The primary objective of this study is to evaluate 12 weeks progression-free survival (PFS)
rate of Palbociclib plus Letrozole in ER/PR positive endometrioid or high-grade serous
ovarian cancer who have disease progression on second-line chemotherapy.
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.
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.