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Dose Escalation Study of Nintedanib (BIBF 1120) in Japanese Patients With Hepatocellular Carcinoma

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ClinicalTrials.gov Identifier: NCT01594125
Recruitment Status : Completed
First Posted : May 8, 2012
Results First Posted : December 22, 2015
Last Update Posted : February 12, 2016
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Tracking Information
First Submitted Date  ICMJE May 2, 2012
First Posted Date  ICMJE May 8, 2012
Results First Submitted Date  ICMJE November 17, 2015
Results First Posted Date  ICMJE December 22, 2015
Last Update Posted Date February 12, 2016
Study Start Date  ICMJE May 2012
Actual Primary Completion Date November 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 11, 2016)
Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Nintedanib [ Time Frame: up to 28 days ]
The MTD is based on the incidence of Dose Limiting Toxicities (DLTs). A drug-related AE was considered as a DLT if one of the following met: CTCAE grade 4 thrombocytopenia of any duration, CTCAE grade 4 neutropenia lasting for ≥8 days, CTCAE grade 4 febrile neutropenia of any duration, CTCAE grade 3 or 4 non-haematologic toxicity (with the following exception: Alopecia, Vomiting, nausea, or diarrhoea with no adequate supportive care, Transient electrolyte abnormality, which resolves spontaneously or can be corrected with appropriate treatment within 3 days, Liver toxicity), Liver enzyme toxicity of AST, ALT, alkaline phosphatase [ALP] elevation >5x ULN, or total bilirubin >3x ULN if baseline liver enzymes are within the normal range, or AST, ALT or ALP > baseline value + 4x ULN if the baseline value is elevated. The MTD was determined to be 200mg bid.
Original Primary Outcome Measures  ICMJE
 (submitted: May 7, 2012)
Determination of Maximum Tolerated Dose (MTD) of Nintedanib [ Time Frame: up to 1 month ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 11, 2016)
  • Number of Participants With Objective Tumour Response According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 [ Time Frame: up to 28 months ]
    Objective response (Complete response (CR) + Partial response (PR), regardless of confirmation) is derived from a patient's best objective response by RECIST. Best objective response is calculated based on the "overall" visit response from each assessment. Best objective response represents the best response a patient has had during their time in the study up until progression, last evaluable assessment in the absence of progression or the start of subsequent anti-cancer therapy. For patients whose progression event is death, best objective response will be calculated based on data up until the last evaluable RECIST assessment prior to death.
  • Progression Free Survival (PFS) [ Time Frame: up to 28 months ]
    PFS is defined as the duration from start date of the study treatment to PD according to RECIST 1.0, or any death whichever occurs earlier.
  • Time to Progression (TTP) [ Time Frame: up to 28 months ]
    TTP is defined as the duration from the start date of the study treatment to PD according to RECIST 1.0.
  • Number of Participants With Response by Alpha Fetoprotein (AFP) [ Time Frame: up to 28 months ]
    Response by AFP is defined as 20% or more decline in AFP between the baseline value and the AFP value after three courses (12 weeks) of therapy. If patients only receive two courses of therapy the AFP value after two courses (8 weeks) will be used for the analysis.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2012)
  • Predose (trough) and maximum measured concentration in plasma at steady state [ Time Frame: up to 2 months ]
  • Terminal rate constant in plasma at steady state [ Time Frame: up to 1 month ]
  • Time from last dosing to the maximum concentration in plasma at steady state [ Time Frame: up to 1 month ]
  • Mean residence time in the body at steady state after administration [ Time Frame: up to 1 month ]
  • Apparent clearance in plasma at steady state [ Time Frame: up to 1 month ]
  • Apparent volume of distribution during the terminal phase at steady state [ Time Frame: up to 1 month ]
  • Amount of drug eliminated in urine at steady state [ Time Frame: up to 1 month ]
  • Terminal half-life in plasma at steady state [ Time Frame: up to 1 month ]
  • Incidence and intensity of adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 [ Time Frame: up to 12 months ]
  • Area under the concentration-time curve in plasma at steady state [ Time Frame: up to 1 month ]
  • Changes of safety laboratory values from baseline [ Time Frame: up to 12 months ]
  • Incidence of hepatitis B virus (HBV) reactivation [ Time Frame: up to 12 months ]
  • Objective Tumour Response According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 [ Time Frame: up to 12 months ]
  • Progression Free Survival (PFS) [ Time Frame: up to 12 months ]
  • Time to Progression (TTP) [ Time Frame: up to 12 months ]
  • Response by Alpha Fetoprotein (AFP) [ Time Frame: up to 12 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dose Escalation Study of Nintedanib (BIBF 1120) in Japanese Patients With Hepatocellular Carcinoma
Official Title  ICMJE An Open Label, Dose Escalation Phase I Study to Evaluate the Safety and Tolerability of Continuous Twice-daily Oral Treatment of Nintedanib in Japanese Patients With Hepatocellular Carcinoma.
Brief Summary The aim of the study is to investigate the safety, tolerability, efficacy and pharmacokinetics (PK) for Japanese hepatocellular carcinoma which are not amenable to curative surgery or loco regional therapy
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Carcinoma, Hepatocellular
Intervention  ICMJE
  • Drug: Nintedanib high dose
    twice daily oral dosing
  • Drug: Nintedanib low dose
    twice daily oral dosing
  • Drug: Nintedanib medium dose
    twice daily oral dosing
Study Arms  ICMJE
  • Experimental: Group I
    patients with mild liver dysfunction according to their AST/ALT values and Child-Pugh score
    Interventions:
    • Drug: Nintedanib high dose
    • Drug: Nintedanib medium dose
  • Experimental: Group II
    patients with moderate liver dysfunction according to their AST/ALT values and Child-Pugh score
    Interventions:
    • Drug: Nintedanib low dose
    • Drug: Nintedanib medium dose
    • Drug: Nintedanib high dose
Publications * Okusaka T, Otsuka T, Ueno H, Mitsunaga S, Sugimoto R, Muro K, Saito I, Tadayasu Y, Inoue K, Loembé AB, Ikeda M. Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment. Cancer Sci. 2016 Dec;107(12):1791-1799. doi: 10.1111/cas.13077. Epub 2016 Dec 12.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 19, 2014)
30
Original Estimated Enrollment  ICMJE
 (submitted: May 7, 2012)
24
Actual Study Completion Date  ICMJE January 2015
Actual Primary Completion Date November 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion criteria:

  1. Histologically/cytologically confirmed hepatocellular carcinoma not amenable to curative surgery or loco-regional therapy
  2. Age 20 years or older
  3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1
  4. Child-Pugh score of 7 or less
  5. Life expectancy more than 3 months
  6. Time interval from last loco-regional therapy more than 4 weeks
  7. Written informed consent in accordance with good clinical practice (GCP)

Exclusion criteria:

  1. More than one line of prior systemic therapy for metastatic/unresectable hepatocellular carcinoma (HCC)
  2. Fibrolamellar HCC
  3. Uncontrolled or refractory ascites
  4. Inadequate organ function
  5. Variceal bleeding within 6 months or the presence of inappropriate varices
  6. History of major thrombotic (except portal vein thrombosis) or clinically relevant major bleeding event in the past 6 months
  7. Major surgery within 4 weeks
  8. Known inherited predisposition to bleeding or thrombosis
  9. Significant cardiovascular diseases
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Japan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01594125
Other Study ID Numbers  ICMJE 1199.120
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Boehringer Ingelheim
Study Sponsor  ICMJE Boehringer Ingelheim
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
PRS Account Boehringer Ingelheim
Verification Date January 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP