Palbociclib Plus Letrozole Treatment After Progression to Second Line Chemotherapy for Women With ER/PR-positive Ovarian Cancer.

Letrozole (Femara®) is an oral non-steroidal aromatase inhibitor that is approved worldwide for the treatment of postmenopausal women with breast cancer. It is administered orally on a continuous 2.5 mg daily dosing regimen and has a good toxicity profile. Palbociclib (Ibrance®) is an active potent and highly selective reversible inhibitor of cyclin- dependent kinases 4 and 6 (CDK4/6). Palbociclib was approved by the United States Food and Drug Administration (U.S. FDA) and the European Medicines Agency (EMA) for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor based on a randomized, double-blind, placebo-controlled, international clinical trial PALOMA-2. It is administered orally on a dose of 125 mg per day in 4-week cycles (3 weeks of treatment followed by 1 week off). This trial was based on preclinical studies that showed a synergistic effect between targeting the ER and cyclin-D-CDK4/6-Rb pathway. The principal toxicity was myelotoxicity but it was managed with appropriate supportive care and dose reductions13.

Based on the results of phase 1 and 2 clinical trials of CDK4/6 inhibitors used as monotherapy to treat patients with recurrent ovarian cancer, we hypothesized that, as Palbociclibe is active in this population and many ovarian cancer show ER/PR expression, its combination with Letrozole can improve outcomes in ER/PR positive endometrioid or high-grade serous Ovarian Cancer who have disease progression on second-line chemotherapy, similar to what is seen in breast cancer studies.

• Drug: Palbociclib 125mg
  The Palbociclib capsules supplied for this study contains 75 mg, 100 mg or 125 mg of Palbociclib. It must be taken orally 125 mg once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days.
  Other Name: Ibrance®
• Drug: Letrozole 2.5mg
  Letrozole will be supplied as a 2.5 mg film-coated tablet. It must be taken at the recommended dose of 2.5 mg once daily.
  Other Name: Femara

Inclusion Criteria:

1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study;
2. Subject is willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
3. 18 years of age or older;
4. Patient agrees not to participate in another interventional study while on treatment;
5. Histologically diagnosed endometrioid or high-grade serous ovarian cancer, estrogen (ER) and/or progesterone (PR) receptor positive (defined as > 10% by immunohistochemistry);

6. Patients must have completed 2 previous courses of chemotherapy:

   1. The penultimate regimen must be a platinum-based chemotherapy course prior to enrolment on the study:

   2. For the last chemotherapy course prior to enrolment on the study:

      • There is no pre-specified regimen;
      • It may contain a Platinum salt or not (depending upon Platinum sensitivity), at discretion of treating Physician;
      • Patients must have demonstrated disease progression by RECIST v1.1 to the last treatment
      • Patients must be treated on the study within 8 weeks of completion of their final dose of second line regimen;
7. Formalin fixed, paraffin embedded tumor sample from the primary tumor must be available for central testing;
8. Eastern Cooperative Oncology Group (ECOG) performance status ? 2;

9. Adequate bone marrow function at screening:

   • Absolute Neutrophil Count (ANC) ? 1,500/mm³ (? 1.5x109/L)
   • Platelets ? 100,000/mm³ or ? 100 x 109/L
   • Hemoglobin ? 9.0 g/dL;

10. Adequate liver function at screening:

    • Total serum bilirubin ? 1.5 x upper limit of normal (ULN) (? 3.0 x ULN if Gilbert Syndrome)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ? 3.0 x ULN (? 5.0 x ULN if there is tumor involvement in the liver)
    • Alkaline phosphatase ? 2.5 x ULN (? 5.0 x ULN if there is tumor involvement in the liver);

11. Adequate renal function at screening:

    - Serum creatinine ? 1.5 x ULN or estimated creatinine clearance ? 50mL/min;

12. Evidence of non-childbearing potential:

    • Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
    • Radiation-induced oophorectomy with last menses >1 year ago, or
    • Surgical sterilisation (bilateral oophorectomy or hysterectomy).

Exclusion Criteria:

1. Patients with a known hypersensitivity to Palbociclib or Letrozole or any of the excipients of the product;
2. Previous treatment with CDK inhibitors or endocrine therapy;
3. Persistent toxicities (grade 2 or greater) caused by previous cancer therapy (excluding alopecia);
4. Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, Ductal Carcinoma in Situ (DCIS), stage 1 grade 1 endometrial carcinoma curatively treated with no evidence of disease for 3 years;
5. Patients receiving any chemotherapy, radiotherapy, within 3 weeks from the last dose prior to study entry;
6. Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required;
7. Major surgical procedure within 3 weeks prior to study randomization, or one is planned during the course of the study;
8. Patients considered poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 6 months) myocardial infarction, cerebrovascular accident, gastrointestinal bleeding, or any psychiatric disorder that prohibits obtaining informed consent;
9. Patients that have difficulty taking oral medication or any digestive tract dysfunction or inflammatory bowel disease that would interfere with the intestinal absorption of drugs (eg, partial bowel obstruction or malabsorption);
10. Patients have received potent inhibitors or inducers of CYP3A4 within 7 days prior to randomization;
11. Pregnant or breast feeding women;
12. Patient has a known history of positive test for human immunodeficiency virus (HIV);
13. Patients with known hepatic disease (ie, Hepatitis B or C);
14. Subjects who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or subject who are Pfizer employees directly involved in the conduct of the trial;
15. Treatment with any investigational product during the last 28 days;
16. QTc > 480ms, QT syndrome, Brugada syndrome, history QTc prolongation or Torsade de Points;
17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.