Safety and Dose Determining Multi-dose Study of BT062 in Patients With Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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This Phase I/IIa clinical study is to test safety and anti-tumor activity of BT062 to define the best dose in treating patients with relapsed or refractory multiple myeloma with multiple doses of BT062.

Detailed Description
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Phase I/IIa, open-label, 3 + 3 multi-dose escalation study. The Phase I part of the study was to include the dose escalation cohort; a conventional dose escalation design, following 3 + 3 rules was chosen to define the MTD. The Phase IIa part was to include the MTD/recommended phase II dose (RPTD) expansion cohort in which descriptive statistical methods for evaluation of response, time to event endpoints, and safety were to be performed. 35 subjects in the Safety population, 34 subjects in the ITT and PP populations.

Official Title
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A Phase I/IIa Multi-Dose Escalation Study to Evaluate Maximum Tolerated Dose (MTD), Pharmacokinetics (PK), Safety and Efficacy of BT062 in Subjects With Relapsed or Relapsed/Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: BT062


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of active multiple myeloma according to the International Myeloma Working Group diagnostic criteria Relapsed or relapsed/refractory multiple myeloma Previous treatment with both an immunomodulator and a proteosome inhibitor therapy Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) performance status (Zubrod) ≤ 2 Ability to understand and willingness to sign a written informed consent document Ability to adhere with the study visit schedule and other protocol procedures Life expectancy of ≥ 12 weeks Normal organ and marrow function Exclusion Criteria: Chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) prior to day 1 or those who have not recovered from AEs due to agents administered more than 3 weeks earlier Treatment with another investigational agent during the study or within 4 weeks before day 1 Major surgery within 4 weeks before day 1 (this does not include placement of vascular access device or tumor biopsies) Antineoplastic therapy with biological agents within 2 weeks before day 1 Known HAHAs, HACAs, or HAMAs in response to previous MAb therapy Previous treatment with BT062 Malignancy within 3 years before day 1, other than the trial indication multiple myeloma and excluding treated non-melanoma skin cancer, superficial bladder cancer and carcinoma in-situ of the cervix Severe diseases of skin, colon, esophagus, or eye within 1 year before day 1, as judged by the Investigator Severe infections necessitating use of antibiotics / antivirals during the screening period Clinically relevant active infection including active hepatitis B or C or human immunodeficiency virus (HBV, HCV, or HIV) or any other concurrent disease which, in the judgment of the investigator, would make the subject inappropriate for enrollment into this study Acute or relevant abnormalities in electrocardiogram (ECG), as judged by the Investigator. These abnormalities can be defined as recent myocardial infarction, uncontrolled cardiac arrhythmias and/or pronounced disturbances of the electrical conduction system of the heart. Significant cardiac disease such as recent myocardial infarction (≤ 6 months prior to day 1), unstable angina, uncontrolled congestive heart failure, uncontrolled hypertension (recurrent or persistent increases in systolic blood pressure ≥ 180 mm Hg or diastolic blood pressure ≥ 110 mm Hg), uncontrolled cardiac arrhythmias, grade 3 (Lown Criteria) or greater cardiac toxicity from prior chemotherapy History of clinically significant drug or alcohol abuse Unwillingness or inability to adhere to the requirements of the study Concomitant therapy with corticosteroids (except as indicated in low dose for other medical conditions such as inhaled steroid for asthma, topical use, or as premedication for administration of certain medications (including BT062) or blood products and for treatment of infusion reactions if needed) Concomitant antineoplastic therapies including chemotherapy, radiotherapy, or biological agents during the study Any condition, including laboratory abnormalities, that in the opinion of the Investigator places the subject at unacceptable risk if he or she are included in the study Breast-feeding Unwillingness to use an effective contraceptive method during the study and at least 3 months after administration of study drug - unless subject is naturally infertile. (Acceptable contraceptive methods include oral or injectable contraceptives, intrauterine devices (IUD), double-barrier method, contraceptive patch, surgical sterilization, or condoms). Positive serum or urine pregnancy test

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BT062<br>BT062 was to be administered as single-dose IV infusions via a 0.22 μm in-line filter preferably in a forearm vein, according to medically accepted procedures on Days 1, 8, and 15 of each 28-day cycle. Alternatively BT062 may have been administered through a central venous line or a peripherally inserted central catheter (PICC). Other administration routes were only to be allowed after approval from Biotest. Each subject was to be monitored carefully for the effects of exposure to BT062. No subject was to have received more than 3 doses of BT062 per 28-day treatment cycle. | Drug: BT062<br>* intravenous administration<br>* Other names: Indatuximab ravtansine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLT) - Number of Participants With at Least 1 DLT | The primary safety variable was to determine the incidence of DLTs in subjects with relapsed or relapsed/refractory multiple myeloma treated with BT062. | Starting with first study drug administration until 30-day follow-up visit (average 4.99 months) | 
| Maximum Tolerated Dose (MTD) | The Phase I part of the study was to include the dose escalation cohort; a conventional dose escalation design, following 3 + 3 rules was chosen to define the MTD. Only DLTs occurring in cycle 1 for each subject were counted in the dose escalation decisions. Three subjects were treated at the first or newest dose level as available. If none of the 3 subjects experienced a DLT during Cycle 1, three subjects could be treated at the next dose level as available. In case of a DLT the cohort was expanded to up to 6 subjects. If not more than 1 of these 6 subjects experienced a DLT during Cycle 1, a first subject could be treated at the next dose level. If 2 or more of the 6 subjects experienced a DLT during Cycle 1 the dose escalation was stopped. The highest dose level at which < 2 of 6 subjects experienced a DLT is defined as the MTD. | First 28-day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Qualitative and Quantitative Toxicities of BT062 | Qualitative and quantitative toxicities assessed by incidence of adverse events and by clinically significant changes in the patient's physical examination, vital signs, and clinical laboratory results. The incidence of treatment emergent adverse events (TEAEs), including serious adverse events (SAEs). | Starting with first study drug administration until 30-day follow-up visit (average 4.99 months) | 
| Multi-dose Pharmacokinetics Properties of BT062 - Cmax | Multi-dose Pharmacokinetics properties of BT062 after intravenous (IV) Administration of escalating doses of BT062 as assessed by measuring intact BT062 conjugate. Please note that not all subjects reached Cycle 4 due to early termination . A lower number of samples could be analyzed for Cycle 4. | Starting with first study drug administration until 30-day follow-up visit (average 4.99 months). | 
| Anti-tumor Activity of BT062 in Subjects With Relapsed or Relapsed/Refractory Multiple Myeloma by Number of Participants With Objective Response(ORR) and/or Clinial Benefit(CBR) Based on the International Myeloma Working Group Uniform Response Criteria | sCR:CR+normal FLC+absence of clonal cells in BM; CR:Negative immunofixation,disappearance of soft tissue plasmacytomas +≤5% plasma cells in BM+normal FLC; VGPR:M-protein detectable by immunofixation,not on electrophoresis or 90% or greater reduction in serum M-protein+urine M-protein level <100mg per 24h,>90% decrease in the difference between involved/uninvolved FLC; PR:≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h or ≥50% decrease in the difference between involved/uninvolved FLC or ≥50% reduction in plasma cells, provided baseline bone marrow plasma cell percentage was ≥30%, ≥50% size reduction of soft tissue plasmacytomas; MR:25%-49% reduction of serum M-protein+reduction in 24h urinary M-protein by 50-89%(still >200 mg/24h),25-49% soft tissue plasmacytomas size reduction,no increase in size or number of lytic bone lesions; SD:no response or PD ORR: %of subjects with MR+PR+VGPR+CR+sCR CBR:ORR + %of subjects with SD. | On day 1 of each treatment cycle (on a monthly basis) starting with first study drug administration until Close Out visit (average 3.84 months). | 
| Time to Progression (TTP), Progression Free Survival (PFS) and Overall Survival (OS) | Progressive disease Requires any one or more of the following: Increase of ≥ 25% from baseline in Serum M-component and/or (the absolute increase must be ≥ 0.5 g/dL) (increases of ≥ 1 g/dL are sufficient to define relapse if starting M-component is ≥ 5 g/dL). Urine M-component and/or (the absolute increase must be ≥ 200mg/24h). Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL. Bone marrow plasma cell percentage: the absolute % must be ≥ 10% (relapse form CR as a 5% cutoff instead of 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 hypercalcemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder. | Starting with first study drug administration until death or 3 years from first study treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple myeloma, Relapsed, Refractory