| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Advanced (unresectable stage III or IV) BRAF V600 wildtype
cutaneous malignant melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The objectives of this study are to characterize the safety and to
estimate the efficacy of nintedanib when combined with paclitaxel
chemotherapy compared with paclitaxel chemotherapy alone in
patients with BRAF wildtype metastatic melanoma not previously
treated with taxanes or kinase inhibitors.
The primary endpoint of Phase I is the definition of the Maximum Tolerable Dose (MTD) of the nintedanib/paclitaxel combination treatment.
The primary endpoint of Phase II is the progression-free survival (PFS) according to RECIST v1.1.
|
|
| E.2.2 | Secondary objectives of the trial |
Overall survival
• Safety and toxicity (graded according to CTCAE, Version 4.0)
• Quality of Life (EORTC QLQ-C30) during therapy (i.e. until
end of treatment visit)
• Translational research project: identification and evaluation of
prognostic and predictive biomarkers by analysis of tumor
tissue and serum samples |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Translational research project: identification and evaluation of prognostic and predictive
biomarkers by analysis of tumor tissue and serum samples |
|
| E.3 | Principal inclusion criteria |
1. Histologically confirmed, (surgically incurable or unresectable) stage III or IV, BRAF
V600 wildtype metastatic cutaneous malignant melanoma.
2. Written informed consent
3. A minimum of 1 measurable lesion according to RECIST v1.1 criteria.
4. ECOG performance status of 0-1.
5. Adequate hematologic, renal and liver function as defined by laboratory values
performed within 14 days prior to initiation of dosing:
• Hematologic:
o Absolute neutrophil count (ANC) ≥1.5 x 109/L
o Hemoglobin ≥ 9 g/dL (5.6 mmol/L; Subjects may not have had a transfusion
within 7 days of screening assessment)
o Platelets: ≥ 100 x 109/L
• Hepatic
o Total bilirubin: ≤ 1.0 x ULN
o AST and ALT: ≤ 1.5 x ULN (In the case of liver metastases: 2.5 x ULN)
• Renal
o Serum creatinine: ≤ 1.5 mg/dL (133 μmol/L) or, if greater than 1.5 mg/dL:
Calculated creatinine clearance: ≥ 50 mL/min
6. Women of childbearing potential (WOCBP) should be using an effective method of
contraception (Pearl-Index <1) to avoid pregnancy for at least 6 months after completion
of paclitaxel treatment and for at least 3 months after completion of nintedanib/placebo
monotherapy as directed by their physician. Women will be considered to be of
childbearing potential unless surgically sterilised by hysterectomy or bilateral tubal
ligation/salpingectomy, or post-menopausal for at least two years. WOCBP must have a
negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units
of HCG) up to 28 days prior to commencement of dosing.
7. Men should use an effective method of contraception during treatment and for at least 6
months after completion of paclitaxel treatment and for at least 3 months after
completion of nintedanib/placebo monotherapy as directed by their physician.
8. Patients must have recovered from all prior treatment-related toxicities to NCI CTCAE
(v4.0) Grade of 0 or 1, except for toxicities not considered a safety risk such as alopecia.
9. Male or female, aged 18 years or older
10. Life expectancy at least 3 months |
|
| E.4 | Principal exclusion criteria |
1. Prior systemic therapy with taxanes or kinase inhibitors. Any prior therapy for metastatic
disease must have been discontinued at least 4 weeks prior to initiation of dosing.
2. Major surgery or radiation therapy within 4 weeks of starting the study treatment (minor
surgical procedures such as biopsies are allowed, however patients must have
recovered).
3. Known inherited predisposition to bleeding or thrombosis and therapeutic
anticoagulation (except low-dose heparin and/or heparin flush as needed for
maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except for
low-dose therapy with acetylsalicylic acid < 325mg per day)
Patients with the following coagulation parameters will be excluded:
o International normalised ratio (INR) > 2
o Prothrombin time (PT) and partial thromboplastin time (PTT): > 50% of deviation
of institutional ULN
4. History of clinically significant haemorrhagic or thromboembolic event in the past 6
months
5. NCI CTCAE (V4.0) grade 3 hemorrhage within 4 weeks of starting the study treatment.
6. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to randomization.
7. Serious, non-healing wound, ulcer, or bone fracture.
8. Known CNS disease.
9. Previous Grade 2 or higher sensory neuropathy.
10. History of or known spinal cord compression, or carcinomatous meningitis, or evidence
of 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 randomization) or leptomeningeal disease on screening CT or MRI scan.
11. Any of the following within the 6 months prior to enrolment: myocardial infarction,
severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic
congestive heart failure, cerebrovascular accident or transient ischemic attack, or
pulmonary embolism.
12. New York Heart Association (NYHA) Grade II or greater congestive heart failure.
13. Ongoing cardiac dysrhythmias of NCI CTCAE Version 4.0 grade ≥ 2.
14. Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or
diastolic blood pressure > 100 mmHg on antihypertensive medications).
15. Symptomatic peripheral vascular disease.
16. Proteinuria at screening as demonstrated by urine dipstick for proteinuria ≥ 2+ (patients
discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a
24 hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).
17. Known hypersensitivity reaction to any of the components of study treatment (e.g.
contrast media) or other severe acute or chronic medical or psychiatric condition or
laboratory abnormality that may increase the risk associated with study participation or
study drug administration, or may interfere with the interpretation of study results, and in
the judgment of the investigator would make the subject inappropriate for entry into this
study.
18. Previous cancer (unless a RFS interval of at least 5 years) with the exception of
surgically cured carcinoma in-situ of the cervix and basal or squamous cell carcinoma of
the skin.
19. Known clinically uncontrolled infectious disease including HIV positivity or AIDS-related
illness and active or chronic hepatitis C and/or B infection.
20. Pregnancy (absence to be confirmed by ß-hCG test) or lactation period.
21. Psychological, familial, sociological or geographical factors potentially hampering
compliance with the study protocol and follow-up schedule
22. Active alcohol or drug abuse
23. Treatment with other investigational drugs or treatments in another clinical trial within the
past four weeks before start of therapy or concomitantly with this trial.
24. Legal incapacity or limited legal capacity
25. Significant weight loss (> 10% of body weight) within past 6 months prior to inclusion into
the trial |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of Phase I is the definition of the Maximum Tolerable Dose (MTD) of
the nintedanib/paclitaxel combination treatment.
The primary endpoint of Phase II is the progression-free survival (PFS) according to RECIST
v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 month after start of treatment |
|
| E.5.2 | Secondary end point(s) |
- Overall survival
- Safety and toxicity (graded according to CTCAE, Version 4.0)
- Quality of Life (EORTC QLQ-C30) during therapy (i.e. until end of treatment visit)
- Translational research project: identification and evaluation of prognostic and predictive
biomarkers by analysis of tumor tissue and serum samples |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 12 month after start of treatment |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Assessment of tolerable dosis of nintedanib when combined with paclitaxel |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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