Study of Tecemotide (L-BLP25) in Subjects With Slowly Progressive Multiple Myeloma With no Symptoms and Who Have Had no Chemotherapy

Study Overview
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Brief Summary
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Tecemotide (L-BLP25) is believed to induce a Mucinous glycoprotein 1 (MUC1)-specific T-cell response after vaccination. The primary purpose of this study is to ascertain whether vaccination with tecemotide (L-BLP25) induces a MUC1-specific T-cell response in slowly progressive or chemotherapy naive multiple myeloma subjects.

Official Title
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A Randomized, Open-label, Phase II Study With Stimuvax® (L-BLP25 or BLP25 Liposome Vaccine) in Subjects With Either Chemotherapy-naïve, Slowly Progressive, Asymptomatic Multiple Myeloma or With Stage II/III Multiple Myeloma in Stable Response/Plateau Phase Following Anti-tumor Therapy

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: Tecemotide (L-BLP25)
* Biological: Tecemotide (L-BLP25)
* Drug: Single low dose cyclophosphamide
* Drug: Multiple low dose cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented previously untreated, Mucinous glycoprotein 1 (MUC1)-expressing, slowly progressive asymptomatic multiple myeloma with an increasing M-protein concentration displayed on two occasions separated by an interval of at least 4 weeks within the last 18 months, or Documented MUC1-expressing stage II or III multiple myeloma with a treatment-free interval of at least 3 months following prior anti-tumor therapy, and fulfilling criteria for having a stable response/plateau phase Signed written informed consent MUC1-expressing myeloma cells in the bone marrow Greater than or equal to (>=) 18 years of age Life expectancy of at least 6 months Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to (<=) 1 at study entry Effective contraception for both male and female subjects, if the possibility of conception exists A platelet count >=100 x 10^9/Liter, white blood cells >=2.5 x 10^9/Liter, and hemoglobin >=90 gram per liter (g/L) Total bilirubin <= 1.5 x upper reference range Aspartate aminotransferase (AST) <= 2.5 x upper reference range Serum creatinine <= 2 x upper reference Exclusion Criteria: Pre-Therapies: Previous exposure to MUC1 targeting therapy Radiotherapy or any investigational drug in the 30 days before the start of treatment in this study Receipt of immunotherapy (Example: interferons, tumor necrosis factor [TNF], interleukins, or biological response modifiers [granulocyte macrophage colony stimulating factor {GM-CSF}, granulocyte colony stimulating factor {G-CSF}, macrophage-colony stimulating factor {M-CSF}], monoclonal antibodies) within 4 weeks (28 days) prior to randomization Any preexisting medical condition requiring chronic oral or intravenous steroid or immunosuppressive therapy except for maintenance doses of prednisone of <=10 milligram per day (mg/day) Medical Conditions: Autoimmune disease that in the opinion of the investigator could compromise the safety of the subject in this study Hereditary or congenital immunodeficiencies Known hypersensitivity reaction to any of the components of study treatments Clinically significant cardiac disease, Example: New York Heart Association (NYHA) classes III-IV; unstable angina, uncontrolled arrhythmia or uncontrolled hypertension, myocardial infarction in the previous 6 months Other previous malignancies within 5 years, with exception of a history of a previous basal cell carcinoma of the skin, carcinoma in situ of uterine cervix, gastrointestinal intramucosal carcinoma Known Hepatitis B and/or C Splenectomy Standard Safety: Known alcohol or drug abuse Medical or psychological conditions that would not permit the subject to complete the study or sign informed consent Significant disease which, in the investigator's opinion, would exclude the subject from the study Pregnant or breast-feeding women, women of childbearing potential, unless using effective contraception as determined by the investigator. Subjects whom the investigator considers may be at risk of pregnancy will have a pregnancy test performed per institutional standard Participation in another clinical study within the past 30 days Legal incapacity or limited legal capacity Concurrent treatment with a non-permitted drug Any other reason that, in the opinion of the investigator, precludes the subject from participating in the study

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tecemotide (L-BLP25) plus single low dose cyclophosphamide<br> | Biological: Tecemotide (L-BLP25)<br>* After receiving single low dose of cyclophosphamide, subjects will receive 8 consecutive weekly subcutaneous vaccinations with 806 microgram (mcg) of tecemotide (L-BLP25) at Weeks 1, 2, 3, 4, 5, 6, 7 and 8 followed by maintenance vaccinations (806 mcg of tecemotide (L-BLP25) at 6-Week intervals, commencing at Week 14, until disease progression requiring anti-tumor therapy is documented.<br>* Other names: Stimuvax;Drug: Single low dose cyclophosphamide<br>* An intravenous (IV) infusion of 300 milligram per square meter (mg/m^2) (to a maximum 600 mg) of cyclophosphamide will be given 3 days before the first vaccine treatment.<br>|
| Experimental: Tecemotide (L-BLP25) plus multiple low dose cyclophosphamide<br> | Biological: Tecemotide (L-BLP25)<br>* After receiving multiple low dose of cyclophosphamide, subjects will receive 8 consecutive weekly subcutaneous vaccinations with 806 mcg of tecemotide (L-BLP25) at Weeks 1, 2, 3, 4, 5, 6, 7 and 8 followed by maintenance vaccinations (806 mcg of tecemotide (L-BLP25) at 6-Week intervals, commencing at Week 14, until disease progression requiring anti-tumor therapy is documented.<br>* Other names: Stimuvax;Drug: Multiple low dose cyclophosphamide<br>* An IV infusion of 300 mg/m^2 (to a maximum 600 mg) of cyclophosphamide will be given 3 days before the first vaccine treatment plus an intravenous dose of cyclophosphamide (300 mg/m^2, to a maximum of 600 mg) 3 days prior to the tecemotide (LBLP25) administration at week 5 of the weekly treatment phase and 3 days prior to every tecemotide (L-BLP25) administration during the treatment phase with 6-Weekly administration of tecemotide (L-BLP25), commencing at Week 14 up to a maximum treatment period of 2 years.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Induced Mucinous Glycoprotein-1 (MUC-1)-Specific Immune Response | The overall immune response was achieved at least for 2 timepoints; that is at least 1 parameter in at least 1 assay (Lymphoproliferation assay, enzyme-linked immunospot (ELISPOT) for interferon [IFN] gamma, and intracellular IFN gamma cytokine assay in peripheral blood mononuclear cell [PBMC]) with ratio to background >=2, and ratio of background-corrected value to baseline >=2;Specific immune response at a given timepoint 't' was considered as differences of log-scale values under stimulation (X vax,t ) to those of the respective unstimulated controls (Xneg,t, background values)were computed after certain assay-specific pre-processing steps: Yt = Xvax,t - Xneg,t; A participant was considered to show positive stimulation-induced immune response at timepoint 't' (POS[t]=1), upon fulfilling the following criteria: Yt =>1 (That is at least a 2-fold higher value under stimulation than without stimulation). AVvax,t-1SEM vax,t > AVneg,t+1SEMneg,t (ELISPOT and proliferation assay only). | From the date of randomization up to Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Baseline Immune Response and Initial Increase of MUC1 Specific Immune Response | Baseline immune response towards MUC1 was defined as an immune response towards BP25, MUC-A2 or MUC-A11 peptide stimulation which was present in at least one of the two baseline assessments; the specific immune responses at baseline were based on the averaged baseline values across the two baseline visits. Initial increase of MUC1-specific immune response was defined as an increase of MUC1-specific immune response during the primary treatment period (up to Week 9). | Baseline and Week 9 | 
| Number of Participants With Overall Induced Immune Response by Human Leukocyte-associated Antigen (HLA) Type | Relationship between immune response with HLA subtypes was determined by analyzing the number of participants with overall induced immune response grouped by the presence versus absence of the given HLA type. | From the date of randomization up to Week 104 | 
| Percentage of Participants With Objective Clinical Response (Complete Response [CR], or Partial Response [PR], or Minimal Response [MR] | OCR (CR, or PR, or MR or NC or PD or NE) was defined per Blade Criteria. OCR rate (CR, or PR, or MR) was defined as the number of participants having experienced at least once a CR, PR, or MR, divided by the number of all participants. CR: negative immunofixation on serum and urine monoclonal paraprotein (M-protein), disappearance of any soft tissue plasmacytomas (STP), <=5% plasma cells in bone marrow (BM); PR: >=50% reduction in serum M-protein, plasma cells in BM, size of STP; >=90% reduction of urinary M-protein in 24 hours, no increase in size/number of the lytic bone lesions (LBL). MR: 25%-49% reduction in serum M-protein, plasma cells in BM aspirate in non-secretory myeloma participants, size of STP; 50%-89% reduction in 24 h urinary light chain reaction (LCR), and no increase in size/number of LBL. PD: >25% increase in the serum M-protein level, 24 hour urinary LCR. Increase in size of existing BL or STP, development of new BL or STP, or development of hypercalcemia | From the date of randomization up to Month 48 | 
| Time to Progression (TTP) | Progression was defined as follows per Blade criteria: The disease was considered to be progressive if it met 1 or more of the following: >25% increase in the level of serum monoclonal paraprotein (M-protein);>25% increase in the 24 h urinary light chain excretion; >25% increase in plasma cells in the bone marrow- definite increase in the size of existing bone lesions or soft tissues plasmacytomas (STP); Development of new bone lesions or STP, or development of hypercalcemia. TTP was defined as time from randomization to disease progression. Participants without events were censored on the date of last tumor assessment. Participants without PD at time of treatment discontinuation were censored at the date of discontinuation. Participants without PD at the time of the analysis but still on treatment were censored at the date of the latest available multiple myeloma status assessment. Participants dying from causes other than PD were treated as censored observations at time of death. | From the date of randomization up to Month 48 | 
| Time to Anti-tumor Therapy | Time from date of randomization to the date of first anti-tumor therapy since end of study treatment. In case a concomitant or concurrent procedure was identified as anti-tumor therapy during the medical review process, the start date of that anti-tumor therapy was used instead. Participants in the survival follow-up phase without subsequent anti-tumor therapy at the time of the analysis were censored at the latest available follow-up date. Participants without anti-tumor therapy and still on treatment at the time of analysis were censored at the data cut-off date if any trial treatment administration was recorded after the data cut-off date. In case no such record exists, the subject was censored at the last available administration date prior or equal to the data cut-off date. Participants dying before start of subsequent anti-tumor therapy were treated as censored observations at time of death. | From the date of randomization up to Month 48 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs),Serious TEAEs, TEAEs of Grade 3 or 4 According to NCI-CTCAE v3.0, TEAEs Leading to Discontinuation and Injection Site Reactions (ISRs) | TEAEs occurred between the first dose of study drug administration and up to 42 days after the last dose of study drug administration that were absent before treatment or that worsened relative to pretreatment state. A Serious TEAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.Grade 3 and 4 TEAES as per National Cancer Institute Common Terminology Criteria for Adverse Experience version 3 (NCI-CTCAE v3.0) were presented. Grade 3 refers to severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care and Activity of daily living (ADL).Grade 4 refers to Life-threatening consequences; where urgent intervention indicated. Injection site reactions, term used per NCI-CTCAE, were also presented. | From the first dose of study drug administration up to 42 days after the last dose of study drug administration or clinical data cut-off date (07 March 2012) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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L-BLP25 liposome, Multiple myeloma