Trial to Determine MTD of BI 836845 Administered Intravenously Once Every Three Weeks in Patients With Advanced Solid Tumours and Later a Weekly Dosing Schedule in Selected Tumour Types
- Registration Number
- NCT01317420
- Lead Sponsor
- Boehringer Ingelheim
- Brief Summary
This study is a phase I, open-label, dose escalation trial to determine the maximum tolerated dose (MTD) of a new drug BI 836845 which blocks the insulin growth factor (IGF) pathway believed to be involved in cancer growth. BI 836845 will be administered for the very first time into cancer patients.
The study will also look at the overall safety of the drug, and examine the drug levels in the body at specific timepoints during the trial (pharmacokinetic profile); the effect the drug may have on tumours will also be examined (pharmacodynamics).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 64
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description BI 836845 10 mg BI 836845 Patients received 10 milligram (mg) of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study BI 836845 320 mg BI 836845 Patients received 320 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study BI 836845 640 mg BI 836845 Patients received 640 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study BI 836845 1280 mg BI 836845 Patients received 1280 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study BI 836845 1800 mg BI 836845 Patients received 1800 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study BI 836845 2400 mg BI 836845 Patients received 2400 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study BI 836845 3600 mg BI 836845 Patients received 3600 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study Ewings sarcoma BI 836845 Patients with Ewing's family of tumours (EFT) or primitive neuroectodermal tumour (PNET) receiving relevant biological dose (RBD) of BI 836845 1000 mg, administered in each course of 21 days by a 1-hour infusion at the start of each week in expansion part of the study. Biopsiable tumours BI 836845 Patients with all solid tumour types who had tumours suitable for biopsy receiving relevant biological dose (RBD) of BI 836845 1000 mg, administered in each course of 21 days by a 1-hour infusion at the start of each week in expansion part of the study. BI 836845 20 mg BI 836845 Patients received 20 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study BI 836845 40 mg BI 836845 Patients received 40 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study BI 836845 80 mg BI 836845 Patients received 80 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study BI 836845 160 mg BI 836845 Patients received 160 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study
- Primary Outcome Measures
Name Time Method Maximum Tolerated Dose (MTD) or Relevant Biological Dose (RBD) of BI 836845 During the First Treatment Course of the Dose Escalation Phase During the first course of treatment, up to 21 days To determine the MTD or relevant biological dose (RBD) of BI 836845 during the first treatment course of the dose escalation phase. The MTD was defined as the highest dose level of BI 836845 below the maximum dose administered at which no more than 1 out of 6 patients experienced a drug-related DLT during the first course of treatment. Starting dose of 10 mg BI 836845, administered once every 3 weeks. Dose levels evaluated were: 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, 640 mg, 1280 mg, 1800 mg, 2400 mg, and 3600 mg. In the absence of the MTD, the RBD, where a plateau in total Insulin-like growth factor 1 (IGF-1) level and total neutralisation of IGF activity is predicted, is reported.
Percentage of Patients With Dose Limiting Toxicities (DLTs) During the First Treatment Course of the Dose Escalation Phase During the first course of treatment, up to 21 days DLTs defined as drug related: CTCAE Grade 4 neutropenia lasting ≥7 days; febrile neutropenia and/or documented infection with Absolute Neutrophil Count \<1.0x109/L; Grade 4 thrombocytopaenia or Grade 3 associated with bleeding needing platelet transfusion; Grade ≥3 increased hepatic enzymes; Grade 3 or 4 non-haematologic toxicity with exceptions; Grade ≥2 infusion reaction despite adequate pre-medication; Grade ≥2 nausea and/or vomiting persisting for ≥7 days despite antiemetic treatment; Grade ≥3 skin toxicity despite adequate supportive care measures for up to 2 weeks if it does not reach an improvement to grade ≤2; Grade ≥3 hyperglycaemia resistant to treatment with anti-diabetic agents; any electrolyte grade 3 AE refractory to optimal correction therapy; no recovery from a non-DLT grade \>2 toxicity to grade 1 within 14 days of administered dose; sustained fatigue/asthenia grade 3 for \>96 h associated with deterioration of Performance score (Eastern Cooperative Oncology Group).
- Secondary Outcome Measures
Name Time Method Best Overall Response Based on Response Evaluation Criteria In Solid Tumours (RECIST) Criteria Version 1.1 First treatment administration, up to 246 days. Best overall response (complete response \[CR\], partial response \[PR\], stable disease \[SD\], progressive disease \[PD\]) based on RECIST criteria version 1.1:
CR for target lesions: Disappearance of all target lesions. CR for non-target lesions: Disappearance of all non-target lesions and normalization of tumour marker level. All lymph nodes must be non-pathological in size (\<10 millimeters \[mm\] short axis).
PR: At least a 30% decrease in the sum of diameters (SoD) of target lesions taking as reference the baseline sum diameters.
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as references the smallest SoD while on study.
PD: At least a 20% increase in the sum of the diameters (SoD) of target lesions taking as reference the smallest SoD recorded since the treatment started, together with an absolute increase in the SoD of at least 5 mm; Appearance of 1 or more new lesions; Unequivocal progression of existing non-target lesions.Objective Tumour Response First treatment administration, up to 246 days. Objective response was defined as best overall response of CR or PR (with no confirmation required).
Duration of Objective Response First treatment administration, up to 246 days. Duration of objective response (days), defined as time from first objective response to the time to progression or death and was only calculated for patients with an objective response (with no confirmation required).
Disease Control First treatment administration, up to 246 days. Disease control was defined as best overall response of CR, PR (confirmation was not required for CR or PR) or confirmed SD (i.e. lasting for at least 24 weeks).
Progression-free Survival (PFS) First treatment administration until tumour progression or death, up to 162 days. PFS was evaluated in expansion phase of the study. PFS was defined as the time from first treatment administration until tumour progression according to RECIST 1.1 or death from any cause, whichever occurred earlier.
Maximum Measured Concentration of the Analyte (BI 836845) in Plasma (Cmax) Part 1: 5 minutes before and 0.5, 1, 2, 4, 7, 24, 72, 168 and 336 h after infusion for Course 1. Part 2: 5 minutes before and 1, 2, 4, 7, 24, 168, 169, 336, 337 h after infusion for Course 1, 2 and 3. Maximum measured concentration of the analyte in plasma (Cmax) in the first cycle of treatment (dose escalation phase, part 1) and in the first 3 cycles of treatment (dose expansion phase, part 2).
Area Under the Plasma Concentration-time Curve (AUC) Part 1: 5 minutes before and 0.5, 1, 2, 4, 7, 24, 72, 168 and 336 h after infusion for Course 1. Part 2: 5 minutes before and 1, 2, 4, 7, 24, 168, 169, 336, 337 h after infusion for Course 1, 2 and 3. Area under the plasma concentration-time curve (AUC) of the analyte (BI 836845); AUC(0-504) in part 1 using 3- weekly dosing and AUC(0-168) in part 2 using weekly dosing.
Time to Maximum Measured Concentration of the Analyte (BI 836845) in Plasma (Tmax) Part 1: 5 minutes before and 0.5, 1, 2, 4, 7, 24, 72, 168 and 336 h after infusion for Course 1. Part 2: 5 minutes before and 1, 2, 4, 7, 24, 168, 169, 336, 337 h after infusion for Course 1, 2 and 3. Time to maximum measured concentration of the analyte in plasma (tmax) in the first cycle of treatment (dose escalation phase, part 1) and in the first 3 cycles of treatment (dose expansion phase, part 2).
Incidence and Intensity of Adverse Events (AEs) According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) From first drug administration, until 21 days after last drug administration, up to 253 days. Percentage of patients with adverse events (AEs) according to the grading as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, 14 June 2010 are presented.
When no CTCAE grading was available for a specific event, the intensity of the AE was judged based on the following:
* Grade 1 - Mild AE; awareness of sign(s) or symptom(s) which were easily tolerated.
* Grade 2 - Moderate AE; enough discomfort to cause interference with usual activity.
* Grade 3 - Severe AE; incapacitating or causing inability to work or to perform usual activities.
* Grade 4 - Life-threatening or disabling AE.
* Grade 5 - Death related to AE.
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Trial Locations
- Locations (2)
St James's University Hospital
🇬🇧Leeds, United Kingdom
The Royal Marsden Hospital, Sutton
🇬🇧Sutton, United Kingdom
St James's University Hospital🇬🇧Leeds, United Kingdom