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Phase I Trial of BI 836845 for Various Solid Cancer

Phase 1
Completed
Conditions
Neoplasms
Interventions
Registration Number
NCT01403974
Lead Sponsor
Boehringer Ingelheim
Brief Summary

This study is a phase I, open-label, dose escalation trial to determine the maximum tolerated dose (MTD) or the relevant biological dose (RBD) in the absence if a MTD of a new drug BI 836845 which blocks the insulin-like 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
61
Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type
INTERVENTIONAL
Study Design
SEQUENTIAL
Arm && Interventions
GroupInterventionDescription
Part 1: BI 836845 10 mgBI 836845Patients received 10 milligram (mg) of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 20 mgBI 836845Patients received 20 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 40 mgBI 836845Patients received 40 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 60 mgBI 836845Patients received 60 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 300 mgBI 836845Patients received 300 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 450 mgBI 836845Patients received 450 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 1800 mgBI 836845Patients received 1800 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 90 mgBI 836845Patients received 90 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 135 mgBI 836845Patients received 135 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 200 mgBI 836845Patients received 200 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study
Part 1: BI 836845 600 mgBI 836845Patients received 600 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 800 mgBI 836845Patients received 800 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 1050 mgBI 836845Patients received 1050 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 1: BI 836845 1400 mgBI 836845Patients received 1400 mg of BI 836845 (concentrate for solution for infusion) given intravenously for 1 hour on Day 1, 8 and 15 of each 3-weekly course of treatment until disease progression or undue toxicities in the dose escalation part of the study.
Part 2: Ewing's sarcoma family of tumoursBI 836845Patients with Ewing's sarcoma family of tumours (ESFT) 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.
Part 2: Biopsiable tumoursBI 836845Patients 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.
Primary Outcome Measures
NameTimeMethod
Part 1: Maximum Tolerated Dose (MTD) of BI 836845 During the First Treatment Course of the Dose Escalation Phase.During the first course of treatment, up to 21 days

In the absence of MTD, the relevant biological dose (RBD) of BI 836845 during the first treatment course of the dose escalation phase was reported. The MTD was defined as the highest dose level of BI 836845 at which no more than 1 out of 6 patients experienced a drug related dose limiting toxicity (DLT) during the first course of treatment. Starting dose of 10 milligrams (mg) BI 836845, administered thrice every 3 weeks. Dose levels evaluated were: 10 mg, 20 mg, 40 mg, 60 mg, 90 mg, 135 mg, 200 mg, 300 mg, 450 mg, 600 mg, 800 mg, 1050 mg, 1400 mg and 1800 mg.

The BI 836845 dose which could achieve a plateau in total Insulin-like growth factor 1 (IGF-1) plasma concentrations was considered the RBD.

Part 1: Number of Patients With Dose Limiting Toxicities (DLTs) During the Maximum Tolerated Dose (MTD) Evaluation PeriodDuring the first course of treatment, up to 21 days

Number of participants with DLTs occurring during the first treatment course of the dose escalation part. DLT was defined as drug-related adverse events meeting the criteria summarized below:

* Common terminology criteria for adverse events (CTCAE) grade 4 neutropenia for ≥ 7 days (d)

* Febrile neutropenia with single temperature of \> 38.3°C/ ≥ 38°C more than 1 hour (h)

* Documented infection with high neutrophile count

* CTCAE grade 4 thrombocytopenia/CTCAE grade 3 thrombocytopenia associated with bleeding requiring transfusion

* AST (Aspartate Amino Transferase)/ALT (Alanine Amino Transferase) \> 5x normal

* CTCAE grade 3/4 non-hematologic toxicity

* CTCAE grade ≥2 infusion reaction

* CTCAE grade ≥2 nausea and/or vomiting for ≥7 d

* CTCAE grade ≥3 skin toxicity

* CTCAE grade ≥3 hyperglycemia

* Any electrolyte grade 3 AE

* No recovery from non-DLT CTCAE grade \>2

* Sustained fatigue/asthenia grade 3 for longer than 96 h

* Other event qualified as DLT by the investigator

Secondary Outcome Measures
NameTimeMethod
Objective Tumour Response Based on Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1First treatment administration until the earliest of disease progression, death, last adequate tumor assessment or the start of subsequent anti-cancer therapy. Up to 72 weeks.

Number of patients with the objective response (OR). Objective response was defined as best overall response of complete response (CR) or partial response (PR) (with no confirmation required) based on Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. CR was defined by the disappearance of all target lesions and PR was defined by a decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. The best overall response was recorded since first administration of the trial medication and until the earliest of disease progression, death, last adequate tumor assessment or the start of subsequent anti-cancer therapy.

Duration of Objective ResponseFirst treatment administration until the earliest of disease progression, death, last adequate tumor assessment or the start of subsequent anti-cancer therapy. Up to 72 weeks.

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).

Best Overall Response Based on Response Evaluation Criteria In Solid Tumours (RECIST) Criteria Version 1.1First treatment administration until disease progression or last evaluable assessment in absence of progression; Up to 72 weeks

Number of patients with best overall response. Best overall response represented the best response (complete response - CR, partial response - PR, stable disease -SD, progressive disease - PD) a patient had during their time in the study from first administration of trial medication until the earliest date of progression, or the last evaluable assessment in the absence of progression or the start of subsequent anti-cancer therapy. CR was defined by the disappearance of all target lesions and PR was defined by a decrease of at least 30% in the sum of the diameter of target lesions taking the baseline sum diameters as reference. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

Disease ControlFirst treatment administration until the earliest of disease progression, death, last adequate tumor assessment or the start of subsequent anti-cancer therapy. Up to 72 weeks.

Number of patients with Disease control. Disease control was defined as best overall response of CR, PR or SD \>24 week, with no confirmation required.

Part 2 - Biopsiable Tumours: Progression-free Survival (PFS)First treatment administration until tumour progression or death. Up to 72 weeks

PFS was evaluated only for cohort 2 (Biopsiable tumors) 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. Median duration along with 95% confidence interval is based on Kaplan-Meier method.

Maximum Measured Concentration of the BI 836845 in Plasma (Cmax)Up to 337 hours. Detailed timeframe is in the description.

Maximum measured concentration of the BI 836845 in plasma (Cmax). Geometric mean (gMean) and Geometric coefficient of variation (gCV) is presented for each course. As defined in the CTP, PK data is presented by BI 836845 dose level and was not collected for Course 4 part 2.

For Course 1 of part 1 and part 2, Course 2 part 1 and part 2, Course 3 part 2, Course 4 part 1 the following timeframe applies : At 0.083 hour before and 0.5, 1, 2, 4, 7, 24, 72\*, 168, 169, 336 and 337 hours after infusion. \* applies only to part 1 administration courses. In Course 3 of part 1 the following timeframe applies: At 0.083 hour before and 0.5, 1, 168, 169, 336 and 337 hours after infusion.

Time to Maximum Measured Concentration BI 836845 in Plasma (Tmax)Up to 337 hours. Detailed timeframe is in the description.

Time to maximum measured concentration of the BI 836845 in plasma (tmax). As defined in the CTP, PK data is presented by BI 836845 dose level and was not collected for Course 4 part 2.

For Course 1 of part 1 and part 2, Course 2 part 1 and part 2, Course 3 part 2, Course 4 part 1 the following timeframe applies : At 0.083 hour before and 0.5, 1, 2, 4, 7, 24, 72\*, 168, 169, 336 and 337 hours after infusion. \* applies only to part 1 administration courses. In Course 3 of part 1 the following timeframe applies: At 0.083 hour before and 0.5, 1, 168, 169, 336 and 337 hours after infusion.

Area Under the Plasma Concentration-time Curve of BI 836845 From Time 0 to 168 Hours (AUC 0-168)Up to 337 hours. Detailed timeframe is in the description.

Area under the plasma concentration-time curve from time 0 to 168 hours (AUC 0-168) of the BI 836845. As defined in the CTP, PK data is presented by BI 836845 dose level and was not collected for Course 4 part 2.

For Course 1 of part 1 and part 2, Course 2 part 1 and part 2, Course 3 part 2, Course 4 part 1 the following timeframe applies : At 0.083 hour before and 0.5, 1, 2, 4, 7, 24, 72\*, 168, 169, 336 and 337 hours after infusion. \* applies only to part 1 administration courses. In Course 3 of part 1 the following timeframe applies: At 0.083 hour before and 0.5, 1, 168, 169, 336 and 337 hours after infusion.

In the arm BI 836845 450 mg, data from 3 participants was available (15800, 20400 and 12700); as these 3 subjects represented less than 2/3 of the participants included in this course and this dose group, no descriptive statistics were presented in the Clinical Trial Report. The gMean and gCV values were calculated post hoc for ClinicalTrials.gov disclosure purpose only.

Incidence and Intensity of Adverse Events (AEs) According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)First treatment administration until end of treatment plus residual effect period; Up to 74 weeks

Number 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. The intensity of AEs was defined based on:

* Grade 1 - Mild AE; awareness of sign(s) or symptom(s) which is/are 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.

Trial Locations

Locations (3)

China Medical University Hospital

🇨🇳

Taichung, Taiwan

NCKUH

🇨🇳

Tainan, Taiwan

National Taiwan University Hospital

🇨🇳

Taipei, Taiwan

China Medical University Hospital
🇨🇳Taichung, Taiwan

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