Conditions

• Metastatic Castration-Resistant Prostate Carcinoma
• Metastatic Prostate Adenocarcinoma
• Stage IVB Prostate Cancer AJCC v8

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

Male

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- PRE-REGISTRATION (STEP 0): Patients must have histological, pathological, and/or
cytological confirmation of prostate adenocarcinoma

- PRE-REGISTRATION (STEP 0): Patients must have a positive PSMA PET/CT scan (either
gallium Ga 68 gozetotide [68Ga-PSMA-11], fluorine F 18 piflufolastat [18F- DCFPyl],
or fluorine F 18 flotufolastat gallium [18F-rhPSMA-7.3]), as defined as uptake
greater than liver with no PSMA negative measurable soft tissue disease

- PRE-REGISTRATION (STEP 0): PSA greater than 2.0 ng/mL

- PRE-REGISTRATION (STEP 0): Patients must have progressive mCRPC. Documented
progressive mCRPC will be based on at least 1 of the following criteria:

- Serum PSA progression defined as 2 consecutive increases in PSA over a previous
reference value measured at least 1 week prior. The minimal start value is 2.0
ng/mL

- Soft-tissue progression defined as an increase ≥ 20% in the sum of the diameter
(SOD) (short axis for nodal lesions and long axis for non-nodal lesions) of all
target lesions based on the smallest SOD since treatment started or the
appearance of one or more new lesions

- Progression of bone disease: evaluable disease or new bone lesions(s) by bone
scan (2+2 Prostate Cancer Clinical Trials Working Group 3 [PCWG3] criteria,
Scher et al 2016)

- PRE-REGISTRATION (STEP 0): Patients must have prior orchiectomy and/or ongoing
androgen-deprivation therapy and a castrate level of serum testosterone (< 50 ng/dL
or < 1.7 nmol/L)

- PRE-REGISTRATION (STEP 0): Patients must have received at least one androgen
receptor pathway inhibitor (ARPI) (to include either apalutamide, darolutamide,
enzalutamide, or abiraterone)

* ARPI must be stopped at least 4 weeks prior to pre-registration

- PRE-REGISTRATION (STEP 0): Patients must not have previously received a taxane based
chemotherapy regimen for mCRPC. Prior docetaxel for metastatic hormone-sensitive
prostate carcinoma (mHSPC) or in the neoadjuvant or adjuvant setting is permitted if
completed at least 12 months prior to pre-registration

- PRE-REGISTRATION (STEP 0): Patients must have recovered to ≤ grade 2 from all
clinically significant toxicities related to prior therapies (i.e. prior
chemotherapy, radiation, immunotherapy, etc.)

- PRE-REGISTRATION (STEP 0): Patients on a stable bisphosphonate or denosumab regimen
for ≥ 30 days prior to pre-registration are eligible

- PRE-REGISTRATION (STEP 0): Previous treatment with strontium Sr-89 (strontium-89),
samarium Sm-153 (samarium-153), rhenium Re 186 (rhenium-186), rhenium Re 188
(rhenium-188), radium Ra 223 (radium-223) or hemi-body irradiation within 6 months
prior to pre-registration is not allowed. Previous PSMA-targeted radioligand therapy
is not allowed

- PRE-REGISTRATION (STEP 0): Any systemic anti-cancer therapy (e.g. chemotherapy,
immunotherapy or biological therapy [including monoclonal antibodies]) within 28
days prior to pre-registration is not allowed

- PRE-REGISTRATION (STEP 0): Age ≥ 18 years

- PRE-REGISTRATION (STEP 0): Eastern Cooperative Oncology Group (ECOG) Performance
Status ≤ 2

- PRE-REGISTRATION (STEP 0): Absolute neutrophil count (ANC) ≥ 1,500/mm^3

- PRE-REGISTRATION (STEP 0): Platelet count ≥ 100,000/mm^3

- PRE-REGISTRATION (STEP 0): Total bilirubin < 1.5 x upper limit of normal (ULN) or <
3 x ULN in patients with Gilbert's syndrome

- PRE-REGISTRATION (STEP 0): Creatinine clearance estimated glomerular filtration rate
(eGFR) ≥ 40 mL/min/1.73m^2 using the Modification of Diet in Renal Disease (MDRD)
equation

- PRE-REGISTRATION (STEP 0): No acute biliary or urinary obstruction

- PRE-REGISTRATION (STEP 0): Patients with treated/stable brain metastases are
eligible if follow-up brain imaging after central nervous system (CNS)-directed
therapy shows no evidence of progression

* Patients with a history of CNS metastases must have received therapy (surgery,
radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not
receiving corticosteroids for the purposes of maintaining neurologic integrity.
Patients with epidural disease, canal disease and prior cord involvement are
eligible if those areas have been treated, are stable, and not neurologically
impaired. For patients with parenchymal CNS metastasis (or a history of CNS
metastasis), baseline and subsequent radiological imaging must include evaluation of
the brain (MRI preferred or CT with contrast)

- PRE-REGISTRATION (STEP 0): Patients with known HIV infection on effective
anti-retroviral therapy with undetectable viral load within 6 months prior to
registration are eligible for this trial

- PRE-REGISTRATION (STEP 0): For patients with evidence of chronic hepatitis B virus
(HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if
indicated

- PRE-REGISTRATION (STEP 0): Patients with a history of hepatitis C virus (HCV)
infection must have been treated and cured. For patients with HCV infection who are
currently on treatment, they are eligible if they have an undetectable HCV viral
load

- PRE-REGISTRATION (STEP 0): Patients with known history or current symptoms of
cardiac disease, or history of treatment with cardiotoxic agents, should have a
clinical risk assessment of cardiac function using the New York Heart Association
Functional Classification. To be eligible for this trial, patients should be class
II or better

- PRE-REGISTRATION (STEP 0): No investigational agents within 28 days prior to
pre-registration

- PRE-REGISTRATION (STEP 0): No other concurrent cytotoxic chemotherapy,
immunotherapy, radioligand therapy, or investigational therapy

- PRE-REGISTRATION (STEP 0): No known hypersensitivity to the components of the study
therapy or its analogs

- PRE-REGISTRATION (STEP 0): No transfusion within 30 days of pre-registration

- PRE-REGISTRATION (STEP 0): No symptomatic cord compression, or clinical or
radiologic findings indicative of impending cord compression

- PRE-REGISTRATION (STEP 0): Ability to read and comprehend English or Spanish

- REGISTRATION (STEP 1): Completion of 2 doses of 177Lu PSMA RLT

- REGISTRATION (STEP 1): PSA decline ≥ 50% between C1 D1 (screening) and C2 D22 +/-3
days

- REGISTRATION (STEP 1): ECOG Performance Status ≤ 2

- REGISTRATION (STEP 1): Absolute neutrophil count (ANC) ≥ 1,500/mm^3

- REGISTRATION (STEP 1): Platelet count ≥ 100,000/mm^3

- REGISTRATION (STEP 1): Creatinine clearance eGFR ≥ 40 mL/min/1.73m^2 using the
Modification of Diet in Renal Disease (MDRD) equation

Recruiting Locations

Study Contact

Detailed Description

The primary and secondary objectives of the study: PRIMARY OBJECTIVES: I. To compare the overall survival (OS) of patients with metastatic castration-resistant prostate carcinoma (mCRPC) receiving prostate-specific antigen (PSA) adaptive dosing of lutetium 177 Lu prostate specific membrane antigen radioligand therapy (177Lu PSMA RLT) to that of patients receiving standard dose 177Lu PSMA RLT every 6 weeks. II. To compare quality of life, as measured by Functional Assessment of Cancer Therapy- Prostate (FACT-P) total scores averaged across the first 30 months, in patients with mCRPC who receive 177Lu PSMA RLT adaptive dosing versus standard dosing. SECONDARY OBJECTIVES: I. To compare the duration of treatment between standard dosing and adaptive dosing. II. To compare the radiographic progression-free survival (rPFS) between the treatment arms. III. To evaluate and compare the toxicity profile of 177Lu PSMA RLT standard dosing and 177Lu PSMA RLT adaptive dosing. IV. To compare the nadir PSA and PSA kinetics between standard and adaptive dosing. V. To compare quality-adjusted life years, which accounts for overall survival and health utility (measured by European Quality of Life Five Dimension Five Level Scale [EQ-5D-5L]), between arms. VI. To compare pain severity, as measured by the Brief Pain Inventory - Short Form (BPI-SF), between arms at 12 and 30 months. EXPLORATORY OBJECTIVES: I. To determine the frequency of tumor genomic aberrations (including but not limited to androgen receptor [AR] mutation/amplification, deoxyribonucleic acid [DNA] repair, retinoblastoma 1 [RB1], phosphatase and tensin homolog [PTEN], TP53) by circulating-tumor deoxyribonucleic acid (ctDNA) in patients achieving > 50% PSA decline versus (vs) < 50% PSA decline after 2 cycles of 177Lu PSMA RLT. II. To evaluate the relationship between OS and initial PSA response (e.g. ≥ 50% decline in PSA level from baseline [PSA50] vs ≥ 75% decline in PSA level from baseline [PSA75] vs ≥ 90% decline in PSA level from baseline [PSA90]) prior to randomization. OUTLINE: PRE-REGISTRATION STEP 0: Patients receive 177Lu PSMA RLT intravenously (IV) on day 1 of each cycle. Cycles repeat every 6 weeks for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients who achieve a PSA50 response at cycle (C) 2 day (D) 22 proceed to Step 1. RANDOMIZATION STEP 1: Patients are randomized to 1 of 2 arms. ARM 1: Patients receive 177Lu PSMA RLT IV on day 1 of each cycle. Cycles repeat every 6 weeks for up to 4 cycles in the absence of disease progression or unacceptable toxicity. ARM 2: Starting cycle 2 day 42, patients undergo blood sample collection and PSA monitoring once every 3 weeks (Q3W) in the absence of disease progression or unacceptable toxicity. Patients with either an absolute PSA rise > 4 ng/dL, PSA rise > 25% above nadir, or clinical progression receive 177Lu PSMA RLT IV three weeks later. Patients then resume PSA monitoring Q3W with adaptive 177Lu PSMA RLT dosing for up to 4 total doses in the absence of disease progression or unacceptable toxicity. Additionally, all patients undergo blood sample collection, computed tomography (CT), and bone scan throughout the trial and PSMA positron emission tomography (PET) during screening. Patients with a history of brain metastases or with clinical indication also undergo magnetic resonance imaging (MRI) throughout the trial. After completion of study treatment, patients are followed up every 12 weeks until disease progression and then every 6 months thereafter for 5 years following registration.