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Common Protocol Template Prostate Library v001Section in Common Protocol Template (CPT)Library Content3. Objectives and Endpoints Objectives and corresponding endpoints for the prostate cancer study5. Study populationInclusion criteria related type of participation, disease characteristics, and concomitant/prior medications11. ReferencesProtocol references3. Objectives and Endpoints (main body)Tailor the primary objective(s) to the appropriate participant population (i.e., RECIST measurable disease vs bone-predominant disease) and disease stage (early stage, androgen-independent prostate cancer, castration-resistant prostate cancer [CRPC], metastatic CRPC). The primary objective should have a corresponding, statistically testable hypothesis. Key secondary objectives may have a corresponding hypothesis. State clearly if the study will not test a hypothesis.Primary ObjectivePrimary EndpointEfficacy ObjectivesThe following objectives/endpoints are generally suitable for use as primary objectives for studies in prostate cancer. Tailor the endpoints appropriately based on the study designOverall Survival (OS) ObjectivesOS is considered a gold standard for oncology studies and is appropriate for all studies in prostate cancer, regardless of clinical phase or stage of disease at presentationFor comparator- or placebo controlled studiesTo compare the overall survival of [study intervention x] with [study intervention y].ORFor single arm studies:To [evaluate/demonstrate] the efficacy of [study intervention x] on overall survival (OS) For comparator- or placebo-controlled studies, OS is measured from the date of randomization. For single arm studies, OS can be measured from either the date of allocation or date of first doOverall Survival EndpointsOS is defined as the time from the date of [randomization/allocation/date of first dose] to date of death due to any cause.Radiographic Progression-Free Survival (rPFS) ObjectivesrPFS is generally an acceptable measure of clinical benefit for a late stage study that demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of the effect is large and the therapy has an acceptable risk/benefit profile. The use of blinded or independent review of imaging according to RECIST 1.1 or current Prostate Cancer Working Group 3 (PCWG) criteria for bone disease to assess rPFS may be considered acceptable by regulatory authorities (Sher et al, 2016). rPFS can be used for all prostate cancer studies regardless of stage of disease at presentation following discussion with regulatory agenciesFor comparator- or placebo-controlled studies in participants with visceral and bone-only/bone-predominant disease:To compare the radiographic progressionfree survival (rPFS) of [study interventionx] with [study intervention y].ORFor single arm studies in participants with visceral and bone-only/bone-predominant disease:To [evaluate/demonstrate] the efficacy of [study intervention x] on radiographic progression-free survival (rPFS)Radiographic Progression-free Survival (rPFS) EndpointsFor studies utilizing a blinded or independent central reviewerrPFS is defined as the time from date of randomization until the earliest date of disease progression, as determined by [blinded/independent] central review of [objective radiographic disease assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group 3 criteria], or death from any cause, whichever occurs first.For studies utilizing a local site radiologist/investigatorrPFS is defined as the time from date of randomization until the earliest date of disease progression, by [objective radiographic disease assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group 3 criteria] as assessed by the investigator/local radiologist, or death from any cause, whichever occurs first.For studies utilizing a blinded or independent central reviewer per current PCWG-modified RECISTrPFS is defined as the time from date of randomization until the earliest date of disease progression, as determined by [blinded/independent] central review of [objective radiographic disease assessment per Prostate Cancer Working Group 3 (PCWG3)-Modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group 3 (PCWG3) criteria], or death from any cause, whichever occurs first.For studies utilizing a local site radiologist/investigator per current PCWG-modified RECISTrPFS is defined as the time from date of randomization until the earliest date of disease progression, by [objective radiographic disease assessment per Prostate Cancer Working Group 3 (PCWG3)-Modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group 3 (PCWG3) criteria] as assessed by the investigator/local radiologist, or death from any cause, whichever occurs first.Objective Response Rate ObjectiveORR is appropriate for studies in participants with advanced or metastatic disease.For comparator- or placebo-controlled studies:To compare the objective response rate (ORR) of [study interventionx] with [study intervention y].ORFor single arm studies:To [evaluate/demonstrate] the efficacy of [study intervention x] on objective response rate (ORR)Objective Response Rate EndpointsFor studies utilizing a blinded or independent central reviewerORR is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR), as determined by [blinded/independent] central review of objective radiographic disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 For studies utilizing a local site radiologist/investigatorORR is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) by objective radiographic disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by the investigator/local radiologistFor studies utilizing a blinded or independent central reviewer per current PCWG-modified RECISTORR is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) as determined by [blinded/independent] central review of objective radiographic disease progression per Prostate Cancer Working Group?3 (PCWG3)-Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1For studies utilizing a local site radiologist/investigator per current PCWG-modified RECISTORR is defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) by objective radiographic disease progression per Prostate Cancer Working Group 3 (PCWG3)-Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, as assessed by the investigator/local radiologistProstate-specific antigen (PSA) response rate ObjectivesPSA response rate is most appropriate as an initial read-out of efficacy in early phase studiesFor comparator- or placebo-controlled studies:To compare the prostatespecific antigen (PSA) response rate of [study intervention x] with [study intervention y].ORFor single arm studies:To [evaluate/demonstrate] the efficacy of [study intervention x] on prostate-specific antigen (PSA) response rateProstate-specific antigen (PSA) response rate EndpointsPercent decline (recommended is ≥50%) and timing (recommended 3 to 4 weeks) can be revised as neededPSA response is defined as the proportion of participants with a reduction in the PSA level of [X%] from baseline measure twice, at least [X] weeks apartSevere skeletal event (SSE) ObjectivesThe rate of SSEs is an appropriate measure for early phase studies and studies in participants with bone-only or bone-predominant diseaseTo compare the proportion of participants with severe skeletal events (SSEs) in [study intervention x] with [study intervention y].ORFor single arm studiesTo [evaluate/demonstrate] the efficacy of [study intervention x] on the proportion of participants with severe skeletal events (SSEs).Endpoint rate of SSEsSevere skeletal events (SSEs) is defined as the proportion of participants with an SSE (i.e., radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change or antineoplastic therapy to treat bone pain) measured from the time of [randomization/allocation/date of first dose].Secondary/Exploritory ObjectivesSecondary EndpointEfficacy ObjectivesDisease control rate (DCR) ObjectivesFor comparator- or placebo-controlled studies:To compare the disease control rate (DCR) of [study intervention x] with [study intervention y]. ORFor single arm studies:To [evaluate/demonstrate] the efficacy of [study intervention x] on disease control rate (DCR)Disease control rate (DCR) EndpointsFor studies utilizing a blinded or independent central reviewerDCR is defined as the proportion of participants who have a confirmed complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months by [blinded/independent] central objective radiographic disease assessment per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1For studies utilizing a local site radiologist/investigator DCR is defined as the proportion of participants who have a confirmed complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months by objective radiographic disease assessment per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by the investigator/local radiologistFor studies utilizing a blinded or independent central reviewer per current PCWG-modified RECISTDCR is defined as the proportion of participants who have a confirmed complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months by [blinded/independent] central objective radiographic disease assessment per Prostate Cancer Working Group 3 (PCWG3)-Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1For studies utilizing a local site radiologist/investigator per current PCWG-modified RECISTDCR is defined as the proportion of participants who have a confirmed complete response (CR), partial response (PR), or stable disease (SD) for at least 6 months by objective radiographic disease assessment per Prostate Cancer Working Group 3 (PCWG3)-Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by the investigator/local radiologist.Time to Prostate-specific Antigen (PSA) Progression ObjectivesTeams may also decide to evaluate PSA doubling time. Refer to Scher et al 2016 for additional detailsFor comparator- or placebo-controlled studies:To evaluate the time to prostate-specific antigen (PSA) progression following [study intervention x] versus [study intervention?y]ORFor single arm studies:To [evaluate/demonstrate] the efficacy of [study intervention x] on time to prostate-specific antigen (PSA) progressionTime to Prostate-specific Antigen (PSA) Progression Endpoints Time to PSA progression is defined as the time from [randomization/date of allocation/date of first dose] to an increase of [≥X%] and an absolute increase of [X ng/mL] or more from nadir are documented.Duration of Response (DOR) ObjectivesFor comparator- or placebo-controlled studies:To compare the duration of response (DOR) of [study intervention x] with [study intervention y]. ORFor single arm studies in participants with bone-only, bone-predominant disease:To [evaluate/demonstrate] the efficacy of [study intervention x] on duration of response (DOR)Duration of Response (DOR) EndpointsFor studies utilizing a blinded or independent central reviewerDOR is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until progressive disease (PD) as determined by [blinded/independent] central review of [objective radiographic disease assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group 3 criteria], or death from any cause, whichever occurs first.For studies utilizing a local site radiologist/investigator.DOR is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until progressive disease (PD) by [objective radiographic disease assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group 3 criteria] as assessed by the investigator/local radiologist, or death from any cause, whichever occurs first.For studies utilizing a blinded or independent central reviewer per current PCWG-modified RECISTDOR is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until progressive disease (PD) as determined by [blinded/independent] central review of [objective radiographic disease assessment per Prostate Cancer Working Group 3 (PCWG3)-Modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group 3 (PCWG3) criteria], or death from any cause, whichever occurs first.For studies utilizing a local site radiologist/investigator per current PCWG-modified RECISTDOR is defined as the time from first documented evidence of complete response (CR) or partial response (PR) until progressive disease (PD) by [objective radiographic disease assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group 3 (PCWG3) criteria] as assessed by the investigator/local radiologist, or death from any cause, whichever occurs first.Duration of PSA Response ObjectivesFor comparator- or placebo-controlled studies:To compare the duration of PSA response of [study intervention x] with [study intervention y].ORFor single arm studies:To [evaluate/demonstrate] the efficacy of [study intervention x] on duration of PSA responseDuration of PSA Response EndpointsPercent decline (recommended is ≥50%) and timing (recommended 3 to 4 weeks) can be revised as neededTime to PSA progression is defined as the time from the time of PSA response (i.e., a reduction in the PSA level by [X%] from baseline measure twice, at least [X]?weeks apart) to the date of PSA progression (i.e., an increase of [≥X%] and an absolute increase of [X?ng/mL] or more from nadir are documented)Time to first severe skeletal-related event ObjectivesFor comparator- or placebo-controlled studies:To compare the time to first severe skeletal-related event of [study intervention x] with [study intervention y].ORFor single arm studies:To [evaluate/demonstrate] the efficacy of [study intervention x] on time to first severe skeletal-related eventTime to first severe skeletal-related event EndpointsTime to first severe skeletal-related event is defined as the time from [randomization/allocation/date of first dose] to the first severe skeletal-related event (i.e., radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change or antineoplastic therapy to treat bone pain)Other Time to Events ObjectivesInclude additional events as determined with the clinical team. Examples could include time to liver metastases; time to bone metastases, time to visceral metastases; time to opioid use; time to biochemical failureFor comparator- or placebo-controlled studies:To compare the time to [event] of [study intervention x] with [study intervention?y]ORFor single arm studies:To [evaluate/demonstrate] the efficacy of [study intervention x] on time to [event]Other Time to events EndpointsEndpoint: Time to [event] is defined as the time from [randomization/allocation/date of first dose] to [event] (i.e., [definition])Progression-free Survival after next-line treatment (PFS2) ObjectivesThe evaluation of PFS after next-line treatment (PFS2) is becoming more common in confirmatory trials and is recommended by the EMA in trials that utilize PFS as a primary endpoint [Mbanya 2014, Oronsky?2015]. The goal of PFS2 is to assess the impact of an experimental regimen on next-line treatmentFor comparator- or placebo-controlled studies in participants with visceral and bone-only/bone-predominant disease:To compare the progressionfree survival after nextline treatment (PFS2) of [study intervention x] with [study intervention y].ORFor single arm studies in participants with visceral and bone-only/bone-predominant disease:To [evaluate/demonstrate] the efficacy of [study intervention x] on progression-free survival after next-line treatment (PFS2)Progression-free Survival after next-line treatment (PFS2) EndpointsFor studies utilizing a blinded or independent central reviewerPFS2 is defined as the time from date of randomization until disease progression on next-line treatment, as determined by [blinded/independent] central review of [objective radiographic disease assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group?3 criteria], or death from any cause, whichever occurs first.For studies utilizing a local site radiologist/investigatorPFS2 is defined as the time from date of randomization until disease progression on next-line treatment, by [objective radiographic disease assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) AND/OR [radionuclide bone scan using Prostate Cancer Working Group 3 criteria] as assessed by the investigator/local radiologist, or death from any cause, whichever occurs first.For studies utilizing a blinded or independent central reviewer per current PCWG-modified RECISTPFS2 is defined as the time from date of randomization until disease progression on next-line treatment, as determined by [blinded/independent] central review of [objective radiographic disease assessment per Prostate Cancer Working Group 3 (PCWG3)-Modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group 3 (PCWG3) criteria], or death from any cause, whichever occurs first.For studies utilizing a local site radiologist/investigator per current PCWG-modified RECISTPFS2 is defined as the time from date of randomization until disease progression on next-line treatment, by [objective radiographic disease assessment per Prostate Cancer Working Group 3 (PCWG3)-Modified Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)] AND/OR [radionuclide bone scan using Prostate Cancer Working Group?3 (PCWG3) criteria] as assessed by the investigator/local radiologist, or death from any cause, whichever occurs first.Patient-reported Outcomes ObjectivesTo evaluate quality of life (QoL) using the [EuroQoL-5 dimension (EQ-5D)] and the [Functional Assessment of Cancer Therapy-Prostate (FACT-P)] AND/OR [Brief Pain Inventory] questionnaires.Patient-reported Outcomes EndpointsChanges from baseline in the [EQ-5D], [FACT-P], AND/OR [BPI] questionhaire scores.Metastatic-free Survival (MFS)/Recurrence-free Survival (RFS)/Disease-free Survival (DFS) ObjectiveGenerally, MFS/RFS/DFS can be used in an adjuvant setting following definitive surgery or radiotherapy. MFS/RFS/DFS could be an acceptable primary objective for adjuvant studies following prostatectomy/radiotherapy of primary/locally advanced disease or primary biochemical failure for non-metastatic (M0), hormone-sensitive disease as discussing with regulatory agenciesFor comparator- or placebo-controlled studies:To compare the [metastaticfree survival (MFS)] OR [recurrencefree survival] OR [radiographic diseasefree survival (DFS)] of [study intervention x] with [study intervention y].ORFor single arm studies:To [evaluate/demonstrate] the efficacy of [study intervention x] on [metastatic-free survival (MFS)] OR [recurrence-free survival] OR [radiographic disease-free survival (DFS)]Metastatic-free Survival (MFS)/Recurrence-free Survival (RFS)/Disease-free Survival (DFS) EndpointFor comparator- or placebo-controlled studies, MFS/RFS/DFS is measured from the date of randomization. For single arm studies, MFS/RFS/DFS can be measured from either the date of allocation or date of first doseMFS/RFS/DFS is defined as the time from [randomization/date of allocation/date of first dose] until [metastatic disease] OR [disease recurrence] or death from any cause, whichever occurs first.5. Study Population5.1 Inclusion CriteriaType of participant and disease characteristicsThe following criteria are suggested for studies in participants with prostate cancer. Revise as needed based on discussions with the clinical team. ECOG status needs to be capturedParticipant has histologically- or cytologically-confirmed adenocarcinoma of the prostate add if needed [without small cell histology]. Diagnosis must be [stated in a pathology report and confirmed by the Investigator].Participant has measurable prostate cancer on computed tomography (CT) or magnetic resonance imaging (MRI) scans for [ORR/PFS] by RECIST 1.1 and/or detectable bone metastases by whole body bone scintigraphy evaluable by PCWG3 criteria.Participant has either metastatic or locally confined inoperable disease that cannot be treated with definitive intent.Participant has non-metastatic (M0) disease verified by computed tomography (CT), magnetic resonance imaging (MRI), and whole body bone scintigraphyParticipant has androgen-dependent prostate cancer (ADPC)Participant has serum testosterone level <50 ng/dL. Castrate testosterone levels must be from [orchiectomy] AND/OR [current therapy with luteinizing hormone-releasing hormone agonist for greater than [X] weeks prior to first dose of study intervention].Participant has evidence of progressive disease [since the most recent change in therapy] OR [within the past X weeks/months]. Progressive disease was defined as any 1 of the following:Radiographic disease progression in soft tissue or bone with or without PSA progression: Objective evidence of increase in radiographic lesions or the appearance of [X] or more new lesionsBone scan progression: Appearance of either of the following: [X] or more new lesions on bone scan attributable to prostate cancer or [X] new lesion on bone scan attributable to prostate cancer in conjunction with a rising PSAPSA progression: [X] consecutively rising PSA levels (≥2-5 ng/mL) separated by [X weeks/months] with a testosterone concentration of ≤50 ng/dL at [X week] intervals OR PSA increase of [X%] or greater measured [X] weeks apartChoose one or more of the following options depending on the study designParticipant has received prior therapy with:[prior anti-androgen therapy][prior chemotherapy regimen][restrictions on number of prior therapies]Participant is [currently] OR [has failed] prior treatment with [anti-androgen therapy(ies)]Participant is [currently] OR [has failed] prior treatment with [chemotherapy(ies)]Participant is [treatment-na?ve] OR [anti-androgen-na?ve] OR [chemotherapy-na?ve]Participant is on a stable dose of bone resorptive therapy for [≥X weeks].Depending on the choice of participant population based on the chosen inclusion criteria, the deselected inclusion criteria above may become exclusion criteria for prostate cancer. Depending on the MOA of the study intervention or the chosen SOC control used in the study, specific agent-related criteria may need to be included for the patient population11. ReferencesScher et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34(12):1402-18.Oronsky et al. Confirmatory Trials in the Evaluation of Anticancer Medicinal Products in Man—PFS2: A Measure of Therapeutic Action-At-A-Distance. Neoplasia. 2015;17(9):716-22.Mbanya et al. Time to second objective disease progression (PFS2): an emerging clinical trial endpoint with regulatory and reimbursement implications. Blood 124(21).Parker et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. NEJM. 2013;369(3):213-23.DeBono et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. NEJM. 2011;364(21):1995-2005.Scher et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. NEJM. 2012;367(13):1187-1197. ................
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