Window of Opportunity Study of Pembrolizumab in Early Stage, High Grade Obesity-driven Endometrial Cancer
Sponsor:
UNC Lineberger Comprehensive Cancer Center
Collaborators:
Information provided by (Responsible Party):
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| Tracking Information | |||
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| First Submitted Date ICMJE | October 1, 2018 | ||
| First Posted Date ICMJE | October 3, 2018 | ||
| Last Update Posted Date | October 3, 2018 | ||
| Actual Study Start Date ICMJE | December 2018 | ||
| Estimated Primary Completion Date | May 1, 2020 (Final data collection date for primary outcome measure) | ||
| Current Primary Outcome Measures ICMJE |
Change in the number of Tumor Infiltrating Lymphocytes[ Time Frame: 3 weeks ] Change in number of tumor-infiltrating lymphocytes in response to single dose of pembrolizumab will be determined by performing histopathologic analysis of H&E-stained tumor sections collected at baseline and at the time of surgery. |
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| Original Primary Outcome Measures ICMJE | Same as current | ||
| Current Secondary Outcome Measures ICMJE |
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| Descriptive Information | |||
| Brief Title ICMJE | Window of Opportunity Study of Pembrolizumab in Early Stage, High Grade Obesity-driven Endometrial Cancer |
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| Official Title ICMJE | Window of Opportunity Study of Pembrolizumab in Early Stage, High Grade Obesity-driven Endometrial Cancer |
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| Brief Summary | Programmed cell death 1 (PD-1) inhibitor treatment may benefit patients with endometrial cancer (EC) based on the following observations: 1) an overwhelming presence of PD-1 in ECs; 2) the well-known effect of obesity which activates pro-inflammatory white blood cells and promotes the development of ECs; and 3) the high prevalence of a specific gene pattern (ie, microsatellite instability hypermutated [MSI high]) among ECs that may be particularly sensitive to this class of drugs. To identify potential biomarkers of response to PD-1 inhibitors in EC, we will conduct a window of opportunity study of pembrolizumab in 20 patients with clinical stage 1, grade 3 EC, encompassing endometrioid, serous and clear cell histologies. Eligible patients will undergo a research biopsy for collection of fresh tissue at the time of enrollment, in addition to the routinely performed endometrial biopsy that led to the diagnosis of their cancer. Patients will receive a single dose of pembrolizumab (200 mg IV) prior to undergoing their scheduled hysterectomy with surgical staging three weeks later. As per standard of care, adjuvant chemotherapy with paclitaxel and carboplatin will be recommended after hysterectomy/surgical staging for women with endometrioid tumors and stage III disease or women with serous/clear cell tumors at all stages of disease. However, in this study pembrolizumab will be added to adjuvant paclitaxel and carboplatin for EC. Pre-treatment endometrial biopsy specimens (fresh frozen tissue and formalin-fixed paraffin embedded (FFPE)) and a post-treatment hysterectomy specimen (fresh frozen tissue and FFPE) will be collected for translational studies. Blood, fecal and vaginal samples will be collected pre-treatment, at the time of surgery and following 3 cycles of adjuvant pembrolizumab/paclitaxel/carboplatin treatment. |
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| Detailed Description | The primary objective of the trial is to measure the change in number and phenotype of tumor-infiltrating lymphocytes, including delineation of effector and regulatory T cells, before and after one cycle of pembrolizumab treatment. Other correlative secondary objectives include investigation of associations among pre-treatment TIL numbers, clonality of TILs and change in number and phenotype of TILs with samples collected after pembrolizumab treatment between MSI and DNA polymerase (POLE) ultramutated ECs versus MSI low/stable ECs versus copy number high (CNH) ECs, among others. To assess the complex interplay between obesity, molecular subtype, the microbiome and immune regulation, gut, vaginal and uterine microbiota profiles will be characterized and potential associations with body mass index (BMI), pre-treatment TIL numbers, clonality of TILs and change in the number and phenotype of TILs will be investigated. Secondary clinical objectives include (1) of the pathologic response rate after one cycle of pembrolizumab following hysterectomy and surgical staging in stage I/II, serous/clear cell EC and stage III, G3 (serous, clear cell or endometrioid histologies) EC and (2) characterization of the toxicity profile of pembrolizumab pre-hysterectomy and in combination with paclitaxel and carboplatin as adjuvant therapy for EC. | ||
| Study Type ICMJE | Interventional | ||
| Study Phase | Early Phase 1 | ||
| Study Design ICMJE | Allocation: Intervention Model: Single Group Assignment Intervention Model Description: Masking: Interventional Masking Description: Primary Purpose: Basic Science |
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| Condition ICMJE | |||
| Intervention ICMJE |
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| Study Arms |
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| Recruitment Information | |||
| Recruitment Status ICMJE | Not yet recruiting | ||
| Estimated Enrollment ICMJE |
20 | ||
| Original Estimated Enrollment ICMJE | Same as current | ||
| Estimated Study Completion Date | May 1, 2022 | ||
| Estimated Primary Completion Date | May 1, 2020 (Final data collection date for primary outcome measure) | ||
| Eligibility Criteria ICMJE | Inclusion Criteria: - Age ≥ 18 years at the time of consent. - ECOG Performance Status of ≤ 1 (See Appendix 11.4). - Diagnosis of histologically confirmed FIGO stage 1, grade 3, endometrioid, serous or clear cell cancer of the uterus. - A medically appropriate candidate for hysterectomy and surgical staging as determined by an attending gynecologic oncologist. - Has received no prior therapy for uterine cancer. - Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 72 hours prior to initiating study treatment. - A female participant is eligible to participate if she is not pregnant not breastfeeding, and at least one of the following conditions applies: 1. Not a woman of childbearing potential (WOCBP) 2. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment. - Have an available endometrial biopsy for correlative studies and willing to undergo a research biopsy prior to initiating study treatment. The research biopsy procedure must be deemed medically safe by the investigator. - Subjects is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee. Exclusion Criteria: - Active infection requiring systemic therapy. - Pregnant or breastfeeding - Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years. - Has received a live vaccine within 30 days prior to the first dose of study drug. 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 (eg, FluMist®) are live attenuated vaccines and are not allowed. - 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. - Subject is receiving prohibited medications or treatments that cannot be discontinued/replaced by an alternative therapy. - Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. - 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 (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 has current pneumonitis. - Has an active infection requiring systemic therapy. - Has a known history of Human Immunodeficiency Virus (HIV). Note: No HIV testing is required unless mandated by local health authority. - 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 a known history of active TB (Bacillus Tuberculosis). - 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. - Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. - Has a history of symptomatic congestive heart failure (e.g. congestive heart failure defined as New York Heart Association (NYHA) Class III or IV functional status), unstable angina pectoris or cardiac arrhythmia. | ||
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| Ages | 18 Years and older (Adult, Older Adult) | ||
| Accepts Healthy Volunteers | No | ||
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| Administrative Information | 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 |
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| IPD Sharing Statement |
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| Responsible Party | ， | ||
| Study Sponsor ICMJE | UNC Lineberger Comprehensive Cancer Center | ||
| Collaborators ICMJE | |||
| Investigators ICMJE |
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| PRS Account | |||
| Verification Date | October 2018 | ||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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