BIBF 1120 + Docetaxel (Japan) in Patients With Advanced Non-small-cell Lung Cancer, Phase I

Study Overview
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Brief Summary
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To confirm the safety of BIBF 1120 at a dose level up to 200 mg x 2/day (i.e., overseas recommended Phase III dose for combination treatment) with standard therapy of docetaxel (60 mg/m2 and 75 mg/m2) in Japanese advanced non small cell lung cancer (NSCLC) patients with stage IIIB/IV or recurrent after failure of first line chemotherapy and to determine the recommended dose for the Phase II trial.

Official Title
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A Phase I Study of Continuous, Concomitant Oral Treatment With BIBF 1120 and Docetaxel - a Phase I, Open-label, Dose-escalation Study in Japanese Patients With Stage IIIB/IV or Recurrent Non-small-cell Lung Cancer After Failure of Chemotherapy

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: BIBF 1120 M + docetaxel M
* Drug: BIBF 1120 M + docetaxel H
* Drug: BIBF 1120 H + docetaxel H
* Drug: BIBF 1120 L + docetaxel M
* Drug: BIBF 1120 H + docetaxel M


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically/cytologically confirmed, locally advanced/metastatic NSCLC of stage IIIB/IV or recurrent NSCLC (all histologies. Existence or nonexistence of measurable lesion according to RECIST is no object.) Patients with one prior chemotherapy regimen including platinum-containing drug. In case of recurrent disease, one additional prior regimen is allowed for adjuvant and/or neoadjuvant therapy. However monotherapy of EGFR-TKI (i.e. erlotinib/Tarceva® and gefitinib/Iressa®) is not counted as 'one regimen'. Male or female patients age >=20 years and =<74 years at the enrolment. Life expectancy of at least three (3) months after the start of administration of the investigational drug. Eastern Cooperative Oncology Group (ECOG) [R01-0787] performance Score 0 or 1. Patients retaining a significant physiological compensatory function and patients with sufficient baseline organ function as follows: Haemoglobin count more than 9.0g/dL Absolute neutrophil count more than 1500/mm3 Platelet count more than 100 000/mm3 Serum creatinine less than or equal to1.5x upper limit of normal range at the investigator site Aspartate aminotransferase (AST) and / or alanine aminotransferase (ALT) less than or equal to 1.5x upper limit of normal range at the investigator site (It is the same if patients have liver metastases) PaO2 or SpO2 more than 60torr or 92% Written informed consent that is consistent with ICH-GCP guidelines. Exclusion criteria: Patients who have received chemotherapy (including other investigational drug), hormonal therapy and immune therapy =<4 weeks prior to registration or who have not recovered from side effects of such therapy. Patients who have received radiotherapy =<4 weeks (limited field (e.g brain or bone metastasis) radiation =<2 weeks) prior to registration. Patients who have active brain metastases. (Patients who have no symptoms and is not needed to receive therapy in the registration may participate in this trial) Patients with active double cancer. (Patients who have skin cancer that is not malignant melanoma and carcinoma in situ of uterine cervix may participate in this trial) Patients with distinct / suspected pulmonary fibrosis or interstitial lung disease by the chest radiographic findings, or patients with a previous history of. History of clinically significant haemoptysis within the past 3 months (more than one tea spoon of fresh blood per day) Therapeutic anticoagulation (except low dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device) or antiplatelet therapy (except for chronic low-dose therapy with acetylsalicylic acid =<325 mg per day) History of major thrombotic or clinically relevant major bleeding event in the past 6 months prior to registration. Known inherited predisposition to bleeding or thrombosis. Significant cardiovascular diseases. (i.e. hypertension not controlled by medical therapy, unstable angina, history of myocardial infarction within the past 6 months, congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion) Significant weight loss (> 10 %) within the past 6 weeks prior to registration in the this trial Current peripheral neuropathy >= CTCAE grade 2 except due to trauma. Accumulation of coelomic fluid (e.g. pleural effusion, ascites fluid, cardiac effusion) requiring treatment Major injuries and/or surgery within the past 10 days prior to registration with incomplete wound healing. Serious infections requiring systemic antibiotic (e.g antiviral, antimicrobial, antifungal) therapy. Decompensated diabetes mellitus or other contraindication to high dose corticosteroid therapy. Gastrointestinal disorders or abnormalities (e.g Crohn's disease, Colitis ulcerosa and extensive gastrectomy) that would interfere with absorption of the study drug. Patients with difficulty in swallowing study medication Patients with positive HBs antigen, HCV antibody, or HIV antibody test Serious illness or concomitant non-oncological disease such as neurologic-, psychiatric-, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with trial participation or investigational drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the trial. Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) during the trial and for at least 12 months after end of active therapy Female patients who are pregnant, breast feeding and may become pregnant. Patients who have or is suspected of having active alcohol or drug abuse. Patient with clinically meaningful drug hypersensitivities. Patients with auto immune disease. Patients unable to comply with the protocol. Other patients judged ineligible for enrolment in the study by the investigator.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBF 1120 + docetaxel<br>Low, medium and high dose of BIBF 1120 and 60 mg/m2, 75 mg/m2 docetaxel every 3 weeks | Drug: BIBF 1120 M + docetaxel M<br>* BIBF 1120 Medium dose bid + docetaxel 60 mg/m2<br>Drug: BIBF 1120 M + docetaxel H<br>* BIBF 1120 Medium dose bid + docetaxel 75mg/m2<br>Drug: BIBF 1120 H + docetaxel H<br>* BIBF 1120 HIgh dose bid + docetaxel 75 mg/m2<br>Drug: BIBF 1120 L + docetaxel M<br>* BIBF 1120 Low dose bid + docetaxel 60 mg/m2<br>Drug: BIBF 1120 H + docetaxel M<br>* BIBF 1120 HIgh dose bid + docetaxel 60 mg/m2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Dose Limited Toxicity in Combination Therapy of Nintedanib and Docetaxel | Number of participants experienced Dose Limited Toxicity (DLT) in combination therapy of nintedanib and docetaxel. Maximum tolerated dose (MTD) of nintedanib combination with docetaxel were to be determined separately in the patient groups of body surface area (BSA) <1.5 m2 and BSA ≥1.5 m2. The MTD were to be determined as a combination of a dose equal to or less than 200 mg b.i.d. of nintedanib and 60 mg/m2 and 75 mg/m2 every 3 weeks of docetaxel at which either 0 out of 3, 1 out of 6, or 2 out of 6 patients experienced DLT. | During the first treatment course, up to 3 weeks | 
| Adverse Events According to Common Terminology Criteria for Adverse Events (CTCAE), Version 3.0 for All Courses | Number of participants with adverse events according to Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 for all courses. The CTCAE grades are: 1 (mild AE), 2 (moderate AE), 3 (severe AE), 4 (life-threatening or disabling AE), 5 (death related to AE). | Between the first administration of docetaxel and 28 days after last administration of docetaxel and/or nintedanib, up to 1367 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Tumor Response | Number of participants with objective response defined as complete response (CR) or partial response (PR) according to the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0 | Pre-treatment, every 6 weeks from treatment course 3, end of treatment (up to 1367 days) | 
| Disease Control | Number of participants with disease control, defined as complete response (CR) or partial response (PR) or stable disease (SD) according to the Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 | Pre-treatment, every 6 weeks from treatment course 3, end of treatment (up to 1367 days) | 
| Progression-Free Survival (PFS) | For participants with known date of progression or death (of any cause): PFS [days] = earlier of date of progression or death - date the study treatment started + 1. For participants known to be alive without progression by the end of trial or follow-up visit: PFS (censored) [days] = date of last imaging when the participant is known to be progression-free and alive - date the study treatment started + 1. Progression is assessed according to RECIST version 1.0. | Pre-treatment, every 6 weeks from treatment course 3, end of treatment (up to 1367 days) | 
| Time to Treatment Failure (TTF) | For participants with known date of discontinuation of the study treatment (or progression [not necessarily confirmed by tumour imaging; can also be based on any clinical sign of tumour progression] or death): TTF [days] = earlier of date of discontinuation of the study treatment, progression, or death - date the study treatment started + 1. For participants known to be alive without progression by the end of trial or follow-up visit: TTF (censored) [days] = date when the patient is known to be progression-free and alive - date the study treatment started + 1. Progression is assessed according to RECIST version 1.0. | Pre-treatment, every 6 weeks from treatment course 3, end of treatment (up to 1367 days) | 
| Clinical Relevant Abnormalities in Laboratory Parameters | Number of participants with clinically relevant abnormalities in laboratory parameters reported as adverse events | Between the first administration of docetaxel and 28 days after last administration of docetaxel and/or nintedanib, up to 1367 days | 
| AUC0-inf of Nintedanib in Course 1 | AUC0-inf (area under the plasma concentration-time curve over the time interval from 0 extrapolated to infinity) after the first administration of nintedanib in course 1 | -0:05 hours (h) before drug administration and 1h, 2h, 3h, 4h, 6h, 7h, 10h and 23:55h after drug administration in course 1 | 
| Cmax of Nintedanib in Course 1 | Cmax (maximum measured plasma concentration) after the first administration of nintedanib in course 1 | -0:05h before drug administration and 1h, 2h, 3h, 4h, 6h, 7h, 10h and 23:55h after drug administration in course 1 | 
| AUC0-inf of Docetaxel in Course 1 | AUC0-inf (area under the plasma concentration-time curve over the time interval from 0 extrapolated to infinity) after the first administration of docetaxel in course 1 | -0:05h before drug administration and 1h, 1.5h, 2h, 3h, 4h, 7h, 23:55h and 47:55h after drug administration | 
| Cmax of Docetaxel in Course 1 | Cmax (maximum measured plasma concentration) after the first administration of docetaxel in course 1 | -0:05h before drug administration and 1h, 1.5h, 2h, 3h, 4h, 7h, 23:55h and 47:55h after drug administration | 
| AUC0-inf of Docetaxel in Course 2 | AUC0-inf (area under the plasma concentration-time curve over the time interval from 0 extrapolated to infinity) after the first administration of docetaxel in course 2. Docetaxel 50 mg/m2 patients were assigned to Docetaxel 60 mg/m2 in Cycle 1, but the dose was reduced to 50 mg/m2 in Cycle 2 as defined in the Clinical Trial Protocol. | -0:05h before drug administration and 1h, 1.5h, 2h, 3h, 4h, 7h, 23:55h and 47:55h after drug administration | 
| Cmax of Docetaxel in Course 2 | Cmax (maximum measured plasma concentration) after the first administration of docetaxel in course 2. Docetaxel 50 mg/m2 patients were assigned to Docetaxel 60 mg/m2 in Cycle 1, but the dose was reduced to 50 mg/m2 in Cycle 2 as defined in the Clinical Trial Protocol. | -0:05h before drug administration and 1h, 1.5h, 2h, 3h, 4h, 7h, 23:55h and 47:55h after drug administration |