Neoplasms
Conditions
Brief summary
This is a Phase I, multi-centre, non-randomized, uncontrolled, open-label, dose escalating study of BI 836880 administered intravenously once a week. The eligible patient population will be patients with advanced solid tumors. The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for BI 836880 in patients with solid tumors. Preliminary safety data will be evaluated as secondary objectives. Subsequently, pharmacokinetic profile, pharmacodynamic changes in circulating biomarkers and Dynamic Contrast-Enhanced Magnetic Resonance Imaging ( DCE-MRI), anti-tumor activity and the immunogenicity of BI 836880 will be explored up to a total of 40 patients with advanced solid tumors. Dose escalation will be guided by a Bayesian logistic regression model with over dose control (EWOC) using at least 2 patients per dose cohorts. Safety criteria will be followed, including adverse events according to Common Terminology Criteria (CTCAE version 4.03), incidence of dose limiting toxicities, physical examination, vital signs, safety laboratory parameters and Eastern Cooperative Oncology Group (ECOG).
Interventions
DRUGBI 836880
Solution for intravenous infusion
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1 Age \>=18 years 2. Histologically confirmed malignancy which is locally advanced or metastatic solid tumor, and either refractory after standard therapy for the disease or for which standard therapy is not reliably effective e.g. patients do not tolerate or have contraindications to otherwise available standard therapy and tumour lesions evaluable for Dynamic contrast-enhanced (DCE)-MRI at MTD. 3\. ECOG performance status \<= 2 4. Adequate hepatic, renal and bone marrow functions as defined by the following criteria: 1. Total bilirubin within normal limits (\<= 1.5x upper limit of normal (ULN) for patient with Gilberts syndrome) 2. Alanine amino transferase (ALT) and aspartate amino transferase (AST) \<= 1.5x ULN (\< 5x upper limit of normal (ULN) for patient known liver metastases) 3. Serum creatinine \< 1.5x ULN 4. International normalized Ratio (INR) 0.8-1.2 or partial thromboplastin time (PTT) \< 1.5x ULN 5. Absolute neutrophil count (ANC) \> 1.5 109/L 6. Platelet count \> 100x109/ L. 7. Haemoglobin \> 10 g/dl (without transfusion within previous week) 5. Signed and dated written informed consent. 6. Life expectancy \>= 3 months in the opinion of the investigator 7. Recovery from all reversible adverse events of previous anti-cancer therapies to baseline or CTCAE grade1, except for alopecia (any grade), sensory peripheral neuropathy CTCAE grade \<= 2 or considered by the investigator as clinically not significant. 8\. Male or female patients. Women of childbearing potential\* must be ready and able to use highly effective methods of birth control per International Conference on Harmonisation \[ICH M3(R2)\] in combination with male condom as double barrier, during the trial and for at least 6 months after the end of treatment with BI 836880, that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. Male patient must always use condoms when sexually active during the trial and for at least 6 months after the end of treatment with BI 836880. \*Women of childbearing potential are defined as: Any female who has experienced menarche and does not meet the criteria for women not of childbearing potential as described below. Women not of childbearing potential are defined as: Women who are postmenopausal (12 months with no menses without an alternative medical cause) or who are permanently sterilized (e.g., hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
Exclusion criteria
1. Known hypersensitivity to the trial drugs or their excipients or risk of allergic of anaphylactic reaction to the study drug according to the investigator judgement (e.g. patient with history of anaphylactic reaction or autoimmune disease that is not controlled by nonsteroidal anti-inflammatory drugs (NSAIDS), inhaled corticosteroids, or the equivalent of \< 10 mg/day prednisone) 2. Current or prior treatment with any systemic anti-cancer therapy either within 28 days or a minimum of 5 half-lives, whichever is shorter at the start of study treatment. 3. Serious concomitant disease (based on investigator judgement), especially those affecting compliance with trial requirements or which are considered relevant for the evaluation of the endpoints of the trial drug, 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 trial drug administration, and in the judgment of the investigator would make the patient inappropriate for entry into the trial. 4. Major injuries and/or surgery (as judged by the investigator) or bone fracture within 4 weeks of start of study treatment, or planned surgical procedures during the trial period. 5. Patients with personal or family history of QT prolongation and/or long QT syndrome, or prolonged QT interval corrected for heart rate according to Fridericia's formula (QTcF) at baseline (\> 470 ms). QTcF will be calculated by Investigator as the mean of the 3 ECGs taken at screening. 6. Significant cardiovascular/ cerebrovascular disease (i.e uncontrolled hypertension, unstable angina, history of infarction within past 6 months, congestive heart failure \> New York heart association ( NYHA II). Uncontrolled hypertension defined as: blood pressure in tested and relaxed condition \>= 140 mmHg, systolic or \> 90 mmHg diastolic (with or without medication), measured according to Section 5.3.2 and Appendix 10.2. 7. History of severe haemorrhagic or thromboembolic event in the past 12 months (excluding central venous catheter thrombosis and peripheral deep vein thrombosis). 8. Known inherited predisposition to bleeding or to thrombosis in the opinion of the investigator. 9. Patient with brain metastases that are symptomatic and/or require therapy. 10. Patients who require full-dose anticoagulation (according to local guidelines). No vitamin K antagonist and other anticoagulation allowed; low-molecular-weight heparin (LMWH) allowed only for prevention not for curative treatment. 11. Use of alcohol or drug incompatible with patient participation in the study in the investigator opinion 12. Patient unable or unwilling to comply with protocol 13. Women who are pregnant, nursing, or who plan to become pregnant while in the trial 14. Previous enrolment in this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | First treatment cycle, 3 weeks from first administration of trial treatment (MTD evaluation period). | Determination of the maximum tolerated dose (MTD) in participants with advanced solid tumors. MTD was defined as the highest dose with less than 25% risk of true DLT rate being above 33% in the MTD evaluation period, and could be considered reached if the probability that the true DLT rate was in the target interval (16% to 33%) was sufficiently large during the MTD evaluation period. The MTD evaluation period was defined as 3 weeks after first administration of treatment. |
| Number of Participants With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | First treatment cycle, 3 weeks from first administration of trial treatment (MTD evaluation period). | The following drug-related adverse events qualified as DLTs: Common Terminology Criteria for Adverse Events (CTCAE) grade 4 neutropenia \>7 days or complicated by infection; grade \>3 febrile neutropenia; grade = 4 thrombocytopenia; grade \> 3 thrombocytopenia with bleeding; grade \> 3 proteinuria \> 3 non haematological toxicity except: Vomiting or diarrhea responding to supporting treatment, fatigue lasting for less than 4 days, transient grade 3 infusion reaction, any laboratory abnormality, which was considered not clinically relevant by the investigator or resolved spontaneously or could be resolved with appropriate treatment. Hypertension: increase of diastolic blood pressure (BP) by 15 mmHg, which could not be controlled by hypertensive medication and requires a dose reduction of BI 836880 for further treatment course. All related AE leading to an interruption of BI 836880 for more than 14 days until recovery to baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Drug-related Adverse Events (AEs) Leading to Dose Reduction or Discontinuation During the Treatment Period | From first trial drug administration until 42 (Residual Effect Period) days after the last trial drug administration, up to 566 days. | Number of Participants with drug-related adverse Events (AEs) leading to dose reduction or discontinuation during the treatment period. |
Countries
France, Spain
Participant flow
Recruitment details
This was an open-label, non-randomised, uncontrolled, dose-escalating trial in patients with advanced solid tumors.
Pre-assignment details
All subjects who were screened for eligibility to participate in the trial signed informed consent. Subject were assigned to the trial drug if the met all the inclusion and none of the exclusion criteria. Abbreviations: AE = Adverse Event.
Participants by arm
| Arm | Count |
|---|---|
| 40 mg BI 836880 40 milligram (mg) solution of BI 836880 was administered as once weekly intravenous infusion in 3 weeks treatment cycles. Participants continued treatment until disease progression or unacceptable toxicity. | 2 |
| 120 mg BI 836880 120 mg solution of BI 836880 was administered as once weekly intravenous infusion in 3 weeks treatment cycles. Participants continued treatment until disease progression or unacceptable toxicity. | 5 |
| 150 mg BI 836880 150 mg solution of BI 836880 was administered as once weekly intravenous infusion in 3 weeks treatment cycles. Participants continued treatment until disease progression or unacceptable toxicity. | 3 |
| 180 mg BI 836880 180 mg solution of BI 836880 was administered as once weekly intravenous infusion in 3 weeks treatment cycles. Participants continued treatment until disease progression or unacceptable toxicity. | 11 |
| 240 mg BI 836880 240 mg solution of BI 836880 was administered as once weekly intravenous infusion in 3 weeks treatment cycles. Participants continued treatment until disease progression or unacceptable toxicity. | 3 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Dose Limiting Toxicity | 0 | 1 | 0 | 0 | 2 |
| Overall Study | Other AE or clinical progression | 0 | 2 | 0 | 2 | 0 |
| Overall Study | Progressive disease | 2 | 2 | 3 | 9 | 1 |
Baseline characteristics
| Characteristic | 40 mg BI 836880 | 120 mg BI 836880 | 150 mg BI 836880 | 180 mg BI 836880 | 240 mg BI 836880 | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 47.0 Years STANDARD_DEVIATION 15.6 | 61.8 Years STANDARD_DEVIATION 9.7 | 56.0 Years STANDARD_DEVIATION 22.1 | 56.0 Years STANDARD_DEVIATION 12.6 | 62.0 Years STANDARD_DEVIATION 4.6 | 57.2 Years STANDARD_DEVIATION 12.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 3 Participants | 2 Participants | 7 Participants | 2 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 1 Participants | 4 Participants | 1 Participants | 10 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants | 7 Participants | 2 Participants | 17 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 1 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 5 | 0 / 3 | 0 / 11 | 0 / 3 | 0 / 24 |
| other Total, other adverse events | 2 / 2 | 5 / 5 | 3 / 3 | 11 / 11 | 3 / 3 | 24 / 24 |
| serious Total, serious adverse events | 1 / 2 | 3 / 5 | 0 / 3 | 6 / 11 | 2 / 3 | 12 / 24 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
Determination of the maximum tolerated dose (MTD) in participants with advanced solid tumors. MTD was defined as the highest dose with less than 25% risk of true DLT rate being above 33% in the MTD evaluation period, and could be considered reached if the probability that the true DLT rate was in the target interval (16% to 33%) was sufficiently large during the MTD evaluation period. The MTD evaluation period was defined as 3 weeks after first administration of treatment.
Time frame: First treatment cycle, 3 weeks from first administration of trial treatment (MTD evaluation period).
Population: Dose-finding cohort treated set: All patients enrolled in dose finding and confirmation of MTD cohort of the trial who were documented to have taken at least 1 dose of trial medication and were evaluable for MTD determination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Total BI 836880 | Maximum Tolerated Dose (MTD) | 180 Milligram (mg) |
Primary
Number of Participants With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period
The following drug-related adverse events qualified as DLTs: Common Terminology Criteria for Adverse Events (CTCAE) grade 4 neutropenia \>7 days or complicated by infection; grade \>3 febrile neutropenia; grade = 4 thrombocytopenia; grade \> 3 thrombocytopenia with bleeding; grade \> 3 proteinuria \> 3 non haematological toxicity except: Vomiting or diarrhea responding to supporting treatment, fatigue lasting for less than 4 days, transient grade 3 infusion reaction, any laboratory abnormality, which was considered not clinically relevant by the investigator or resolved spontaneously or could be resolved with appropriate treatment. Hypertension: increase of diastolic blood pressure (BP) by 15 mmHg, which could not be controlled by hypertensive medication and requires a dose reduction of BI 836880 for further treatment course. All related AE leading to an interruption of BI 836880 for more than 14 days until recovery to baseline.
Time frame: First treatment cycle, 3 weeks from first administration of trial treatment (MTD evaluation period).
Population: Dose finding cohort treated set: All patients enrolled in dose finding and confirmation of MTD cohort of the trial who were documented to have taken at least 1 dose of trial medication and were evaluable for the MTD determination.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Total BI 836880 | Number of Participants With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
| 120 mg BI 836880 | Number of Participants With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 1 Participants |
| 150 mg BI 836880 | Number of Participants With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 0 Participants |
| 180 mg BI 836880 | Number of Participants With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 1 Participants |
| 240 mg BI 836880 | Number of Participants With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 2 Participants |
| Total BI 836880 | Number of Participants With Dose Limiting Toxicities (DLTs) in the Maximum Tolerated Dose (MTD) Evaluation Period | 4 Participants |
Secondary
Number of Participants With Drug-related Adverse Events (AEs) Leading to Dose Reduction or Discontinuation During the Treatment Period
Number of Participants with drug-related adverse Events (AEs) leading to dose reduction or discontinuation during the treatment period.
Time frame: From first trial drug administration until 42 (Residual Effect Period) days after the last trial drug administration, up to 566 days.
Population: Treated Set: The treated set includes all participants enrolled in the Trial who were documented to have taken at least one dose of study medication.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Total BI 836880 | Number of Participants With Drug-related Adverse Events (AEs) Leading to Dose Reduction or Discontinuation During the Treatment Period | 0 Participants |
| 120 mg BI 836880 | Number of Participants With Drug-related Adverse Events (AEs) Leading to Dose Reduction or Discontinuation During the Treatment Period | 3 Participants |
| 150 mg BI 836880 | Number of Participants With Drug-related Adverse Events (AEs) Leading to Dose Reduction or Discontinuation During the Treatment Period | 0 Participants |
| 180 mg BI 836880 | Number of Participants With Drug-related Adverse Events (AEs) Leading to Dose Reduction or Discontinuation During the Treatment Period | 1 Participants |
| 240 mg BI 836880 | Number of Participants With Drug-related Adverse Events (AEs) Leading to Dose Reduction or Discontinuation During the Treatment Period | 2 Participants |
| Total BI 836880 | Number of Participants With Drug-related Adverse Events (AEs) Leading to Dose Reduction or Discontinuation During the Treatment Period | 6 Participants |