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Efficacy and Safety of Nintedanib Combined With Paclitaxel Chemotherapy for Patients With BRAF wt Metastatic Melanoma (NIPAWILMA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02308553
Recruitment Status : Completed
First Posted : December 4, 2014
Last Update Posted : October 14, 2020
Sponsor:
Collaborators:
Boehringer Ingelheim
medac GmbH
Alcedis GmbH
Information provided by (Responsible Party):
Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen

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.

Condition or disease Intervention/treatment Phase
Cutaneous Malignant Melanoma Drug: Nintedanib Drug: Nintedanib-Placebo Drug: Paclitaxel Phase 1 Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 33 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 17, 2015
Actual Primary Completion Date : October 17, 2019
Actual Study Completion Date : November 2019


Arm Intervention/treatment
Experimental: 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
Drug: Nintedanib
Nintedanib (150 mg or 200 mg BID)
Other Name: Vargatef

Drug: Paclitaxel
Paclitaxel as 90mg/mw infusion day 1, 8, 15 q28 (6 cycles)
Other Name: Taxomedac

Placebo Comparator: 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
Drug: Nintedanib-Placebo
Placebo (150 mg or 200 mg BID)

Drug: Paclitaxel
Paclitaxel as 90mg/mw infusion day 1, 8, 15 q28 (6 cycles)
Other Name: Taxomedac




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. Overall survival [ Time Frame: 12 months after LPI ]
    Time from the date of first administration of study drug to the date of death due to any cause.

  2. Safety and toxicity (graded according to CTCAE, Version 4.0) [ Time Frame: 12 months after LPI ]
    Reporting of adverse events from the date of first administration of study drug until 30 days after last administration of study drug

  3. Quality of Life (EORTC QLQ-C30) [ Time Frame: 12 months after LPI ]
    Quality of life during therapy (i.e. until end of treatment visit)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 of 0-1.
  5. 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
    • Hepatic

      • Total bilirubin: ≤ 1.0 x ULN
      • 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. effective method of contraception for at least 3 months after completion of nintedanib/placebo monotherapy as directed by their physician.
  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

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:

    • International normalised ratio (INR) > 2
    • 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:

    • Previous Grade 2 or higher sensory neuropathy.
    • 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.
  9. 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.
  10. New York Heart Association (NYHA) Grade II or greater congestive heart failure.
  11. Ongoing cardiac dysrhythmias of NCI CTCAE Version 4.0 grade ≥ 2.
  12. Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications).
  13. Symptomatic peripheral vascular disease.
  14. 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).
  15. 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.
  16. 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.
  17. Known clinically uncontrolled infectious disease including HIV positivity or AIDS-related illness and active or chronic hepatitis C and/or B infection.
  18. Pregnancy (absence to be confirmed by ß-hCG test) or lactation period.
  19. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule
  20. Active alcohol or drug abuse
  21. 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.
  22. Legal incapacity or limited legal capacity
  23. Significant weight loss (> 10% of body weight) within past 6 months prior to inclusion into the trial

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02308553


Locations
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Germany
University Hospital Essen
Essen, NRW, Germany, 45147
Elbeklinikum Buxtehude
Buxtehude, Germany, 21614
SRH Wald-Klinikum Gera
Gera, Germany, 07548
National Centre for Tumour Diseases (NCT)
Heidelberg, Germany, 69120
Universitätsklinikum des Saarlandes
Homburg, Germany, 66421
Klinikum der Stadt Ludwigshafen am Rhein gGmbH
Ludwigshafen, Germany, 67063
Universitätsklinikum Schleswig-Holstein, Campus Lübeck
Lübeck, Germany, 23538
University Hospital München
München, Germany, 80337
University Hospital Münster
Münster, Germany, 48149
Fachklinik Hornheide
Münster, Germany, 48157
Sponsors and Collaborators
Prof. Dr. med. Dirk Schadendorf
Boehringer Ingelheim
medac GmbH
Alcedis GmbH
Investigators
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Principal Investigator: Dirk Schadendorf, Prof. Dr. University Hospital, Essen
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Responsible Party: Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen
ClinicalTrials.gov Identifier: NCT02308553    
Other Study ID Numbers: Nipawilma_2013
First Posted: December 4, 2014    Key Record Dates
Last Update Posted: October 14, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen:
BRAF V600 wildtype
cutaneous malignant melanoma
nintedanib
paclitaxel
kinase inhibitor
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Paclitaxel
Nintedanib
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors