177Lu−J591 and 177Lu−PSMA−617 Combination for mCRPC

This is an open−label, single−center Phase I dose−escalation study designed to determine the
dose−limiting toxicity (DLT) and the maximum tolerated dose (MTD) of combination of
177Lu−J591 and 177Lu−PSMA−617 in a two−week dose−fractionation regimen. 177Lu−J591 will be
given as a fixed dose x2 infusions two weeks apart. For 177Lu−PSMA−617 the dose escalation
will start at 3.7 GBq (100 mCi) and escalate in increments of 1.85 GBq (50 mCi) for each dose
to a planned maximum of 9.25 GBq(250 mCi) x2 doses, 2 weeks apart. Should there be
unacceptable toxicity at the initial dose level, we will de-escalate to dose level -1 (1.85
GBq / 50 mCi per dose). After the phase I study has established a MTD, the Phase II,
single-arm trial will start.

Patients must have documented progressive metastatic CRPC disease based on Prostate Cancer
Working Group 3 (PCWG3) criteria in order to be eligible for enrollment. Upon meeting the
inclusion and exclusion criteria and signing the informed consent and HIPPA form, subjects
will undergo the screening. As part of the screening, subjects will get a single dose of
68Ga−PSMA−HBED−CC and will have a PET/CT. Nuclear Medicine physician(s) will review the
PET/CT scans to document PSMA expression at tumor site(s).

Subjects will have Lutetium−177 Planar/SPECT Imaging on Day 8 (±1 day) after the first dose
of 177Lu−J591 + 177Lu−PSMA−617. Optimal images will be performed on selected consenting
subjects between the initial treatment visit #1 on Day 1 and Day 4 and prior to treatment
visit #2 on D15 ±1. Subjects will be closely monitored for AEs (weekly x2 weeks, then every 2
weeks for one month, at 8 and 12 weeks, and then every 4 weeks for next 3 months).

Upon completion of investigational treatment with dose−fractionation regimen of the
combination of 177Lu−J591 + 177Lu−PSMA−617, subjects will undergo 68Ga−PSMA−HBED−CC injection
and same day PET/CT at the end of study visit to document treatment response. Subsequently
survival data and additional treatment(s) information will be captured from their routine
Standard of care (SOC) visits.

Inclusion Criteria:

1. Histologically or cytologically confirmed adenocarcinoma of prostate

2. Documented progressive metastatic CRPC based on Prostate Cancer Working Group 3
(PCWG3) criteria, which includes at least one of the following criteria:

i. PSA progression ii. Objective radiographic progression in soft tissue iii. New bone
lesions

3. ECOG performance status of 0−2

4. Have serum testosterone < 50 ng/dL. Subjects must continue primary androgen
deprivation with an LHRH/GnRH analogue (agonist/antagonist) if they have not undergone
bilateral orchiectomy.

5. Have previously been treated with at least one of the following:

- Androgen receptor signaling inhibitor (such as enzalutamide)

- CYP 17 inhibitor (such as abiraterone acetate)

6. Have previously received taxane chemotherapy, been determined to be ineligible for
taxane chemotherapy by their physician, or refused taxane chemotherapy.

7. Age > 18 years

8. Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count >2,000 cells/mm3

- Hemoglobin ≥9 g/dL

- Platelet count >150,000 x 109/μL

- Serum creatinine <1.5 x upper limit of normal (ULN) or calculated creatinine
clearance ≥ 60 mL/min/1.73 m2 by Cockcroft−Gault

- Serum total bilirubin <1.5 x ULN (unless due to Gilbert's syndrome in which case
direct bilirubin must be normal)

- Serum AST and ALT <1.5 x ULN in the absence of liver metastases; <3 x ULN if due
to liver metastases (in both circumstances bilirubin must meet entry criteria)

9. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Implantation of investigational medical device ≤4 weeks of Treatment visit #1 (Day 1)
or current enrollment in oncologic investigational drug or device study

2. Use of investigational drugs ≤4 weeks or <5 half−lives of Treatment visit # 1(Day 1)
or current enrollment in investigational oncology drug or device study

3. Prior systemic beta−emitting bone−seeking radioisotopes

4. Known active brain metastases or leptomeningeal disease

5. History of deep vein thrombosis and/or pulmonary embolus within 1 month of Treatment
visit #1

6. 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

7. Radiation therapy for treatment of PC ≤4 weeks of Treatment visit #1

8. Patients on stable dose of bisphosphonates or Denosumab, which have been started no
less than 4 weeks prior to treatment start, may continue on this medication, however
patients are not allowed to initiate bisphosphonate/Denosumab therapy during the
DLT−assessment period of the study.

9. Having partners of childbearing potential and not willing to use a method of birth
control deemed acceptable by the principle investigator and chairperson during the
study and for 1 month after last study drug administration

10. Currently active other malignancy other than non−melanoma skin cancer. Patients are
considered not to have "currently active" malignancy if they have completed any
necessary therapy and are considered by their physician to be at less than 30% risk of
relapse.

11. Known history of known myelodysplastic syndrome