Clinical Trial 23067

• Overview

  Study Title:

  Phase 2 Study of Alpelisib and Fulvestrant for PIK3CA-mutated Estrogen Receptor (ER)-positive Endometrioid Endometrial Cancers

  Objective:

  Primary Objective: *To determine the objective response rate of the combination of alpelisib and fulvestrant in patients with advanced, persistent or recurrent PIK3CA-mutated ER-positive endometrioid endometrial cancer. Secondary Objectives: *To describe the nature and degree of toxicity of the combination in this patient population. *To estimate the progression free survival (PFS) of this population while receiving the combination. *To estimate the duration of response (DOR) to therapy in this population. *To estimate the 24-month overall survival (OS) rate of this population while receiving the combination.

• Treatments

  Therapies:

  Hormonal Therapy; Therapy (NOS)

  Medications:

  Alpelisib (); Faslodex (fulvestrant); fulvestrant ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Patient must have advanced (FIGO 2014 Stage III or IV), persistent, or recurrent endometrial carcinoma, which is not likely to be curable by surgery or radiotherapy. Histologic confirmation of recurrent disease is required. For cases of persistent disease, histologic confirmation of the primary disease with radiologic evidence of progression is required.
  • Patients must have endometrioid histology (all grades allowed) based on hysterectomy or biopsy specimen and have positive expression of ER and oncogenic PIK3CA mutation per criteria below. PIK3CA mutations considered oncogenic or likely oncogenic. Estrogen receptor (ER) status will be considered positive if ≥1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. Pathology report documenting ER status must be provided at enrollment.
  • All patients must have measurable disease. Measurable disease is defined by RECIST version 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be greater than or equal to 10mm when measured by CT, MRI or caliper measurement by clinical exam; or greater than or equal to 20mm when measured by chest x-ray. Lymph nodes must be greater than or equal to 15mm in short axis when measured by CT or MRI.
  • Prior chemotherapy in the adjuvant setting for Stage I, II, or III or metastatic/recurrent/Stage IV is permitted. Prior chemoradiotherapy for a pelvic recurrence is permitted.
  • Patient must be able to swallow oral medications.
  • Patient must have an ECOG performance status of 0 to 2.
  • Patients must have adequate glucose control as defined by the following (both criteria must be met): Fasting blood glucose (FBG) ≤140/dL (7.7mmol/L). Hemoglobin A1c (HbA1c) ≤6.4%.
  • Patients must have adequate organ and marrow function.
  • Patients must have signed an approved informed consent and authorization permitting release of personal health information.
  • Patients must be at least 18 years of age.
  • Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and be practicing a highly effective form of contraception during the study treatment and for 8 weeks after stopping the treatment.
  • Other inclusion criteria may apply.

• Exclusion Criteria

  Key Exclusion Criteria:
  • Patients who have previously received fulvestrant or any PIK3CA, PI3K, mTOR, or AKT inhibitor.
  • Patients with clear cell, serous, carcinosarcoma, mixed histology endometrial cancers, or uterine sarcomas.
  • Patients with known intolerance or hypersensitivity to alpelisib or fulvestrant, or any of their excipients.
  • Patient has had major surgery within 14 days prior to study treatment start and/or has not recovered from major side effects.
  • Patients with an established diagnosis of diabetes mellitus type I or uncontrolled type II (based on fasting blood glucose [FBG] and HemoglobinA1c [HbA1c], see inclusion criterion 7).
  • Patients with history of osteonecrosis of the jaw.
  • Patients with concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol.
  • Patients with active bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment, fungal infection, or detectable viral infection (such as known human immunodeficiency virus (HIV) positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]). Screening is not required for enrollment.
  • Patients with a serious pre-existing medical condition(s) that would preclude participation in this study (for example: interstitial lung disease or pneumonitis, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (i.e. estimated creatinine clearance > Patients with a known history of cardiac disease.
  • Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of the treatment: Strong CYP3A4 inducers or Inhibitors of BCRP.
  • Patients who are pregnant or breast-feeding.
  • Patients with an impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study drugs (i.e. ulcerative disease; uncontrolled nausea, vomiting and/or diarrhea; malabsorption syndrome; clinical signs and symptoms of gastrointestinal obstruction; and/or patients who require parenteral hydration and/or nutrition).
  • Patients who plan to receive live attenuated vaccines within 1 week of start of alpelisib and during the study. Patients should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG> Patients with active bleeding or pathologic conditions that carry high risk of bleeding such as known bleeding disorder or coagulopathy.
  • Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 30 days prior to dosing, or within 5 half-lives of the investigational product, whichever is longer.
  • Patient is not able to understand and to comply with study instructions and requirements, including oral administration of study treatment.
  • Other exclusion criteria may apply.

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