Combination Chemotherapy With Nintedanib / Placebo in Endometrial Cancer

ENGOT-EN1/FANDANGO: A Randomized Phase II Trial of First-line Combination Chemotherapy With Nintedanib / Placebo for Patients With Advanced or Recurrent Endometrial Cancer

This study will evaluate the role of addition of an anti-angiogenic agent (Nintedanib/placebo) to conventional combination chemotherapy as concomitant and maintenance treatment in primary advanced or with first relapse of endometrial cancer.

Study Overview

• Status: Completed
• Conditions: Endometrial Cancer
• Intervention / Treatment: Drug: Nintedanib or Placebo; Carboplatin, Paclitaxel

Detailed Description

This multicenter, prospective, double-blind, placebo-controlled, randomised phase 2 study is evaluating combination chemotherapy with nintedanib in patients with primary advanced stage (3C2 & 4), or with first relapse of endometrial cancer.

Patients are stratified according to:

1. Stage of disease (stage 3C2 vs. stage 4 vs. recurrent disease)
2. Prior adjuvant chemotherapy (yes/no)
3. Disease status (Measurable disease vs. non-measurable /RECIST 1.1)

Patients are randomized to one of the two treatment arms 1:1 randomization:

• Arm A: Paclitaxel and Carboplatin (6 courses) and Nintedanib (until PD). (Experimental arm)
• Arm B: Paclitaxel and Carboplatin (6 courses) and Placebo (until PD) (Control Arm)

Primary endpoint is PFS. 148 patients to be enrolled.

• Study Type: Interventional
• Enrollment (Actual): 146
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Aalst, Belgium, 9300
    • Onze Lieve Vrouwziekenhuis
  • Bruxelles, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Edegem, Belgium, 2650
    • Antwerp University Hospital
  • Gent, Belgium, 9000
    • Ghent University Hospital
  • Leuven, Belgium, 3000
    • University Hospitals Leuven
• Denmark
  • Fyn
    • Odense, Fyn, Denmark, 5000
      • Odense Universitetshospital
  • Jylland
    • Aalborg, Jylland, Denmark, 9000
      • Aalborg Universitetshospital
    • Vejle, Jylland, Denmark, 7100
      • Vejle Sygehus
  • Sjaelland
    • Copenhagen, Sjaelland, Denmark, 2100
      • Rigshospitalet
• Finland
  • Kuopio, Finland, 70029
    • Kuopio University Hospital
  • Tampere, Finland, 33520
    • Tampere University Hospital
• France
  • Bordeaux, France, 33076
    • Institute Bergonie
  • Caen, France, 14076
    • Centre Francois Baclesse
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Lyon, France, 69008
    • Léon Bérard Center
  • Marseille, France, 13009
    • Institut Paoli Calmettes
  • Montpellier, France
    • ICM (Cancer Institute of Montpellier)
  • Nice, France, 06189
    • Centre Antoine Lacassagne
  • Paris, France, 75012
    • Hospital Group Diaconesses Croix Saint-Simon
  • Plérin, France, 22 190
    • Private Hospital Of Côtes D'armor
  • Saint-Herblain, France, 44800
    • Institut de Cancérologie de l'Ouest
• Germany
  • Berlin, Germany, 13353
    • Charité Campus Virchow Clinic
  • Chemnitz, Germany, 09116
    • Klinik Chemnitz gGmbH
  • Dresden, Germany, 01307
    • University Hospital Carl Gustav Carus Dresden
  • Essen, Germany, 45122
    • Universitätsklinikum Essen
  • Essen, Germany, 45135
    • Kliniken Essen Mitte
  • Frankfurt, Germany, 60596
    • Center of Gynecology and Obstetrics
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf
  • Karlsruhe, Germany, 76137
    • St. Vincentius-Kliniken gAG Frauenklinik mit Hebammenlehranstalt
  • Mainz, Germany, 55131
    • Universitätsfrauenklinik Mainz
  • Rostock, Germany, 18059
    • Universitätsfrauenklinik am Klinikum Südstadt Rostock
  • Ulm, Germany, 89075
    • Universitätsfrauenklinik Ulm
• Norway
  • Oslo, Norway, 0450
    • Oslo University Hospital
• Sweden
  • Linköping, Sweden, 58185
    • Linköping University Hospital
  • Lund, Sweden, 221 85
    • Skåne University Hospital
  • Stockholm, Sweden, 171 76
    • Karolinska University Hospital
  • Uppsala, Sweden, 751 85
    • Uppsala University Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Histological confirmed endometrial cancer. (FIGO 2009)

   1. Stage 3C 2
   2. Stage 4 A & B
   3. Relapsed after adjuvant therapy for stage 1-3 disease
2. Patients may have undergone primary surgery.
3. Patients may have received adjuvant chemotherapy for stage 1 - 3.
4. Patients may have received vaginal brachytherapy
5. Patients may have received external beam radiotherapy. Patients who are to be enrolled for stage 3C2 diseases are allowed to receive external beam radiotherapy prior to trial entry.
6. Patients may have received hormonal treatment
7. Patients must have measurable disease or non-measurable disease on CT scan according to RECIST 1.1 outside irradiated field. For stage 3C2 disease patients without measureable or non-measureable disease are accepted.
8. Patients must give informed consent
9. ECOG performance status of 0 -1
10. Patients must have an adequate organ function
11. Life expectancy of at least 12 weeks
12. Patients must be fit to receive combination chemotherapy
13. Patient's age >18 years
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. Sarcomas, small cell carcinoma with neuroendocrine differentiation or non-epithelial cancers.
2. Concurrent cancer therapy
3. Previous Chemotherapy for stage 4 disease or for relapsed disease.
4. Previous treatment with anti-angiogenic/anti VEGF therapy including nintedanib.
5. Concurrent treatment with an investigational agent or participation in another clinical trial.
6. Treatment within 28 days prior to randomisation with any investigational drug, radiotherapy, immunotherapy, chemotherapy, hormonal therapy or biological therapy. Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases in extremities, provided that the radiotherapy does not involve target lesions, and the reason for the radiotherapy does not reflect progressive disease.
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. Relapse within six months after adjuvant chemotherapy (treatment-free interval < 182 days).
9. 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.
10. Active infection or other serious underlying medical condition, which might prevent the patient from receiving treatment or to be followed.
11. Evidence of significant medical illness, abnormal laboratory finding or psychiatric illness/social situation that would, in the Investigator's judgement, make the patient inappropriate for this study.
12. Known contraindications to VEGF directed therapy Target Disease Exceptions
13. Known uncontrolled hypersensitivity to the investigational drugs.

14. History of major thromboembolic event defined as:

    • Uncontrolled pulmonary embolism (PE)
    • Deep venous thrombosis (DVT)
    • Other related conditions, though patients with stable therapeutic anticoagulation for more than three months prior randomization are eligible for this study.
15. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 3 months.
16. History of clinically significant haemorrhage in the past 3 months.
17. Radiotherapy to the target lesion within the past 3 months prior to baseline imaging
18. Persistant grade 3 or 4 toxicity from previous chemotherapy and/or radiotherapy, except alopecia. Patients with ongoing ≥ Grade 2 neuropathy are to be excluded.
19. Active brain metastases (e.g. stable for <4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexamethasone therapy will be allowed if administered as stable dose for at least one month before randomisation).
20. Leptomeningeal disease
21. Significant cardiovascular diseases ( i.e. uncontrolled hypertension, unstable angina, history of infarction within the past 12 months prior to start of study treatment, congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion) See Appendix 12.
22. 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.
23. Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels.
24. Active or chronic hepatitis C and/or B infection
25. Known hypersensitivity to the trial drugs, or to their excipients.
26. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug
27. 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: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: A: Nintedanib; Nintedanib 200mg twice daily days 2-21 every 21 days for 6 courses during simultaneous treatment with carboplatin-paclitaxel; afterwards in maintenance 200mg twice daily days 1-21 every 21 days. Treatment continues until progression or unacceptable toxicity.	Drug: Nintedanib or Placebo; Carboplatin, Paclitaxel; Arm A: Nintedanib: 200mg orally twice daily d 2-21 q 21 days x 6 courses; afterwards daily dosing, until PD Arm B: Placebo: orally twice daily d 2-21 q 21 days x 6 courses; afterwards daily dosing, until PD In both arms: 6 courses of standard carboplatin and paclitaxel: Carboplatin AUC 5 iv every 21 days; Paclitaxel 175mg/m2 iv every 21 days. Both drugs are continued for maximum six courses or until unacceptable toxicity
Placebo Comparator: B: Placebo; Placebo twice daily days 2-21 every 21 days for 6 courses during simultaneous treatment with carboplatib-paclitaxel; afterwards in maintenance 200mg twice daily days 1-21 every 21 days. Treatment continues until progression or unacceptable toxicity.	Drug: Nintedanib or Placebo; Carboplatin, Paclitaxel; Arm A: Nintedanib: 200mg orally twice daily d 2-21 q 21 days x 6 courses; afterwards daily dosing, until PD Arm B: Placebo: orally twice daily d 2-21 q 21 days x 6 courses; afterwards daily dosing, until PD In both arms: 6 courses of standard carboplatin and paclitaxel: Carboplatin AUC 5 iv every 21 days; Paclitaxel 175mg/m2 iv every 21 days. Both drugs are continued for maximum six courses or until unacceptable toxicity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS: Difference in months of Median Progression-Free Survival in experimental arm versus comparator arm	Superiority of Nintedanib arm vs. placebo arm by median PFS increase of 4 months (from 10 months to 14 months) HR: 1.4; power80%; one-sided alpha: 15%. Inclusion period 18 months. Median PFS matures after 14 months of end inclusion	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS in the sub-populations as described under stratification factors	To be measured (in months) and reported	32 months
PFS after consecutive treatment (PFS2). To be measured (in months) and reported	PFS2 is defined along the same timelines as PFS but accounts for the time from randomization to progression or death by any cause on any subsequent line of anticancer therapy.	48 months
Disease Specific Survival (DSS)	To be measured (in months) and reported	48 months
TSST (Time to Second Subsequent Therapy)	To be measured (in months) and reported	48 months
TFST (Time to First Subsequent Therapy)	To be measured (in months) and reported	48 months
Overall Survival (OS)	To be measured (in months) and reported	48 months
Response Rate (RR).	To be measured (CRs & PRs in %) and reported	32 months
Disease Control Rate (DCR)	Disease Control Rate (DCR = Complete Response, Partial Response or Stable Disease for at least 12 weeks). To be measured (CRs, PRs & SDs in %) and reported	32 months
Patient Related Outcomes (PROs)	Patient questionnaire results to be presented as as narrative (1-10 scale)	48 months
Number of patients with Grade 3 through Grade 5 Adverse Events that are related to study drug.	NCI CTCAE Version 4.0	36 months
Compliance in the two treatment arms	Percentage of missed dosages during the treatment	32 months

Collaborators and Investigators

• Sponsor: Nordic Society of Gynaecological Oncology - Clinical Trials Unit
• Collaborators: ARCAGY/ GINECO GROUP; Belgian Gynaecological Oncology Group; North Eastern German Society of Gynaecological Oncology
• Investigators: Study Chair: Mansoor R Mirza, MD, NSGO

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2016
• Primary Completion (Actual): October 20, 2021
• Study Completion (Actual): November 25, 2021

Study Registration Dates

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

Study Record Updates

• Last Update Posted (Actual): July 29, 2025
• Last Update Submitted That Met QC Criteria: July 28, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Uterine Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Uterine Neoplasms; Endometrial Neoplasms; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Carboplatin; Paclitaxel; Nintedanib
• Other Study ID Numbers: ENGOT-EN1/FANDANGO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Upon request.
• IPD Sharing Time Frame: From January 2024.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

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