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

A Phase I Dose Escalation Trial of BI 836845 Administered Intravenously Once Every Three Weeks in Patients With Advanced Solid Tumours During Escalation and Weekly in Selected Tumour Types During Expansion, With Repeated Administrations in Patients Showing Clinical Benefit

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).

Study Overview

• Status: Completed
• Conditions: Neoplasms
• Intervention / Treatment: Drug: BI 836845

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Leeds, United Kingdom, LS9 7TF
    • St James's University Hospital
  • Sutton, United Kingdom, SM2 5PT
    • The Royal Marsden Hospital, Sutton

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Male or female patients with cytologically or histologically confirmed solid tumours that are refractory to standard therapy or that have no standard therapy.
2. Patients should have evaluable disease, or at least one measurable lesion according to Response Evaluation Criteria In Solid Tumours (RECIST) criteria version 1.1
3. Age, equal, or more than, 18 years old.
4. Life expectancy of at least 3 months.
5. Written informed consent that is consistent with ICH-GCP guidelines.
6. Eastern Cooperative Oncology Group (ECOG) performance score 0, 1 or 2.
7. Patients must have recovered from any previous surgery and no major surgery within the last 28 days prior to start of trial medication.
8. Cardiac left ventricular function with resting ejection fraction >50% as determined by Echocardiography (ECHO) or Multiple Gated Acquisition scan (MUGA).
9. Absolute neutrophil count equal, or more than, 1,500/µl.
10. Platelets equal, or more than, 100,000/µl.
11. Total bilirubin equal, or less than 1.5 x institution upper limit of normal.
12. Aspartate Amino Transferase (AST) (Serum glutamic oxaloacetic transaminase (SGOT)) / Alanine Amino Transferase (ALT) (Serum glutamic pyruvic transaminase (SGPT )) equal, or less than, 2.5 x upper limit of normal (in case of known liver metastases AST and/or ALT, equal, or less than, 5 x upper limit of normal).
13. Creatinine equal, or less than, 1.5 x institution upper limit of normal.
14. Haemoglobin equal, or more than, 9g/dL.
15. Haemoglobin A1c less than 8% and fasting glucose, equal, or less than, 8.9 mmol/L (= 160 mg/dL).
16. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) for the duration of trial participation. Female patients with reproductive potential must have a negative serum pregnancy test within 7 days of trial enrolment.
17. Patients entering part II of the study should have cytologically or histologically confirmed disease from the Ewing's family of tumours/PNET (cohort 1), or solid tumours suitable for biopsy (cohort 2), that are refractory to standard therapy or that have no standard therapy.
18. Patients eligible to undergo biopsy should have normal coagulation parameters (INR and PTT within normal ranges) and platelet count (equal, or more than, 100,000/µl) prior to biopsy tissue collection.

Exclusion criteria:

1. Active infectious disease.
2. Serious illness or concomitant non-oncological disease considered by the investigator to be incompatible with the protocol.
3. History of thrombosis within 1 year of study or if concurrent anticoagulation required.
4. Patients not recovered from any therapy-related toxicities from previous chemo-, hormone-, immuno-, molecular targeted, or radiotherapies to at least Common Terminology Criteria for Adverse Events (CTCAE) equal, or less than, Grade 1. Prior chemotherapy is allowed if completed at least 4 weeks prior to first trial treatment (6 weeks for mitomycin C or nitrosoureas) and the patient has recovered from the acute toxicities of that therapy.
5. Patients with untreated or symptomatic brain metastases. Patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least 4 weeks before starting trial medication, no history of cerebral oedema or bleeding in the past 4 weeks before starting trial medication and must be on a stable or reducing dose of dexamethasone. Anti-epileptic therapy will be allowed if the patient is stable on antiepileptic treatment for 4 weeks, or more, without adjustments before starting trial medication.
6. Patients who have been treated with any of the following within 4 weeks of starting trial medication: chemotherapy, immunotherapy, radiotherapy, biological therapies (including trastuzumab), molecular targeted, hormone therapy for breast cancer within 2 weeks of starting trial medication (excluding Luteinizing-hormone-releasing hormone (LHRH) agonists in prostate cancer, or bisphosphonates), or treatment with other investigational drugs.
7. Use of any investigational drug within 4 weeks before start of therapy or concomitantly with this trial.
8. Patients unable to comply with the protocol.
9. Active alcohol abuse or active drug abuse (at the discretion of the investigator).
10. Patients with unstable arrhythmias or unstable angina or severe obstructive pulmonary disease within the last year.
11. For patients entering part II of the study, prior use of any insulin growth factor (IGF) inhibitor.
12. Patients with a history of diabetes mellitus.
13. Pregnancy or breast feeding.
14. Patients that are to undergo biopsy should not have a history of a hereditary bleeding disorder as judged by the investigator.
15. Patients that are to undergo biopsy should pause acetylsalicylic acid treatment for at least 7 days prior to biopsy tissue collection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 836845 10 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: BI 836845 20 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: BI 836845 40 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: BI 836845 80 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: BI 836845 160 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: BI 836845 320 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: BI 836845 640 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: BI 836845 1280 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: BI 836845 1800 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: BI 836845 2400 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: BI 836845 3600 mg; 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	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: Ewings sarcoma; 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.	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab
Experimental: Biopsiable tumours; 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.	Drug: BI 836845; Intravenous infusion; Other Names: Xentuzumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD) or Relevant Biological Dose (RBD) of BI 836845 During the First Treatment Course of the Dose Escalation Phase	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.	During the first course of treatment, up to 21 days
Percentage of Patients With Dose Limiting Toxicities (DLTs) During the First Treatment Course of the Dose Escalation Phase	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).	During the first course of treatment, up to 21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response Based on Response Evaluation Criteria In Solid Tumours (RECIST) Criteria Version 1.1	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.	First treatment administration, up to 246 days.
Objective Tumour Response	Objective response was defined as best overall response of CR or PR (with no confirmation required).	First treatment administration, up to 246 days.
Duration of Objective Response	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).	First treatment administration, up to 246 days.
Disease Control	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).	First treatment administration, up to 246 days.
Progression-free Survival (PFS)	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.	First treatment administration until tumour progression or death, up to 162 days.
Maximum Measured Concentration of the Analyte (BI 836845) in Plasma (Cmax)	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).	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)	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.	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 (BI 836845) in Plasma (Tmax)	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).	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.
Incidence and Intensity of Adverse Events (AEs) According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)	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.	From first drug administration, until 21 days after last drug administration, up to 253 days.

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Investigators: Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Publications and helpful links

General Publications

• de Bono J, Lin CC, Chen LT, Corral J, Michalarea V, Rihawi K, Ong M, Lee JH, Hsu CH, Yang JC, Shiah HS, Yen CJ, Anthoney A, Jove M, Buschke S, Fuertig R, Schmid U, Goeldner RG, Strelkowa N, Huang DC, Bogenrieder T, Twelves C, Cheng AL. Two first-in-human studies of xentuzumab, a humanised insulin-like growth factor (IGF)-neutralising antibody, in patients with advanced solid tumours. Br J Cancer. 2020 Apr;122(9):1324-1332. doi: 10.1038/s41416-020-0774-1. Epub 2020 Mar 12.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2011
• Primary Completion (Actual): February 15, 2016
• Study Completion (Actual): February 15, 2016

Study Registration Dates

• First Submitted: March 15, 2011
• First Submitted That Met QC Criteria: March 16, 2011
• First Posted (Estimated): March 17, 2011

Study Record Updates

• Last Update Posted (Actual): July 11, 2025
• Last Update Submitted That Met QC Criteria: June 23, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Other Study ID Numbers: 1280.2; 2010-021714-29 (EudraCT Number: EudraCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents. Exceptions might apply, e.g. studies in products where Boehringer Ingelheim is not the license holder; studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; studies conducted in a single center or targeting rare diseases (in case of low number of patients and therefore limitations with anonymization).

For more details refer to:

https://www.mystudywindow.com/msw/datatransparency