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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03490838
Recruitment Status : Recruiting
First Posted : April 6, 2018
Last Update Posted : February 5, 2020
Sponsor:
Information provided by (Responsible Party):
Advanced Accelerator Applications

Tracking Information
First Submitted Date  ICMJE March 26, 2018
First Posted Date  ICMJE April 6, 2018
Last Update Posted Date February 5, 2020
Actual Study Start Date  ICMJE May 24, 2018
Estimated Primary Completion Date June 24, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2019)
  • Phase 1: Incidence of dose limiting toxicities during first cycle of study treatment. [ Time Frame: dosing through 5-years post-treatment ]
  • Phase 2: PSA response rate 50 [ Time Frame: up to 5 years post-treatment ]
    reduction ≥ 50% in PSA level from basseline at 12 weeks after the first 177Lu-PSMA-R2 administration
Original Primary Outcome Measures  ICMJE
 (submitted: March 30, 2018)
  • Phase 1: Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: dosing through 5-years post-treatment ]
  • Phase 1: Maximum Tolerated Dose (MTD) [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 1: Dose Limiting Toxicity (DLT) [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 1: Characterization of Recommended Phase 2 Dose [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 1: Biodistribution [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 1: Pharmacokinetic Profile - systemic exposure [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 1: Pharmacokinetic Profile - clearance [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 1: Pharmacokinetic Profile - volume of distribution [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 1: Pharmacokinetic Profile - terminal half life [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 1: Radiation Dosimetry [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 2: radiographic progression-free survival (rPFS) per PCa working group 3 (PCWG3) [ Time Frame: up to 5 years post-treatment ]
Change History Complete list of historical versions of study NCT03490838 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2019)
  • Phase 1: Incidence Treatment-Emergent Adverse Events [ Time Frame: dosing through 5 years post-treatment ]
    safety and tolerability
  • Phase 1: Objective Response Rate (ORR) [ Time Frame: up to 5 years post-treatment ]
  • Phase 1: Duration of response [ Time Frame: up to 5 years post-treatment ]
  • Phase 1: PSA response of 30% and 50% decrease from baseline [ Time Frame: up to 5 years post-treatment ]
  • Phase 1: 177Lu-PSMA-R2 plasma concentration [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 1: Cmax 177Lu-PSMA-R2 [ Time Frame: Days 1 through 8 post-treatment ]
    maximum concentration of 177Lu-PSMA-R2 achieved
  • Phase 1: Cmin 177Lu-PSMA-R2 [ Time Frame: Days 1 through 8 post-treatment ]
  • Phase 1: AUC 177Lu-PSMA-R2 [ Time Frame: Days 1 through 8 post-treatment ]
    PK parameter (area under curve)
  • Phase 1: Dosimetry [ Time Frame: Days 1 through 8 post-treatment ]
    Radiation (Gy, Gy/MBq) update by critical organs and metastatic lesions
  • Phase 1: Patient Reported Outcome Xerostomia questionnaire [ Time Frame: every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
  • Phase 1: Patient Reported Outcome Xerophthalmia questionnaire [ Time Frame: every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
  • Phase 1: Patient Reported Outcome Brief Pain Inventory [ Time Frame: every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
  • Phase 2: Treatment Emergent Adverse Event (TEAE) rate [ Time Frame: dosing through 5 years post-treatment ]
  • Phase 2: Disease Control Rate (DCR) [ Time Frame: up to 5 years post-treatment ]
  • Phase 2: Objective Response Rate (ORR) [ Time Frame: up to 5 years post-treatment ]
  • Phase 2: Duration of Response (DoR) [ Time Frame: up to 5 years post-treatment ]
  • Phase 2: PSA response rate 30 [ Time Frame: 12 weeks after the first 177Lu-PSMA-R2 administration ]
    reduction ≥ 30% in PSA level from baseline
  • Phase 2: rPFS per PCa working group 3 (PCWG3) [ Time Frame: up to 5 years post-treatment ]
  • Phase 2: Overall Survival (OS) [ Time Frame: up to 5 years post-treatment ]
  • Phase 2: Time to PSA progression [ Time Frame: up to 5 years post-treatment ]
  • Phase 2: Change from Baseline Xerostomia questionnaire [ Time Frame: every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
  • Phase 2: Change from Baseline Xerohthalmia questionnaire [ Time Frame: every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
  • Phase 2: Change from Baseline Brief Pain Inventory [ Time Frame: every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
  • Phase 2: Change from Baseline Quality of Life Questionnaire for cancer patients (QLQ-C30) [ Time Frame: every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
  • Phase 2: Change from Baseline Quality of Life Questionnaire for patients with prostate cancer (QLQ-PR25) [ Time Frame: every 12 weeks until 1 year after disease progression or early study termination whichever comes first ]
Original Secondary Outcome Measures  ICMJE
 (submitted: March 30, 2018)
  • Phase 1: PSA response [ Time Frame: weeks 7, 13, and 19 and up to 5 years post-treatment ]
  • Phase 1: Time to PSA progression [ Time Frame: 5 years post-treatment ]
  • Phase 1: rPFS per PCWG3 [ Time Frame: 5 years post-treatment ]
  • Phase 1: Overall Survival (OS) [ Time Frame: 5 years post-treatment ]
  • Phase 2: Treatment-Emergent Adverse Events [ Time Frame: dosing up to 5 years post-treatment ]
  • Phase 2: PSA response [ Time Frame: weeks 7, 13, 19 and up to 5 years post-treatment ]
  • Phase 2: Time to PSA progression [ Time Frame: 5 years post-treatment ]
  • Phase 2: Overall Survival [ Time Frame: 5 years post-treatment ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 177Lu-PSMA-R2 in Patients With PSMA Positive Progressive, Metastatic, Castration Resistant Prostate Cancer
Official Title  ICMJE 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
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 Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:
Phase 1 dose escalation: patients enrolled in parallel to one of up to seven dose groups Phase 2 dose expansion: single group, enrolled after Phase 1 dose escalation completed
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Prostatic Neoplasm
Intervention  ICMJE Drug: 177Lu-PSMA-R2
radio-ligand therapy
Study Arms  ICMJE
  • Experimental: Phase I: Dose Escalation Cohort 1
    3.70 GBq (100 mCi) x 3 times
    Intervention: Drug: 177Lu-PSMA-R2
  • Experimental: Phase I: Dose Escalation Cohort 2
    7.40 GBq (200 mCi) up to 4 times
    Intervention: Drug: 177Lu-PSMA-R2
  • Experimental: Phase I: Dose Escalation Cohort 3
    11.1 GBq (300 mCi) up to 4 times
    Intervention: Drug: 177Lu-PSMA-R2
  • Experimental: Phase I: Dose Escalation Cohort 4
    14.8 GBq (400 mCi) up to 4 times
    Intervention: Drug: 177Lu-PSMA-R2
  • Experimental: Phase I: Dose Escalation Cohort 5
    18.5 GBq (500 mCi) up to 4 times
    Intervention: Drug: 177Lu-PSMA-R2
  • Experimental: Phase I: Dose Escalation Cohort 6
    22.2 (600 mCi) up to 4 times
    Intervention: Drug: 177Lu-PSMA-R2
  • Experimental: Phase II: Dose Expansion Cohort
    Dose to be chosen from Phase I
    Intervention: Drug: 177Lu-PSMA-R2
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 30, 2018)
96
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 24, 2022
Estimated Primary Completion Date June 24, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 4.03 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Noella Gilbert 917-843-0321 noella.gilbert@adacap.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03490838
Other Study ID Numbers  ICMJE A206T-G01-001
2017-004034-29 ( EudraCT Number )
CAAA602A12101 ( Other Identifier: Novartis )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Advanced Accelerator Applications
Study Sponsor  ICMJE Advanced Accelerator Applications
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Darhsan Dalal, MD Advanced Accelerator Applications
PRS Account Advanced Accelerator Applications
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP