carcinoma. Prior radiation therapy may have included pelvic radiation therapy, extended field pelvic/para-aortic radiation therapy, and/or intravaginal brachytherapy. Chemotherapy used for radiation sensitization is allowed. Chemotherapy used for radiation sensitization will not count as second chemotherapy regimen. Palliative radiation given primarily for symptom relief, without the intent to treat or cure the patient's endometrial cancer is excluded from the above criteria. Treatment-directed radiation will be defined as more than 30 Gy of radiation. No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the subject has been disease-free for at least 5 years. Female subjects must be of non-childbearing potential. Women of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥1 year. Laboratory values must be obtained within 14 days prior to registration for protocol therapy. Note: Institutional/laboratory upper limit of normal (ULN) Hemoglobin (Hgb) > 9 g/dL (without transfusion or EPO dependency within 7 days of assessment) Platelets > 100 K/mm3 Absolute neutrophil count (ANC) ≥ 1.5 K/mm3 Creatinine or measured/calculated creatinine clearance (as calculated by institutional standard) ≤ 1.5 X institutional ULN OR ≥60mL/min for subjects with creatinine levels > 1.5 x institutional ULN Serum total bilirubin ≤ 1.5 ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN AST, ALT or alkaline phosphatase < 2.5 ULN OR ≤ 5 x ULN for subjects with liver metastases Albumin ≥ 2.5 mg/dL International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless subject is receiving anti-coagulant therapy as long as PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless subject is receiving anti-coagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Exclusion Criteria: Subjects with carcinosarcoma. Subjects who have a solitary central pelvic recurrence, which can be curatively resected. Hypersensitivity to pembrolizumab or any of its excipients. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to registration for protocol therapy or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Has known active central nervous system (CNS) 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 four weeks prior to registration for protocol therapy 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 registration for protocol therapy. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. NOTE: Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. Treatment with any investigational agent within 28 days prior to registration for protocol therapy. Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Active autoimmune disease that has required systemic treatment in 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 received systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to registration for protocol therapy. (Prednisone (or equivalent) < 10mg/ day is allowed). Has a known history of active TB (Bacillus Tuberculosis). Pulmonary conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, or hypersensitivity pneumonitis. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis. Evidence of interstitial lung disease. Has an active infection requiring systemic therapy with the exception of an uncomplicated urinary tract infection. Pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE v4 criteria. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 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. Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority. Has received a live vaccine within 30 days prior to registration for protocol therapy. o NOTE: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed. History of solid organ or stem cell transplant requiring immunosuppressive medications.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational Treatment<br>Subjects with no prior therapy: Pembrolizumab administered at 200 mg Paclitaxel administered at 175mg/m2 Carboplatin administered at an AUC of 6 Subjects with prior external beam radiation therapy (XRT) and/or platinum-based chemotherapy must initiate paclitaxel and carboplatin at a reduced dose: Pembrolizumab administered at 200 mg Paclitaxel administered at 135mg/m2 Carboplatin administered at an AUC of 5 | Drug: Pembrolizumab<br>* Pembrolizumab 200 mg will be administered every 3 weeks for all subjects<br>* Other names: Keytruda®;Drug: Paclitaxel<br>* For subjects with no prior therapy, paclitaxel will be dosed at 175mg/m2 and be administered as a 3-hour continuous IV infusion. Subjects with prior XRT/platinum-based chemotherapy must initiate paclitaxel at 135mg/m2 and be administered as a 3-hour continuous IV infusion.<br>* Other names: Taxol®;Drug: Carboplatin<br>* For subjects with no prior therapy, carboplatin will be dosed at an AUC of 6 and given as an IV infusion in 250ml of D5W over 30 minutes. Subjects with prior XRT/platinum-based chemotherapy must initiate carboplatin at an AUC of 5 given as an IV infusion in 250ml of D5W over 30 minutes.<br>* Other names: Paraplatin®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rates (ORR) | Objective response rate(ORR) is defined as the percentage of subjects with a partial response or complete response according to immune-related RECIST criteria. Immune-Related Response Criteria: Complete Response(irCR): Disappearance of all lesions in two consecutive observations not less than 4 wk apart. Partial Reponse (irPR): decrease in tumor burden ≥50 %relative to baseline confirmed by a consecutive assessment at least 4 wk after first documentation Stable Disease (irSD): not meeting criteria for irCR or irPR, in absence of irPD | From start of treatment Day 1 (D1) and assessed for a maximum of 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects Who Experience ≥ Grade 3 Toxicity According Per Common Toxicity Criteria for Adverse Effects (CTCAE) v4 Criteria | Proportion of subjects who experience ≥ Grade 3 toxicity regardless of relation according per Common Toxicity Criteria for Adverse Effects (CTCAE) v4 criteria while receiving pembrolizumab in combination with standard carboplatin/paclitaxel therapy | From time of consent to up to a maximum of 7 months(30 days following cessation of treatment ) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Pembrolizumab, Keytruda, Anti-Programmed [Cell] Death Protein 1 (PD-1) Antibody, Carboplatin, Paclitaxel