177Lu-PSMA-617 and Pembrolizumab in Treating Patients With Metastatic Castration-Resistant Prostate Cancer

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose and schedule of lutetium Lu 177-PSMA-617
(177Lu-PSMA-617) in combination with pembrolizumab in patients with metastatic
castration-resistant prostate carcinoma (mCRPC). (Part A) II. To determine the objective
response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. (Part B
[Dose Expansion])

SECONDARY OBJECTIVES:

I. To characterize the safety profile of the combination. II. To determine the median
duration of response by RECIST 1.1 criteria. III. To determine the proportion of patients who
experience >= 50% decline from baseline in serum prostate-specific antigen (PSA).

IV. To determine the median PSA progression-free survival. V. To determine the median time to
symptomatic skeletal related event. VI. To determine the 6 month radiographic
progression-free survival rate and median radiographic progression-free survival.

VII. To determine the median overall survival.

CORRELATIVE OBJECTIVES:

I. To assess the lesion-specific response rate by baseline PSMA avidity on gallium Ga
68-labeled PSMA-11 (68Ga-PSMA-11) positron emission tomography (PET).

II. To quantify the change from baseline in T cell repertoire, circulating T cell subsets,
tumor infiltrating lymphocytes, and tumor PD-L1 expression by immunohistochemistry after one
priming dose of Lu-PSMA radioligand therapy (RLT).

III. To explore the relationship between timing of the 177Lu-PSMA-617 priming dose with
initiation of pembrolizumab with respect to immunologic, safety, and efficacy outcomes.

IV. To descriptively characterize the patterns of uptake on 68Ga-PSMA-11 PET at the time of
disease progression.

OUTLINE: Patients are assigned sequentially to 1 of 3 treatment schedules.

SCHEDULE 1: Patients receive lutetium Lu 177-PSMA-617 intravenously (IV) over 20-30 minutes
on day 1. Beginning in cycle 2, patients receive pembrolizumab IV over 30 minutes on day 1.

SCHEDULE 2: Patients receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes and pembrolizumab
IV over 30 minutes on day 1.

SCHEDULE 3: Starting day -21, patients receive pembrolizumab IV over 30 minutes. Patients
also receive lutetium Lu 177-PSMA-617 IV over 20-30 minutes on day 1.

In all schedules, treatment with pembrolizumab repeats every 21 days for up to 35 cycles (2
years) in the absence of disease progression or unacceptable toxicity. Patients who achieve
stable disease (SD) or better may receive 17 additional cycles (approximately 1 year) of
pembrolizumab.

After completion of study treatment, patients are followed up at 30 and 90 days.

Inclusion Criteria:

- The subject is able and willing to comply with study procedures and provide signed and
dated informed consent

- Histologically confirmed prostate adenocarcinoma. De novo small cell neuroendocrine
prostate cancer will not be allowed due to putative lower PSMA expression in this
tumor subtype. Treatment-emergent small cell neuroendocrine prostate cancer detected
in metastatic tumor biopsy is not an exclusion

- A minimum of three PSMA-avid lesions on baseline 68Ga-PSMA-11 PET, with positive
lesions defined as those with maximum standardized uptake value (SUVmax) values
greater than mediastinal blood pool

- Progressive metastatic castration-resistant prostate cancer by Prostate Cancer Working
Group (PCWG)3 criteria at the time of study entry

- Castrate level of serum testosterone at study entry (< 50 ng/dL). Patients without
prior bilateral orchiectomy are required to remain on luteinizing hormone-releasing
hormone (LHRH) analogue treatment for duration of study

- Prior progression on at least one second generation androgen signaling inhibitor
including abiraterone, apalutamide, and/or enzalutamide

- Absolute neutrophil count > 1.5 x 10^9/L

- Hemoglobin > 9.0 g/dL

- Platelet count > 100,000/microliter

- Serum creatinine =< 1.5 x upper limit of normal (ULN) or estimated glomerular
filtration rate (GFR) > 50 ml/min by Cockcroft-Gault or 24 hour urine collection

- Total bilirubin =< 1.5 x ULN. In patients with known or suspected Gilbert?s disease,
direct bilirubin =< ULN

- Aspartate aminotransferase and alanine aminotransferase =< 2.5 x ULN

- No other systemic anti-cancer therapies administered other than LHRH analogue within
28 days, or 5 half-lives, whichever is shorter, prior to initiation of study
treatment. Adverse events related to prior anti-cancer treatment must have recovered
to grade =< 1 with the exclusion of alopecia

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0 or 1

- Patients must use appropriate methods of contraception during study treatment and for
at least 60 days after last study treatment

- Patients who are sexually active should consider their female partner to be of
childbearing potential if she has experienced menarche and is not postmenopausal
(defined as amenorrhea > 24 consecutive months) or has not undergone successful
surgical sterilization. Even women who use contraceptive hormones (oral,
implanted, or injected), an intrauterine device, or barrier methods (diaphragms,
condoms, spermicide) should be considered to be of childbearing potential

- Patients who have undergone vasectomy themselves should also be considered to be
of childbearing potential

- Acceptable methods of contraception include continuous total abstinence, or
double-barrier method of birth control (e.g. condoms used with spermicide, or
condoms used with oral contraceptives). Periodic abstinence and withdrawal are
not acceptable methods of contraception

- Patients must provide consent to comply to recommended radioprotection precautions
during study

- Patients willing to undergo metastatic tumor biopsy and have at least one metastatic
lesion safely accessible to tumor biopsy. Bone or soft tissue lesion is allowed

- Measurable disease by RECIST 1.1 criteria

Exclusion Criteria:

- Untreated brain metastases at study entry. Patients with previously treated brain
metastases are eligible provided the following criteria are all met:

- Last treatment was > 28 days prior to cycle 1 day 1 (C1D1)

- No evidence of new/progressive brain metastases is observed on magnetic resonance
imaging (MRI) obtained during screening window

- Patient is clinically stable without requirement of steroid treatment for at
least 14 days prior to first dose of study treatment

- Receipt of prior PSMA-directed treatment (e.g. radiotherapy, immunotherapy, or
antibody-drug conjugate)

- Prior treatment with radium-223 or other radioisotope for the treatment of prostate
cancer

- Has received prior radiotherapy within 2 weeks of start of study treatment.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (=< 2 weeks of radiotherapy) to non-CNS disease

- Receipt of prior pembrolizumab or another immune checkpoint inhibitor (e.g. nivolumab,
ipilimumab)

- Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to initiation of study treatment.

- Note: Participants must have recovered from all adverse events (AEs) due to
previous therapies to =< grade 1 or baseline. Participants with =< grade 2
neuropathy may be eligible

- Note: If participant received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
study treatment

- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study treatment

- Note: Participants who have entered the follow-up phase of an investigational
study may participate as long as it has been 4 weeks after the last dose of the
previous investigational agent

- Receipt of chemotherapy applied in the castration-resistant setting. Prior receipt of
chemotherapy in the hormone-sensitive setting is allowed

- Grade >= 2 peripheral neuropathy at the time of study entry

- Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients

- Has an active autoimmune disease or grade >= 3 pneumonitis that has required systemic
treatment in the past 2 years (i.e., with use of disease modifying agents,
corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine,
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency) or treatment with drugs (e.g. neomercazol, carbimazole, etc.) that
function to decrease the generation of thyroid hormone by a hyperfunctioning thyroid
gland (e.g. in Graves? disease) is not considered a form of systemic treatment of an
autoimmune disease

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a
prednisone equivalent dose of > 10 mg daily or other form of immunosuppressive therapy
within 7 days prior to first dose of study drug

- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis

- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette?Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed

- Patients who because of age, general medical or psychiatric condition, or physiologic
status cannot give valid informed consent

- Has clinically significant cardiovascular disease including, but not limited to:

- Uncontrolled or any New York Heart Association class 3 or 4 congestive heart
failure

- Uncontrolled angina, history of myocardial infarction, unstable angina or stroke
within 6 months before study entry

- Clinically significant arrhythmias not controlled by medication. Chronic rate
controlled or paroxysmal atrial fibrillation/flutter is not an exclusion to study
participation

- Prior external beam radiation involving >= 25% of bone marrow or within 14 days of
start of protocol therapy

- Major surgery within 28 days of study treatment

- Has an active infection requiring systemic therapy

- Has a known history of human immunodeficiency virus (HIV) (screening not required)

- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]
reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA]
[qualitative] is detected) infection (screening not required)

- Has a known history of active TB (Bacillus tuberculosis)

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

- Any condition that, in the opinion of the principal investigator, would impair the
patient?s ability to comply with study procedures

- History of bleeding diathesis and not currently on anti-coagulation therapy that
cannot be safely discontinued for the tumor biopsy procedure