An Open-label Study Comparing Lutetium (177Lu) Vipivotide Tetraxetan Versus Observation in PSMA Positive OMPC. (PSMA-DC)

• ClinicalTrials.gov Identifier: NCT05939414
• Recruitment Status: Recruiting
• First Posted: July 11, 2023
• Last Update Posted: May 3, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

The purpose of this study is to evaluate the efficacy and safety of lutetium (177Lu) vipivotide tetraxetan (AAA617) in participants with oligometastatic prostate cancer (OMPC) progressing after definitive therapy to their primary tumor. The data generated from this study will provide evidence for the treatment of AAA617 in early-stage prostate cancer patients to control recurrent tumor from progressing to fatal metastatic disease while preserving quality of life by delaying treatment with androgen deprivation therapy (ADT).

Condition or disease	Intervention/treatment	Phase
Oligometastatic Prostate Cancer (OMPC)	Drug: AAA617	Phase 3

Detailed Description:

All participants will be assessed for eligibility and will undergo baseline disease assessments including a mandatory gallium (68Ga) gozetotide (also known as [68Ga]Ga-PSMA-11) or piflufolastat (18F) ( also known as[18F]DCFPyL) PET/CT scan and conventional imaging (i.e., CT/MRI and bone scans).

Piflufolastat (18F) PET/CT scan will be performed in countries where it is approved.

Stereotactic Body Radiation Therapy (SBRT) will be administered to all metastatic Prostate Cancer (PC) lesions after randomization and before the start of treatment with AAA617 or observation.

• The duration of SBRT procedures is approximately 3 weeks.
• For participants randomized to the investigational arm (AAA617), the treatment duration will be up to 4 cycles of AAA617. For participants randomized to the control arm (observation) the treatment duration will end at the last fraction of SBRT administration.
• The visit frequency will be every week 1 and 3 of each of the 4 cycles and every 16 weeks thereafter (for both arms) until first event of disease progression (RECIST 1.1)
• The study duration is approximately 6.5 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 450 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An International, Prospective, Open-label, Multi-center, Randomized Phase III Study Comparing Lutetium (177Lu) Vipivotide Tetraxetan (AAA617) Versus Observation to Delay Castration or Disease Recurrence in Adult Male Patients With Prostate-specific Membrane Antigen (PSMA) Positive Oligometastatic Prostate Cancer (OMPC)
• Actual Study Start Date: March 12, 2024
• Estimated Primary Completion Date: January 6, 2028
• Estimated Study Completion Date: June 3, 2030

Arms and Interventions

Arm	Intervention/treatment
Experimental: Investigational Arm: lutetium (177Lu) vipivotide tetraxetan (AAA617); All participants will be treated with Stereotactic Body Radiation Therapy (SBRT) to all metastatic lesions followed by a dose of 7.4 GBq (200 mCi) +/- 10% of AAA617 which will be administered once every 6 weeks (1 cycle) for a planned 4 cycles.	Drug: AAA617; Stereotactic Body Radiation Therapy (SBRT) followed by AAA617 will be administered once every 6 weeks (1 cycle) for a planned 4 cycles to participants randomized to the Investigational arm; Other Name: (177Lu) vipivotide tetraxetan
No Intervention: Control arm: observation (watchful waiting); All participants will be treated with Stereotactic Body Radiation Therapy (SBRT) to all metastatic lesions followed by observation only.

Outcome Measures

Primary Outcome Measures :

1. Blinded Independent Review Committee (BIRC) assessed Metastasis Free Survival (MFS) [ Time Frame: From date of randomization until first evidence of radiographically detectable bone or soft tissue distant metastasis or death due to any cause, whichever occurs first, assessed up to approximately 30 months ]

   Blinded Independent Review Committee (BIRC) assessed Metastasis Free Survival (MFS) is defined as the time from randomization to first evidence of radiographically detectable bone or soft tissue distant metastasis by conventional imaging (i.e., Computed Tomography (CT)/Magnetic Resonance Imaging (MRI) and bone scans) as assessed by BIRC using RECIST 1.1 or death due to any cause, whichever occurs first.

   Participants who are alive without distant metastasis at the analysis data cut-off or are lost to follow-up at the time of analysis will be censored for MFS at the time of their last adequate radiographic assessment. Clinical deterioration without objective radiographic evidence will not be considered as documented distant metastasis.

Secondary Outcome Measures :

1. Key secondary endpoint: Time to Hormonal Therapy (TTHT) [ Time Frame: From date of randomization until date of Androgen Deprivation Therapy (ADT), assessed up to approximately 74 months ]
   Time to Hormonal Therapy (TTHT) is defined as the time from randomization to the time to Androgen Deprivation Therapy (ADT). The type of hormonal therapy will be at the discretion of the Investigator.
2. Investigator assessed Metastasis Free Survival (MFS) [ Time Frame: From date of randomization until first evidence of radiographically detectable bone or soft tissue distant metastasis or death from any cause, whichever occurs first, assessed up to approximately 74 months ]
   Investigator assessed Metastasis Free Survival (MFS) is defined as the time from randomization to the first evidence of radiographically detectable bone or soft tissue distant metastasis by conventional imaging (i.e., CT/MRI and bone scans) as assessed by Investigator using RECIST 1.1 or death from any cause, whichever occurs first.
3. Time to prostate specific antigen (PSA) progression (TTPSAP) [ Time Frame: From date of randomization until date of first PSA progression, assessed up to approximately 74 months ]
   Time to prostate specific antigen (PSA) progression (TTPSAP) is defined as time from randomization to first PSA progression 1. First PSA progression 1 is defined as a rising PSA confirmed on repeated measurement at least 3 weeks later, and at least greater than 25% and >= 2 ng/mL above nadir or baseline, whichever is lower. In the absence of PSA progression, TTPSAP will be censored at the last PSA measurement.
4. 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 approximately 74 months ]
   Radiographic progression free survival (rPFS) is defined as the time from randomization to first documentation of confirmed radiographic progressive disease or death due to any cause (whichever occurs first) by conventional imaging (i.e., CT/MRI and bone scans) using RECIST 1.1. The rPFS will be analyzed based on BIRC and Investigator assessments respectively.
5. Time to next therapy (local or systemic) [ Time Frame: From date of randomization until initiation of the next line of therapy (local or systemic), assessed up to approximately 74 months ]
   Time to next therapy (local or systemic) is defined as the time from randomization to initiation of the next line of therapy (local or systemic). Next-line therapy is defined as the first new (local or systemic) anti-neoplastic therapy initiated after discontinuation of study treatment regardless of end of treatment (EOT) reason.
6. 24-month prostate-specific antigen (PSA) progression free survival (PFS) [ Time Frame: From date of randomization until date of first documented PSA progression 2 or death from any cause, whichever occurs first, assessed up to approximately 74 months ]
   24-month PSA PFS is defined as PSA PFS at 24 months. PSA PFS is defined as the time from date of randomization to the date of first documented PSA progression 2 or death from any cause, whichever occurs first. PSA progression 2 is defined as a PSA concentration above the nadir (or baseline if lower) of >= 0.5 ng/mL, confirmed by repeated measurement at least 3 weeks later. PSA PFS will be censored if no PSA PFS event is observed before the first to occur analysis cut-off date. The censoring date will be the date of the last adequate tumor assessment prior to cut-off.
7. Time to symptomatic progression [ Time Frame: From date of randomization until date of first documented symptomatic progression, assessed up to approximately 74 months ]
   Time to symptomatic progression is defined as time from randomization to the date of first documented event for any of the following, whichever occurs first: development of symptomatic skeletal event, escalation in cancer-related pain or worsening of disease-related symptoms leading to the initiation of a new systemic anticancer therapy, development of clinically significant symptoms due to local or regional tumor progression leading to surgery or radiation therapy.
8. Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire [ Time Frame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months ]
   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 FACTGeneral (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.
9. Functional Assessment of Cancer Therapy - Radionuclide Therapy (FACT-RNT) Questionnaire [ Time Frame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months ]

   The FACT-RNT (Functional Assessment of Cancer Therapy - Radionuclide Therapy) is a Patient Reported Outcomes (PRO) new measure developed using FACIT specific questions (items), selected from FACIT item bank, to assess treatment-related symptoms of special interest associated with radioligand therapies.

   The FACT-RNT contains items assessing dry mouth, dry eyes, vomiting, diarrhea, constipation, loss of appetite, fatigue, impact of fatigue, bone pain, and isolation due to illness or treatment. FACT-RNT score range 0 to 60, with higher score indicating better quality of life.

10. Brief Pain Inventory - Short Form (BPI-SF) Questionnaire [ Time Frame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months ]
    The BPI-SF is a publicly available instrument to assess the pain and includes severity and interference scores. BPI-SF is an 11-item selfreport 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.
11. European Quality of Life (EuroQol) - 5 Domain 5 Level scale (EQ-5D- 5L) [ Time Frame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months ]
    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.
12. Time to First Symptomatic Skeletal Event (TTSE) [ Time Frame: From date of randomization till end of treatment (EOT) or death, whichever happens first, assessed up to approximately 74 months ]
    Time to first symptomatic skeletal event (TTSSE) is defined as date of randomization to the date of first new SSE or death from any cause, whichever occurs first. Symptomatic skeletal events (SSE) will be defined by the occurrence of any of the following (whichever occurs earlier): symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain.
13. Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: From date of randomization up till 42 day safety Follow-up, assessed up to approximately 74 months ]
    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.
14. Dose modifications and intensity for AAA617 [ Time Frame: From date of randomization until end of treatment (EOT), assessed up to approximately 30 months ]
    Dose modifications (dose interruptions and reductions) and dose intensity for AAA617 will be assessed and summarized using descriptive statistics.
15. Overall survival (OS) [ Time Frame: From date of randomization until date of death from any cause, assessed up to approximately 74 months ]
    Overall Survival (OS) is defined as the time from the date of randomization to the date of death due to any cause. OS time for participants who are alive at the end of the study or are lost to follow-up will be censored at the date of last contact.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Key Inclusion criteria:

1. Histologically confirmed prostate cancer prior to randomization
2. Participants must have biochemically recurrent disease after definitive treatment to prostate by Radical Prostatectomy ((RP), (alone or with post-operative radiation to prostate bed/pelvic nodes)) or External beam Radiation Therapy (XRT), (prostate alone or prostate with seminal vesicle and/or pelvic nodes) and/or brachytherapy prior to randomization. Biochemical recurrence is defined as: nadir PSA + 2 ng/mL post XRT (if participant received-radiation therapy to intact prostate) and PSA > 0.2 ng/mL and rising post RP (with or without post-operation Radiation Therapy (RT))
3. Participants must have OMPC with =< 5 PSMA-positive metastatic lesions on screening PSMA PET/CT scan (with either gallium (68Ga) gozetotide or piflufolastat (18F)) as visually assessed by BIRC based on the methodology proposed in the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE v2) (Seifert et al 2023); for further details, please refer to Section 8.1 and the Imaging Manual. Metastatic lesions may include regional/pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lung and others visceral (M1c) except liver and brain classified using AJCC 8. When counting the number of oligometastatic lesions, each lesion is counted as distinct metastasis irrespective of its anatomical location (e.g., one pelvic and one extra-pelvic lymph node will be counted as two metastatic lesions)
4. At least 1 PSMA-positive lesion should be a distant metastasis (M1) per AJCC8 classification at screening. For AJCC M staging, PSMA PET information should be used

5. Participants must have a negative conventional imaging for M1 disease at screening.

   Note:

   • For a participant not to be eligible, CI positive M1 lesions should be unequivocal in CI scans, i.e., potentially not attributable to findings thought to represent something other than tumor (e.g., degenerative, or post-traumatic changes or Paget's disease in bone lesions). For conventional imaging assessments, bone lesions must be assessed by bone scan only and soft tissue lesions must be assessed by CT/MRI scans only at screening.
   • Prior knowledge of PSMA PET positivity should not influence the radiologist (reader) in determination of CI positivity. Two different readers will be involved, one reader for PSMA PET scan and one reader for CI: Reader will be blinded to PSMA PET scan results while reading CI scans. Reader should not modify their assessment of CI scans (e.g. changing a lesion previously identified as equivocal in CI to unequivocal) after reading the PSMA PET scan. Similarly, biopsy positivity should not influence the reader in the assessment of CI positivity. More details on the reading paradigm will be provided in the imaging charter
   • MRI for radiation treatment planning may show M1 disease but this will not exclude the participant from the study if the lesion is deemed negative per baseline CT or bone scans
   • Participants with pelvic disease (N1) seen in conventional imaging are allowed if the local spread is below common iliac bifurcation (per AJCC 8 definition of local disease)
   • Distant lymph node disease (M1a) that is visible per CI and less than 10mm in the short axis is not exclusionary irrespective of PSMA PET positivity.
   • If a previously surgically removed lesion was unequivocal for M1 by bone scan or CT, the participant is not eligible.
6. All metastatic lesions detected at screening should be amenable to SBRT
7. Non-castration testosterone level >100 ng/dL at screening

Key Exclusion criteria:

1. Participants with de novo OMPC at screening
2. Unmanageable concurrent bladder outflow obstruction or urinary incontinence at screening. Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed

3. Prior therapy with:

   1. ADT including bilateral orchiectomy

      • Participants who had XRT or RP and completed adjuvant ADT (or ADT+ARPI) prior to recurrence are eligible to participate if the last dose of ADT (or ADT+ARPI) was before 12 months from randomization. Participants who had prior SBRT with short term ADT (3-6 months) are also allowed if the ADT was stopped at least 12 months before randomization.
      • Participants who discontinued ADT due to disease progression are not allowed (i.e., Castration-Resistant Prostate Cancer (CRPC) participants)

   2. Other hormonal therapy. e.g.,

      • Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethimide) if used in the context of prostate cancer treatment. Same medications are allowed if used for other indications: e.g., Benign Prostatic Hyperplasia (BPH), if stopped at least 5 half-lives before randomization.
      • First-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone)
      • Second generation anti-androgens (e.g., enzalutamide, apalutamide and darolutamide)
      • CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole). Short term ketoconazole treatment (<28 days) is permitted
   3. Radiopharmaceutical agents (e.g., Strontium-89, PSMA-targeted radioligand therapy)
   4. Immunotherapy (e.g., sipuleucel-T)
   5. Chemotherapy, except if administered in the adjuvant/neoadjuvant setting completed > 12 months before randomization
   6. Any other investigational or systemic agents for metastatic disease
4. Radiation therapy external beam radiation therapy (EBRT) and brachytherapy within 28 days before randomization
5. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormonal therapy (see ADT initiation guidance in Section 6.8.2), Poly Adenosine Diphosphate-Ribose Polymerase (PARP) inhibitor, biological therapy or investigational therapy
6. Diagnosed at screening with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease/treatment free for more than 3 years are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer.

7. History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants participating in the study such as:

   • Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second or third degree Atrioventricular (AV) block without a pacemaker
   • History of familial long QT syndrome or known family history of Torsades de Pointe
8. Participants in immediate need of ADT as assessed by the investigator.

Other protocol defined Inclusion/Exclusion may apply.

Contacts and Locations

Contacts

Contact: Novartis Pharmaceuticals; 1-888-669-6682; novartis.email@novartis.com

Contact: Novartis Pharmaceuticals; +41613241111; novartis.email@novartis.com

Locations

United States, Virginia

Virginia Oncology Associates .; Recruiting

Norfolk, Virginia, United States, 23502

Contact: Teri Raymond 757-466-8683 teri.raymond@usoncology.com

Principal Investigator: Mark Fleming

Australia, New South Wales

Novartis Investigative Site; Recruiting

Darlinghurst, New South Wales, Australia, 2010

Australia, South Australia

Novartis Investigative Site; Recruiting

Adelaide, South Australia, Australia, 5000

Canada, Quebec

Novartis Investigative Site; Recruiting

Montreal, Quebec, Canada, H2X 3E4

Novartis Investigative Site; Recruiting

Montreal, Quebec, Canada, H3T 1E2

Israel

Novartis Investigative Site; Recruiting

Haifa, Israel, 3109601

Novartis Investigative Site; Recruiting

Jerusalem, Israel, 9112001

Novartis Investigative Site; Recruiting

Tel Aviv, Israel, 6423906

Japan

Novartis Investigative Site; Recruiting

Kobe-city, Hyogo, Japan, 650-0047

Singapore

Novartis Investigative Site; Recruiting

Singapore, Singapore, 119228

Novartis Investigative Site; Recruiting

Singapore, Singapore, 168583

Switzerland

Novartis Investigative Site; Recruiting

Geneve, Switzerland, 1205

Novartis Investigative Site; Recruiting

Luzern, Switzerland, 6006

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT05939414
• Other Study ID Numbers: CAAA617D12302; 2022-502956-29-00 ( Other Identifier: EU CT number )
• First Posted: July 11, 2023
• Last Update Posted: May 3, 2024
• Last Verified: May 2024

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

• 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 (177Lu) vipivotide tetraxetan; Oligometastatic Prostate Cancer (OMPC); Metastasis Free Survival (MFS); gallium (68Ga) gozetotide; piflufolastat (18F); prostate-specific membrane antigen (PSMA); Delay Castration; Stereotactic Body Radiation Therapy (SBRT); metastasis-directed therapy; Androgen Deprivation Therapy (ADT)-free survival.

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; Chelating Agents; Sequestering Agents; Molecular Mechanisms of Pharmacological Action