An Open-label, Dose-escalation Safety and Tolerability Trial Assessing Anti-KIR (1-7F9) in Subjects With Multiple Myeloma

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open-label, Dose-escalation Safety and Tolerability Trial Assessing Multiple Dose Administrations of Anti-KIR (1-7F9) Human Monoclonal Antibody in Subjects With Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Anti-KIR (1-7F9)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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.) Bone marrow plasmacytosis > 10% (as determined by bone marrow aspirate) or plasmacytoma 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: Known or suspected allergy to trial product or related products Previous participation in this trial (dosed) 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) 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. Use of an investigational agent within 30 days of the first dose of study drug (or five half-lives of any antibody). Current treatment with any other anti-MM therapy excluding prophylactic bisphosphonates. Radiotherapy against bone lesions within 4 weeks or visceral lesions within 8 weeks of Screening. Thalidomide or bortezomib treatment within 14 days of Screening. Cytotoxic chemotherapy (excluding thalidomide or bortezomib) or corticosteroid treatment within 28 days of Screening. Subjects with non-secretory multiple myeloma Subjects on dialysis Use of myeloid growth factor within 28 days of screening G-CSF treatment within 28 days of screening Active autoimmune disease Active infectious disease (e.g. HIV, chronic hepatitis, etc.) as judged by the investigator. New York Heart Association (NYHA) class III-IV heart failure Severe neurological / psychiatric disorder as judged by the investigator Clinical evidence of an active second malignancy, with the exception of basal cell carcinoma or in situ carcinoma of cervix. Subjects with a history of allogenic transplantation. Subject who have undergone autologous transplantation within the last 3 months. Mental incapacity or inadequate understanding of English. Any serious medical condition that in the opinion of the investigator, disqualifies the subject for inclusion in the trial.

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

| Intervention/Treatment |
| --- |
|Drug: Anti-KIR (1-7F9)|human monoclonal antibody|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From start of the treatment to end of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 
| 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. | 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 | 
| 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 | From start of the treatment to end of study or disease progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple myeloma, Anti-KIR (1-7F9)