NRGGU 008 A Phase III Randomized Trial Incorporating
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NRG-GU 008 A Phase III Randomized Trial Incorporating Abiraterone Acetate with Prednisone and Apalutamide and Advanced Imaging into Salvage Treatment for Patients with Node. Positive Prostate Cancer After Radical Prostatectomy
Study Team Contact Information Principal Investigator/Radiation Oncology Ronald Chen, MD, MPH University of Kansas 913. 588. 3612 / 913. 588. 3663 rchen 2@kumc. edu
Study Team Contact Information Principal Investigator/Radiation Oncology Co-Chair Ronald Chen, MD, MPH University of Kansas Department of Radiation Oncology 4001 Rainbow Boulevard, MS 4033 Kansas City, KS 66160 913 -588 -3612/FAX 913 -588 -3663 rchen 2@kumc. edu Colleen Lawton, MD Medical College of Wisconsin Department of Radiation Oncology 8701 West Watertown Plank Road Milwaukee, WI 53226 414 -805 -4462/FAX 414 -805 -4369 clawton@mcw. edu Jason Efstathiou, MD, DPhil Massachusetts General Hospital Department of Radiation Oncology 55 Fruit Street, Cox 3 Boston, MA 02114 617 -726 -5866/ FAX 617 -726 -3603 jefstathiou@partners. org Radiation Oncology Co-Chair Translational Science Co-Chair Michael Seider, MD University Hospitals Cleveland Medical Center Department of Radiation Oncology 1110 Euclid Avenue, LTR 6068 Cleveland, OH 44106 330 -332 -7360/FAX 330 -332 -7359 michael. seider@uhhospitals. org Edwin Posadas, MD Cedars-Sinai Medical Center Department of Medicine 8700 Beverly Boulevard Los Angeles, CA 90048 310 -423 -7600/FAX 310 -967 -3841 edwin. posadas@csmc. edu Medical Oncology Co-Chair Medical Physics Co-Chair Imaging Co-Chair Hala Borno, MD University of California, San Francisco Department of Medicine/Hematology/Oncology 550 16 th Street, 6 th Floor, Box 3211, Office 6554 San Francisco, CA 94158 415 -476 -4616/FAX 415 -353 -7104 hala. borno@ucsf. edu Mihaela Rosu-Bubulac, Ph. D Virginia Commonwealth University Department of Radiation Oncology 401 College Street Richmond, VA 23298 -0058 804 -628 -0980/FAX 804 -828 -6042 mihaela. rosu@vcuhealth. org Ashesh Jani, MD Emory University Department of Radiation Oncology 1365 Clifton Road, NE, Suite A 1300 Atlanta, GA 30322 404 -778 -3827/FAX 404 -778 -4139 abjani@emory. edu Translational Science/Genomics Co. Chair Paul Nguyen, MD Dana-Farber / Harvard Cancer Center Department of Radiation Oncology 75 Francis Street Boston, MA 02115 617 -732 -7936/FAX 617 -384 -2906 pnguyen@lroc. harvard. edu
Study Team Contact Information Imaging Co-Chair Quality of Life Co-Chair Statistician David Schuster, MD Emory University Department of Radiology and Imaging Sciences 1364 Clifton Road, NE; EUH Room E 152 Atlanta, GA 30322 404 -712 -4859/FAX 404 -712 -4860 dschust@emory. edu William Hall, MD Medical College of Wisconsin Department of Radiation Oncology 8701 West Watertown Plank Road Milwaukee, WI 53226 414 -805 -4477/FAX 414 -805 -4369 whall@mcw. edu Theodore Karrison, Ph. D University of Chicago / NRG Oncology 1818 Market Street, Suite 1720 Philadelphia, PA 19013 773 -702 -9326 karrisont@nrgoncology. org
NRG Oncology HQ Contact Information Data Management For questions concerning eligibility or data submission Elaine Motyka-Welsh, RN, MSN, CCRP 215 -574 -3216 motyka-welshe@nrgoncology. org Margaret Kennish 215 -574 -3240 kennishm@nrgoncology. org RTQA For questions concerning RT data submission and RT-related eligibility questions Joanne Hunter, BS, RT(T)(R) 215 -574 -3222 hunterj@nrgoncology. org RT Credentialing http: //irochouston. mdanderson. org or IROC-Credentialing@mdanderson. org RT Data Submission to TRIAD Triad-Support@acr. org Protocol Development For questions concerning protocol and informed consent versions & amendments Sara Mc. Cartney 267 -9404 mccartneys@nrgoncology. org Project Managers For questions concerning miscellaneous study issues Sheralee Miller 215 -940 -8807 millers@nrgoncology. org Treena Davis-Trotman 215 -574 -3205 davis-trotmant@nrgoncology. org
Trial Collaboration Partner This trial is being conducted in collaboration with Janssen Pharmaceuticals, Inc.
Study Design Overview • • • Background and Rationale Objectives / Schema Key Eligibility / Exclusion Criteria Statistical Considerations Treatment Overview / RT Credentialing Adverse Event Reporting Protocol / Regulatory Logistics Drug Distribution Data Submissions Biospecimen Submissions Auditing
Background and Rationale • Node positive prostate cancer represents about 12% of all prostate cancers • Stage 4 disease, but potentially curable • Very few clinical trials to guide standard of care in this patient population • Very aggressive disease • Treatment intensification likely needed to maximize cure and survival • This trial will include patients who have had a radical prostatectomy, and found to have p. N+ disease • Standard arm: RT plus 2 years of LHRH • Experimental arm: RT plus 2 years of LHRH/abiraterone/apalutamide • Abiraterone & apalutamide have both been shown to improve overall survival in patients with metastatic prostate cancer
Primary Objective To compare metastasis-free survival (MFS) of salvage RT and Gn. RH agonist/antagonist vs. RT/Gn. RH agonist / antagonist with abiraterone acetate with prednisone and apalutamide for patients with pathologic node-positive prostate cancer after radical prostatectomy with detectable PSA
Secondary Objectives • To compare health-related quality of life (EPIC-26, EQ 5 D-5 L, Brief Pain Inventory, PROMIS-Fatigue) among the treatment arms • To compare overall survival, biochemical progressionfree survival, time to local-regional progression, time to castrate resistance, and cancer-specific survival among the treatment arms • To compare the short-term and long-term treatmentrelated adverse events among the treatment arms
Schema REGISTRATION STRATIFICATION Pathologically PSA never node-positive undetectable after prostate cancer prostatectomy vs. patients at the rising PSA after time of radical being prostatectomy and undetectable after currently having a prostatectomy detectable PSA R A Arm 1* N RT + Gn. RH agonist/antagonist x 2 years D O M I Z Arm 2* A RT + Gn. RH agonist/antagonist + T I abiraterone acetate with prednisone and O apalutamide x 2 years N *See Protocol Section 5. 1 for drug treatment details and Section 5. 2 for radiation therapy details
Key Eligibility Criteria • Prostate cancer status-post radical prostatectomy • p. N+ in the pelvis (internal iliac, external iliac, and/or obturator) • PSA >0 at least 30 days after RP, before starting ADT • Advanced imaging (Axumin PET, PSMA PET, or choline PET) showing no M 1 disease Section 3. 0 of the Protocol for Complete Eligibility Criteria
Key Exclusion Criteria • Prior systemic chemotherapy for prostate cancer – Prior chemotherapy for a different cancer is allowed (completed >3 years prior to registration) • Prior RT that would result in overlap of fields • History of seizure or known condition that may predispose to seizure • Any chronic medication condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily See Section 3. 0 of the Protocol for Complete Exclusion Criteria
Statistical Considerations Targeted Accrual: 586 patients (1: 1 ratio between treatment arms) Study Duration: ~ 7. 5 years • 90% power at one-sided alpha=0. 025 to detect a hazard ratio (HR) of 0. 53 • Assuming a 4 -year MFS rate in the control arm of 79%, this corresponds to a 4 -year MFS rate in the experimental arm of approximately 88%
Data Monitoring Committee (DMC) • DMC meetings are held at least twice yearly • DMC review may include but is not limited to: accrual, toxicity data, protocol compliance, treatment armspecific data including toxicity and compliance (blinded trials), interim analysis of safety results, efficacy outcome analysis results
Protocol & Regulatory Logistics
Protocol and Regulatory Logistics • Protocol and Other Documents • Available via CTSU website • The NCI CIRB will serve as the central IRB • Regulatory documentation must be submitted to the CTSU via the Regulatory Submission Portal • • Sign in at www. ctsu. org and select the Regulatory Submission sub-tab under the Regulatory tab Institutions with patients waiting that are unable to use the portal should alert the CTSU Regulatory Office immediately at 1 -866 -6512878 for support
Protocol Deviations • NCI/CTEP will not issue or approve any waivers for protocol deviations. This applies to all components of the approved protocol, including eligibility criteria, treatment schedules, dose modifications, toxicity assessment, response criteria, and statistical aspects. • NRG recognizes that deviations may occur during a trial and NRG’s process is to have sites report all deviations to NRG and to the IRB.
Regulatory Logistics • Maintenance of Regulatory Records is IMPORTANT! • • • Retain correspondence Maintain IRB approval (amendments and continuing review) Keep IRB registration current throughout the study • Keep local staff current with the NCI Registration and Credential Repository (RCR): https: //ctep. cancer. gov/investigator. Resources/default. htm • All staff contributing to NCI sponsored trials will need to register. Questions related to RCR can be directed to RCRHelp. Desk@nih. gov
Required Regulatory Documents for ALL Participating Sites • IRB approval (initial, continuing reviews and amendments) • Study Agent Shipment Form (SASF) • IROC Credentialing Status Inquiry Form (CSI) • Site must be aligned with the radiation therapy and/or imaging provider (more information in Section 8. 1 of the protocol)
Treatment Overview
Treatment Regimen Protocol Therapy Arm 1: Pelvis and prostate bed radiotherapy + Gn. RH agonist/antagonist x 2 years Arm 2: Pelvis and prostate bed radiotherapy + Gn. RH agonist/antagonist x 2 years + abiraterone acetate with prednisone and apalutamide beginning day 1 of radiotherapy (+/- 14 days) x 2 years Randomization to each arm is 1: 1 and will be stratified by PSA status (never undetectable after prostatectomy vs rising PSA after being undetectable)
Treatment Regimen Systemic Therapy • Gn. RH agonist/antagonist therapy (leuprolide, goserelin, buserelin, histerlin, triptorelin, or degarelix) is permitted to start up to 45 days prior to registration (Note: Patients also started on an oral antiandrogen are eligible if started ≤ 45 days and stopped prior to registration) • Abiraterone acetate with prednisone and apalutamide should begin the same day as radiotherapy treatment (+/ - 14 days allowed) • Protocol therapy will consist of 90 -day cycles (8 cycles total, 24 months) of treatment • Please do pill counts after each 90 day cycle of these orally administered drugs
Treatment Regimen Apalatumide Apalutamide will be given at a dose of 240 mg (four 60 mg tablets) by mouth once daily for 24 months (2 years), at approximately the same time every day; 1 cycle = 90 days (total of 8 cycles) Abiraterone Acetate with Prednisone Abiraterone acetate will be given at a dose of 1, 000 mg (four 250 mg tablets) by mouth once daily for 24 months (2 years); 1 cycle = 90 days (total of 8 cycles) Abiraterone acetate should be taken on an empty stomach; empty stomach is defined as one hour before meals or two hours after meals; the tablets should be swallowed whole with water Abiraterone acetate is administered with low-dose prednisone; the dosage of prednisone is 10 mg daily (5 mg twice daily or 10 mg once daily); following completion of treatment period, patients will taper off prednisone per institutional guidelines; for a recommended tapering plan, see protocol section 5. 1. 2
Treatment Regimen Radiation Therapy Schema Radiation doses (1. 8 Gy or 2. 0 Gy/fx) Bilateral pelvis: 45 -50 Gy • PET positive pelvic disease: boost to 54 -63 Gy allowed Prostate bed +/- seminal vesicle remnants: 64 -70 Gy • PET positive local disease: boost up to 72 Gy allowed Sequential boost or SIB both allowed See Section 5 of the protocol for further details
Treatment Technology • 3 D-CRT and IMRT techniques including Tomotherapy and VMAT; MRLinac is also allowed; proton therapy not allowed. • Some form of image guidance is required: e. g. planar k. V imaging, CBCT); electromagnetic transponders, fiducial markers, and spacers may be used, at the discretion of the treating physician • Management of Radiation Dose to the Patient from IGRT (See Section 5. 2. 10) RT Credentialing • Please refer to the Section 8. 2 of the protocol for details
Treatment Modifications & Management Dose Modifications • If one drug (abiraterone or apalutamide) is discontinued, the other may continue • Abiraterone acetate with prednisone dose modification guidance is available for: • • • LFT Abnormalities Hypokalemia Hypertension Edema/Fluid Retention Apalutamide dose modification guidance available for: • Rash See Section 6 of the protocol for further details
Drug Distribution
Drug Supply Supplied Drugs • Apalutamide, abiraterone acetate, and prednisone will be supplied for all participants. Drug will be distributed by Clinical Research Services, a division of Rx. Crossroads by Mc. Kesson. Please see Section 9. 0 of the protocol for further details. Commercial Drugs • Gn. RH agonist/antagonist: is available via commercial prescription. Please see Section 5. 1. 3 of the protocol for administration instructions
Drug Ordering & Accountability Apalutamide, Abiraterone Acetate, and Prednisone • Distributed to institutions that have identified a single individual as responsible for receipt and accountability of shipments; Study Agent Shipment Form (SASF) must be on file with the CTSU prior to registration • The drug supply will not be shipped by Clinical Research Services until the subject has been registered and randomized • Drug Accountability Logs are required; strongly recommend using NCI DARF • A drug destruction form is available on the website for sites to record all drug destroyed on site Section 9 of the protocol for further details
Data Submission
Online Study Entry & Data Submission • Data collection for this study will be done exclusively through Medidata RAVE; please see the data submission summary posted on the CTSU website for further information • Users will need an i. Medidata RAVE login and password • Registration will be through OPEN • PDF versions of all RAVE forms are available for reference on the CTSU website under the Case Report Forms tab • All patient completed Quality of Life Forms will be available on the CTSU website under the CIRB tab
Medidata Patient Cloud e. PRO • This study will allow patients to participate in electronic data submission using their own personal device (smartphone or tablet) by downloading an app and using it to complete three (3) of the four (4) Quality of Life Forms at designated follow up time points (EQ-5 D; EPIC; PROMIS-Fatigue) • This is optional for patients or they may choose to continue to complete these forms on paper • Site staff must complete the e. PRO online training in Rave prior to their first patient enrollment; Access to GU 008 will not be given until this e-learning is completed • Information on the Medidata Patient Cloud e. PRO application is located on the CTSU website on the study protocol page under the Education and Promotion tab
Key Essentials/Timely Data Submissions • All baseline data should be submitted within 1 week of registration • All treatment data (RT and each 90 day cycle of drug administration) should be submitted within 15 days of completion and/or assessment • Follow up forms are to be submitted per the assessment table specifications within 30 days of the visit • Patients should be counseled about self-administration of the study drugs and frequent contact with the patient is encouraged to be sure that he understands how the study drugs are to be administered • The patient should be given a pill diary (institutional or the one provided on the CTSU website) to log drug administration daily and should be instructed to bring back pill bottles for assessment of each cycle • Missed or held drug doses are not made up
RT Case Data Submissions • All RT treatment planning and delivery data submitted via TRIAD (See Section 13. 2) • Complementary imaging studies (DICOM Planning MR/PET scans) used to enhance the CT-based contouring should be submitted via TRIAD, when applicable • Sites should obtain access to TRIAD prior to enrolling first patient • Note: Sites must utilize the instance of TRIAD using a CTEP IAM username to access. Details on TRIAD are in Section 8 • RT Treatment Record must be uploaded in RAVE The RT Treatment Record pages should include documentation of the date, daily dose, fraction #, total dose and the treatment prescription for the case prior to the start of RT **Prior to upload, ensure all pages of the RT Treatment Record do NOT contain any Personal Health Information (PHI). **
Biospecimen Submissions
FFPE Biospecimen Submissions For ALL consenting patients submit the following • ST Form with Pathology report (redacted) • Prior Decipher report if available- include Decipher ID, redact all other PHI • H&E Slide • FFPE Block (matching H&E) OR punches from same block: ONE 1. 5 mm punch (for decipher testing) AND ONE 5 mm punch (for banking) • Unstained slides are not acceptable for this study • Ship FFPE samples to the NRGBB-SF as per section 10 Questions: Email NRGBB@ucsf. edu
Biospecimen Submissions Optional Collection for Subjects Who Consent Optional Study #1 Decipher Biosciences, Inc. Decipher Analysis and Biobanking for Potential Future Research: Send all FFPE samples to the NRG Oncology Biospecimen Biobank – San Francisco (NRGBB-SF) Optional Study #2 Circulating Tumor Cells to Translate PAM 50 Findings into Blood-Based Assay: Send all fresh CTC specimens overnight to Uro. Oncology Laboratories: Posadas Lab Optional Study #3 Analysis of SNPs Associated with Androgen Deprivation Therapy Response & Biobanking for Potential Future Research: Send all specimens to the NRGBB-SF Optional Study #4 Biobanking for Potential Future Research: Send all specimens to the NRGBB-SF See Section 10 of the protocol for further details
Optional Study #2: CTC Analysis • 2 ACD tubes with blood shipped fresh priority overnight to Cedars Sinai (Posadas) Lab as per Section 10 of protocol • Study specific ST Form • Kits provided by NRGBB-SF • Package Blood in Styrofoam holder as shown here • Do NOT ship to NRGBB-SF • Notify Cedars Sinai (Posadas) Lab via email the day of shipment • Questions: edwin. posadas@csmc. edu and/or Group. Hem-Oncology. Posadas. Lab. Specimen. Collection@cshs. orgp. Hem- Oncology. Posadas. Lab. Specimen. Collection@cshs. org
Adverse Event Reporting
Adverse Event Reporting The following slides highlight discrete adverse event reporting requirements, refer to Protocol Section 7 for complete Adverse Event and Serious Adverse Event reporting requirements. • Adverse Event (AE) reporting begins at time of consent • Report all AEs that start after consent is signed • Report serious adverse events that meet expedited reporting criteria via CTEP-AERS
Adverse Event Reporting Report the following medicinal product-related events as routine AEs (expedited reporting requirements apply): • Drug exposure during pregnancy (maternal and paternal) • Overdose of a Janssen medicinal product • Suspected abuse/misuse of a Janssen medicinal product • Inadvertent or accidental exposure to a Janssen medicinal product • Any failure of expected pharmacological action (i. e. , lack of effect) of a Janssen medicinal product • Medication error involving a Janssen medicinal product (with or without patient exposure to the Janssen medicinal product, e. g. , name confusion) • Suspected transmission of any infectious agent via administration of a medicinal product • Unexpected therapeutic or clinical benefit from use of a Janssen medicinal product
Expedited Adverse Event Reporting • Assess adverse events for seriousness • See protocol section 7. 5. 2 for expedited reporting timelines for serious adverse events o There are limited expedited reporting requirements for the standard of care arm, Arm 1 • From time of consent for 30 days after last treatment, report all SAEs that meet expedited reporting requirements regardless of relationship to protocol treatment o In follow-up, AE and SAE reporting is limited to AEs reasonably related to protocol treatment
Apalutamide Adverse Events Very Common (>10%) Common (1 -10%) Uncommon (< 1%) Fatigue Itching Seizure Skin rash Changes in thyroid function (Hypothyroidism) Joint pain (Arthralgia) or muscle spams Increase in cholesterol Weight loss Increase in triglycerides Fall Change in experience of taste (Dysgeusia) Fracture Reduced or blocked blood flow to the heart, including heart attack (Ischemic Heart Disease, including Myocardial Infarction) Increased blood pressure (Hypertension) Hot flush Diarrhea
Abiraterone Acetate Adverse Events Frequent (20%) Common (1 -10%) Dyspepsia Adrenal insufficiency Hypokalemia Hematuria Bone density decreased Hypertension Fractures Cardiac failure Urinary tract infection Arrhythmia ALT increase Abnormal ECG with QT prolongation AST increase Myopathy Very Common (>10%) Less Common (< 5%) Unknown Peripheral Edema Increase in triglycerides Acute hepatic failure Uncommon (< 1%) Allergic alveolitis Angina pectoris Severe allergic reaction Rhabdomyolysis Atrial fibrillation Torsades de Pointes Tachycardia
Auditing
Audit Procedures • Audits will be conducted in accordance with the NCI guidelines for Auditing Clinical Trials for the National Clinical Trials Network (NCTN) Program. https: //ctep. cancer. gov/branches/ctmb/clinical. Trials/docs/ ctmb_audit_guidelines. pdf
Auditing • Routine audits are conducted at Main Member/NCORP • At least every three (3) years • Regulatory information, Informed Consent content and drug logs/receipts reviewed centrally (NRG Oncology) just prior to audit • Patient case review conducted on site
NRG Oncology Audit Site Visit Process Site Selection Protocol Case Selection CAPA Submission to NRG Oncology CAPA Reviewed by NRG Oncology Institution Notification 2 - 4 Months in Advance Report sent to NCI and Institution Site Visit: • Regulatory, Informed Consent Content & Pharmacy document review (prior to audit) • Pharmacy visit • Case review Report Writing & Review Submission to NCI / Acceptance to Institution
NRG Oncology Audit Site Visits Regulatory Requirements • Documentation of all re-approvals since prior audit or CIRB Study Specific Worksheet • Documentation for all amendment approvals since previous audit • Documentation of submission of external safety reports if not using CIRB or per IRB policy • Informed Consent content- current consent
NRG Oncology Audit Site Visits Drug Accountability • Authorized Prescriptions • Proper Use of Logs • Documentation of Drug Returns/Destruction • Shipment Records • Proper Storage of Drugs • Comparison of Shelf Inventory and Logs • Comparison of Drug Accountability Records and Patient Records (i. e. cross checking of patient doses against logs)
NRG Oncology Audit Site Visits Patient Case Review • Verification of proper Informed Consent prior to patient entry • Verification of signed HIPAA authorization for patients enrolled in the U. S. • Verification of eligibility and all dates and results of all pertinent preentry examinations • Verification of all dates of therapy and appropriate dosing and scheduling • Verification of adherence to protocol requirements, and if not, accurate and appropriate reporting of non-adherence • Assurance that all adverse events were appropriately reported and triggered appropriate responses • Verification of patient disease status and adequacy of follow-up examinations • Review of data, Targeted Source Data Verification, and data timeliness
Auditing Requirements • Room with internet access • All relevant materials are available for review at the time of the audit • If the institution utilizes electronic medical records (EMRs) and/or scans, the records may be printed for viewing by the auditor(s), or computers with EMR access must be provided; also, a staff member must be present to assist with navigating through the system • To facilitate the review process, it is recommended that institution staff label all documents such as hospital/clinic records, medication prescriptions, drug administration records, research notes, on-study labs, scans and imaging studies, consent forms, etc.
Auditing Questions Jerome Koss, Senior QC Auditor Email: kossj@nrgoncology. org
Thank you!
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