Combination Chemotherapy With Nintedanib / Placebo in Endometrial Cancer

Endometrial Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02730416
• Other study ID #: ENGOT-EN1/FANDANGO
• Status: Completed
• Phase: Phase 2
• Start date: December 12, 2016
• Est. completion date: November 25, 2021

Study information

• Verified date: September 2023
• Source: Nordic Society of Gynaecological Oncology - Clinical Trials Unit
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 146
• Est. completion date: November 25, 2021
• Est. primary completion date: October 20, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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 (ß-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

Related Conditions & MeSH terms

• Endometrial Cancer
• Endometrial Neoplasms

Intervention

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

Locations

Country	Name	City	State
Belgium	Onze Lieve Vrouwziekenhuis	Aalst
Belgium	Cliniques universitaires Saint-Luc	Bruxelles
Belgium	Antwerp University Hospital	Edegem
Belgium	Ghent University Hospital	Gent
Belgium	University Hospitals Leuven	Leuven
Denmark	Aalborg Universitetshospital	Aalborg	Jylland
Denmark	Rigshospitalet	Copenhagen	Sjaelland
Denmark	Odense Universitetshospital	Odense	Fyn
Denmark	Vejle Sygehus	Vejle	Jylland
Finland	Kuopio University Hospital	Kuopio
Finland	Tampere University Hospital	Tampere
France	Institute Bergonié	Bordeaux
France	Centre François Baclesse	Caen
France	Centre Oscar Lambret	Lille
France	Léon Bérard Center	Lyon
France	Institut Paoli Calmettes	Marseille
France	ICM (Cancer Institute of Montpellier)	Montpellier
France	Centre Antoine Lacassagne	Nice
France	Hospital Group Diaconesses Croix Saint-Simon	Paris
France	Private Hospital Of Côtes D'armor	Plérin
France	Institut de Cancérologie de l'Ouest	Saint-Herblain
Germany	Charité Campus Virchow Clinic	Berlin
Germany	Klinik Chemnitz gGmbH	Chemnitz
Germany	University Hospital Carl Gustav Carus Dresden	Dresden
Germany	Kliniken Essen Mitte	Essen
Germany	Universitätsklinikum Essen	Essen
Germany	Center of Gynecology and Obstetrics	Frankfurt
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	St. Vincentius-Kliniken gAG Frauenklinik mit Hebammenlehranstalt	Karlsruhe
Germany	Universitätsfrauenklinik Mainz	Mainz
Germany	Universitätsfrauenklinik am Klinikum Südstadt Rostock	Rostock
Germany	Universitätsfrauenklinik Ulm	Ulm
Norway	Oslo University Hospital	Oslo
Sweden	Linköping University Hospital	Linköping
Sweden	Skåne University Hospital	Lund
Sweden	Karolinska University Hospital	Stockholm
Sweden	Uppsala University Hospital	Uppsala

Sponsors (4)

Lead Sponsor	Collaborator
Nordic Society of Gynaecological Oncology - Clinical Trials Unit	ARCAGY/ GINECO GROUP, Belgian Gynaecological Oncology Group, North Eastern German Society of Gynaecological Oncology

Countries where clinical trial is conducted

Belgium,  Denmark,  Finland,  France,  Germany,  Norway,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	PFS in the sub-populations as described under stratification factors	To be measured (in months) and reported	32 months
Secondary	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
Secondary	Disease Specific Survival (DSS)	To be measured (in months) and reported	48 months
Secondary	TSST (Time to Second Subsequent Therapy)	To be measured (in months) and reported	48 months
Secondary	TFST (Time to First Subsequent Therapy)	To be measured (in months) and reported	48 months
Secondary	Overall Survival (OS)	To be measured (in months) and reported	48 months
Secondary	Response Rate (RR).	To be measured (CRs & PRs in %) and reported	32 months
Secondary	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
Secondary	Patient Related Outcomes (PROs)	Patient questionnaire results to be presented as as narrative (1-10 scale)	48 months
Secondary	Number of patients with Grade 3 through Grade 5 Adverse Events that are related to study drug.	NCI CTCAE Version 4.0	36 months
Secondary	Compliance in the two treatment arms	Percentage of missed dosages during the treatment	32 months