Multiple Myeloma
Conditions
Brief summary
This is an open randomised phase II study evaluating the anti-tumour activity, safety and pharmacology of two dose regimens of IPH2101, a human monoclonal anti-KIR antibody, in patients with multiple myeloma in stable partial response after a first line therapy.
Detailed description
Development of new treatments for diseases such as multiple myeloma is a focus for research. The research being conducted is on treatment called Anti-KIR, which activates the body's own cells to kill tumor cells. This is different from many other treatments where chemicals are given to kill tumor cells.The primary objective of the study is to evaluate the clinical activity of two different dose regimens (0.2 mg/kg, leading to an intermittent saturation of NK receptors and 2mg/kg leading to a sustained saturation of NK receptors) of IPH2101 administered as a single agent in multiple myeloma patients who achieved, after the completion of any first line treatment, including conventional or high dose chemotherapies, a stable partial or very good partial response (PR or VGPR).
Interventions
DRUGIPH2101
One infusion of IPH2101 every 4 weeks
Sponsors
Innate Pharma
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. MM which initially required a systemic therapy and received a first line treatment, conventional doses of chemotherapies or high dose chemotherapy and an autologous transplantation of hematopoietic cells, followed or not by a consolidation treatment. 2. Residual disease considered as evaluable with: * Quantifiable serum M-protein: ≥ 3 g/l, except for spike in the beta globulin area. In this particular case serum M-protein is considered quantifiable if ≥ 10g/l * If serum M-protein is \< 3g/l, measurable involved Free Light Chains ≥ 100 mg/l and an abnormal Free Light chains ratio (\<0.26 or \> 1.65) 3. Responses which are partial (PR and VGPR) and in plateau * Partial response should meet the IMWG uniform response criteria: a ≥ 50% reduction from value of serum M-protein before the first line chemotherapy treatment and a reduction in 24h urinary M-protein by ≥ 90% or to \< 200 mg /24h; * Very good partial response according to the IMWG uniform response criteria with 90% or greater reduction in serum M-protein plus urine M-protein level \< 100 mg/24h; furthermore the M-protein should spike in the gamma globulin area; * Plateau phase is defined by : * For patients with serum M-protein ≥ 3g/l: stable levels of M-protein in serum during at least 2 months checked on at least 3 consecutive samples, with the third evaluation performed within 4 weeks before study entry. Fluctuations of ± 25 % and ± 2 g/l in Serum M-protein levels are allowed. * For Patients with serum M-protein \< 3g/l: stable levels Free Light Chains in serum during at least 2 months checked on at least 3 consecutive samples, with the third evaluation performed within 4 weeks before study entry. Fluctuations of ± 25 % of involved serum Free Light Chain are allowed. 4. ECOG performance status of 0, 1 or 2. 5. Clinical laboratory values at screening: * Calculated creatinine clearance (according to MDRD) \> 50 ml/min * Platelet \> 50 x 109 /l * ANC \> 1 x 109 /l * Bilirubin levels \< 1.5 ULN; ALT and AST \< 2.5 ULN 6. Male or female patient who accepts and is able to use recognised effective contraception (oral contraceptives, IUCD, barrier method of contraception in conjunction with spermicidal jelly) throughout the study. 7. Signed inform consent obtained before any trial-related activities
Exclusion criteria
1. Age \< 18 years old or \> 75 years old 2. Previous consolidation/ maintenance therapy by Imid (thalidomide, lenalidomid) or bortezomib within the last 2 months 3. Treatment with chemotherapy, systemic corticosteroid within the previous 2 months 4. Treatment with growth factors (EPO, G- or GM-CSF) within the previous 1 month 5. Radiotherapy for bone or visceral lesion within the last 3 months 6. Use of any investigational agent within the last 2 months 7. Primary or associated amyloidosis 8. Peripheral neuropathy of grade ≥ III according to the CTCAE of the NCI 9. Abnormal cardiac status with any of the following 1. NYHA stage III or IV congestive heart failure 2. myocardial infarction within the previous 6 months 3. symptomatic cardiac arrhythmia despite treatment 10. Current active infectious disease or positive serology for HIV, HCV or positive Hbs Antigen 11. History of or current auto-immune disease 12. Serious concurrent uncontrolled medical disorder 13. History of other malignancy for less then 5 years (apart from basal cell carcinoma of the skin, or in situ cervix carcinoma) 14. History of allogenic hematopoietic cell or solid organ transplantation 15. Pregnant or lactating women 16. Any medical condition which is regarded by the investigator as incompatible with the study participation 17. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Patients Achieving a Response Based on M-protein or Free Light Chains | From the start of the treatment to the End of Study and during the post study follow up during 2 years according to standard practices | Response was defined: * In patients with a serum M-protein \> 5 g/l, as a reduction of at least 25% (minor response according to European society for Blood and Marrow Transplantation (EBMT)) from baseline of serum M-protein confirmed on two consecutive determinations at 4 weeks interval; * In patients with a serum M-protein ≤ 5 g/l and ≥ 3g/l, as a negative electrophoresis * In patients with serum M-protein \< 3 g/l but a measurable involved serum free light chains ≥ 100 mg/l and an abnormal Free Light Chains ratio (\<0.26 or \> 1.65), as a ≥ 50 % decrease in the difference between involved and uninvolved Free Light Chains levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biological Activity of IPH2101 on Killer Immunogloblin Like Receptors (KIR) Occupancy at End of Treatment | From the start up to the end of study (15 months) | KIR-occupancy is a relative measure of the fraction of cell surface KIR that is occupied by the IPH2101 monoclonal antibody, and hence is unavailable for binding to HLA ligands. |
| Safety Assessment | from screening visit to the End of Study (at each study visit) | Adverse Events, Serious Adverse Events, physical examination and biological changes. |
Countries
France
Participant flow
Recruitment details
Patients were recruited in France at the public hospital (10 actives center), from mid of November 2009 to end of October 2011.
Pre-assignment details
All patients enrolled in the study were analyzed. There was no screen failure during the trial conduct.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: IPH2101 0.2mg/Kg every 4 weeks by intravenous route over 1 hour, for 4 or up to 8 cycles. | 14 |
| Arm B: IPH2101 2mg/kg every 4 weeks by intravenous route over 1 hour, for 4 or up to 8 cycles. | 13 |
| Total | 27 |
Baseline characteristics
| Characteristic | Arm B: IPH2101 2mg/kg | Arm A: IPH2101 0.2mg/Kg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 24 Participants |
| Age, Continuous | 55.9 years STANDARD_DEVIATION 10.2 | 58.6 years STANDARD_DEVIATION 5.6 | 57.3 years STANDARD_DEVIATION 8.1 |
| Region of Enrollment France | 13 participants | 14 participants | 27 participants |
| Sex: Female, Male Female | 6 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Male | 7 Participants | 11 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 14 | 11 / 13 |
| serious Total, serious adverse events | 2 / 14 | 0 / 13 |
Outcome results
Primary
Rate of Patients Achieving a Response Based on M-protein or Free Light Chains
Response was defined: * In patients with a serum M-protein \> 5 g/l, as a reduction of at least 25% (minor response according to European society for Blood and Marrow Transplantation (EBMT)) from baseline of serum M-protein confirmed on two consecutive determinations at 4 weeks interval; * In patients with a serum M-protein ≤ 5 g/l and ≥ 3g/l, as a negative electrophoresis * In patients with serum M-protein \< 3 g/l but a measurable involved serum free light chains ≥ 100 mg/l and an abnormal Free Light Chains ratio (\<0.26 or \> 1.65), as a ≥ 50 % decrease in the difference between involved and uninvolved Free Light Chains levels.
Time frame: From the start of the treatment to the End of Study and during the post study follow up during 2 years according to standard practices
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: IPH2101 0.2mg/Kg | Rate of Patients Achieving a Response Based on M-protein or Free Light Chains | 0 participants |
| Arm B: IPH2101 2mg/kg | Rate of Patients Achieving a Response Based on M-protein or Free Light Chains | 1 participants |
Secondary
Biological Activity of IPH2101 on Killer Immunogloblin Like Receptors (KIR) Occupancy at End of Treatment
KIR-occupancy is a relative measure of the fraction of cell surface KIR that is occupied by the IPH2101 monoclonal antibody, and hence is unavailable for binding to HLA ligands.
Time frame: From the start up to the end of study (15 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: IPH2101 0.2mg/Kg | Biological Activity of IPH2101 on Killer Immunogloblin Like Receptors (KIR) Occupancy at End of Treatment | 80.5 % of occupancy |
| Arm B: IPH2101 2mg/kg | Biological Activity of IPH2101 on Killer Immunogloblin Like Receptors (KIR) Occupancy at End of Treatment | 96.8 % of occupancy |
Secondary
Safety Assessment
Adverse Events, Serious Adverse Events, physical examination and biological changes.
Time frame: from screening visit to the End of Study (at each study visit)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: IPH2101 0.2mg/Kg | Safety Assessment | 14 participants |
| Arm B: IPH2101 2mg/kg | Safety Assessment | 11 participants |