Pembro/Carbo/Taxol in Endometrial Cancer
Condition: Endometrial Cancer; Endometrial Adenocarcinoma
MeSH terms: Adenocarcinoma; Endometrial Neoplasms; Uterine Neoplasms
Intervention: Pembrolizumab; Paclitaxel; Carboplatin
Intervention description: Pembrolizumab 200 mg will be administered every 3 weeks for all subjects; 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.; 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.
Intervention MeSH terms: Paclitaxel; Carboplatin; Pembrolizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Masking description: Open-Label
Enrollment: 46.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pembrolizumab; Keytruda; Anti-Programmed [Cell] Death Protein 1 (PD-1) Antibody; Carboplatin; Paclitaxel

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.
    

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.