Radioimmunotherapy in Prostate Cancer Using 177Lu-J591 Antibody

Study Design: We plan to perform a phase I dose-escalation study. The trial is designed to
determine the cumulative MTD in a FDR in which 177Lu-J591 will be given in 2 doses, 2 weeks
apart. The dose escalation will start at 20 mCi/m2 and escalate in increments of 5 mCi/m2 to
55 mCi/m2 in up to 8 cohorts.We plan to recruit a maximum of 68 subjects in this trial.

Specific Aims: 1. Determine the cumulative MTD of 177Lu-J591 in a 2 week dose-fractionation
regimen.

2. Perform imaging and pharmacokinetic (PK) studies with 177Lu-J591 in order to define the PK
and dosimetry of 177Lu-J591 3. Determine the myelotoxicity of fractionated dose of 177Lu-J591
4. Monitor biochemical (PSA) and/or measurable disease response and duration.

Following the administration of 177Lu-J591 mAb on day 0, blood samples may be obtained at 10
min, 1, 2, 4 hrs, days 1, once during days 3-6, day 7 and 14. In addition, total body images
may be obtained on day 0 at 1-4 hours after study treatment, day 1, once during days 3-6,
days 7 and 14 using a gamma camera. (Amendment dated 15 July 2009: As investigators have
gained ample information from the initial cohorts, PK and 177Lu-J591 imaging studies (other
than the day 6-8 scan) will be considered optional.) Patients will be followed for a minimum
of 12 weeks after the 2nd dose of 177Lu-J591 (total 14 weeks) or until toxicities resolve,
disease progression or administration of alternative therapy for the patient¿s prostate
cancer. Various clinical and laboratory evaluations will be performed during the first week
and then every week until 12 weeks. These include, blood chemistries, CBCs, serum PSA levels,
etc. If the patient¿s disease is stable or responding at 12 weeks after his last dose, he
will continue to be followed until progression of disease. During the long-term follow-up,
the patient¿s PSA will be monitored at least every 6 weeks and CT/bone scans will be
evaluated at least every 18 weeks until disease progression.

Inclusion Criteria:

1. Histologic diagnosis (recent or remote) of prostate adenocarcinoma.

2. Progressive, castrate metastatic carcinoma of the prostate defined by presence of
metastatic disease on imaging and:

- progressive tumor lesions on CT or MRI and/or

- new osseous lesions on bone scan and/or

- rising PSA

3. Rising PSA on 3 serial determinations over a period of ≥ 2 weeks.

4. If patient is being treated with an LHRH analog, the drug:

- must be maintained for the duration of this study or

- must be terminated ≥ 10 weeks prior to entry (for 28 day depot preparations) or
24 weeks (for 3 month depot preparations) or 32 weeks (for 4 month depot
preparation).

5. Platelet count > 150,000/mm3.

6. Absolute neutrophil count (ANC) ≥ 2,000/mm3

7. Normal coagulation profile (PT, PTT), unless on a stable anticoagulation regimen

8. Hematocrit > 30% or Hemoglobin > 10g/dL without blood transfusion dependency

9. Patients of child bearing potential must agree to use an effective method of
contraception.

10. Patient must have progressed following discontinuation of anti-androgen therapy, if
received.

11. Serum testosterone < 50 ng/ml.

Exclusion Criteria:

1. Prior aspirin and/or non-steroidal anti-inflammatory agents within 1 week of study
treatment.

2. Prior corticosteroids and/or adrenal hormone inhibitors within 4 weeks of treatment,
except for low dose maintenance prednisone or hydrocortisone (i.e. for adrenal
insufficiency) on a stable dose at the investigator's discretion.

3. Prior cytotoxic chemotherapy and/or radiation therapy within 4 weeks of treatment.

4. Prior radiation therapy encompassing >25% of expected red marrow distribution.

5. Prior treatment with 89Strontium (Metastron®) or 153Samarium (Quadramet®). CNS
metastasis.

6. History of seizure and/or stroke within past 2 years

7. History of HIV

8. Serum creatinine > 2.0

9. SGOT > 2x ULN

10. Bilirubin (total) >1.5x ULN

11. Serum calcium > 12.5

12. Active infection

13. Active angina pectoris or NY Heart Association Class III-IV.

14. Karnofsky Performance Status < 60; ECOG Performance Status > 2.

15. Life expectancy < 6 months

16. Other serious illness(es) involving the cardiac, respiratory, CNS, renal, hepatic or
hematological organ systems which might preclude completion of this study or interfere
with determination of causality of any adverse effects experienced in this study.

17. Prior treatment with monoclonal Ab J591 labeled with therapeutic doses of 177Lu or 90Y

18. Other investigational therapy within 4 weeks of treatment