Trial of Letrozole + Palbociclib/Placebo in Metastatic Endometrial Cancer

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.

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

Study Overview

• Status: Completed
• Conditions: Endometrial Cancer
• Intervention / Treatment: Drug: Letrozole; Drug: Palbociclib/placebo

Detailed Description

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:

1. Number of prior lines of therapy (primary advanced disease vs. 1st relapse vs. ≥2 relapses)
2. Measurable vs. evaluable disease
3. 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

• Study Type: Interventional
• Enrollment (Actual): 78
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Sjaelland
    • Copenhagen, Sjaelland, Denmark, 2100
      • NSGO-CTU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. 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.
2. Patients may have received adjuvant chemotherapy for stage 1 or 2.
3. Patients may have received any lines of chemotherapy for primary advanced (stage 3-4) or relapsed disease.
4. Patients may have received external beam radiotherapy, brachytherapy, and surgery.
5. Patient may have received maximum one line of endocrine therapy containing MPA/Megace only.
6. Patients must have measureable disease or evaluable disease on CT scan according to RECIST 1.1 outside irradiated field.
7. Patients must give informed consent
8. Patients must have a WHO performance status of 0-1
9. Patients must have an adequate bone-marrow, renal and hepatic function
10. Life expectancy of at least 12 weeks
11. Patients must be fit to receive combination therapy
12. Patient's age >18 years
13. Patient is post-menopausal. Patients under the age of 55 with intact ovaries shall undergo hormonal verification.
14. 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:

1. Non-endometrioid adenocarcinomas, sarcomas, small cell carcinoma with neuroendocrine differentiation or non-epithelial cancers.
2. Previous anti-cancer endocrine therapy other than MPA/Megace. This means that eg. tamoxifen is not allowed prior to study entry.
3. Concurrent cancer therapy
4. Previous treatment with Palbociclib or other CDK inhibitors.
5. Concurrent treatment with an investigational anticancer agent or participation in another anticancer clinical trial within 21 days before entering into study.
6. Treatment within 21 days prior to randomization with any investigational drug, radiotherapy,
7. 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.
8. 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.
9. Active infection or other serious underlying medical condition, which might prevent the patient from receiving treatment or to be followed.
10. 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.
11. Known uncontrolled hypersensitivity to the investigational drugs.
12. History of major thromboembolic event defined as:
13. History of a cerebral vascular accident, transient ischemic attack or subarachnoid hemorrhage within the past 3 months.
14. History of clinically significant hemorrhage in the past 3 months.
15. 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).
16. 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.
17. 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.
18. Active or chronic hepatitis C and/or B infection
19. Persistence of clinically relevant grade 3-4 therapy related toxicity from previous chemo and/or radiotherapy
20. Known hypersensitivity to the trial drugs, or to their excipients.
21. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
22. Unable or unwilling to swallow tablets/capsules

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Letrozole + placebo; 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; Letrozole is standard of care in both arms
Experimental: Letrozole + palbociclib; 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: Letrozole; Letrozole is standard of care in both arms; Drug: Palbociclib/placebo; Palbociclib or a placebo is administered together with standard of care letrozole

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Nordic Society of Gynaecological Oncology - Clinical Trials Unit
• Collaborators: European Network of Gynaecological Oncological Trial Groups (ENGOT); Grupo Español de Investigación en Cáncer de Ovario; North Eastern German Society of Gynaecological Oncology; Gynecologic Cancer Intergroup (GCIG); Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO)

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2017
• Primary Completion (Actual): December 15, 2020
• Study Completion (Actual): December 15, 2021

Study Registration Dates

• First Submitted: January 14, 2016
• First Submitted That Met QC Criteria: March 31, 2016
• First Posted (Estimate): April 6, 2016

Study Record Updates

• Last Update Posted (Actual): February 15, 2023
• Last Update Submitted That Met QC Criteria: February 14, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Endometrial Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Protein Kinase Inhibitors; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole; Palbociclib
• Other Study ID Numbers: ENGOT-EN3-NSGO/PALEO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: As all endpoints are matured, the individual participant data will be shared.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No