Trial of Letrozole + Palbociclib/Placebo in Metastatic Endometrial Cancer

This multicenter, prospective, randomized, double-blind, placebo-controlled phase 2 study is evaluating the efficacy of letrozole-palbociclib combination against letrozole-placebo combination in women with ER+ advanced or relapsed endometrial cancer.

Stratification

Patients are stratified according to:

• Number of prior lines of therapy (primary advanced disease vs. 1st relapse vs. ≥2 relapses)
• Measurable vs. evaluable disease
• Prior use of MPA/Megace

Randomization 1:1 randomization The patients with prior MPA/Megace treatment will be capped to a maximum of 50%.

Study arms

Patients are randomized to one of the two treatment arms:

• Arm A: (comparator) letrozole-placebo combination therapy until progression.
• Arm B: (experimental arm): Letrozole- palbociclib combination therapy until progression

Inclusion criteria

• Histological confirmed endometrial cancer of endometrioid type. Mixed tumor histology is allowed if the non-endometrioid component is less than 5%. Tumor must be estrogen receptor positive.
• Patients may have received adjuvant chemotherapy for stage 1 or 2.
• Patients may have received any lines of chemotherapy for primary advanced (stage 3-4) or relapsed disease.
• Patients may have received external beam radiotherapy, brachytherapy, and surgery.
• Patient may have received maximum one line of endocrine therapy containing MPA/Megace only.
• Patients must have measureable disease or evaluable disease on CT scan according to RECIST 1.1 outside irradiated field.
• Patients must give informed consent
• Patients must have a WHO performance status of 0-1
• Patients must have an adequate bone-marrow, renal and hepatic function
• Life expectancy of at least 12 weeks
• Patients must be fit to receive combination therapy
• Patient's age >18 years
• Patient is post-menopausal. Patients under the age of 55 with intact ovaries shall undergo hormonal verification.
• Patients with preserved reproductive capacity must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment

Exclusion criteria

• Non-endometrioid adenocarcinomas, sarcomas, small cell carcinoma with neuroendocrine differentiation or non-epithelial cancers.
• Previous anti-cancer endocrine therapy other than MPA/Megace. This means that eg. tamoxifen is not allowed prior to study entry.
• Concurrent cancer therapy
• Previous treatment with Palbociclib or other CDK inhibitors.
• Concurrent treatment with an investigational anticancer agent or participation in another anticancer clinical trial within 21 days before entering into study.
• Treatment within 21 days prior to randomization with any investigational drug, radiotherapy,
• Major injuries or surgery within the past 21 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.
• Previous malignant disease, except patients with other malignant disease, for which the patient has been disease-free for at least three years. Concurrent other malignant disease except for curatively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin.
• Active infection or other serious underlying medical condition, which might prevent the patient from receiving treatment or to be followed.
• Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situation that would, in the Investigator's judgment, makes the patient inappropriate for this study.
• Known uncontrolled hypersensitivity to the investigational drugs.
• History of major thromboembolic event defined as:
• History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 3 months.
• History of clinically significant hemorrhage in the past 3 months.
• Uncontrolled and/or symptomatic CNS metastasis or leptomeningeal carcinomatosis (dexamethasone/prednisone therapy will be allowed if administered as stable dose for at least one month prior randomization).
• Significant cardiovascular diseases, including uncontrolled hypertension, uncontrolled clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within 6 months prior to randomization, congestive heart failure > NYHA III, severe peripheral vascular disease, clinically significant pericardial effusion.
• Pregnancy or breastfeeding. Patients with preserved reproductive capacity, unwilling to use a medically acceptable method of contraception for the duration of the trial and for 3 months afterwards.
• Active or chronic hepatitis C and/or B infection
• Persistence of clinically relevant grade 3-4 therapy related toxicity from previous chemo and/or radiotherapy
• Known hypersensitivity to the trial drugs, or to their excipients.
• Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
• Unable or unwilling to swallow tablets/capsules