Multiple Myeloma
Conditions
Keywords
multiple myeloma, Anti-KIR (1-7F9)
Brief summary
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 (1-7F9), 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 purpose of the study is to determine a safe dose of Anti-KIR (1-7F9) to administer in humans and to gain information about its effectiveness in the treatment of multiple myeloma.
Detailed description
Trial Design: The trial is an open-label, dose-escalation trial to determine the safety and tolerability of Anti-KIR (1-7F9) in subjects with relapsed or refractory multiple myeloma (RRMM). A 3+3 design will be employed for the first dosing cycle at each dose level. The 7 planned dose levels are 0.0003 mg/kg, 0.003 mg/kg, 0.015 mg/kg, 0.075 mg/kg, 0.3 mg/kg, 1.0 mg/kg and 3.0 mg/kg. The subjects will receive up to a total of 4 administrations of Anti-KIR (1-7F9) with a dosing interval between each administration of 4 weeks. Safety, toxicity, PK (pharmacokinetic) and PD (pharmacodynamic) obtained in the first 4 weeks after dosing per group will be the basis for dose-escalation decisions. There will be follow-up visits every week the one month after the first administration and every two weeks following the second, third and fourth administrations. After the last administration there will be follow-up visits every month until KIR occupancy is no longer detected.
Interventions
DRUGAnti-KIR (1-7F9)
human monoclonal antibody
Sponsors
Innate Pharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject.) 2. Bone marrow plasmacytosis \> 10% (as determined by bone marrow aspirate) or plasmacytoma 3. Relapse or progression after at least one prior systemic treatment regimen for Multiple Myeloma (MM) as evidenced by ≥ 25% increase in the M-protein as compared to the best response from the previous treatment regimen. 3a. One prior therapy for multiple myeloma, Measurable disease, as defined by persistent presence of serum and/or urine monoclonal protein or abnormal serum free light chain ratio following the prior treatment. a. Only for the last seven patients enrolled into the cohort 7 or Maximal Tolerated Dose (MTD). 4\. Full recovery from acute toxicities of prior anti-MM therapies. 5. Peripheral blood (Natural Killer) NK cells (Absolute CD16, 56)≥ 0.05 x 109/L (50/mm3) 6. Detectable binding of Anti-KIR (1-7F9) to subject NK cells 7. Age ≥ 18 years 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0,1 or 2 9. Clinical laboratory values at screening: * serum creatinine \< grade 2 toxicity i.e. 1.5x upper limit of institutional normal value * total bilirubin \< 1.5x upper limit of institutional normal value * Aspartate aminotransferase (AST) \< or = 3x upper limit of institutional normal value * Absolute Neutrophil Count (ANC) \>1.2 x109/L * Platelets \>70x109/L
Exclusion criteria
1. Known or suspected allergy to trial product or related products 2. Previous participation in this trial (dosed) 3. Females of childbearing potential who are pregnant, breast-feeding or intend to become pregnant or are not using adequate contraceptive methods (appropriate methods include abstinence and the following methods: diaphragm, condom (by the partner), intrauterine device, sponge, spermicide or oral contraceptives) 4. Male subjects who are sexually active and have not been surgically sterilized must be informed that they must either use a condom during intercourse, ensure that their partners practices contraception, or they must refrain from sexual intercourse during the study and until 1 month after completion of the trial. 5. Use of an investigational agent within 30 days of the first dose of study drug (or five half-lives of any antibody). 6. Current treatment with any other anti-MM therapy excluding prophylactic bisphosphonates. 7. Radiotherapy against bone lesions within 4 weeks or visceral lesions within 8 weeks of Screening. 8. Thalidomide or bortezomib treatment within 14 days of Screening. 9. Cytotoxic chemotherapy (excluding thalidomide or bortezomib) or corticosteroid treatment within 28 days of Screening. 10. Subjects with non-secretory multiple myeloma 11. Subjects on dialysis 12. Use of myeloid growth factor within 28 days of screening 13. G-CSF treatment within 28 days of screening 14. Active autoimmune disease 15. Active infectious disease (e.g. HIV, chronic hepatitis, etc.) as judged by the investigator. 16. New York Heart Association (NYHA) class III-IV heart failure 17. Severe neurological / psychiatric disorder as judged by the investigator 18. Clinical evidence of an active second malignancy, with the exception of basal cell carcinoma or in situ carcinoma of cervix. 19. Subjects with a history of allogenic transplantation. 20. Subject who have undergone autologous transplantation within the last 3 months. 21. Mental incapacity or inadequate understanding of English. 22. Any serious medical condition that in the opinion of the investigator, disqualifies the subject for inclusion in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of IPH2101 as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to IPH2101 Treatment | From start of the treatment to end of study | The maximum tolerated dose (MTD) is the highest dose level below the maximum administered dose (MAD) where none or 1 out of 6 subjects have a DLT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of IPH2101 After Cycle 1 Administration | Anti-KIR (1-7F9) concentrations were measured prior to infusion at 0.167, 1, 3, 6, 12 and 24 hours and then on Days 7, 14 and 21 after the start of the first dose administration | Cmax was obtained from the plasma concentration versus time data after IV administration of IPH2101. |
| Area Under the Plasma-concentration-time Curve [AUC (INF)] of IPH2101 After Cycle 1 Administration | Anti-KIR (1-7F9) concentrations were measured prior to infusion at 0.167, 1, 3, 6, 12 and 24 hours and then on Days 7, 14 and 21 after the start of the first dose administration | AUC(INF), area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration within the dosing interval was calculated for Cycle 1. |
| Number of Evaluable Patients With Stable Disease. Evaluable is Defined as 2 Consecutive M Protein Assessments | From start of the treatment to end of study or disease progression | Disease Response Assessment by Principal Investigator and Sponsor(Efficacy Population).Stable Disease was defined as not meeting criteria for complete response, very good partial response, partial response, or progressive disease |
Countries
United States
Participant flow
Recruitment details
32 subjects were enrolled and 21 subjects were screen failures
Participants by arm
| Arm | Count |
|---|---|
| 0.0003 mg/kg | 4 |
| 0.003 mg/kg | 3 |
| 0.015 mg/kg | 3 |
| 0.075 mg/kg | 6 |
| 0.3 mg/kg | 3 |
| 1 mg/kg | 3 |
| 3 mg/kg | 10 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | protocol withdrawal criteria | 3 | 3 | 3 | 6 | 3 | 3 | 9 |
Baseline characteristics
| Characteristic | 0.003 mg/kg | 0.015 mg/kg | 0.075 mg/kg | 0.3 mg/kg | 0.0003 mg/kg | 1 mg/kg | 3 mg/kg | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 3 Participants | 2 Participants | 1 Participants | 1 Participants | 3 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 7 Participants | 21 Participants |
| Age, Continuous | 49.7 years STANDARD_DEVIATION 2.52 | 66 years STANDARD_DEVIATION 11.53 | 64 years STANDARD_DEVIATION 5.51 | 62.7 years STANDARD_DEVIATION 11.02 | 62.3 years STANDARD_DEVIATION 4.03 | 60.3 years STANDARD_DEVIATION 7.57 | 60.6 years STANDARD_DEVIATION 18.68 | 61.1 years STANDARD_DEVIATION 10.78 |
| Region of Enrollment United States | 3 participants | 3 participants | 6 participants | 3 participants | 4 participants | 3 participants | 10 participants | 32 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 2 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 6 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 | 10 / 10 |
| serious Total, serious adverse events | 1 / 4 | 0 / 3 | 0 / 3 | 5 / 6 | 0 / 3 | 0 / 3 | 3 / 10 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of IPH2101 as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to IPH2101 Treatment
The maximum tolerated dose (MTD) is the highest dose level below the maximum administered dose (MAD) where none or 1 out of 6 subjects have a DLT.
Time frame: From start of the treatment to end of study
Population: All treated participants who received at least one dose of the study drug and were evaluable for DLT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IPH2101 0.0003 mg/kg | Maximum Tolerated Dose (MTD) of IPH2101 as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to IPH2101 Treatment | 0 Number of participants with DLT |
| IPH2101 0.003 mg/kg | Maximum Tolerated Dose (MTD) of IPH2101 as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to IPH2101 Treatment | 0 Number of participants with DLT |
| IPH2101 0.015 mg/kg | Maximum Tolerated Dose (MTD) of IPH2101 as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to IPH2101 Treatment | 0 Number of participants with DLT |
| IPH2101 0.075 mg/kg | Maximum Tolerated Dose (MTD) of IPH2101 as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to IPH2101 Treatment | 1 Number of participants with DLT |
| IPH2101 0.3mg/kg | Maximum Tolerated Dose (MTD) of IPH2101 as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to IPH2101 Treatment | 0 Number of participants with DLT |
| IPH2101 1mg/kg | Maximum Tolerated Dose (MTD) of IPH2101 as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to IPH2101 Treatment | 0 Number of participants with DLT |
| IPH2101 3 mg/kg | Maximum Tolerated Dose (MTD) of IPH2101 as Determined by Number of Participants With Dose-Limiting Toxicities (DLTs) Related to IPH2101 Treatment | 0 Number of participants with DLT |
Secondary
Area Under the Plasma-concentration-time Curve [AUC (INF)] of IPH2101 After Cycle 1 Administration
AUC(INF), area under the plasma concentration-time curve from zero to the last time of the last quantifiable concentration within the dosing interval was calculated for Cycle 1.
Time frame: Anti-KIR (1-7F9) concentrations were measured prior to infusion at 0.167, 1, 3, 6, 12 and 24 hours and then on Days 7, 14 and 21 after the start of the first dose administration
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IPH2101 0.0003 mg/kg | Area Under the Plasma-concentration-time Curve [AUC (INF)] of IPH2101 After Cycle 1 Administration | 0 ng*hours/ml | Geometric Coefficient of Variation 0 |
| IPH2101 0.003 mg/kg | Area Under the Plasma-concentration-time Curve [AUC (INF)] of IPH2101 After Cycle 1 Administration | 808 ng*hours/ml | Geometric Coefficient of Variation 49.7 |
| IPH2101 0.015 mg/kg | Area Under the Plasma-concentration-time Curve [AUC (INF)] of IPH2101 After Cycle 1 Administration | 16593 ng*hours/ml | Geometric Coefficient of Variation 273.3 |
| IPH2101 0.075 mg/kg | Area Under the Plasma-concentration-time Curve [AUC (INF)] of IPH2101 After Cycle 1 Administration | 161811 ng*hours/ml | Geometric Coefficient of Variation 61.5 |
| IPH2101 0.3mg/kg | Area Under the Plasma-concentration-time Curve [AUC (INF)] of IPH2101 After Cycle 1 Administration | 596308 ng*hours/ml | Geometric Coefficient of Variation 0 |
| IPH2101 1mg/kg | Area Under the Plasma-concentration-time Curve [AUC (INF)] of IPH2101 After Cycle 1 Administration | 4331537 ng*hours/ml | Geometric Coefficient of Variation 60.7 |
| IPH2101 3 mg/kg | Area Under the Plasma-concentration-time Curve [AUC (INF)] of IPH2101 After Cycle 1 Administration | 9292602 ng*hours/ml | Geometric Coefficient of Variation 41.7 |
Secondary
Maximum Plasma Concentration (Cmax) of IPH2101 After Cycle 1 Administration
Cmax was obtained from the plasma concentration versus time data after IV administration of IPH2101.
Time frame: Anti-KIR (1-7F9) concentrations were measured prior to infusion at 0.167, 1, 3, 6, 12 and 24 hours and then on Days 7, 14 and 21 after the start of the first dose administration
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IPH2101 0.0003 mg/kg | Maximum Plasma Concentration (Cmax) of IPH2101 After Cycle 1 Administration | 0 ng/mL | Geometric Coefficient of Variation 0 |
| IPH2101 0.003 mg/kg | Maximum Plasma Concentration (Cmax) of IPH2101 After Cycle 1 Administration | 45.8 ng/mL | Geometric Coefficient of Variation 41.3 |
| IPH2101 0.015 mg/kg | Maximum Plasma Concentration (Cmax) of IPH2101 After Cycle 1 Administration | 316 ng/mL | Geometric Coefficient of Variation 53.8 |
| IPH2101 0.075 mg/kg | Maximum Plasma Concentration (Cmax) of IPH2101 After Cycle 1 Administration | 1620 ng/mL | Geometric Coefficient of Variation 38.4 |
| IPH2101 0.3mg/kg | Maximum Plasma Concentration (Cmax) of IPH2101 After Cycle 1 Administration | 4510 ng/mL | Geometric Coefficient of Variation 30.9 |
| IPH2101 1mg/kg | Maximum Plasma Concentration (Cmax) of IPH2101 After Cycle 1 Administration | 24800 ng/mL | Geometric Coefficient of Variation 25.5 |
| IPH2101 3 mg/kg | Maximum Plasma Concentration (Cmax) of IPH2101 After Cycle 1 Administration | 55200 ng/mL | Geometric Coefficient of Variation 31.7 |
Secondary
Number of Evaluable Patients With Stable Disease. Evaluable is Defined as 2 Consecutive M Protein Assessments
Disease Response Assessment by Principal Investigator and Sponsor(Efficacy Population).Stable Disease was defined as not meeting criteria for complete response, very good partial response, partial response, or progressive disease
Time frame: From start of the treatment to end of study or disease progression
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IPH2101 0.0003 mg/kg | Number of Evaluable Patients With Stable Disease. Evaluable is Defined as 2 Consecutive M Protein Assessments | 1 Number of participants |
| IPH2101 0.003 mg/kg | Number of Evaluable Patients With Stable Disease. Evaluable is Defined as 2 Consecutive M Protein Assessments | 1 Number of participants |
| IPH2101 0.015 mg/kg | Number of Evaluable Patients With Stable Disease. Evaluable is Defined as 2 Consecutive M Protein Assessments | 1 Number of participants |
| IPH2101 0.075 mg/kg | Number of Evaluable Patients With Stable Disease. Evaluable is Defined as 2 Consecutive M Protein Assessments | 3 Number of participants |
| IPH2101 1mg/kg | Number of Evaluable Patients With Stable Disease. Evaluable is Defined as 2 Consecutive M Protein Assessments | 2 Number of participants |
| IPH2101 3 mg/kg | Number of Evaluable Patients With Stable Disease. Evaluable is Defined as 2 Consecutive M Protein Assessments | 3 Number of participants |