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

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.

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).

• 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.