Maximum tolerated dose of 67Cu-2IT-BAT-LYM-1 for fractionated radioimmunotherapy of non-Hodgkin's lymphoma: a pilot study.
OBJECTIVE
Lym-1, a monoclonal antibody (MoAb) that preferentially targets malignant lymphocytes, has induced therapeutic responses in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine-131 (131I). Radiometal labeled antibodies provide a higher tumor radiation dose than the corresponding 131I labeled antibodies. Based on the strategy of fractionating the total radiation dose, this study was designed to define the maximum tolerated dose (MTD) of the first 2, of a maximum of 4, doses of 67Cu-2IT-BAT-Lym-1 given 4 weeks apart. Additionally, toxicity, radiation dosimetry and efficacy were assessed.


METHODS
Patients had Ann Arbor stage IVB NHL, resistant to standard therapy, including multiple chemotherapy regimens. Each dose of 67Cu-2IT-BAT-Lym-1 was given after a preload of unmodified Lym-1. A 10 mCi imaging dose of 67Cu-2IT-BAT-Lym-1 was given in order to assess pharmacokinetics and radiation dosimetry prior to therapy. Based on the MTD for 131I-Lym-1 and comparative dosimetry for 131I-Lym-1 and 67Cu-2IT-BAT-Lym-1, the trial was initiated at 60 millicuries per square meter of body surface area (mCi/m2) in cohorts of 3 patients.


RESULTS
A single cohort of patients proved sufficient to define the MTD as 60 mCi/m2 for each of the first 2 doses of 67Cu-2IT-BAT-Lym-1. The dose-limiting toxicities were grade 3-4 thrombocytopenia and neutropenia. Neutropenic sepsis and bleeding did not occur. Mean radiation dose contributed to the bone marrow by 67Cu in the body and blood was 0.2 (range, 0.2 to 0.3) rads/mCi. Copper-67 incorporated into ceruloplasmin contributed 25% of the dose to marrow from blood. Non-hematologic toxicities did not exceed grade 2. The three patients had substantial tumor regression even after imaging doses of 67Cu-2IT-BAT-Lym-1. After therapy, one response was complete with a duration of 12 months. Radiation doses to tumors in this patient varied from 7.0-21.9 rads/mCi or 5420-7000 total rads from the course of therapy.


CONCLUSIONS
67Cu-2IT-BAT-Lym-1 provided good imaging, favorable radiation dosimetry and a remarkably high therapeutic index (ratio of tumor to marrow radiation doses). The non-myeloablative MTD for each of 2 doses was 60 mCi/m2.
Denardo
G L
GL
Department of Internal Medicine, University of California Davis Medical Center, Sacramento 95816, USA.
Denardo
S J
SJ
Kukis
D L
DL
O'Donnell
R T
RT
Shen
S
S
Goldstein
D S
DS
Kroger
L A
LA
Salako
Q
Q
Denardo
D A
DA
Mirick
G R
GR
Mausner
L F
LF
Srivastava
S C
SC
Meares
C F
CF
D000328:Adult; D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D002570:Ceruloplasmin / Q000032:analysis; D002851:Chromatography, High Pressure Liquid; D003301:Copper Radioisotopes / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D019583:Dose Fractionation, Radiation; D005260:Female; D006571:Heterocyclic Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000097:blood / Q000000981:diagnostic imaging / Q000532:radiotherapy*; D008297:Male; D008452:Maximum Allowable Concentration; D008875:Middle Aged; D009942:Organometallic Compounds / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D010865:Pilot Projects; D016499:Radioimmunotherapy / Q000009:adverse effects; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity*; D012709:Serum Albumin / Q000032:analysis; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D012709:Serum Albumin; C097568:copper-67-2IT-BAT-Lym-1; D002570:Ceruloplasmin