PSMACare: A Phase II Study of AAA617 Alone and AAA617 in Combination With ARPI in Patients With PSMA PET Scan Positive CRPC
Study Details
Study Description
Brief Summary
The purpose of this study is to evaluate the efficacy and safety of AAA617 alone (Lutetium [177Lu] vipivotide tetraxetan) and in combination with an Androgen Receptor Pathway Inhibitors (ARPI) in participants with PSMA-positive, castration-resistant prostate cancer and no evidence of metastasis in conventional imaging (CI) (i.e., CT/MRI and bone scans). Approximately 120 participants will be randomized.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm A Participants will receive 7.4 GBq (+/- 10%) of AAA617 (Lutetium [177Lu] vipivotide tetraxetan) once every 6 weeks for 6 cycles. ADT must be ongoing; Best supportive care is allowed. |
Drug: AAA617
Administration intravenously once every 6 weeks (1 cycle) for 6 cycles
Other Names:
Drug: AAA517
Single intravenous dose of approx. 150 Megabecquerel (MBq) prior PSMA-PET scans
Other Names:
Drug: Piflufolastat F 18
Single intravenous dose of approx. 333 Megabecquerel (MBq) prior PSMA-PET scans
Drug: ADT
as prescribed by the local investigator
Other: Best supportive care
as prescribed by the local investigator
|
| Experimental: Arm B Participants will receive 7.4 GBq (+/- 10%) of AAA617 (Lutetium [177Lu] vipivotide tetraxetan) once every 6 weeks for 6 cycles. In addition of SOC (ADT plus choice of ARPI as per physician's decision), Best supportive care is allowed. |
Drug: AAA617
Administration intravenously once every 6 weeks (1 cycle) for 6 cycles
Other Names:
Drug: AAA517
Single intravenous dose of approx. 150 Megabecquerel (MBq) prior PSMA-PET scans
Other Names:
Drug: Piflufolastat F 18
Single intravenous dose of approx. 333 Megabecquerel (MBq) prior PSMA-PET scans
Drug: ARPI
Enzalutamide, Darolutamide, Apalutamide as prescribed by the local investigator
Drug: ADT
as prescribed by the local investigator
Other: Best supportive care
as prescribed by the local investigator
|
Outcome Measures
Primary Outcome Measures
- PSA response [From randomization until PSA nadir value of ≤0.2 ng/mL that is confirmed by a second (the next) PSA measurement ≥4 weeks later, up to 5 years]
PSA response is defined as the time of PSA nadir value of ≤0.2 ng/mL is confirmed by a second (the next) PSA measurement at least 4 weeks later
Secondary Outcome Measures
- Metastasic Free Survival (MFS) [From date of randomization until date of progression or date of death whichever occurs first, up to 5 years]
MFS is defined as the time from date of randomization to the first evidence of radiographically detectable bone or soft tissue distant metastasis by conventional imaging using RECIST 1.1 or death.
- Radiographic Progression Free Survival (rPFS) [From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, up to 5 years]
rPFS is defined as the time from the date of randomization to the date of first documented radiographic disease progression by conventional imaging assessed using RECIST 1.1 or death.
- Overall Survival (OS) [From date of randomization until date of death from any cause, up to 5 years]
OS defined as date of death due to any cause
- second Progression Free Survival (PFS2) [From date of randomization until date of second progression or date of death from any cause, whichever comes first, assessed up to 5 years]
PFS2 defined as time from the date of randomization to the date of first documented disease progression by investigator's assessment (PSA, radiographic, symptomatic, or any combination) on next line of therapy subsequent to MFS event or death due to any cause, whichever occurs first
- Time to symptomatic progression [From date of randomization until development of a symptomatic skeletal event, new systemic anti-cancer therapy, surgical intervention or radiation therapy, whichever occurs first, up to 5 years]
Time to symptomatic progression will be defined as the time from the date of randomization to the date of first documented event for any of the following: Development of a symptomatic skeletal event (SSE) Pain progression or worsening of disease-related symptoms requiring initiation of a new systemic anti-cancer therapy Development of clinically significant symptoms due to loco-regional tumor progression requiring surgical intervention or radiation therapy
- Time to initiation of cytotoxic chemotherapy [From the date of randomization to the date of first documented dose of new cytotoxic chemotherapy administered to the participant, up to 5 years]
Time to initiation of cytotoxic chemotherapy will be defined as the time from the date of randomization to the date of first documented dose of new cytotoxic chemotherapy being administered to the participant
- Time to first symptomatic skeletal event (TTSSE) [From the date of randomization to the date of the first new symptomatic pathological bone fracture, spinal cord compression, orthopedic surgical intervention, radiation therapy or death due to any cause, whichever occurs first, up to 5 years]
TTSSE is defined as the time from the date of randomization to the first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death due to any cause, whichever occurs first
- Time to distant metastasis development [From the date of randomization to the date of first evidence of radiographically detectable bone or soft tissue distant metastasis, up to 5 years]
Time to distant metastasis development is defined as the time from the date of randomization to the date of first evidence of radiographically detectable bone or soft tissue distant metastasis by conventional imaging using RECIST 1.1
- Time to local radiological progression [From the date of randomization to the date of first documented local radiographic disease progression, up to 5 years]
Time to local radiological progression is defined as the time from the date of randomization to the date of first documented local radiographic disease progression by conventional imaging using RECIST 1.1
- Time to initiation or change in therapy [From the date of randomization to the date of first dose of a new / change in therapy, up to 5 years]
Time to initiation or change in therapy is defined as the time from the date of randomization to the date of first documented dose of a new / change in therapy being administered to the participant
- Time to PSA response [From randomization to PSA response, up to 5 years]
Time to PSA response is calculated as the time from randomization to PSA response with a PSA nadir value of ≤0.2ng/mL.
- PSA50 response [From date of randomization until end of efficacy follow-up, up to 5 years]
PSA50 response is defined as the proportion of participants who have a ≥50% decrease in PSA from baseline that is confirmed by a second (the next) PSA measurement ≥4 weeks later
- PSA90 response [From date of randomization until end of efficacy follow-up, up to 5 years]
PSA90 response is defined as the proportion of participants who have a ≥90% decrease in PSA from baseline that is confirmed by a second (the next) PSA measurement ≥4 weeks later
- Functional Assessment of Cancer Therapy - Prostate (FACT-P) [From date of randomization until end of efficacy follow-up, up to 5 years]
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.
- Functional Assessment of Cancer Therapy - Radiotherapies (FACT-RNT) Questionnaire [From date of randomization until end of efficacy follow-up, up to 5 years]
The FACT-RNT is assessing treatment-related symptoms of special interest/associated with Radionuclides Therapies. The FACT-RNT contains 15 items assessing dry mouth, dry eyes, difficulty urinating, nausea, vomiting, diarrhea, constipation, loss of appetite, fatigue, impact of fatigue, pain, bone pain, pain interference, bothered by of side effects of treatment and isolation due to illness or treatment.
- Brief Pain Inventory - Short Form (BPI-SF) Questionnaire [From date of randomization until end of efficacy follow-up, up to 5 years]
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.
Eligibility Criteria
Criteria
Inclusion Criteria:
articipants eligible for inclusion in this study must meet all of the following criteria:
-
Signed informed consent must be obtained prior to participation in the study
-
Participants must be adults ≥18 years of age at the time of informed consent
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at screening
-
Participants must have a life expectancy ≥12 months as determined by the Investigator
-
Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell, or small cell features prior to randomization
-
CRPC demonstrated during continuous androgen deprivation therapy (ADT)/post orchiectomy, defined as 3 consecutive rises of PSA, at least 1 week apart, resulting in two ≥ 50% increases over the nadir
-
Participants must have ongoing androgen deprivation therapy with a GnRH agonist/antagonist or prior bilateral orchiectomy at the time of randomization
-
Castrate level of serum testosterone (< 1.7 nmol/l [50 ng/dL]) on GnRH agonist or antagonist therapy or after bilateral orchiectomy prior to randomization
-
PSADT of ≤ 10 months (PSADT will be calculated using a linear regression model of the normal logarithm of PSA and time (Pound et al 1999)
-
The most recent local PSA and the screening PSA should be ≥ 2 μg/L (2 ng/mL). In the event of prior first-generation anti-androgen (e.g., bicalutamide, flutamide, nilutamide) use, the most recent local PSA and the central PSA assessed at screening must be obtained at least 4 weeks after the last dose of the androgen receptor inhibitor
-
Participants must have evidence of PSMA-positive disease as seen on a AAA517 or piflufolastat F 18 PET/CT scan at baseline as determined by BICR (refer to Section 8.5.2 for details) and must have a negative conventional imaging for M1 disease.
-
Participants must have adequate organ function including the following laboratory values at the screening visit:
Bone marrow reserve
-
Absolute neutrophil count (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 participants with known Gilbert's Syndrome ≤3 x ULN is permitted
-
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN.
-
Albumin ≥2.5 g/dL Renal
-
eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation
- Human immunodeficiency virus -infected participants who are healthy and have a low risk of acquired immune deficiency syndrome -related outcomes can participate in this trial
Exclusion Criteria:
Participants meeting any of the following criteria are not eligible for inclusion in this study.
-
Prior or present evidence of metastatic disease as assessed locally by CT/MRI for soft tissue disease and whole-body radionuclide bone scan for bone disease where only radionuclide bone scan reading will be used for assessment of inclusion/exclusion. Exception: Participants with soft tissue pelvic disease may be eligible (e.g., lymph nodes below bifurcation of common iliac arteries (N1) is permissible if the short axis of the largest lymph node is <20 mm). Participants with M1 disease on PSMA PET scans are also allowed to participate.
-
Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable with best available standard of care (incl. pads, drainage) are allowed
-
Participants who could benefit from local therapy (e.g., surgery or radiation) to the prostate or pelvis. Such participants could be enrolled after completing local therapy if their PSA levels continue to rise and meet trial entry criteria.
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Prior therapy with
-
Second generation anti-androgens (e.g., enzalutamide, apalutamide and darolutamide)
-
CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole). Short duration ketoconazole treatment (<28 days) is permitted.
-
Radiopharmaceutical agents (e.g., Strontium-89), PSMA-targeted radioligand therapy
-
Immunotherapy (e.g., sipuleucel-T)
-
Chemotherapy, except if administered in the adjuvant/neoadjuvant setting, completed > 2 years before randomization
-
Any other investigational agents for CRPC
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Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethamide) or first-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone) within 28 days before randomization
-
Initiation of treatment with bisphosphonate or denosumab within 12 weeks before randomization. Note: Participants receiving bone loss prevention treatment on a stable dose (e.g. bisphosphonate or denosumab) for at least 28 days before randomization can continue the treatment during the study
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Herbal and non-herbal products that may decrease PSA levels (i.e., saw palmetto, pomegranate juice) within 28 days before randomization
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Systemic (oral/IV/IM) corticosteroids within 28 days before randomization. Note: Short term use (≤ 4 weeks) of corticosteroids during the study is allowed if clinically indicated
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Radiation therapy (external beam radiation therapy [EBRT] and brachytherapy) within 28 days before randomization
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Other concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy or investigational therapy at the time of randomization
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Use of other investigational drugs within 28 days prior to day of randomization
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Known hypersensitivity or contraindication to any of the study treatments or its excipients or to drugs of similar chemical classes, or to PSMA-targeted PET imaging agents
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Transfusion during the screening period for the sole purpose of making a subject eligible for study inclusion
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Diagnosed 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 free for more than 3 years are eligible, as are participants with adequately treated non-melanoma skin cancer, superficial bladder cancer
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Concurrent serious (as determined by the 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)
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History of seizure or condition that may pre-dispose to seizure (e.g., prior cortical stroke or transient ischemic attack within 1 year prior to randomization, brain arteriovenous malformation, schwannoma, meningioma, or other benign Central Nervous System or meningeal disease which may require treatment with surgery or radiation therapy)
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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 atrio-ventricularblock without a pacemaker
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History of familial long QT syndrome or known family history of Torsades de Pointe
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Resting heart rate (physical exam or 12 lead ECG) <60 bpm
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History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
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Any condition that precludes raised arms position
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Sexually active males unwilling to use a condom during intercourse for the period specified in Section 8.4.6
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Participants not able to understand and to comply with study instructions and requirements
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- CAAA617B12203