Clinical Trials /

Pembro/Carbo/Taxol in Endometrial Cancer

NCT02549209

Description:

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.

Related Conditions:
  • Endometrial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembro/Carbo/Taxol in Endometrial Cancer
  • Official Title: Phase II Study of Pembrolizumab in Combination With Carboplatin and Paclitaxel for Advanced or Recurrent Endometrial Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: BTCRC GYN15-013
  • NCT ID: NCT02549209

Conditions

  • Endometrial Cancer
  • Endometrial Adenocarcinoma

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, Keytruda®Investigational Treatment
PaclitaxelTaxol®Investigational Treatment
CarboplatinParaplatin®Investigational Treatment

Purpose

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
    

Trial Arms

NameTypeDescriptionInterventions
Investigational TreatmentExperimentalSubjects 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
  • Pembrolizumab
  • Paclitaxel
  • Carboplatin

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rates (ORR)
Time Frame:From start of treatment Day 1 (D1) and assessed for a maximum of 18 months
Safety Issue:
Description:Proportion of confirmed partial response (PR) and complete response (CR) rates per Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria for evaluable subjects receiving pembrolizumab in combination with standard carboplatin/paclitaxel therapy.

Secondary Outcome Measures

Measure:Incidence of Adverse Events as a Measure of Safety and Tolerability
Time Frame:From start of treatment D1 and every treatment visit thereafter up to a maximum of 18 months
Safety Issue:
Description:Proportion of subjects who experience ≥ Grade 3 toxicity according per Common Toxicity Criteria for Adverse Effects (CTCAE) v4 criteria while receiving pembrolizumab in combination with standard carboplatin/paclitaxel therapy

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Daniela Matei, MD

Trial Keywords

  • Pembrolizumab
  • Keytruda
  • Anti-Programmed [Cell] Death Protein 1 (PD-1) Antibody
  • Carboplatin
  • Paclitaxel

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