J591 in Patients With Advanced Prostate Cancer and Unfavorable Circulating Tumor Cell Counts

J591 is a de-immunized monoclonal antibody against the extracellular domain of prostate-specific membrane antigen (PSMA). Background data demonstrate that mAb Hu-J591 doses as low as 20 mg may lead to a decrease in CTCs and that doses up to 300 mg are safe. With a goal of establishing less frequent, potentially more convenient and cost-effective future therapy, the investigators propose a single-center, open-label, dose de-escalation study to determine the effect of mAb Hu-J591 on circulating tumor cells in subjects with metastatic PC. Four dose levels are planned with a minimum of 6 and maximum of 24 subject enrollment starting with a single infusion of 300 mg of mAb Hu-J591.

In the initial phase of the study a cohort of 6 subjects will receive 300 mg of mAb Hu-J591 and blood samples will be collected pre and post-infusion for the detection of CTCs, PSA and to assess hematological toxicity at screening, baseline, week 1, week 4, week 8, and week 12. In addition, patients will receive a dose of 89Zr-DFO-huJ591 (5 mCi) 2-4 weeks prior to treatment and will undergo 89Zr-DFO-huJ591 PET imaging 1-3 weeks pre-treatment (optional) as well as repeat 89Zr-DFO-huJ591 infusion (5 mCi) at 11 weeks and PET/CT imaging at 12 weeks (optional).

If less than four subjects respond by dropping their CTC counts from more than or equal to 5 CTCs/7.5 mL whole blood to less than 5 CTCs/7.5 mL whole blood in the initial cohort, the trial will be ended at this dose. If four or more subjects respond, an additional 6 subjects will be accrued to the second dose level (200 mg). The same decision rule will be applied to evaluate two additional lower dose levels (100 mg, 50 mg) with 6 subjects enrolled in each cohort. Imaging studies will be performed prior to treatment at screening and at 3 months or as clinically indicated to assess disease response.

Subjects who tolerate the initial infusion well (< grade 2 toxicities) may be re-treated every 3 months (12 weeks) at the same dose-level until progression.

Inclusion criteria

• Histologic/Cytologic diagnosis of prostate carcinoma
• Subject must have progressive metastatic prostate cancer as defined as at least any one of the following:

• New lesions on bone scan
• Progression of disease on CT/MRI as defined by RECIST
• PSA progression defined by an absolute value 2 ng/mL with an increase in PSA determined by two separate measurements taken at least one week apart and confirmed by a third, and if necessary, a fourth measurement. If the third measurement is not greater than the second measurement, then a fourth measurement must be taken; the fourth measurement must be greater than the second measurement for the subject to be eligible for enrollment in the study. Furthermore, the confirmatory PSA measurement (i.e., the third or, if applicable, fourth PSA measurement) must be 2 ng/mL and ≥ 25% above the previous nadir.
• Increase in circulating tumor cell (CTC) count via CellSearch methodology in the absence of responding tumor by other criteria.
• Subjects must remain on a stable hormonal therapy regimen.

• Subjects who have received traditional anti-androgen (i.e. bicalutamide, nilutamide, flutamide) therapy with a resulting PSA decline must continue anti-androgen therapy or demonstrate progression following discontinuation of anti-androgen therapy (not necessary for those who never responded to anti-androgen addition).
• Medical or surgical castration will be continued for the duration of the trial in all subjects.
• Subjects who have any measure of progression on androgen receptor signaling inhibitors (such as enzalutamide or apalutamide) or CYP17 inhibitors (such as abiraterone acetate) and wish to continue must remain on a stable regimen.
• CTCs ≥ 5 per 7.5ml of whole blood performed by CellSearch system within 1 month of enrollment (may be performed as part of screening).
• Subjects capable of fathering children must agree to use an effective method of contraception for the duration of the trial.

Exclusion criteria

• Prior cytotoxic chemotherapy and/or radiation therapy within 4 weeks of treatment
• AST or ALT > 2.5x ULN unless secondary to liver metastasis (then AST/ALT > 5x ULN is exclusionary provided subject meets bilirubin requirements)
• Bilirubin (total) > 1.5x ULN; subjects with known Gilbert's syndrome are eligible if direct bilirubin is within normal limits
• Serum Creatinine > 3x ULN
• Absolute Neutrophil Count <1000/µL
• Hemoglobin <8 g/dL
• Platelet Count <50,000/µL
• ECOG Performance Status >2
• Life expectancy < 6 months
• Any serious illness(es) involving the cardiac, respiratory, CNS, renal, hepatic or hematological organ systems which in the investigator's opinion might preclude completion of this study or interfere with determination of causality of any adverse effects experienced in this study
• Prior investigational therapy (medications or devices) within 4 weeks of treatment. Furthermore, other investigational anti-cancer therapy is not permitted during the treatment phase.