Trial of Letrozole + Palbociclib/Placebo in Metastatic Endometrial Cancer

Study Overview
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Brief Summary
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This randomized double-blind, placebo-controlled phase 2 trial is evaluating superiority of Letrozole-palbociclib combination versus letrozole-placebo combination in ER positive endometrioid adenocarcinoma of endometrium

Detailed Description
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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

Official Title
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ENGOT-EN3-NSGO/PALEO: A Randomized, Double-blind, Placebo-controlled, Phase II Trial of Palbociclib in Combination With Letrozole Versus Placebo in Combination With Letrozole for Patients With Estrogen Receptor Positive Advanced or Recurrent Endometrial Cancer.

Conditions
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Endometrial Cancer

Intervention / Treatment
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* Drug: Palbociclib/placebo
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized, double-blind, placebo-controlled
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Letrozole + placebo<br>letrozole 2.5mg once daily days 1-28 every 28 days shall be administered until progression of disease or unacceptable toxicity. Letrozole is administered as standard of care in both study arms. Placebo for palbociclib once daily days 1-21 every 28 days shall be administered until progression of disease or unacceptable toxicity. | Drug: Letrozole<br>* Letrozole is standard of care in both arms<br>|
| Experimental: Letrozole + palbociclib<br>Palbociclib 125mg once daily days 1-21 every 28 days shall be administered until progression of disease or unacceptable toxicity. letrozole 2.5mg once daily days 1-28 every 28 days shall be administered until progression of disease or unacceptable toxicity. Letrozole is administered as standard of care in both study arms. | Drug: Palbociclib/placebo<br>* Palbociclib or a placebo is administered together with standard of care letrozole<br>Drug: Letrozole<br>* Letrozole is standard of care in both arms<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS). Increase in median PFS in experimental arm versus comparator arm | To be measured (in months) and reported | 26 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS of patients in the sub-populations as described under stratification factors. Increase in median PFS in experimental arm versus comparator arm | To be measured (in months) and reported | 26 months | 
| Overall Response Rate (ORR) according to RECIST | To be measured (in %) and reported | 26 months | 
| Disease Control Rate (DCR) for at least 12 weeks | To be measured (in %) and reported | 26 months | 
| Time to First Subsequent Therapy (TFST) | TFST: time from randomization to first subsequent therapy or death. To be measured (in months) and reported | 36 months | 
| Progression-Free Survival 2 (PFS2) | PFS2: time from randomization to second objective disease progression or death. To be measured (in months) and reported | 48 months | 
| Time to Second Subsequent Therapy (TSST) | TSST: time from randomization to second subsequent therapy or death.To be measured (in months) and reported | 48 months | 
| Patient Reported Outcomes (PROs) like Quality of Life questionnaire EORTC-QLQ-C30 & EORTC-QLQ-EN24 | These are the validated questionnaires to be answered by patients. Results to be reported as descriptive and on a scale of 1-10 | 48 months | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | To be reported on % | 48 months | 
| Compliance in the two treatment arms. | Missed dosages in both arm will be reported. | 48 months | 
| Dose reductions/interruptions in the two treatment arms | To be reported on % | 48 months |