Inhibition of Interleukin-6 with CNTO328, an Anti-Interleukin-6 Monoclonal Antibody, Inhibits Conversion of Androgen-Dependent Prostate Cancer to an Androgen-Independent Phenotype in Orchiectomized Mice

Purpose To determine the maximum-tolerated dose (MTD), toxicity, human antihuman antibody (HAHA) response, pharmacokinetics, organ dosimetry, targeting, and preliminary efficacy of yttrium-90–labeled anti–prostate-specific membrane antigen monoclonal antibody J591 (90Y-J591) in patients with androgen-independent prostate cancer (PC). Patients and Methods Patients with androgen-independent PC and evidence of disease progression received indium-111–J591 for pharmacokinetic and biodistribution determinations followed 1 week later by 90Y-J591 at five dose levels: 5, 10, 15, 17.5, and 20 mCi/m2. Patients were eligible for up to three re-treatments if platelet and neutrophil recovery was satisfactory. Results Twenty-nine patients with androgen-independent PC received 90Y-J591, four of whom were re-treated. Dose limiting toxicity (DLT) was seen at 20 mCi/m2, with two patients experiencing thrombocytopenia with non–life-threatening bleeding episodes requiring platelet transfusions. The 17.5-mCi/m2 dose level was determined to be the MTD. No re-treated patients experienced DLT. Nonhematologic toxicity was not dose limiting. Targeting of known sites of bone and soft tissue metastases was seen in the majority of patients. No HAHA response was seen. Antitumor activity was seen, with two patients experiencing 85% and 70% declines in prostate-specific antigen (PSA) levels lasting 8 and 8.6 months, respectively, before returning to baseline. Both patients had objective measurable disease responses. An additional six patients (21%) experienced PSA stabilization. Conclusion The recommended dose for 90Y-J591 is 17.5 mCi/m2. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation of 90Y-J591 in the treatment of patients with PC.

Download Full-text

Phase I Trial of 177Lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients With Androgen-Independent Prostate Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.05.160 ◽

2005 ◽

Vol 23 (21) ◽

pp. 4591-4601 ◽

Cited By ~ 301

Author(s):

Neil H. Bander ◽

Matthew I. Milowsky ◽

David M. Nanus ◽

Lale Kostakoglu ◽

Shankar Vallabhajosula ◽

...

Keyword(s):

Prostate Cancer ◽

Monoclonal Antibody ◽

Specific Antigen ◽

Maximum Tolerated Dose ◽

Magnetic Resonance Images ◽

Prostate Specific Membrane Antigen ◽

Biologic Activity ◽

Nonhematologic Toxicity ◽

Specific Membrane ◽

Androgen Independent

Purpose To determine the maximum tolerated dose (MTD), toxicity, human anti-J591 response, pharmacokinetics (PK), organ dosimetry, targeting, and biologic activity of 177Lutetium-labeled anti–prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (177Lu-J591) in patients with androgen-independent prostate cancer (PC). Patients and Methods Thirty-five patients with progressing androgen-independent PC received 177Lu-J591. All patients underwent 177Lu-J591 imaging, PK, and biodistribution determinations. Patients were eligible for up to three retreatments. Results Thirty-five patients received 177Lu-J591, of whom 16 received up to three doses. Myelosuppression was dose limiting at 75 mCi/m2, and the 70-mCi/m2 dose level was determined to be the single-dose MTD. Repeat dosing at 45 to 60 mCi/m2 was associated with dose-limiting myelosuppression; however, up to three doses of 30 mCi/m2 could be safely administered. Nonhematologic toxicity was not dose limiting. Targeting of all known sites of bone and soft tissue metastases was seen in all 30 patients with positive bone, computed tomography, or magnetic resonance images. No patient developed a human anti-J591 antibody response to deimmunized J591 regardless of number of doses. Biologic activity was seen with four patients experiencing ≥ 50% declines in prostate-specific antigen (PSA) levels lasting from 3+ to 8 months. An additional 16 patients (46%) experienced PSA stabilization for a median of 60 days (range, 1 to 21+ months). Conclusion The MTD of 177Lu-J591 is 70 mCi/m2. Multiple doses of 30 mCi/m2 are well tolerated. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation.

Download Full-text