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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02514239
Recruitment Status : Completed
First Posted : August 3, 2015
Results First Posted : July 22, 2021
Last Update Posted : February 24, 2022
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Description
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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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: BI 836909 Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 43 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 8, 2015
Actual Primary Completion Date : July 17, 2018
Actual Study Completion Date : July 2, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Multiple Myeloma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Intravenous Infusion of BI 836909 (0.2 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (0.4 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (0.8 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (1.6 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (3.2 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (6.5 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (13 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (25 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (50 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (100 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (200 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (400 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420
Experimental: Intravenous Infusion of BI 836909 (800 μg/d) Drug: BI 836909
Intravenous Infusion of BI 836909.
Other Name: AMG 420


Outcome Measures
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Primary Outcome Measures :
  1. The Maximum Tolerated Dose (MTD) of BI 836909 [ Time Frame: Cycle 1, up to 6 weeks. ]
    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.

  2. The Number of Patients With Dose-limiting Toxicities (DLTs) [ Time Frame: Cycle 1, up to 6 weeks. ]
    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.


Secondary Outcome Measures :
  1. Number of Participants With an Objective Response [ Time Frame: 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. ]
    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.

  2. Duration of Objective Response - on Treatment [ Time Frame: From start of treatment till end of trial (EOT) visit, up to 61 weeks. ]
    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.

  3. Duration of Objective Response - Including Extended Follow up Visits [ Time Frame: 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. ]
    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.

  4. Number of Participants With a Minimal Residual Disease (MRD) Response [ Time Frame: 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. ]
    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.

  5. Duration of Minimal Residual Disease (MRD) Response - on Treatment [ Time Frame: From start of treatment till end of trial (EOT) visit, up to 61 weeks. ]
    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.

  6. Duration of Minimal Residual Disease (MRD) Response - Including Extended Follow up Visits [ Time Frame: 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 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.

  7. Progression-free Survival (PFS) - on Treatment [ Time Frame: From start of treatment till end of trial (EOT) visit, up to 61 weeks. ]
    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.

  8. Progression-free Survival (PFS) - Including Extended Follow up Visits [ Time Frame: 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. ]
    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

  9. Serum Concentration at Steady State of BI 836909 (Css) [ Time Frame: 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. ]
    Serum concentration at steady state of BI 836909 (Css).


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02514239


Locations
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France
HOP Claude Huriez
Lille, France, 59037
HOP Hôtel-Dieu
Nantes, France, 44000
INS Universitaire du Cancer
Toulouse, France, 31059
Germany
Universitätsklinikum Ulm
Ulm, Germany, 89081
Universitätsklinikum Würzburg
Würzburg, Germany, 97080
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
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Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:
Study Protocol  [PDF] November 26, 2018
Statistical Analysis Plan  [PDF] September 7, 2018

More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02514239    
Other Study ID Numbers: 1351.1
2014-004896-22 ( EudraCT Number )
First Posted: August 3, 2015    Key Record Dates
Results First Posted: July 22, 2021
Last Update Posted: February 24, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
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
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
 Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases