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177Lu-PSMA-R2 in Patients With PSMA Positive Progressive, Metastatic, Castration Resistant Prostate Cancer (PROter)

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ClinicalTrials.gov Identifier: NCT03490838
Recruitment Status : Active, not recruiting
First Posted : April 6, 2018
Last Update Posted : October 27, 2021
Sponsor:
Information provided by (Responsible Party):
Advanced Accelerator Applications

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.

Condition or disease Intervention/treatment Phase
Prostatic Neoplasm Drug: 177Lu-PSMA-R2 Phase 1

Detailed Description:
Based on the totality of the available data, the Safety Review Board (SRB) recommendation Novartis has decided to halt recruitment for PROter A206T-G01-001 (NCT03490838) and not initiate the phase II expansion portion of the study. Importantly, this recruitment halt is not a consequence of any safety concern. The treatment of the patients currently enrolled will continue according to protocol with the 1 year safety follow-up and subsequent 4 years of survival follow-up.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 27 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : May 24, 2018
Estimated Primary Completion Date : July 7, 2022
Estimated Study Completion Date : May 22, 2026

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: Phase I: Dose Escalation Cohort 1
3.70 GBq (100 mCi) x 3 times
Drug: 177Lu-PSMA-R2
radio-ligand therapy

Experimental: Phase I: Dose Escalation Cohort 2
7.40 GBq (200 mCi) up to 4 times
Drug: 177Lu-PSMA-R2
radio-ligand therapy

Experimental: Phase I: Dose Escalation Cohort 3
11.1 GBq (300 mCi) up to 4 times
Drug: 177Lu-PSMA-R2
radio-ligand therapy

Experimental: Phase I: Dose Escalation Cohort 4
14.8 GBq (400 mCi) up to 4 times
Drug: 177Lu-PSMA-R2
radio-ligand therapy

Experimental: Phase I: Dose Escalation Cohort 5
18.5 GBq (500 mCi) up to 4 times
Drug: 177Lu-PSMA-R2
radio-ligand therapy

Experimental: Phase I: Dose Escalation Cohort 6
18.5 GBq (500 mCi) up to 3 times
Drug: 177Lu-PSMA-R2
radio-ligand therapy




Primary Outcome Measures :
  1. 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 a clinically relevant adverse event or abnormal laboratory value where the relationship to study treatment cannot be ruled out, and which is unrelated to disease, disease progression, intercurrent illness, or concomitant medications that occurs within the DLT monitoring period and meets any of the criteria included in Table 5 (Dose Escalation And Stopping Rules).

  2. Phase II: Prostate-Specific Antigen 50 (PSA50) response rate [ 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) modified RECIST 1.1 criteria.


Secondary Outcome Measures :
  1. Phase I and II: Incidence of Adverse Events (AEs) rate [ Time Frame: From randomization till 30 days safety follow-up, assessed up to 5 years (estimated final OS analysis) ]
    The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

  2. Phase I and II: Objective Response Rate (ORR) [ Time Frame: From date of randomization till 30 days safety fup, assessed up to 5 years (estimated final OS analysis) ]
    ORR is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) according to PCWG3 modified RECIST 1.1.

  3. Phase I and II: Duration of Response (DoR) [ Time Frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 5 years (estimated final OS analysis) ]
    DOR is defined as the duration of time between the date of first documented response (CR or PR) in soft tissue according to PCWG3 modified RECIST 1.1, and the date of first documented progression or death due to any cause.

  4. Phase I and II: Prostate-Specific Antigen 30 (PSA30) response rate [ Time Frame: Week 13 (12 weeks after the first 177Lu-PSMA-R2 injection) ]
    PSA response rate 30 is defined as the proportion of participants who have a greater or equal 30% in PSA from Baseline that is confirmed by a second PSA measurement 4 weeks later, as per Prostate Cancer Working Group 3 (PCWG3) modified RECIST 1.1 criteria.

  5. Phase I: Prostate-Specific Antigen 50 (PSA50) response rate [ 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) modified RECIST 1.1 criteria.

  6. Phase 1: 177Lu-PSMA-R2 plasma concentration [ Time Frame: Days 1 through 8 post-treatment ]
  7. Phase I: Maximum plasma concentration (Cmax) of 177Lu-PSMA-R2 [ Time Frame: 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 ]
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.

  8. Phase I: Minimum plasma concentration (Cmin) of 177Lu-PSMA-R2 [ Time Frame: 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 ]
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmin will be listed and summarized using descriptive statistics.

  9. Phase I: Area under the plasma concentration-time curve (AUC) of 177Lu-PSMA-R2 [ Time Frame: 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 ]
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUC will be listed and summarized using descriptive statistics.

  10. Phase 1: Dosimetry [ Time Frame: Days 1 through 8 post-treatment ]
    Radiation (Gy, Gy/MBq) update by critical organs and metastatic lesions

  11. Phase I and II: Patient Reported Outcomes (PRO) of Mouth Dryness using Xerostomia Questionnaire [ Time Frame: Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
    The Xerostomia questionnaire is a questionnaire used to describe mouth dryness and its effects on daily life. It consists of 8 questions with each question score ranging from 0 ("never"/"none") to 10 ("worst"). The sum of the 8 scores produces a total score (score range from 0-80). A low score corresponds to a good quality of life while a high score means a poor quality of life due to the dry mouth.

  12. Phase I and II: Patient Reported Outcomes (PRO) of Eye Dryness using Xerophthalmia Questionnaire [ Time Frame: Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
    The Xerophthalmia questionnaire is a questionnaire used to describe eye dryness and its effects on daily life. It consists of 3 questions. The first 2 questions scores range from 1 ("never") to 4 ("constantly") and the last question is a Yes/No question about previous dry eye diagnosis. The sum of the scores of the first 2 questions produces a total score (score range from 2-8). A low score corresponds to a good quality of life while a high score means a poor quality of life due to the dry eye.

  13. Phase I and II: Brief Pain Inventory-short Form (PBI-SF) [ Time Frame: Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
    The BPI-SF is a publicly available instrument to assess the pain and includes severity and interference scores. BPI-SF is an 11-item self report questionnaire that is designed to assess the severity and impact of pain on daily functions of a participant. Pain severity score is a mean value for BPI-SF questions 3, 4, 5 and 6 (questions inquiring about the extent of pain, where the extent is ranked from 0 [no pain] to 10 [pain as bad as you can imagine]). Pain severity progression is defined as an increase in score of 30% or greater from baseline without decrease in analgesic use.

  14. Phase II: Disease Control Rate (DCR) [ Time Frame: From date of randomization till 30 days safety fup, assessed up to 5 years (estimated final OS analysis) ]
    DCR is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) or Stable Disease (SD) in soft tissue according to PCWG3 modified RECIST 1.1.

  15. Phase II: Radiographic Progression Free Survival (rPFS) [ Time Frame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 50 months (estimated final OS analysis) ]
    rPFS is defined as the time to radiographic progression by PCWG3-modified RECIST v1.1 or death.

  16. Phase II: Overall Survival (OS) [ Time Frame: From date of randomization until date of death from any cause, assessed up to 5 years (estimated final OS analysis) ]
    OS is defined as the time to death for any cause.

  17. Phase II: Time to Prostate Specific Antigen (PSA) progression [ Time Frame: From date of randomization until date of death from any cause, assessed up to 5 years (estimated final OS analysis) ]
    PSA progression is defined as the time from the date of first dose of 177Lu-PSMA-R2 injection to the first date that a >= 25% increase in PSA and an absolute increase of 2 ng/mL or more from the nadir was documented and confirmed by a second consecutive value obtained 3 or more weeks later.

  18. Phase II: Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Score [ Time Frame: Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
    The EORTC QLQ-C30 contains 30 questions assessed by the participant. There are 9 multiple-item scales: 5 scales that assess aspects of functioning (physical, role functioning, cognitive, emotional, and social); 3 symptom scales (Fatigue, Pain, and Nausea and Vomiting); and a global health status/Quality of Life (QOL) scale. There are 5 single-item measures assessing additional symptoms (i.e., dyspnea, loss of appetite, insomnia, constipation, and diarrhea) and a single item concerning perceived financial impact of the disease. All but two questions have 4 point scales ranging from "Not at all" to "Very much." The two questions concerning global health status/ QOL have 7 point scales with ratings ranging from "Very poor" to "Excellent." For each of the 14 domains, final scores are transformed such that they range from 0-100, where higher scores indicate improvement.

  19. Phase II: Change from Baseline in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Prostate Module (EORTC QLQ-PR25) Score [ Time Frame: Prior to dosing on Day 1 and every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
    The EORTC QLQ-PR25 is a prostate cancer module for the assessment of health-related quality of life (HRQoL). It consists of 25 questions distributed on 6 domains: urinary symptoms (8 items), incontinence aid (1 item), bowel symptoms (4 items), hormonal treatment-related symptoms (HTRS) (6 items), sexual activity (2 items), and sexual functioning (4 items). Questions use a 4 point scale (1 'Not at all' to 4 'Very much'). All raw domain scores are linearly transformed to a 0-100 scale, with higher scores reflecting either more symptoms (urinary, bowel, hormonal treatment-related symptoms) or higher levels of activity or functioning (sexual).



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Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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/L 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 disease progression on or after prior systemic treatment administered for the advanced disease including CYP 17 inhibitors and/or androgen-pathway inhibitors (i.e. abiraterone and/or enzalutamide when available) and no more than one line of chemotherapy for the advanced disease, or patients who were ineligible (unfit) to receive chemotherapy. Disease progression defined as increasing serum PSA (per PCWG3), radiological progression or ≥ 2 new bone lesions. (Chemical castration is required unless surgically orchiectomized.)
  • 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
  • Adequate bone marrow reserve and organ function as demonstrated by complete blood count, and biochemistry in blood and urine at baseline

    1. Platelet count of >100 x109/L
    2. White blood cell (WBC) count 3,000/mL
    3. Neutrophil count of > 1,500/mL
    4. Hemoglobin ≥ 10 g/dL
    5. Serum creatinine < 1.5 x upper limit normal (ULN) or estimated glomerular filtration rate (GFR) > 50 mL/min based upon Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation. Patients with estimated GFR between 50 - 60 mL/min at baseline will require a 99mTc-DTPA GFR test and only patients with non-obstructive pathology will be included in the study.
    6. Total bilirubin < 3 x ULN (except if confirmed history of Gilbert's disease)
    7. Baseline serum albumin > 30 g/L
    8. Aspartate aminotransferase (AST) < 3 times the ULN
  • For male patients with partners of childbearing potential, agreement to use barrier contraceptive method (condom) and to continue its use for 6 months from receiving the last dose of IP

Exclusion Criteria:

  • Pathological finding consistent with small cell, neuroendocrine carcinoma of the prostate or any other histology different than adenocarcinoma
  • Previously administered chemotherapy or 223Ra-therapy within the context of diffuse bone or 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)
  • 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 relevant 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).
    • Any factor increasing the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives, or any concomitant medication known to prolong the QT interval.
  • Other known co-existing malignancies except non-melanoma skin cancer unless definitively treated and proven no evidence of recurrence for 5 years.
  • History of deep vein thrombosis and/or pulmonary embolism within 4 weeks of enrollment.
  • Known incompatibility to CT or PET scans.
  • Any evidence of severe or uncontrolled systemic or psychiatric diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol
  • Active infection including human immunodeficiency virus (HIV) and untreated hepatitis B, and hepatitis C. Screening for chronic conditions is not required.
  • Patients who have received any investigational treatment agent within the last 28 days.
  • Known allergies, hypersensitivity, or intolerance to the IP or its excipients
  • Known history of myelodysplastic syndrome/leukemia at any time
  • Patient is unlikely to comply with study procedures, restrictions and requirements and judged by the Investigator that the patient is not suitable for participation in the study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03490838


Locations
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United States, Arizona
Pheonix Molecular Imaging Center
Phoenix, Arizona, United States, 85040
United States, California
University of California San Francisco
San Francisco, California, United States, 94158
Stanford University Medical Center
Stanford, California, United States, 94305
United States, Connecticut
Yale New Haven Children Hospital
New Haven, Connecticut, United States, 06520
United States, Louisiana
Tulane Cancer Center Tulance Cancer
New Orleans, Louisiana, United States, 70112
United States, Maryland
John Hopkins University - Kimmel Comp. Cancer Center
Baltimore, Maryland, United States, 21231
National Institute of Health
Bethesda, Maryland, United States, 20892
United States, Minnesota
Mayo Clinic Rochester
Rochester, Minnesota, United States, 55905
United States, New York
Mount Sinai Hospital School of Medicine
New York, New York, United States, 10029
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
United States, Texas
MD Anderson Cancer Center/University of Texas
Houston, Texas, United States, 77030
United States, Wisconsin
University of Wisconsin / Paul P. Carbone Comp Cancer Center
Madison, Wisconsin, United States, 53792
Spain
Hospital Vall Hebrón
Barcelona, Spain
Hospital Universitario 12 de Octubre
Madrid, Spain
United Kingdom
The Royal Marsden Hospital
Sutton, United Kingdom
Sponsors and Collaborators
Advanced Accelerator Applications
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Advanced Accelerator Applications
ClinicalTrials.gov Identifier: NCT03490838    
Other Study ID Numbers: A206T-G01-001
2017-004034-29 ( EudraCT Number )
CAAA602A12101 ( Other Identifier: Novartis )
First Posted: April 6, 2018    Key Record Dates
Last Update Posted: October 27, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Advanced Accelerator Applications:
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Cancer of Prostate
Cancer of the Prostate
Neoplasms, Prostate
Neoplasms, Prostatic
Prostate Cancer
Prostate Neoplasms
Prostatic Cancer
Prostate-Specific Membrane Antigen
PSMA
PSMA radioligand therapy
Additional relevant MeSH terms:
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Prostatic Neoplasms
Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Prostatic Diseases