Phase I Dose Escalation of i.v. BI 836909 Monotherapy in Last Line Multiple Myeloma Patients

Study Overview
=================
Brief Summary
-----------------
The primary objective of this trial is to determine the maximum tolerated dose (MTD) of BI 836909 administered by continuous i.v. infusion in patients with relapsed and/or refractory multiple myeloma. If the MTD is not reached based on safety findings, a recommended dose for further development will be determined. This will depend on the safety data, pharmacokinetic/pharmacodynamics data and potentially preliminary efficacy data. Secondary objectives are to document the safety and tolerability of BI 836909, to perform pharmacokinetic and pharmacodynamic analyses and to evaluate relevant biological effects in terms of parameters of efficacy.

Official Title
-----------------
An Open Label, Phase I, Dose Escalation Study to Characterize the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Intravenous Doses of BI 836909 in Relapsed and/or Refractory Multiple Myeloma Patients

Conditions
-----------------
Multiple Myeloma

Intervention / Treatment
-----------------
* Drug: BI 836909


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Patients with a documented diagnosis of relapsed and/or refractory multiple myeloma who progressed after at least two prior treatment regimens, including both proteasome inhibitor as well as an immune-modulatory drug at time of screening must have measurable disease, defined by one or more of following at time of screening: a serum M protein > 0.5 g/dl measured by serum protein electrophoresis urinary M protein excretion > 200 mg/24 hours serum free light chain (FLC) measurement > 10 mg/dl, provided that the serum FLC ratio is abnormal Relapse or progression of disease with an indication for therapy as per investigator´s judgement at time of screening ECOG Performance Status 0, 1 or 2 at time of screening Age >= 18 years at time of screening Written informed consent which is consistent with ICH_GCP guidelines and local legislation Able to adhere to the study visit schedule e.g. ability to come to the clinic and to other protocol requirements Indwelling central venous catheter or willingness to undergo intra venous central line placement. Exclusion criteria: Plasma cell leukemia Extramedullary relapse of multiple myeloma Known central nervous system involvement by multiple myeloma Last anticancer treatment < 2 weeks prior to visit 1 Last treatment with a therapeutic antibody less than 6 weeks prior to visit 1 Prior allogeneic stem cell transplantation or solid organ transplantation Autologous bone marrow transplantation < than 90 days at time of treatment start Last corticosteroid < 2 weeks prior to visit 1 unless the dose is <= 10 mg/day prednisolone or equivalent AST or ALT > 3 x upper limit of normal (CTCAE version 4.03 grade 2 or higher) at time of screening Total conjugated bilirubin > 1.5 x upper limit of normal (CTCAE version 4.03 grade 2 or higher) at time of screening Absolute neutrophil count < 1.0 x 109/L (without growth factor support) at time of screening Platelets < 25 x 109/L (without transfusions) at time of screening Calculated GFR < 30 mL/min (Cockcroft-Gault Formula) at time of screening Clinical relevant concurrent medical disease or condition which according to the investigator's judgement would either compromise patient safety or interfere with the evaluation of the safety of the test drug, e.g. symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia requiring therapy at time of screening clinically not controlled chronic or ongoing infectious disease requiring treatment at the time of enrolment or within the previous two weeks Active hepatitis B or C, or laboratory evidence for a chronic infection with hepatitis B or C at time of screening; HIV infection at time of screening Women of childbearing potential not using highly effective method of birth control during the trial until one year after the last dose. Highly effective methods of birth control are defined as those which result in a low failure rate (i.e. less than 1% per year)when used consistently and correctly used such as implants, injectables, combined oral contraceptives, intrauterine devises (IUDs), sexual abstinence or vasectomised partner. Barrier methods of contraception are accepted if condom or occlusive cap is used together with spermicides (e.g. foam, gel). Female patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy or bilateral tubal ligation/salpingectomy, or postmenopausal (12 months with no menses without an alternative medical cause Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second medically acceptable method of contraception during the trial and for a minimum of 6 months after treatment Pregnancy or breast feeding Known or suspected active alcohol or drug abuse as per investigator's judgement Treatment with another investigational drug within the past four weeks before start of therapy or concomitantly with this trial Patients with known hypersensitivity to any component of the study drug Patients with other malignancies within 5 years at time of screening (except basal cell or squamous cell carcinoma of the skin or carcinoma in situ treated with curative therapy) Known autoimmune diseases requiring systemic treatment in past 5 years and interfering with evaluation of study drug Pre-existing disorders of the central nervous system

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous Infusion of BI 836909 (0.2 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (0.4 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (0.8 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (1.6 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (3.2 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (6.5 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (13 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (25 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (50 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (100 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (200 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (400 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|
| Experimental: Intravenous Infusion of BI 836909 (800 μg/d)<br> | Drug: BI 836909<br>* Intravenous Infusion of BI 836909.<br>* Other names: AMG 420;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Tolerated Dose (MTD) of BI 836909 | The Maximum tolerated dose (MTD) of BI 836909, which was defined as the highest dose of the dose level tested where ≤1 patient out of 6 developed a Dose-limiting toxicity (DLT). The MTD was defined based on DLTs observed during Cycle 1. However, all Adverse Events corresponding to the definition of a DLT (see below) were to be considered for confirming the MTD. A DLT was defined as any drug-related non-haematological Adverse Event of Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade 3 or higher. | Cycle 1, up to 6 weeks. | 
| The Number of Patients With Dose-limiting Toxicities (DLTs) | The number of patients with Dose-limiting toxicities (DLTs) in cycle 1. A Dose-limiting toxicity was defined as any drug-related non-haematological Adverse Event of Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade 3 or higher. | Cycle 1, up to 6 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Objective Response | Objective responses: Stringent complete response (sCR): CR + normal Free light chain (FLC) ratio and no clonal cells in bone marrow by immunohistochemistry or immunofluorescence. CR: negative immunofixation on serum and urine, disappearance of soft tissue plasmacytomas, and <5% plasma cells in bone marrow. Very good partial response (VGPR): serum and urine M protein detectable by immunofixation but not on electrophoresis or >90% reduction in serum M protein plus urine M protein level <100 mg/24h. PR: >50% reduction of serum and 24 h urinary M protein by >90% or to <200mg/24h. If unmeasurable, a >50% decrease in difference between involved and uninvolved FLC levels instead of M protein criteria. if FLC assay was not measurable, a >50% reduction in plasma cells was required instead of M protein, provided baseline bone marrow plasma cell was >30%. In addition to the listed criteria, a >50% reduction in the size of soft tissue plasmacytomas was also required, if present at baseline. | On-treatment: From start of treatment till end of trial (EOT) visit, up to 61 weeks. Extended follow-up: From start of treatment till the last extended follow-up visit which was scheduled at 12 months after end of treatment, up to 113 weeks. | 
| Duration of Objective Response - on Treatment | For patients with objective response, the duration of response was calculated from the time of first recorded achievement of a response (sCR, CR, PR, or VGPR) until documented progression or death. The Kaplan-Meier method was used to calculate the estimates. | From start of treatment till end of trial (EOT) visit, up to 61 weeks. | 
| Duration of Objective Response - Including Extended Follow up Visits | For patients with objective response, the duration of response was calculated from the time of first recorded achievement of a response (sCR, CR, PR, or VGPR) until documented progression or death. The Kaplan-Meier method was used to calculate the estimates. | From start of treatment till the last extended follow-up visit which is scheduled at 12 months after end of treatment, up to 113 weeks. | 
| Number of Participants With a Minimal Residual Disease (MRD) Response | Minimal residual disease (MRD) response was defined as <1 tumour cell within 10000 normal cells in bone marrow. MRD was determined using Fluorescence-activated cell sorting (FACS) analysis. | On-treatment: From start of treatment till end of trial (EOT) visit, up to 61 weeks. Follow-up: From start of treatment till the last extended follow-up visit which was scheduled at 12 months after end of treatment, up to 113 weeks. | 
| Duration of Minimal Residual Disease (MRD) Response - on Treatment | Duration of MRD response was calculated from the time of first recorded achievement of a MRD response to documented progression or death. The Kaplan-Meier method was used to calculate the estimates. | From start of treatment till end of trial (EOT) visit, up to 61 weeks. | 
| Duration of Minimal Residual Disease (MRD) Response - Including Extended Follow up Visits | Duration of MRD response was calculated from the time of first recorded achievement of a MRD response to documented progression or death. The Kaplan-Meier method was used to calculate the estimates. | From start of treatment till the last extended follow-up visit which was scheduled at 12 months after end of treatment, up to 113 weeks. | 
| Progression-free Survival (PFS) - on Treatment | PFS was defined as time from first treatment with BI 836909 till disease progression or death. Progression was defined according to International Myeloma Working Group (IMWG 2006) response criteria as an increase >25% from lowest response value in any of the following parameters: -Serum M protein (absolute increase had to be >0.5 gram/ deciliters (dL)) -Urine M protein (absolute increase had to be >200 milligram (mg)/24 hour) -Only in patients without measurable serum and urine M protein levels The difference between involved and uninvolved FLC levels. Absolute increase had to be >10 mg/dL -Bone marrow plasma cell percentage; absolute percentage had to be >10% -Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas -Development of hypercalcaemia (corrected serum calcium >11.5 mg/dL or 2.65 Millimole/Liter) that was attributed solely to the plasma cell proliferative disorder. | From start of treatment till end of trial (EOT) visit, up to 61 weeks. | 
| Progression-free Survival (PFS) - Including Extended Follow up Visits | PFS was defined as time from first treatment with BI 836909 till disease progression or death. Progression was defined according to International Myeloma Working Group (IMWG 2006) response criteria as an increase >25% from lowest response value in any of the following parameters: -Serum M protein (absolute increase had to be >0.5 gram/ deciliters (dL)) -Urine M protein (absolute increase had to be >200 milligram (mg)/24 hour) -Only in patients without measurable serum and urine M protein levels The difference between involved and uninvolved FLC levels. Absolute increase had to be >10 mg/dL -Bone marrow plasma cell percentage; absolute percentage had to be >10% -Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing bone lesions or soft tissue plasmacytomas -Development of hypercalcaemia (corrected serum calcium >11.5 mg/dL or 2.65 Millimole/Liter) that was attributed solely to the plasma cell proliferative disorder | From start of treatment till the last extended follow-up visit which was scheduled at 12 months after end of treatment, up to 113 weeks. | 
| Serum Concentration at Steady State of BI 836909 (Css) | Serum concentration at steady state of BI 836909 (Css). | Pharmacokinetic samples were collected at 48:00 hours (h):minutes (min), 168:00, 336:00, 504:00 and 671:50 h after the start of infusion of BI 836909 of the first cycle. |