Modulation of plasma lipidomic signature in metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS331-TPS331
Author(s):  
Blossom Mak ◽  
Kate Lynette Mahon ◽  
Martin R. Stockler ◽  
Anthony M. Joshua ◽  
Alison Yan Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Lipid Profile ◽  
Primary Objective ◽  
Lipid Lowering ◽  
Castration Resistant Prostate Cancer ◽  
Prognostic Signature ◽  
Open Label ◽  
Metabolic Characteristics ◽  
Type 1 Error ◽  
The Poor

TPS331 Background: Altered lipid metabolism and its impact on prostate cancer (PC) is increasingly recognised, in light of the association between obesity and worse PC outcomes. Our exploratory study was the first to identify baseline plasma lipidomic profiles in men with mCRPC commencing docetaxel that were associated with survival. A prognostic three-lipid signature was derived, consisting of ceramide, sphingomyelin and phosphatidylcholine (HR 4.8, 95% CI 2.06-11.1, p = 0.0003). This signature was independently prognostic when modelled with clinicopathological factors and metabolic characteristics. A key question is whether therapeutic modulation of a patient’s lipid profile is possible. Statins significantly reduce the plasma levels of ceramides, sphingomyelin and cholesterol in cardiovascular disease, suggesting that this therapy could change the poor prognostic lipid profile of mCRPC patients. This trial assesses whether addition of simvastatin to docetaxel for mCRPC can reverse the poor prognostic lipid signature with the aim of developing a precision medicine strategy for metabolic targeting. Methods: This investigator-initiated, multi-centre, open-label, single arm, pilot study enrols patients with mCRPC commencing docetaxel for disease progression, not already receiving a lipid-lowering agent. Patients are treated with simvastatin 40mg orally once daily for 12 weeks, commencing on day 1 of the first cycle of docetaxel. Blood is taken at baseline and after 12 weeks of simvastatin and the plasma lipidomic profile is determined using liquid chromatography and electrospray ionisation-tandem mass spectrometry. The lipidomic profile is classified as either good or poor prognostic as per our three-lipid signature model derived by logistic regression. The primary objective is to assess the rates of conversion from a poor prognostic lipid signature to good prognostic after simvastatin. A sample size of 60 men provides over 90% power, with a 1-sided type 1 error of 10%, to detect conversion to the good prognostic signature in 50% of patients, assuming 25% of patients have the poor prognostic signature at baseline as previously detected. To date, 6 patients have been enrolled to the trial. Clinical trial information: ACTRN12617000965303.

A multicenter, randomized, controlled phase II study: Efficacy and safety of PSMA-targeted radioligand therapy I-131-1095 (1095) plus enzalutamide (enza) in 18F-DCFPyL PSMA scan avid, metastatic castration-resistant prostate cancer (mCRPC) patients post-abiraterone (abi) progression (ARROW).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS5596-TPS5596
Author(s):  
Evan Y. Yu ◽  
David Laidley ◽  
Frederic Pouliot ◽  
Stephan Probst ◽  
Robert Sabbagh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
Radiographic Progression ◽  
Objective Response ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Radioligand Therapy ◽  
Open Label ◽  
Recist 1.1 ◽  
Modified Recist

TPS5596 Background: PSMA is a transmembrane glycoprotein expressed in normal human prostate epithelium at low levels, but highly upregulated in metastatic prostate cancer (PC). 18F-DCFPyL is a novel PSMA-targeted PET imaging agent that has shown highly promising diagnostic performance for detection of metastatic disease, with potential to identify disease amenable to theranostic targeting. 1095 is a novel PSMA-targeted small molecule that binds to the extracellular domain of PSMA selectively with high affinity. The complex is internalized, allowing the beta emitter, I-131, to kill PC cells. Methods: ARROW is an open-label, randomized (2:1) trial of enza plus 1095 or enza alone in pts with progressive mCRPC who previously received abi. ~120 pts (80: 1095 + enza; 40: enza alone) will be treated at ~40 sites in the US and Canada. Eligible male pts must be at least 18 yo with metastatic disease documented by bone scan or soft tissue lesions measurable per RECIST 1.1 on CT/MRI, be PSMA-avid as determined by 18F-DCFPyL PET/CT, have evidence of biochemical or radiographic progression on abi, and be ineligible for or refuse to receive chemotherapy. Pts will receive enza (prescribed per approved labeling) with or without 1095 (100 mCi dose, followed by up to 3 additional dose(s) administered at least 8 weeks apart, as determined by dosimetry evaluation and occurrence of dose-limiting events). The primary objective is to determine the efficacy of 1095 plus enza compared to enza alone, based on PSA response (confirmed PSA decline ≥50%) rate according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Additional objectives include objective response rate based on PCWG3-modified RECIST 1.1, progression-free survival (PFS) defined as the first occurrence of radiographic progression (PCWG3-modified RECIST 1.1), unequivocal clinical progression, or death from any cause, duration of response, overall survival, and the safety and tolerability of 1095 radioligand therapy. Clinical trial information: NCT03939689 .

A multicenter, randomized, controlled phase II study: Efficacy and safety of PSMA-targeted radioligand therapy I-131-1095 (1095) plus enzalutamide (enza) in 18F-DCFPyL PSMA scan avid, metastatic castration-resistant prostate cancer (mCRPC) patients post-abiraterone (abi) progression (ARROW).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS260-TPS260
Author(s):  
Evan Y. Yu ◽  
David Laidley ◽  
Frederic Pouliot ◽  
Stephan Probst ◽  
Fred Saad ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
Radiographic Progression ◽  
Objective Response ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Radioligand Therapy ◽  
Open Label ◽  
Recist 1.1 ◽  
Modified Recist

TPS260 Background: PSMA is a transmembrane glycoprotein expressed in normal human prostate epithelium at low levels, but highly upregulated in metastatic prostate cancer (PC). 18F-DCFPyL is a novel PSMA-targeted PET imaging agent that has shown highly promising diagnostic performance for detection of metastatic disease, with potential to identify disease amenable to theranostic targeting. 1095 is a novel PSMA-targeted small molecule that binds to the extracellular domain of PSMA selectively with high affinity. The complex is internalized, allowing the beta emitter, I-131, to kill PC cells. Methods: ARROW is an open-label, randomized (2:1) trial of enza plus 1095 or enza alone in pts with progressive mCRPC who previously received abi. ~120 pts (80: 1095 + enza; 40: enza alone) will be treated at ~40 sites in the US and Canada. Eligible male pts must be at least 18 yo with metastatic disease documented by bone scan or soft tissue lesions measurable per RECIST 1.1 on CT/MRI, be PSMA-avid as determined by 18F-DCFPyL PET/CT, have evidence of biochemical or radiographic progression on abi, and be ineligible for or refuse to receive chemotherapy. Pts will receive enza (prescribed per approved labeling) with or without 1095 (100 mCi dose, followed by up to 3 additional dose(s) administered at least 8 weeks apart, as determined by dosimetry evaluation and occurrence of dose-limiting events). The primary objective is to determine the efficacy of 1095 plus enza compared to enza alone, based on PSA response (confirmed PSA decline ≥50%) rate according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Additional objectives include objective response rate based on PCWG3-modified RECIST 1.1, progression-free survival (PFS) defined as the first occurrence of radiographic progression (PCWG3-modified RECIST 1.1), unequivocal clinical progression, or death from any cause, duration of response, overall survival, and the safety and tolerability of 1095 radioligand therapy. Clinical trial information: NCT03939689.

A multicenter, randomized, controlled phase II study: Efficacy and safety of PSMA-targeted radioligand therapy I-131-1095 (1095) plus enzalutamide (enza) in 18F-DCFPyL PSMA scan avid, metastatic castration-resistant prostate cancer (mCRPC) patients post-abiraterone (abi) progression (ARROW).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS187-TPS187
Author(s):  
A. Oliver Sartor ◽  
David Laidley ◽  
Frederic Pouliot ◽  
Stephan Probst ◽  
Robert Sabbagh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Radioligand Therapy ◽  
Open Label ◽  
Recist 1.1 ◽  
Modified Recist

TPS187 Background: PSMA is a transmembrane glycoprotein overexpressed in prostate cancer (PC) and further upregulated in castrate resistant disease. 1095 is a novel PSMA-targeted small molecule radioligand therapeutic that binds to the extracellular domain of PSMA selectively with high affinity, internalized, and delivers a targeted lethal radiation dose to PC cells. 18F-DCFPyL is a novel PSMA-targeted PET imaging agent that has shown robust diagnostic performance for detecting recurrent and metastatic PC. In the ARROW study, pts must demonstrate 18F-DCFPyL avidity prior to 1095 treatment. Methods: ARROW is an open-label, randomized (2:1) trial of enza plus 1095 or enza alone in pts with progressive mCRPC who previously received abi. ~120 pts (80: 1095 + enza; 40: enza alone) will be treated at multiple sites in the US and Canada. Eligible male pts must have metastatic disease documented by bone scan or soft tissue lesions measurable per RECIST 1.1 on CT/MRI, be PSMA-avid as determined by 18F-DCFPyL PET/CT, have evidence of biochemical or radiographic progression on abi, and be ineligible for or refuse to receive chemotherapy. Pts will receive enza (prescribed per approved labeling) with or without 1095 (100 mCi dose, followed by up to 3 additional doses administered at least 8 weeks apart, as determined by dosimetry evaluation and occurrence of dose-limiting events). The primary objective is to determine the efficacy of 1095 plus enza compared to enza alone, based on PSA response (confirmed PSA decline ≥50%) rate according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria. Additional objectives include objective response rate based on PCWG3-modified RECIST 1.1, progression-free survival (PFS) defined as the first occurrence of radiographic progression (PCWG3-modified RECIST 1.1), unequivocal clinical progression, or death from any cause, duration of response, overall survival, and the safety and tolerability of 1095 radioligand therapy. Due to the COVID-19 pandemic, enrollment was halted in April 2020 but is reopening in October 2020. Clinical trial information: NCT03939689.

VISION: An international, prospective, open-label, multicenter, randomized phase 3 study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5099-TPS5099 ◽  
Author(s):  
A. Oliver Sartor ◽  
Michael J. Morris ◽  
Bernd J Krause
Keyword(s):  
Prostate Cancer ◽  
Alternative Hypothesis ◽  
Standard Of Care ◽  
Primary Objective ◽  
Therapeutic Drug ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Phase 3 ◽  
Eligibility Criteria ◽  
Castration Resistant

TPS5099 Background: The novel therapeutic drug 177Lu-PSMA-617 is a prostate specific membrane antigen (PSMA) targeting agent to deliver radionuclide therapy for the treatment of pts with metastatic castration resistant prostate cancer. Based on preclinical data that demonstrated high PSMA binding affinity & compound internalization, prolonged tumor uptake, rapid kidney clearance, & high tumor-to-background ratio, 177Lu-PSMA-617 proceeded into clinical development. Preliminary clinical evidence indicates 177Lu-PSMA-617 may demonstrate clinical benefit in pts with mCRPC in a setting where pts had no recommended standard of care. This Phase 3 study will assess the efficacy of 177Lu-PSMA-617 in patients with progressive PSMA-positive mCRPC by measuring overall survival (OS) and radiographic progression free survival (rPFS) in a randomized, prospective, open-label trial. Methods: The primary objective of this study is to compare the 2 alternative endpoints of rPFS & OS in pts with progressive PSMA-positive mCRPC who receive 177Lu-PSMA-617 in addition to best supportive/standard of care vs pts treated with best supportive/best standard of care alone. Eligibility criteria are: PSMA expressing tumor; prior exposure to a taxane and novel androgen axis drug. Pts will be randomized in a 2:1 ratio in favor of the investigational arm with stratification factors of LDH, liver disease, ECOG score, and use of NAAD at time of randomization as a standard of care. Under the alternative hypothesis, median OS on active is assumed to be 13.7 mo for a HR of 0.7306 and rPFS on the active is assumed to be 6 mo for a HR of 0.67. Planned enrollment for this study is 750 patients. Enrollment began in June 2018 and continues; the IDMC last reviewed the trial for safety in January 2019 and suggested that the trial continue as planned. Clinical trial information: NCT03511664.

A multicenter phase IIb trial to evaluate the efficacy and tolerability of ModraDoc006/r in subjects with metastatic castration-resistant prostate cancer (mCRPC), suitable for treatment with a taxane (NCT04028388).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS268-TPS268
Author(s):  
Ulka N. Vaishampayan ◽  
Edwin J. De Wit ◽  
Neal D. Shore ◽  
Robert Dreicer ◽  
Daniel J. George ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Oral Prednisone ◽  
Objective Response ◽  
Cancer Therapeutics ◽  
Standard Of Care ◽  
Primary Objective ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Oral Tablet ◽  
Patient Reported

TPS268 Background: Docetaxel IV and prednisone is a standard of care in mCRPC with demonstrated overall survival benefit. ModraDoc006 is a novel oral tablet formulation of docetaxel and to enhance bioavailability, it is co-administered with ritonavir (/r), an inhibitor of cytochrome p450 3A4 and P-glycoprotein. The oral combination, denoted as ModraDoc006/r, could be preferable due to patient convenience and elimination of infusion reactions and prophylactic steroids administration. Due to its weekly administration and exposure levels, increased efficacy may be demonstrated. Methods: The study is an open label 1:1 randomized phase 2b trial of ModraDoc006/r bi-daily QW versus docetaxel IV 75 mg/m2 Q3W. Thirty (30) mg ModraDoc006 combined with 200 mg /r in morning and 20 mg ModraDoc006 with 100 mg /r in evening is administered on days 1, 8 and 15 of a 21 day cycle. Safety and preliminary efficacy of ModraDoc006/r have been established in a phase Ib trial in mCRPC pts. All patients will receive 5 mg oral prednisone twice daily. Treatment is continued until progression, unacceptable toxicity or patient wish. mCRPC pts with measurable disease per RECIST 1.1, suitable for docetaxel therapy, are eligible. No prior treatment with taxanes is allowed. Primary objective is objective response rate (ORR) as assessed by investigators. Secondary objectives include PSA response, PSA-PFS, time to skeletal related events and progression, duration of response, disease control rate and safety assessments. Patient reported outcomes and health-related quality of life will be captured with treatment satisfaction and FACT-P questionnaires. It is expected that ModraDoc006/r will be at least as effective as docetaxel IV. A sample size of 50 evaluable pts per arm will evaluate an estimated ORR of 25% in each arm, with a 5% two-sided alpha and power of 83.7%. Conclusions: ModraDoc006/r represents an advance in prostate cancer therapeutics with convenience of oral administration, reduced myelosuppressive toxicity and potential improved efficacy over IV docetaxel. Clinical trial information: NCT04028388.

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