A Phase 1/2 Open-label, Multi-center, Dose-escalation Study of Safety, Tolerability, Pharmacokinetics, Dosimetry, and Response to Repeat Dosing of 177Lu-PSMA-R2 Radio-ligand Therapy in Patients With Prostate Specific Membrane Antigen (PSMA) Positive (68Ga-PSMA-R2) Progressive Metastatic Castration-resistant Prostate Cancer, Following Previous Systemic Treatment
Overview
- Phase
- Phase 1
- Intervention
- 177Lu-PSMA-R2
- Conditions
- Prostatic Neoplasm
- Sponsor
- Advanced Accelerator Applications
- Enrollment
- 27
- Locations
- 11
- Primary Endpoint
- Phase II: Prostate-Specific Antigen (PSA) response rate 50
- Status
- Terminated
- Last Updated
- 11 months ago
Overview
Brief Summary
This Phase 1/2 study is intended to investigate the safety, tolerability, and radiation dosimetry of 177Lu-PSMA-R2 and further assess preliminary efficacy data in patients with metastatic castration-resistant prostate cancer (mCRPC). The Phase 1 portion of the study will determine the recommended dose of 177Lu-PSMA-R2 for radio-ligand therapy (RLT) of mCRPC, and the Phase 2 portion will expand into approximately 60 patients documenting the preliminary activity (anti-tumor response) of repeated treatments administered, continuing safety assessments and collecting QoL data.
Detailed Description
Recruitment for PROter A206T-G01-001 (NCT03490838) was halted in Phase I by sponsor decision. Phase II expansion portion of the study was never initiated. Importantly, this recruitment halt was not a consequence of any safety concern. Ongoing patients at the time of recruitment halt continued per protocol and completed the 1 year safety follow-up prior to early study termination. The primary objective of the Phase I portion of the study to assess the safety and tolerability of 177Lu-PSMA-R2 and to assess Dose Limiting Toxicities (DLTs) and determine the maximum tolerated dose (MTD) (if reached) and the recommended Phase II dose was not reached due to early recruitment halt.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Male patients, 18 years of age or older
- •Signed and dated written ICF by the patient or legally acceptable representative prior to any study-specific procedures
- •Histologically confirmed adenocarcinoma of the prostate
- •Serum testosterone levels \< 50 ng/dL after surgical or continued chemical castration
- •Metastatic disease documented by CT/MRI or bone scan (not older than 28 days at enrollment) revealing at least one metastatic lymph-node, visceral metastasis and/or bone metastasis
- •Positive 68Ga-PSMA-R2 PET/CT scan for central eligibility assessment. Patients who receive 68Ga-PSMA-R2 as part of separate clinical protocol are eligible (must meet all study eligibility criteria)
- •Documented progressive mCRPC on or after the last systemic treatment administered for the advanced disease including metastatic disease. Disease progression defined as increasing serum PSA (per PCWG3), radiological progression or ≥ 2 new bone lesions.
- •Must have received prior systemic treatment for mCRPC including CYP17 inhibitors and/or androgen-pathway inhibitors (i.e. abiraterone and/or enzalutamide when available) and one and no more than one line of chemotherapy for the advanced disease (unless ineligible (unfit) to receive chemotherapy).
- •At least 28 days elapsed between last anti-cancer treatment administration and the initiation of study treatment (except for Luteinizing Hormone-releasing Hormone \[LHRH\] or Gonadotropin-releasing Hormone \[GnRH\]), or resolution of all previous treatment related toxicities to CTCAE version 5.0 grade of ≤ 1 (except for chemotherapy induced alopecia and grade 2 peripheral neuropathy or grade 2 urinary frequency which are allowed). Prior major surgery must be at least 12 weeks prior to study entry.
- •Eastern cooperative oncology group (ECOG) performance status of 0-2 with a life expectancy ≥ 6 months
Exclusion Criteria
- •Pathological finding consistent with small cell, neuroendocrine carcinoma of the prostate or any other histology different than adenocarcinoma.
- •Diffuse bone-marrow involvement (i.e. "superscan" defined as bone scintigraphy in which there is excessive skeletal radioisotope uptake \[\>20 bone lesions\] in relation to soft tissues along with absent or faint activity in the genitourinary tract due to diffuse bone/ bone marrow metastases)
- •Prior exposure to radioligand therapy radioisotope therapy (e.g. 89Sr), systemic radiotherapy or 223Ra-therapy.
- •Current severe urinary incontinence, hydronephrosis, severe voiding dysfunction, any level of urinary obstruction requiring indwelling/condom catheters
- •Spinal cord compression or brain metastases
- •Uncontrolled pain that results in patient's lack of compliance with the imaging procedures
- •Uncontrolled cardiovascular history, defined as:
- •Congestive heart failure (New York Heart Association \[NYHA\] II, III, IV)
- •Mean resting corrected QT interval (QTc) \>450 millisecond (msec), obtained from 3 ECGs recordings, using the screening clinic ECG machine-derived QTc value.
- •Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval \>250 msec).
Arms & Interventions
Phase I: Dose Escalation Cohort 1
3.70 GBq (100 mCi) x 3 times
Intervention: 177Lu-PSMA-R2
Phase I: Dose Escalation Cohort 2
7.40 GBq (200 mCi) up to 4 times
Intervention: 177Lu-PSMA-R2
Phase I: Dose Escalation Cohort 3
11.1 GBq (300 mCi) up to 4 times
Intervention: 177Lu-PSMA-R2
Phase I: Dose Escalation Cohort 4
14.8 GBq (400 mCi) up to 4 times
Intervention: 177Lu-PSMA-R2
Phase I: Dose Escalation Cohort 5
18.5 GBq (500 mCi) up to 4 times
Intervention: 177Lu-PSMA-R2
Phase I: Dose Escalation Cohort 6
18.5 GBq (500 mCi) up to 3 times
Intervention: 177Lu-PSMA-R2
Outcomes
Primary Outcomes
Phase II: Prostate-Specific Antigen (PSA) response rate 50
Time Frame: Week 13 (12 weeks after the first 177Lu-PSMA-R2 injection)
PSA response rate 50 is defined as the proportion of participants who have a greater or equal 50% in PSA from Baseline that is confirmed by a second PSA measurement 4 weeks later, as per Prostate Cancer Working Group 3 (PCWG3) criteria.
Phase I: Incidence of dose limiting toxicities (DLTs) during first cycle of study treatment.
Time Frame: Up to 8 weeks after the first 177Lu-PSMA-R2 dose
A dose-limiting toxicity (DLT) is defined as any toxicity not attributable to the disease or disease-related processes under investigation, the time window for DLT assessment period is Cycle 1. To be considered a DLT, it must be related to the IP (attributions: possible, probable, and definite) while fulfilling one of the following criteria as per the NCI Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0.
Secondary Outcomes
- Phase I and II: Patient Reported Outcomes (PRO) of Eye Dryness using Xerophthalmia Questionnaire(Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first)
- Phase I and II: Objective Response Rate (ORR)(From date of randomization assessed up to 4 years (estimated final OS analysis))
- Phase I: 177Lu-PSMA-R2 plasma concentration(Days 1 through 8 post-treatment)
- Phase II: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Score(Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first)
- Phase I and II: Treatment Emergent Adverse Event (TEAE) rate(From randomization till 30 days safety follow-up, assessed up to 4 years (estimated final OS analysis))
- Phase I and II: Duration of Response (DoR)(From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 4 years (estimated final OS analysis))
- Phase I: Prostate-Specific Antigen (PSA) response rate 50(Week 13 (12 weeks after the first 177Lu-PSMA-R2 injection))
- Phase I: Maximum plasma concentration (Cmax) of 177Lu-PSMA-R2(Day 1 (before the start of infusion, at the mid-point, and just before the end of infusion, then at post infusion at approximately 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24, 40 (+/- 4 hours), 48 hours), Day 4 (+2 days) and Day 8 post end of infusion)
- Phase I: Minimum plasma concentration (Cmin) of 177Lu-PSMA-R2(Day 1 (before the start of infusion, at the mid-point, and just before the end of infusion, then at post infusion at approximately 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24, 40 (+/- 4 hours), 48 hours), Day 4 (+2 days) and Day 8 post end of infusion)
- Phase I and II: Patient Reported Outcomes (PRO) of Mouth Dryness using Xerostomia Questionnaire(Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first)
- Phase II: Radiographic Progression Free Survival (rPFS)(From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 4 years (estimated final OS analysis))
- Phase II: Time to Prostate Specific Antigen (PSA) progression(From date of randomization until date of death from any cause, assessed up to 4 years (estimated final OS analysis))
- Phase I and II: Prostate-Specific Antigen (PSA) response rate 30(Week 13 (12 weeks after the first 177Lu-PSMA-R2 injection))
- Phase I: Area under the plasma concentration-time curve (AUC) of 177Lu-PSMA-R2(Day 1 (before the start of infusion, at the mid-point, and just before the end of infusion, then at post infusion at approximately 5, 15, 30 minutes, 1, 2, 4, 6, 8, 24, 40 (+/- 4 hours), 48 hours), Day 4 (+2 days) and Day 8 post end of infusion)
- Phase II: Disease Control Rate (DCR)(From date of randomization till 30 days safety fup, assessed up to 4 years (estimated final OS analysis))
- Phase I: Dosimetry(Days 1 through 8 post-treatment)
- Phase II: Overall Survival (OS)(From date of randomization until date of death from any cause, assessed up to 4 years (estimated final OS analysis))
- Phase II: Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Prostate Module (EORTC QLQ-PR25) Score(Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first)
- Phase I and II: Brief Pain Inventory-short Form (PBI-SF)(Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first)