Combination Chemotherapy With Nintedanib / Placebo in Endometrial Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Stage of disease (stage 3C2 vs. stage 4 vs. recurrent disease) Prior adjuvant chemotherapy (yes/no) 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.

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

Conditions
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Endometrial Cancer

Intervention / Treatment
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* Drug: Nintedanib or Placebo; Carboplatin, Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmed endometrial cancer. (FIGO 2009) Stage 3C 2 Stage 4 A & B Relapsed after adjuvant therapy for stage 1-3 disease Patients may have undergone primary surgery. Patients may have received adjuvant chemotherapy for stage 1 - 3. Patients may have received vaginal brachytherapy 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. Patients may have received hormonal treatment 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. Patients must give informed consent ECOG performance status of 0 -1 Patients must have an adequate organ function Life expectancy of at least 12 weeks Patients must be fit to receive combination chemotherapy Patient's age >18 years 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: Sarcomas, small cell carcinoma with neuroendocrine differentiation or non-epithelial cancers. Concurrent cancer therapy Previous Chemotherapy for stage 4 disease or for relapsed disease. Previous treatment with anti-angiogenic/anti VEGF therapy including nintedanib. Concurrent treatment with an investigational agent or participation in another clinical trial. 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. 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. Relapse within six months after adjuvant chemotherapy (treatment-free interval < 182 days). 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 judgement, make the patient inappropriate for this study. Known contraindications to VEGF directed therapy Target Disease Exceptions Known uncontrolled hypersensitivity to the investigational drugs. 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. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 3 months. History of clinically significant haemorrhage in the past 3 months. Radiotherapy to the target lesion within the past 3 months prior to baseline imaging Persistant grade 3 or 4 toxicity from previous chemotherapy and/or radiotherapy, except alopecia. Patients with ongoing ≥ Grade 2 neuropathy are to be excluded. 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). Leptomeningeal disease 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. 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. Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels. Active or chronic hepatitis C and/or B infection 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Nintedanib<br>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<br>* 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<br>|
| Placebo Comparator: B: Placebo<br>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<br>* 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<br>|

What is the study measuring?
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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 |