Phase I/II,Multicenter,Randomized,Double-blind,Placebo-controlled Trial Evaluating the Efficacy and Safety of Nintedanib/Vargatef in Combination With Paclitaxel Chemotherapy for Treatment of Patients With BRAF Wildtype Metastatic Melanoma
Overview
- Phase
- Phase 1
- Intervention
- Nintedanib
- Conditions
- Cutaneous Malignant Melanoma
- Sponsor
- Prof. Dr. med. Dirk Schadendorf
- Enrollment
- 33
- Locations
- 10
- Primary Endpoint
- progression-free survival (PFS)
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
This is a multicenter, randomized, double-blind, placebo-controlled phase I/II trial designed to characterize the safety and estimate the efficacy of nintedanib when combined with paclitaxel chemotherapy compared with paclitaxel chemotherapy alone in patients with BRAF wild type metastatic melanoma not previously treated with taxanes or kinase inhibitors.
Detailed Description
Study Phase I: Run-In-Phase Based on acceptable safety data for nintedanib monotherapy, a rapid dose finding will be conducted in a classical 3+3 design. Predefined dose levels are 150 mg (dose level 1) and 200 mg (dose level 2) nintedanib, twice daily, with weekly paclitaxel 90 mg/m2. Study Phase II Patients with advanced (unresectable Stage III or IV) BRaf V600 wild type melanoma (n=120) will be randomized (1:1) to receive either Nintedanib (150 or 200 mg BID depending on results of phase I) in combination with paclitaxel or Placebo in combination with paclitaxel. Total study duration per patient: approximately 12 months of therapy + Follow up until end of study All patients enrolled in either phase I or phase II will be treated according to the following treatment plan: Week 1 - 24: Chemotherapy with paclitaxel combined with nintedanib/placebo Week 25 - 48: Extended monotherapy with nintedanib/placebo Week 52 (or approximately 4 weeks after last treatment dose): End of Treatment visit Follow up: After end of treatment the survival, disease status and further therapies of each patient will be assessed every 3 months until death, progression of disease or end of study whichever occurs first
Investigators
Prof. Dr. med. Dirk Schadendorf
Prof. Dr. med. Dirk Schadendorf
University Hospital, Essen
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed, (surgically incurable or unresectable) stage III or IV, BRAF V600 wildtype metastatic cutaneous malignant melanoma.
- •Written informed consent
- •A minimum of 1 measurable lesion according to RECIST v1.1 criteria.
- •Adequate hematologic, renal and liver function within 14 days prior to initiation of dosing:
- •Hematologic:
- •Absolute neutrophil count (ANC) ≥1.5 x 109/L
- •Hemoglobin ≥ 9 g/dL (5.6 mmol/L; Subjects may not have had a transfusion within 7 days of screening assessment)
- •Platelets: ≥ 100 x 109/L
- •Total bilirubin: ≤ 1.0 x ULN
- •AST and ALT: ≤ 1.5 x ULN (In the case of liver metastases: 2.5 x ULN)
Exclusion Criteria
- •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.
- •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).
- •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:
- •International normalised ratio (INR) \> 2
- •Prothrombin time (PT) and partial thromboplastin time (PTT): \> 50% of deviation of institutional ULN
- •History of clinically significant haemorrhagic or thromboembolic event in the past 6 months
- •NCI CTCAE (V4.0) grade 3 hemorrhage within 4 weeks of starting the study treatment.
- •History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to randomization.
- •Serious, non-healing wound, ulcer, or bone fracture.
Arms & Interventions
Nintedanib + Paclitaxel
Nintedanib (150 or 200mg BID) for up to 48 weeks combined with paclitaxel 90mg/m2 BSA day 1, 8, 15 q28 days for a maximum of 6 courses
Intervention: Nintedanib
Nintedanib + Paclitaxel
Nintedanib (150 or 200mg BID) for up to 48 weeks combined with paclitaxel 90mg/m2 BSA day 1, 8, 15 q28 days for a maximum of 6 courses
Intervention: Paclitaxel
Nintedanib-Placebo + Paclitaxel
Placebo (150 or 200mg BID) for up to 48 weeks combined with paclitaxel 90mg/m2 BSA day 1, 8, 15 q28 days for a maximum of 6 courses
Intervention: Nintedanib-Placebo
Nintedanib-Placebo + Paclitaxel
Placebo (150 or 200mg BID) for up to 48 weeks combined with paclitaxel 90mg/m2 BSA day 1, 8, 15 q28 days for a maximum of 6 courses
Intervention: Paclitaxel
Outcomes
Primary Outcomes
progression-free survival (PFS)
Time Frame: 12 months after LPI
Time from administration of first study drug to the date of first documented progression or death due to any cause, whichever occurs first
Secondary Outcomes
- Overall survival(12 months after LPI)
- Safety and toxicity (graded according to CTCAE, Version 4.0)(12 months after LPI)
- Quality of Life (EORTC QLQ-C30)(12 months after LPI)