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An International Prospective Open-label, Randomized, Phase III Study Comparing 177Lu-PSMA-617 in Combination With Soc, Versus SoC Alone, in Adult Male Patients With mHSPC (PSMAddition)

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: NCT04720157
Recruitment Status : Recruiting
First Posted : January 22, 2021
Last Update Posted : December 2, 2021
Sponsor:
Collaborators:
Alliance Foundation Trials, LLC.
RTOG Foundation, Inc.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
The purpose of this study is to evaluate the efficacy and safety of 177Lu-PSMA-617 in combination with Standard of Care, versus Standard of Care alone, in adult male patients with mHSPC. In this study, the SoC is defined as a combination of Androgen Receptor Directed Therapy + Androgen Deprivation Therapy. Approximately 1126 patients will be randomized in this study.

Condition or disease Intervention/treatment Phase
Prostatic Neoplasms Drug: 177Lu-PSMA-617 Diagnostic Test: 68Ga-PSMA-11 Drug: ARDT Drug: ADT Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1126 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Patient randomized to SOC arm have an option to crossover to 177Lu-PSMA-617 treatment after rPFS
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-label, Randomized, Phase III Study Comparing 177Lu-PSMA-617 in Combination With Standard of Care, Versus Standard of Care Alone, in Adult Male Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)
Actual Study Start Date : June 9, 2021
Estimated Primary Completion Date : August 29, 2024
Estimated Study Completion Date : December 18, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Prostate Cancer

Arm Intervention/treatment
Experimental: 177Lu-PSMA-617
Participant will receive 7.4 GBq (+/- 10%) 177Lu-PSMA-617, once every 6 weeks (+/- 1 week) for a planned 6 cycles, in addition to the Standard of Care (SOC); ARDT +ADT is considered as SOC and treatment will be administered per the physician's order
Drug: 177Lu-PSMA-617
administered intravenously once very 6 weeks (1 cycle) for 6 cycles

Diagnostic Test: 68Ga-PSMA-11
Single intravenous dose of approx. 150 Megabecquerel (MBq)

Drug: ARDT
Administered orally on a continuous basis as per package insert and guideline

Drug: ADT
ADT are administered as per physician order

Active Comparator: Standard of Care
For participants randomized to Standard of Care arm, ARDT +ADT is considered as SOC and treatment will be administered per the physician's order
Diagnostic Test: 68Ga-PSMA-11
Single intravenous dose of approx. 150 Megabecquerel (MBq)

Drug: ARDT
Administered orally on a continuous basis as per package insert and guideline

Drug: ADT
ADT are administered as per physician order




Primary Outcome Measures :
  1. 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 of radiographic progression by Prostate Cancer Working Group 3 (PCWG3)-modified RECIST V1.1 as assessed by blinded independent central review, or death


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: From date of randomization until date of death from any cause, assessed up to 50 months (estimated final OS analysis) ]
    OS is defined as time to death for any cause

  2. Prostate-specific antigen 90 (PSA90) response [ Time Frame: From date of randomization till 30 days safety fup, assessed up to 50 months (estimated final OS analysis) ]
    PSA90 response is defined as the proportion of patients who have a more/equal 90% decrease in PSA from baseline, it will be calculated at 3, 6 and 12 months

  3. time to development of mCRPC [ Time Frame: From date of randomization till End Of Treatment (EOT) or death, which ever happen first, assessed up to 50 months (estimated final OS analysis) ]
    Time to development of mCRPC is defined as the time from date of randomization to disease progression despite androgen deprivation therapy (ADT) presenting as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre existing disease, and/or the appearance of new metastases.

  4. Progression Free Survival (PFS) [ Time Frame: From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 50 months (estimated final OS analysis) ]
    PFS is defined as the time from date of randomization to the date of first documented progression by investigator assessment (radiographic progression, clinical progression, PSA progression) or death from any cause, whichever occurs first

  5. second Progression Free Survival (PFS2) [ Time Frame: From date of randomization until date of second progression or date of death from any cause, whichever comes first, assessed up to 50 months (estimated final OS analysis) ]
    PFS2 is defined as time from date of randomization to the first documented progression by investigator assessment (radiographic progression, clinical progression, PSA progression) on next-line therapy or death from any cause, whichever occurs first.

  6. Change in nadir level of PSA lower than 0.2 ng/ml [ Time Frame: From date of randomization till 30 days safety fup, whichever occur first, assessed up to 50 months (estimated final OS analysis) ]
    Proportion of patients with PSA < 0.2 ng/mL at months 3, 6 and 12 months

  7. Time to radiographic soft tissue progression (TTSTP) [ Time Frame: From date of randomization until date of soft tissue radiographic progression or date of death from any cause, whichever comes first, assessed up to 50 months (estimated final OS analysis) ]
    TTSTP is defined as time from randomization to radiographic soft tissue progression per PCWG3-modified RECIST v1.1 (Soft Tissue Rules of Prostate Cancer Working Group modified Response Evaluation Criteria in Solid Tumors Version 1.1) as assessed by Blinded Independent Central Review (BICR)

  8. Time to first symptomatic skeletal event (SSE). [ Time Frame: From date of randomization till EOT or death, whichever happens first, assessed up to 50 months (estimated final OS analysis) ]
    Time to SSE (TTSSE) is defined as date of randomization to the date of first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first

  9. Overall Response Rate (ORR) [ Time Frame: From date of randomization till 30 days safety fup, assessed up to 50 months (estimated final OS analysis) ]
    ORR is defined as the proportion of participants with best overall response of complete response or partial response in soft tissue as per BIRC and according to PCWG3 modified RECIST 1.1

  10. Disease Control Rate (DCR) [ Time Frame: From date of randomization till 30 days safety fup, assessed up to 50 months (estimated final OS analysis) ]
    DCR is defined as the proportion of participants with best overall response of complete response or partial response or Stable disease in soft tissue as per BIRC and according to PCWG3 modified RECIST 1.1

  11. 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 50 months (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 as per BIRC and according to PCWG3 modified RECIST 1.1, and the date of first documented progression or death due to any cause

  12. Time to Response (TTR) [ Time Frame: From date of randomization till 30 days safety fup, assessed up to 50 months (estimated final OS analysis) ]
    TTR is defined as the time from the date of randomization to the date of first documented response (CR or PR).

  13. Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire [ Time Frame: From randomization up till 30 day safety Follow-up or week 48 of long term Follow-up for patients prematurely discontinued, assessed up to 50 months (estimated final OS analysis) ]
    FACT-P assesses symptoms/problems related to prostate carcinoma and its treatment. It is a combination of the FACT-General + the Prostate Cancer Subscale (PCS). The FACT-General (FACT-G) is a 27 item Quality of Life (QoL) measure that provides a total score as well as subscale scores: Physical (0-28), Functional (0-28), Social (0-28), and Emotional Well-being (0-24). The total score range is between 1-108, higher scores indicates better for total score and subscale scores. PCS is a 12-item prostate cancer subscale that asks about symptoms and problems specific to prostate cancer (Range 0-48, higher scores better). The FACT-P total score is the sum of all 5 subscale scores of the FACT-P questionnaire and ranges from 0-156. Higher scores indicate higher degree of functioning and better quality of life.

  14. European Quality of Life ( EuroQoL) -5 Domain 5 Level Scale (EQ-5D-5L) [ Time Frame: From screening up till 30 day safety follow-up or week 48 of long term follow up for patient prematurely discontinued, assessed up to 50 months (estimated final OS analysis) ]
    EQ-5D-5L is a standardized participant completed questionnaire that measures health-related quality of life and translates that score into an index value or utility score. EQ-5D-5L consists of two components: a health state profile and an optional visual analogue scale (VAS). EQ-5D health state profile is comprised of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3=moderate problems, 4= severe problems, and 5= extreme problems. Higher scores indicated greater levels of problems across each of the five dimensions.

  15. Brief Pain Inventory-short Form (PBI-SF) [ Time Frame: From screening up till 30 day safety follow-up or week 48 of long term follow up for patient prematurely discontinued, assessed up to 50 months (estimated final OS analysis) ]
    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.

  16. Number of participants with Treatment Emergent Adverse Events [ Time Frame: From randomization till 30 days safety follow-up, assessed up to 50 months (estimated final OS analysis) ]
    The distribution of adverse events (AE) 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.



Information from the National Library of Medicine

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
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Prostate cancer patients
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Participants eligible for inclusion in this study must meet all of the following criteria:

  1. Signed informed consent must be obtained prior to participation in the study
  2. Patients must be adults ≥18 years of age
  3. Patients must have an ECOG performance status of 0 to 2
  4. Patients must have a life expectancy >9 months as determined by the study investigator
  5. Patients must have metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma (current or prior biopsy of the prostate and/or metastatic site)
  6. Patients must have evidence of PSMA-positive disease as seen on a 68Ga-PSMA-11 PET/CT scan, and eligible as determined by the sponsor's central reader
  7. Patients must have documented metastatic disease to bone and/or soft tissue/visceral sites documented in one of the following manners within 28 days prior randomization:

    1. Metastatic disease to the bone (in any distribution) visible on 99Tc-MDP bone scintigraphy on either pre-ADT scans or baseline scans. OR
    2. Lymph node metastases of any size or distribution. If lymph nodes are the only site of metastasis, then at least one must be at least 1.5 cm in short axis AND outside of the pelvis. OR
    3. Visceral metastases of any size or distribution. If a subject has a history of visceral metastases at any time prior to registration, he should be coded as having visceral metastases at baseline (i.e., patients with visceral metastases prior to ADT that disappear at baseline will be counted as having visceral metastases and would therefore have high volume disease for stratification purposes).
  8. Patients must have adequate organ function:

    • Bone marrow reserve ANC ≥1.5 x 109/L Platelets ≥100 x 109/L Hemoglobin ≥9 g/dL
    • Hepatic Total bilirubin ≤2 x the institutional upper limit of normal (ULN). For patients with known Gilbert's Syndrome ≤3 x ULN is permitted Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN OR ≤5.0 x ULN for patients with liver metastases
    • Renal eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation
  9. Albumin ≥2.5 g/dL
  10. Human immunodeficiency virus (HIV)-infected patients who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes can participate in this trial
  11. Patients must be:

Treatment naïve OR minimally treated with:

  • Up to 45 days of luteinizing hormone-releasing hormone (LHRH) agonist /antagonists or bilateral orchiectomy with or without first generation anti-androgen (e.g. bicalutamide, flutamide) for metastatic prostate cancer is allowed prior to ICF signature. If given, first generation anti-androgen must be discontinued prior to start of therapy.
  • If received, prior LHRH agonist/antagonist use in the adjuvant/neo-adjuvant setting must have been discontinued > 12 months prior to ICF signature AND must not have exceeded 24 months of therapy AND must not have shown disease progression within 12 months of completing adjuvant/neo-adjuvant therapy.
  • Up to 45 days of CYP17 inhibitor or ARDT exposure for metastatic prostate cancer is allowed prior to ICF signature. No exposure for earlier stages of prostate cancer is allowed.

Exclusion Criteria:

Participants meeting any of the following criteria are not eligible for inclusion in this study.

  1. Patients with rapidly progressing tumor that requires urgent exposure to taxane-based chemotherapy
  2. Any systemic anti-prostate cancer therapy (with the exception of the drugs listed on inclusion criteria 11), including chemotherapy, PARP inhibitors, immunotherapy or biological therapy (including monoclonal antibodies).
  3. Other concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, or investigational therapy
  4. Previous treatment with any of the following within 6 months of randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation. Previous PSMA-targeted radioligand therapy is not allowed
  5. Ongoing participation in any other clinical trial
  6. Use of other investigational drugs within 30 days prior to day of randomization
  7. Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes
  8. Transfusion for the sole purpose of making a subject eligible for study inclusion
  9. Patients with CNS metastases that are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose 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 (magnetic resonance imaging (MRI) preferred or CT with contrast).
  10. Diagnosed with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, patients with a prior history of malignancy that has been adequately treated and who have been disease free for more than 3 years are eligible, as are patients with adequately treated non-melanoma skin cancer, superficial bladder cancer. Note: Patients with a history of CNS metastases that have received prior therapy and are neurologically stable, asymptomatic and not receiving corticosteroids are allowed.
  11. Concurrent serious (as determined by the Principal Investigator) medical conditions, including, but not limited to, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the investigator would impair study participation or cooperation. Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance) and had no symptoms for at least 28 days before the first dose of study medication
  12. No active clinically significant cardiac disease defined as any of the following:

    • NYHA class 3/4 congestive heart failure within 6 months prior to ICF signature unless treated with improvement and echocardiogram or MUGA demonstrates EF > 45% with improvement in symptoms to class < 3.
    • History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants in the study such as: Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third degree AV block)
    • History of familial long QT syndrome or known family history of Torsades de Pointes
    • Cardiac or cardiac repolarization abnormality, including any of the following: History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to ICF signature
  13. History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
  14. Symptomatic cord compression, or clinical or radiologic findings indicative of impending cord compression
  15. Any condition that precludes raised arms position
  16. Concurrent bladder outflow obstruction or unmanageable urinary incontinence
  17. Sexually active males unwilling to use a condom during intercourse while taking study treatment and for 6 months after stopping study treatment. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above. If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF

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): NCT04720157


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com

Locations
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United States, Florida
Cancer Specialists of North Florida Recruiting
Jacksonville, Florida, United States, 32256
Contact: Jacob Andring    904-538-3667    Jacob.Andring@CSNF.us   
Principal Investigator: Miten Patel         
United States, Louisiana
Tulane Cancer Center Recruiting
New Orleans, Louisiana, United States, 70112
Contact    +1 504 585-6077      
Principal Investigator: Alton Oliver Sartor         
United States, Nebraska
Nebraska Cancer Specialists Recruiting
Omaha, Nebraska, United States, 68130
Contact: Marlene Bridwell    402-691-6972    mbridwell@nebraskacancer.com   
Principal Investigator: Ralph Hauke         
Urology Cancer Center PC Recruiting
Omaha, Nebraska, United States, 68130
Contact: Jennifer Johnson    402-697-2229    jjohnson@gucancer.com   
Principal Investigator: Luke Nordquist         
Austria
Novartis Investigative Site Recruiting
Innsbruck, Tyrol, Austria, 6020
Novartis Investigative Site Recruiting
Linz, Austria, A-4010
Novartis Investigative Site Recruiting
Wien, Austria, 1090
Belgium
Novartis Investigative Site Recruiting
Gent, Belgium, 9000
France
Novartis Investigative Site Recruiting
Bordeaux Cedex, France, 33075
Novartis Investigative Site Recruiting
Clermont-Ferrand, France, 63011
Novartis Investigative Site Recruiting
Lyon Cedex, France, 69373
Novartis Investigative Site Recruiting
Nantes Cedex 1, France, 44093
Novartis Investigative Site Recruiting
Paris, France, 75015
Novartis Investigative Site Recruiting
Paris, France, 75018
Novartis Investigative Site Recruiting
Strasbourg, France, 67200
Novartis Investigative Site Recruiting
Vandoeuvre Cedex, France, 54511
Novartis Investigative Site Recruiting
Villejuif Cedex, France, 94800
Netherlands
Novartis Investigative Site Recruiting
Nijmegen, Netherland, Netherlands, 6525 GA
Poland
Novartis Investigative Site Recruiting
Gliwice, Slaskie, Poland, 44-101
Novartis Investigative Site Recruiting
Warszawa, Poland, 02 781
Spain
Novartis Investigative Site Recruiting
Sabadell, Barcelona, Spain, 08208
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08036
Novartis Investigative Site Recruiting
Hospitalet de LLobregat, Catalunya, Spain, 08907
Novartis Investigative Site Recruiting
Santiago de Compostela, Galicia, Spain, 15706
Novartis Investigative Site Recruiting
El Palmar, Murcia, Spain, 30120
Novartis Investigative Site Recruiting
Madrid, Spain, 28034
Novartis Investigative Site Recruiting
Madrid, Spain, 28040
Novartis Investigative Site Recruiting
Madrid, Spain, 28041
Novartis Investigative Site Recruiting
Madrid, Spain, 28046
Novartis Investigative Site Recruiting
Madrid, Spain, 28222
Novartis Investigative Site Recruiting
Valencia, Spain, 46026
Sweden
Novartis Investigative Site Recruiting
Goteborg, Sweden, 413 45
Novartis Investigative Site Recruiting
Lund, Sweden, 221 85
Sponsors and Collaborators
Novartis Pharmaceuticals
Alliance Foundation Trials, LLC.
RTOG Foundation, Inc.
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04720157    
Other Study ID Numbers: CAAA617C12301
2020-003968-56 ( EudraCT Number )
First Posted: January 22, 2021    Key Record Dates
Last Update Posted: December 2, 2021
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


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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 Novartis ( Novartis Pharmaceuticals ):
Lutetium-177 PSMA-617
177Lu-PSMA-617
Androgen receptor-directed therapy
ARDT
Androgen Deprivation Therapy
ADT
Metastatic Hormone sensitive prostate cancer
mHSPC
Radiographic progression free survival
rPFS
Prostate-specific membrane antigen
PSMA
Gallium-68 PSMA-11
68Ga-PSMA-11
Radioligand Therapy
RLT
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Gallium 68 PSMA-11
177Lu-PSMA-617
Radiopharmaceuticals
Molecular Mechanisms of Pharmacological Action