Conditions: Oligodendroglioma Oligoastrocytoma
Keywords: Palbociclib oligodendroglioma oligoastrocytoma anaplastic
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
This multicenter, open-label, phase II trial aims to assess the safety and efficacy of palbociclib in adult patients with Oligodendroglioma or recurrent oligoastrocytoma anaplastic with the activity of the protein RB preserved.

Detailed description:

Arms:
arm 1: Palbociclib will be administrated orally at a dose of 125 mg/day during 21 days followed by a break of 7 days. All patients included will be treated in the same arm. Treatment will be administrated until disease progression, unacceptable adverse side effects or study end.

Interventions: intervention 1: Palbociclib
Intervention descriptions: intervention 1: Palbociclib will be administered orally at a dose of 125 mg/day, until disease progression, unacceptable adverse side effects or study end.

Protocol document:
Prot_000.pdf: 
‭Title:‬‭Pilot,‬‭open-label,‬‭multicenter‬‭and‬‭prospective‬‭Phase‬‭II‬‭Clinical‬‭Trial‬‭to‬‭evaluate‬‭the‬‭safety‬
‭and‬‭efficacy‬‭of‬‭Palbociclib‬‭(PD0332991),‬‭an‬‭inhibitor‬‭of‬‭cyclin-dependent‬‭kinases‬‭4‬‭and‬‭6‬‭(CDK4‬
‭and‬‭CDK6),‬‭in‬‭patients‬‭with‬‭recurrent‬‭Oligodendroglioma‬‭with‬‭preservation‬‭of‬‭activity‬‭of‬‭the‬‭RB‬
‭protein.‬
‭Protocol Code:‬‭GEINO-13‬
‭Nº EudraCT:‬ ‭2015-001722-42‬
‭Version:‬‭4.0 (July 1, 2019)‬
‭District Attorney:‬‭Spanish Neuro-oncology Research‬‭Group - GEINO‬
‭Coordinator:‬‭Juan Manuel Sepúlveda, 12 de Octubre University‬‭Hospital (Madrid)‬
‭The‬ ‭information‬ ‭contained‬ ‭in‬ ‭this‬ ‭document‬ ‭is‬ ‭confidential‬ ‭and‬ ‭may‬ ‭not‬ ‭be‬ ‭revealed‬ ‭to‬ ‭other‬ ‭people‬ ‭without‬ ‭written‬
‭authorization‬‭from‬‭the‬‭researchers,‬‭except‬‭for‬‭the‬‭use‬‭that‬‭may‬‭be‬‭made‬‭of‬‭it‬‭to‬‭obtain‬‭the‬‭informed‬‭consent‬‭of‬‭the‬‭people‬
‭who‬‭are‬‭going‬‭to‬‭receive‬‭the‬‭investigational‬‭drug.‬‭as‬‭well‬‭as‬‭in‬‭communications‬‭to‬‭health‬‭authorities,‬‭clinical‬‭trial‬‭committees‬
‭or those who will carry out the study.‬
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‭PROTOCOL SIGNATURE PAGE‬
‭Protocol Code: GEINO-13‬
‭Version: 4.0 (July 1, 2019)‬
‭I‬‭have‬‭read‬‭this‬‭protocol‬‭and‬‭agree‬‭to‬‭conduct‬‭this‬‭trial‬‭in‬‭accordance‬‭with‬‭all‬‭stipulations‬‭of‬‭the‬‭protocol‬
‭and the Declaration of Helsinki.‬
‭Signature of the Coordinating Investigator and representative of the promoter‬
‭Dr. Juan Manuel Sepúlveda Sánchez‬
‭12 de Octubre University Hospital (Madrid)‬
‭President GEINO‬
‭I‬‭have‬‭read‬‭this‬‭protocol‬‭and‬‭agree‬‭to‬‭conduct‬‭this‬‭trial‬‭in‬‭accordance‬‭with‬‭all‬‭stipulations‬‭of‬‭the‬
‭protocol and the Declaration of Helsinki.‬
‭Signature of Principal Investigator: __________________________________________‬
‭Name: _____________________________________________________________‬
‭Center: ______________________________________________________________‬
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‭1. SUMMARY‬
‭1.1. Type of request‬
‭Clinical Trial of a Medicine Not Authorized by the EMA.‬
‭1.2. Promoter Data‬
‭Spanish Neuro-oncology Research Group (GEINO)‬
‭Velázquez, 7, 3rd floor‬
‭28001, Madrid‬
‭1.3. Essay Title‬
‭Pilot,‬‭open-label,‬‭multicenter‬‭and‬‭prospective‬‭Phase‬‭II‬‭Clinical‬‭Trial‬‭to‬‭evaluate‬‭the‬‭safety‬‭and‬‭efficacy‬‭of‬
‭Palbociclib‬‭(PD0332991),‬‭an‬‭inhibitor‬‭of‬‭cyclin-dependent‬‭kinases‬‭4‬‭and‬‭6‬‭(CDK4‬‭and‬‭CDK6),‬‭in‬‭patients‬
‭with recurrent Oligodendroglioma with preservation of activity of the RB protein.‬
‭1.4. Protocol Code‬
‭GEINO-13‬
‭1.5. Nº EudraCT‬
‭2015-001722-42‬
‭1.6. Coordinating researcher‬
‭Dr. Juan Manuel Sepúlveda Sánchez.‬
‭12 de Octubre University Hospital (Madrid)‬
‭1.7. Principal researchers‬
‭See appendix‬
‭1.8. Participating Centers‬
‭See appendix‬
‭1.9. Name of the Organization in charge of Monitoring‬
‭MFAR (Pharmaceutical Marketing & Clinical Research) S.L.‬
‭C/ Pau Alsina, 64-68, esc. B, Entlo. 5a‬
‭08024 - Barcelona‬
‭Telephone: +34 93 434 44 12‬
‭Fax: +34 93 253 11 68‬
‭investigacion@mfar.net‬
‭www.mfar.es‬
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‭1.10. Treatment description‬
‭All‬‭patients‬‭included‬‭in‬‭the‬‭study‬‭will‬‭be‬‭treated‬‭with‬‭the‬‭experimental‬‭drug,‬‭Palbociclib,‬‭at‬‭a‬‭dose‬‭of‬‭125‬
‭mg/day‬ ‭on‬ ‭days‬ ‭1-21‬ ‭in‬ ‭28-day‬ ‭cycles.‬ ‭That‬ ‭is,‬ ‭administered‬ ‭21‬‭days‬‭followed‬‭by‬‭7‬‭days‬‭of‬‭rest.‬‭The‬
‭treatment‬‭cycles‬‭will‬‭continue‬‭until‬‭there‬‭is‬‭unacceptable‬‭toxicity,‬‭tumor‬‭progression,‬‭withdrawal‬‭of‬‭consent‬
‭or death of the patient.‬
‭1.11. Clinical trial phase‬
‭Phase II pilot clinical trial.‬
‭1.12. Main goal‬
‭To‬ ‭evaluate‬ ‭six-month‬ ‭progression-free‬ ‭survival‬ ‭(PFS)‬ ‭(6mPFS)‬ ‭in‬ ‭patients‬ ‭with‬ ‭recurrent‬ ‭anaplastic‬
‭oligodendroglial tumors.‬
‭1.13. Disease under study‬
‭Recurrent oligodendroglioma with preservation of RB protein activity.‬
‭1.14. Variable Principal‬
‭Percentage of patients who have relapsed/not relapsed to the study treatment 6 months after starting it.‬
‭1.15. Study population‬
‭Patients‬ ‭with‬ ‭anaplastic‬ ‭Oligodendroglioma,‬ ‭defined‬ ‭according‬ ‭to‬ ‭the‬ ‭2016‬ ‭Edition‬ ‭of‬ ‭the‬ ‭WHO,‬
‭histologically confirmed and with preservation of RB protein activity, may be included in this study.‬
‭1.16. Sample size‬
‭40 patients will be included in the study.‬
‭1.17. Treatment duration‬
‭Treatment‬‭will‬‭continue‬‭until‬‭disease‬‭progression,‬‭unacceptable‬‭toxicity,‬‭non-compliance‬‭or‬‭revocation‬‭of‬
‭consent by the patient.‬
‭1.18. Planned schedule‬
‭Start Closing: 2nd quarter of 2015‬
‭Inclusion of the 1st patient: 4th quarter of 2015‬
‭Estimated recruitment period: 28 months‬
‭Follow-up period: 6 months‬
‭End of study: 4th quarter 2019‬
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‭Table of Contents‬
‭1. SUMMARY‬
‭3‬
‭1.1. Type of request‬
‭3‬
‭1.2. Promoter Data‬
‭3‬
‭1.3. Essay Title‬
‭3‬
‭1.4. Protocol Code‬
‭3‬
‭1.5. Nº EudraCT‬
‭3‬
‭1.6. Coordinating researcher‬
‭3‬
‭1.7. Principal researchers‬
‭3‬
‭1.8. Participating Centers and Ethical Committees‬
‭3‬
‭1.9. Name of the Organization in charge of Monitoring‬
‭3‬
‭1.10. Treatment description‬
‭4‬
‭1.11. Clinical trial phase‬
‭4‬
‭1.12. Main goal‬
‭4‬
‭1.13. Disease under study‬
‭4‬
‭1.14. Variable Principal‬
‭4‬
‭1.15. Study population‬
‭4‬
‭1.16. Sample size‬
‭4‬
‭1.17. Treatment duration‬
‭4‬
‭1.18. Planned schedule‬
‭4‬
‭2. LIST OF ABBREVIATIONS‬
‭9‬
‭3. GENERAL INFORMATION‬
‭10‬
‭3.1. Type of Clinical Trial‬
‭10‬
‭3.2. Description of the Study Treatment Scheme‬
‭10‬
‭3.3. District Attorney‬
‭10‬
‭3.4. Name of the Organization responsible for Monitoring‬
‭10‬
‭3.5. Researcher Coordinator‬
‭10‬
‭3.6. Participating centers‬
‭10‬
‭3.7. Planned schedule‬
‭11‬
‭4. JUSTIFICATION AND OBJECTIVES‬
‭12‬
‭4.1. Introduction‬
‭12‬
‭4.2. Background‬
‭12‬
‭4.2.1. Histology of oligodendroglial tumors‬
‭12‬
‭4.2.2. Epidemiology of oligodendroglial tumors‬
‭12‬
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‭4.2.3. Molecular biology of oligodendroglial tumors‬
‭13‬
‭4.2.4. Treatment of Anaplastic Oligodendroglioma‬
‭13‬
‭4.3. Implications of CDK4 and CDK6 in Oligodendroglial Tumors‬
‭14‬
‭4.3.1.CDK4/6 in Cancer‬
‭14‬
‭4.3.2. CDK4/6 in High Grade Gliomas‬
‭15‬
‭4.3.3. CDK4/6 in Oligodendrogliomas‬
‭15‬
‭4.4. Palbociclib (PD0332991)‬
‭16‬
‭4.4.1. Background on preclinical pharmacokinetics and drug metabolism‬
‭16‬
‭4.4.2. Background on the preclinical toxicology of the drug‬
‭17‬
‭4.4.3. Pharmacokinetics, Toxicity and Metabolism of the product in humans‬
‭17‬
‭4.4.4. Clinical experience with Palbociclib in humans‬
‭19‬
‭4.5. Justification‬
‭19‬
‭4.6. Goals‬
‭20‬
‭4.6.1. Main goal‬
‭20‬
‭4.6.2. Secondary objectives‬
‭21‬
‭5. DESIGN AND TYPE OF CLINICAL TRIALS‬
‭22‬
‭5.1. Tumor Screening Period‬
‭22‬
‭5.2. Centralized block review‬
‭22‬
‭5.3. Patient Screening Period‬
‭23‬
‭5.4. Screening Failures‬
‭23‬
‭5.5. Patient inclusion procedure‬
‭23‬
‭5.6. Start of treatment‬
‭24‬
‭5.7. Associated Molecular Substudy‬
‭24‬
‭6. PATIENT SELECTION CRITERIA‬
‭25‬
‭6.1. Inclusion criteria‬
‭25‬
‭6.2. Exclusion criteria‬
‭26‬
‭6.3. Criteria provided for the permanent interruption of the IMP‬
‭28‬
‭6.4. Criteria for withdrawal from the study‬
‭28‬
‭7. DESCRIPTION OF THE TREATMENT‬
‭29‬
‭7.1. Preparation and dispensing‬
‭29‬
‭7.2. Administration‬
‭29‬
‭7.3. Therapeutic compliance‬
‭30‬
‭7.4. Dose modifications‬
‭30‬
‭7.4.1. Treatment interruptions‬
‭31‬
‭7.4.2. Administration delays‬
‭31‬
‭7.4.3. Dose reductions‬
‭32‬
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‭7.5. Medication errors and overdoses‬
‭35‬
‭7.6. Conservation and accounting of medication‬
‭35‬
‭7.7. Concomitant medication‬
‭36‬
‭8. DEVELOPMENT OF THE TEST AND EVALUATION OF THE RESPONSE‬
‭37‬
‭8.1. Study procedures‬
‭37‬
‭8.2. Determinations in the selection phase (baseline determinations)‬
‭39‬
‭8.3. Tests during treatment‬
‭40‬
‭8.4. Security Visit‬
‭41‬
‭8.5. Follow-up visits from the end of treatment without progression to PE‬
‭42‬
‭8.6. Post-progression follow-up‬
‭42‬
‭8.7. Response evaluation‬
‭42‬
‭8.8. Centralized image review‬
‭43‬
‭9. ADVERSE EVENTS‬
‭44‬
‭9.1. Definition‬
‭44‬
‭9.2. Notification and Documentation of Adverse Events‬
‭46‬
‭9.3. Pregnancy notification‬
‭47‬
‭10. STATISTICAL CONSIDERATIONS‬
‭48‬
‭10.1. Study variables‬
‭48‬
‭10.2. Primary objective‬
‭48‬
‭10.3. Hypothesis‬
‭48‬
‭10.4. Statistic analysis‬
‭48‬
‭11. ETHICAL AND LEGAL CONSIDERATIONS‬
‭49‬
‭11.1. Ethics Committee‬
‭49‬
‭11.2. Authorities‬
‭49‬
‭11.3. Informed consent‬
‭49‬
‭11.4. Confidentiality‬
‭50‬
‭11.5. Safe‬
‭50‬
‭11.6. End of study‬
‭50‬
‭11.7. Premature end of study‬
‭50‬
‭12. PRACTICAL CONSIDERATIONS‬
‭51‬
‭12.1. Diagnostic Criteria for the Pathology Under Study‬
‭51‬
‭12.2. Researcher Responsibilities According to Good Clinical Practices‬
‭51‬
‭12.3. Instructions for completing the CRD‬
‭51‬
‭12.4. Supply of study medication‬
‭51‬
‭12.5. Conditioning and Labeling‬
‭51‬
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‭12.6. Articles and Publications‬
‭51‬
‭12.7. Monitoring‬
‭52‬
‭12.8. Amendments to the Protocol‬
‭53‬
‭12.9. Data processing‬
‭53‬
‭12.10. Documentation‬
‭53‬
‭13. BIBLIOGRAPHY‬
‭54‬
‭ANNEX I - PATIENT INFORMATION SHEET AND INFORMED CONSENT‬
‭56‬
‭ANNEX II - BARTHEL INDEX‬
‭57‬
‭ANNEX III - MINI MENTAL STATE EXAMINATION (MMSE) - Adapted ESPAÑA‬
‭58‬
‭ANNEX IV - RANO RESPONSE CRITERIA‬‭59‬
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‭2. LIST OF ABBREVIATIONS‬
‭AA‬
‭Adverse event‬
‭AAG‬
‭Serious adverse event‬
‭EVERYTHING‬
‭Alanine transaminase‬
‭AST‬
‭Aspartate transaminase‬
‭BPC‬
‭Good Clinical Practice‬
‭CRD‬
‭Data collection notebook‬
‭ECG‬
‭Electrocardiogram‬
‭ECOG‬
‭Eastern Cooperative Oncology Group Performance Status‬
‭Eastern Cooperative)‬
‭MOTHER‬
‭European Medicines Agency‬
‭EP‬
‭Progressive disease‬
‭FDA‬
‭Food and Drug Administration (Departamento Salud U.S.)‬
‭INR‬
‭International normalized index‬
‭HERE‬
‭intention to treat‬
‭LDH‬
‭Lactate dehydrogenase‬
‭LIN‬
‭Lower limit of normal‬
‭LSN‬
‭Upper limit of normal‬
‭MUI‬
‭Millions of international units‬
‭NCI-CTCAE v4.0‬
‭Common toxicity criteria for adverse events according to the Institute‬
‭Cancer National, version 4.0‬
‭OH‬
‭Oligodendroglioma Anaplastic‬
‭FROM‬
‭Oligodendroglioma‬
‭RC‬
‭Complete answer‬
‭RM‬
‭Magnetic resonance‬
‭SG‬
‭Global Survival‬
‭SLP‬
‭Progression Free Survival‬
‭TAC‬
‭Axial computed tomography‬
‭TLD‬
‭Dose Limiting Toxicity‬
‭City‬
‭Prothrombin Time‬
‭TTP‬
‭Activated partial thromboplastin time‬
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‭3. GENERAL INFORMATION‬
‭3.1. Type of Clinical Trial‬
‭Clinical Trial of a Medicine Not Authorized by the EMA.‬
‭3.2. Description of the Study Treatment Scheme‬
‭Palbociclib (PD0332991) is a selective inhibitor of Cyclin-dependent Kinases 4 and 6 (CDK4 and CDK6).‬
‭Pharmacotherapeutic group:‬‭Antineoplastic agents‬
‭Presentation:‬‭hard capsules containing 125, 100 and‬‭75 mg of Palbociclib‬
‭Pharmaceutical form:‬‭hard capsules‬
‭Route of administration:‬‭oral‬
‭Supplied by the Promoter through an agreement signed with the laboratory producing the molecule.‬
‭3.3. District Attorney‬
‭Spanish Neuro-oncology Research Group‬
‭Velázquez, 7, 3rd floor-28001 Madrid‬
‭3.4. Name of the Organization responsible for Monitoring‬
‭PHARMACEUTICAL MARKETING & CLINICAL RESEARCH – MFAR S.L.‬
‭C/ Pau Alsina 64-68, esc. B, entlo. 5th‬
‭08024 – Barcelona‬
‭Tel: +34 93 434 44 12‬
‭Fax: +34 93 253 11 68‬
‭e-mail:‬‭investigacion@mfar.net‬
‭3.5. Researcher Coordinator‬
‭Dr. Juan Manuel Sepúlveda Sánchez.‬
‭12 de Octubre University Hospital (Madrid).‬
‭3.6. Participating centers‬
‭See attached document‬
‭3.7. Planned schedule‬
‭Start Closing: 2nd quarter of 2015‬
‭Inclusion of the 1st patient: 4th quarter of 2015‬
‭Estimated recruitment period: 28 months‬
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‭Follow-up period: 6 months‬
‭End of study: 4th quarter 2019‬
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‭4. JUSTIFICATION AND OBJECTIVES‬
‭4.1. Introduction‬
‭Palbociclib‬ ‭(PD0332991)‬‭is‬‭a‬‭selective‬‭inhibitor‬‭of‬‭cyclin-dependent‬‭kinases‬‭4‬‭and‬‭6‬‭(CDK4‬‭and‬‭CDK6)‬
‭whose‬‭function‬‭is‬‭to‬‭facilitate‬‭the‬‭transition‬‭from‬‭the‬‭G1‬‭phase‬‭to‬‭the‬‭S‬‭phase‬‭of‬‭the‬‭cell‬‭cycle‬‭through‬‭the‬
‭phosphorylation‬‭of‬‭the‬‭retinoblastoma‬‭protein‬‭(‬‭RB).‬‭Palbociclib‬‭is‬‭being‬‭evaluated‬‭in‬‭different‬‭tumors‬‭such‬
‭as‬‭breast‬‭cancer‬‭or‬‭glioblastoma.‬‭In‬‭metastatic‬‭breast‬‭cancer‬‭RH‬‭+/Her2‬‭-‬‭has‬‭shown‬‭an‬‭important‬‭and‬
‭significant‬ ‭increase‬ ‭in‬ ‭Progression‬ ‭Free‬ ‭Survival‬ ‭(PFS)‬ ‭when‬ ‭associated‬ ‭with‬ ‭letrozole‬ ‭compared‬ ‭to‬
‭treatment‬‭with‬‭letrozole‬‭monotherapy‬‭(20.2‬‭months‬‭of‬‭the‬‭combination‬‭versus‬‭10.2‬‭months)‬‭1‬‭,‬‭which‬‭has‬‭led‬
‭to‬‭its‬‭approval‬‭by‬‭the‬‭FDA‬‭in‬‭February‬‭2015‬‭as‬‭a‬‭first-line‬‭hormonal‬‭treatment‬‭associated‬‭with‬‭letrozole‬‭in‬
‭this patient population‬
‭Anaplastic‬‭oligodendroglioma‬‭(AO)‬‭responds‬‭to‬‭alkylating‬‭chemotherapy‬‭agents‬‭such‬‭as‬‭temozolomide‬‭or‬
‭the‬‭PCV‬‭regimen‬‭and‬‭also‬‭to‬‭focal‬‭radiotherapy.‬‭However,‬‭when‬‭it‬‭has‬‭progressed‬‭to‬‭these‬‭treatments,‬‭the‬
‭prognosis‬‭is‬‭very‬‭poor,‬‭with‬‭survival‬‭of‬‭a‬‭few‬‭months‬‭and‬‭no‬‭treatment.‬‭This‬‭neoplasm‬‭is‬‭a‬‭type‬‭of‬‭glioma‬
‭that‬‭frequently‬‭presents‬‭alterations‬‭in‬‭the‬‭BR‬‭pathway,‬‭so‬‭blocking‬‭CDK4‬‭and‬‭CDK6‬‭with‬‭palbociclib‬‭may‬‭be‬
‭a‬ ‭therapeutic‬ ‭approach‬ ‭of‬ ‭greatest‬ ‭interest‬ ‭when‬ ‭conventional‬ ‭treatment‬ ‭with‬ ‭chemotherapy‬ ‭and‬
‭radiotherapy has failed.‬
‭4.2. Background‬
‭4.2.1. Histology of oligodendroglial tumors‬
‭The‬ ‭classic‬ ‭image‬ ‭of‬‭oligodendroglioma‬‭(OD)‬‭is‬‭cells‬‭with‬‭a‬‭round‬‭central‬‭nucleus‬‭and‬‭clear‬‭cytoplasm‬
‭around‬‭them.‬‭They‬‭have‬‭a‬‭characteristic‬‭growth‬‭pattern,‬‭with‬‭cells‬‭very‬‭close‬‭to‬‭each‬‭other.‬‭There‬‭are‬‭no‬
‭immunohistochemical‬‭markers‬‭that‬‭allow‬‭specific‬‭recognition‬‭of‬‭oligodendroglioma.‬‭When‬‭astrocytes‬‭also‬
‭appear‬‭in‬‭the‬‭sample,‬‭they‬‭are‬‭considered,‬‭according‬‭to‬‭the‬‭2007‬‭WHO‬‭classification‬‭2‬ ‭Oligoastrocytomas‬
‭(OA),‬‭which‬‭can‬‭be‬‭low‬‭or‬‭high‬‭grade.‬‭However,‬‭in‬‭the‬‭new‬‭WHO‬‭classification‬‭that‬‭will‬‭be‬‭published‬‭in‬
‭2016‬‭(although‬‭the‬‭changes‬‭that‬‭concern‬‭oligodendroglial‬‭tumors‬‭have‬‭already‬‭been‬‭presented)‬‭23,24,25‬‭.‬‭In‬
‭this‬ ‭new‬ ‭classification,‬ ‭molecular‬‭alterations‬‭determine‬‭whether‬‭cases‬‭are‬‭classified‬‭as‬‭astrocytomas‬‭or‬
‭oligodendrogliomas when patients have mixed morphological characteristics.‬
‭Anaplastic‬‭oligodendroglioma‬‭(OA)‬‭presents‬‭features‬‭of‬‭focal‬‭or‬‭diffuse‬‭malignancy,‬‭usually‬‭marked‬‭atypia‬
‭and‬‭elevated‬‭mitotic‬‭activity.‬‭The‬‭presence‬‭of‬‭microvascular‬‭proliferation‬‭or‬‭necrosis‬‭are‬‭signs‬‭of‬‭grade‬‭III‬
‭(anaplastic).‬‭There‬‭is‬‭no‬‭such‬‭thing‬‭as‬‭grade‬‭IV‬‭oligodendroglioma.‬‭Anaplastic‬‭oligoastrocytomas‬‭(AOA)‬
‭with‬ ‭areas‬ ‭of‬ ‭necrosis‬ ‭or‬ ‭vascular‬ ‭proliferation‬ ‭are‬ ‭classified‬ ‭as‬ ‭Glioblastomas‬ ‭with‬ ‭oligodendroglial‬
‭differentiation (Grade IV)‬‭2‬‭.‬
‭The‬‭finding‬‭of‬‭allelic‬‭losses‬‭on‬‭chromosomes‬‭1p‬‭and‬‭19q‬‭favors‬‭the‬‭diagnosis‬‭of‬‭OD,‬‭given‬‭the‬‭frequency‬‭of‬
‭said‬‭losses‬‭in‬‭these‬‭tumors‬‭(above‬‭50%‬‭and‬‭up‬‭to‬‭80%‬‭in‬‭low-grade‬‭cases)‬‭and‬‭in‬‭the‬‭last‬‭classification‬‭it‬
‭passes to be a mandatory condition to have this molecular alteration.‬
‭4.2.2. Epidemiology of oligodendroglial tumors‬
‭Oligodendroglial‬‭tumors‬‭are‬‭rare‬‭neoplasms.‬‭The‬‭Central‬‭Tumor‬‭Registry‬‭of‬‭the‬‭United‬‭States‬‭reported‬‭in‬
‭1995‬‭an‬‭annual‬‭incidence‬‭for‬‭all‬‭oligodendroglial‬‭tumors‬‭of‬‭9.3‬‭cases‬‭per‬‭100,000‬‭inhabitants/year.‬‭3‬‭.‬‭The‬
‭Norwegian‬ ‭Tumor‬ ‭Registry,‬ ‭which‬ ‭analyzed‬ ‭data‬ ‭from‬ ‭the‬ ‭previous‬ ‭25‬ ‭years‬ ‭in‬ ‭1985,‬ ‭determined‬‭that‬
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‭oligodendroglial‬ ‭tumors‬ ‭accounted‬ ‭for‬ ‭4.2%‬ ‭of‬ ‭all‬ ‭brain‬ ‭neoplasms.‬‭4‬‭.‬ ‭In‬ ‭other‬ ‭studies,‬ ‭these‬ ‭tumors‬
‭represent between 5% and 18% of intracranial neoplasias‬‭5‬‭.‬
‭Within‬‭oligodendrogliomas,‬‭the‬‭proportion‬‭of‬‭the‬‭two‬‭WHO‬‭grades‬‭differs‬‭in‬‭different‬‭studies.‬‭Celli‬‭et‬‭al.‬‭6‬‭y‬
‭Nijjar‬ ‭et‬ ‭al.‬‭7‬ ‭They‬ ‭found‬ ‭20%‬ ‭of‬‭anaplastic‬‭oligodendrogliomas.‬‭In‬‭the‬‭Mayo‬‭Clinic‬‭series,‬‭the‬‭group‬‭of‬
‭anaplastic tumors represented 54% of oligodendrogliomas‬‭8‬‭.‬
‭4.2.3. Molecular biology of oligodendroglial tumors‬
‭Table‬‭1‬‭summarizes‬‭the‬‭current‬‭knowledge‬‭on‬‭the‬‭molecular‬‭and‬‭genetic‬‭alterations‬‭that‬‭are‬‭present‬‭in‬‭the‬
‭development‬ ‭and‬ ‭progression‬ ‭of‬ ‭oligodendrogliomas.‬ ‭Deletions‬ ‭in‬ ‭chromosomes‬ ‭1p‬ ‭and‬ ‭19q‬ ‭(loss‬ ‭of‬
‭heterozygosity,‬ ‭PH)‬ ‭are‬ ‭the‬ ‭most‬ ‭frequent‬ ‭and‬ ‭earliest‬ ‭alterations‬ ‭in‬ ‭the‬ ‭tumor‬ ‭progression‬ ‭of‬
‭oligodendrogliomas.‬ ‭In‬ ‭fact,‬ ‭the‬ ‭frequency‬ ‭of‬ ‭PH‬ ‭1p‬ ‭and‬ ‭19q‬ ‭in‬ ‭WHO‬ ‭grade‬ ‭II‬ ‭oligodendrogliomas‬ ‭is‬
‭80-90%,‬‭while‬‭in‬‭anaplastic‬‭oligodendrogliomas‬‭it‬‭is‬‭31-70%.‬‭5‬‭.‬‭In‬‭most‬‭cases,‬‭the‬‭losses‬‭of‬‭1p‬‭and‬‭19q‬‭are‬
‭combined,‬‭and‬‭the‬‭mechanism‬‭of‬‭the‬‭associated‬‭loss‬‭of‬‭these‬‭two‬‭chromosomal‬‭portions‬‭is‬‭currently‬‭not‬
‭known.‬‭In‬‭recent‬‭years,‬‭it‬‭has‬‭been‬‭determined‬‭that‬‭the‬‭loss‬‭of‬‭1p/19q‬‭is‬‭closely‬‭associated‬‭with‬‭mutations‬
‭in IDH1/2 and also with the existence of a methylator phenotype.‬
‭The‬‭transformation‬‭of‬‭a‬‭low-grade‬‭tumor‬‭into‬‭anaplastic‬‭oligodendroglioma‬‭occurs‬‭due‬‭to‬‭the‬‭accumulation‬
‭of‬‭genetic‬‭alterations‬‭(Table‬‭1).‬‭The‬‭most‬‭important‬‭are‬‭the‬‭deletions‬‭of‬‭9p‬‭and‬‭10q.‬‭These‬‭alterations‬‭were‬
‭found‬‭in‬‭a‬‭small‬‭number‬‭of‬‭WHO‬‭grade‬‭II‬‭oligodendrogliomas,‬‭being‬‭much‬‭more‬‭common‬‭in‬‭grade‬‭III.‬‭The‬
‭CDKN2A‬‭gene,‬‭which‬‭is‬‭located‬‭at‬‭9p21,‬‭presents‬‭homozygous‬‭deletions‬‭in‬‭more‬‭than‬‭1/3‬‭of‬‭anaplastic‬
‭oligodendrogliomas‬‭9-11‬‭.‬‭It‬‭is‬‭also‬‭interesting‬‭that‬‭homozygous‬‭deletions‬‭of‬‭CDKN2A‬‭are‬‭particularly‬‭common‬
‭in‬‭oligodendrogliomas‬‭that‬‭do‬‭not‬‭have‬‭loss‬‭of‬‭1p‬‭and‬‭19q.‬‭The‬‭suppressor‬‭genes‬‭CDKN2A‬‭and‬‭CDKN2B‬
‭encode‬ ‭the‬ ‭proteins‬ ‭p16‬ ‭(INK4a)‬ ‭and‬ ‭p15‬‭(INK4b),‬‭respectively,‬‭whose‬‭function‬‭is‬‭to‬‭inhibit‬‭CDK4‬‭and‬
‭CDK6.‬‭Similar‬‭to‬‭what‬‭happens‬‭in‬‭astrocytomas,‬‭the‬‭pRb‬‭pathway‬‭is‬‭altered‬‭in‬‭a‬‭significant‬‭percentage‬‭of‬
‭anaplastic‬‭oligodendrogliomas,‬‭either‬‭through‬‭homozygous‬‭deletion‬‭or‬‭hypermethylation‬‭of‬‭CDKN2A;‬‭the‬
‭amplification and elevated expression of CDK4A; or hypermethylation and loss of pRb expression.‬
‭Figure 1. Most important genetic alterations in oligodendrogliomas‬‭5‬
‭4.2.4. Treatment of Anaplastic Oligodendroglioma‬
‭Regarding‬‭treatment,‬‭the‬‭first‬‭approach‬‭is‬‭surgical‬‭intervention.‬‭In‬‭this‬‭sense,‬‭retrospective‬‭studies‬‭as‬‭well‬
‭as‬‭subgroup‬‭analyzes‬‭reach‬‭the‬‭same‬‭conclusion:‬‭a‬‭wide‬‭resection‬‭improves‬‭the‬‭patient's‬‭prognosis.‬‭Given‬
‭the‬ ‭high‬ ‭possibility‬ ‭of‬ ‭tumor‬‭progression,‬‭in‬‭the‬‭1980s‬‭radiotherapy‬‭was‬‭established‬‭as‬‭the‬‭standard‬‭of‬
‭post-surgical treatment in high-grade gliomas.‬
‭In‬‭the‬‭90s,‬‭studies‬‭were‬‭published‬‭that‬‭showed‬‭that‬‭they‬‭are‬‭chemosensitive‬‭tumors‬‭(PCV),‬‭unlike‬‭other‬
‭brain‬ ‭tumors.‬‭12‬‭.‬ ‭With‬ ‭these‬ ‭data,‬ ‭two‬ ‭studies‬ ‭were‬ ‭then‬ ‭designed,‬ ‭from‬ ‭which‬ ‭we‬ ‭have‬ ‭just‬ ‭obtained‬
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‭results.‬‭13,14‬‭:‬ ‭the‬ ‭RTOG‬ ‭9402‬ ‭study‬ ‭and‬ ‭the‬‭EORTC‬‭study‬‭26951.‬‭In‬‭both‬‭cases,‬‭after‬‭an‬‭initial‬‭surgical‬
‭approach,‬ ‭the‬ ‭question‬ ‭of‬ ‭whether‬ ‭chemotherapy‬ ‭(PCV:‬ ‭Procarbazine,‬‭CCNU‬‭and‬‭Vincristine)‬‭provided‬
‭benefit to the radiotherapy treatment was attempted. , so the 2 randomized phase III studies were designed.‬
‭The‬‭primary‬‭endpoint‬‭in‬‭the‬‭EORTC‬‭study‬‭was‬‭PFS‬‭and‬‭OS.‬‭A‬‭total‬‭of‬‭368‬‭patients‬‭with‬‭oligodendroglial‬
‭tumor‬‭were‬‭included‬‭between‬‭1995‬‭and‬‭2002,‬‭aged‬‭between‬‭16‬‭and‬‭70‬‭years.‬‭The‬‭branches‬‭were‬‭well‬
‭balanced‬‭for‬‭known‬‭prognostic‬‭factors.‬‭Adding‬‭PCV‬‭to‬‭radiotherapy‬‭increases‬‭median‬‭PFS‬‭from‬‭13‬‭to‬‭24‬
‭months‬‭and‬‭OS‬‭from‬‭31‬‭to‬‭42‬‭months,‬‭statistically‬‭significantly.‬‭These‬‭results‬‭were‬‭further‬‭maintained‬‭when‬
‭performing‬‭an‬‭analysis‬‭that‬‭included‬‭risk‬‭stratification‬‭by‬‭age,‬‭type‬‭of‬‭surgery,‬‭PS,‬‭and‬‭prior‬‭surgery‬‭for‬
‭low-grade‬ ‭glioma.‬‭15‬‭.‬ ‭The‬ ‭next‬‭question‬‭he‬‭tried‬‭to‬‭answer‬‭is‬‭whether‬‭there‬‭is‬‭any‬‭way‬‭to‬‭identify‬‭those‬
‭patients‬‭who‬‭will‬‭benefit‬‭the‬‭most.‬‭The‬‭results‬‭analyzed‬‭prospectively‬‭for‬‭1p/19q,‬‭and‬‭retrospectively‬‭for‬
‭MGMT‬‭and‬‭IDH,‬‭can‬‭help‬‭with‬‭this.‬‭1p/19‬‭was‬‭analyzed‬‭in‬‭316‬‭patients‬‭and‬‭25%‬‭were‬‭co-deleted.‬‭MGMT‬
‭was‬‭analyzed‬‭in‬‭183‬‭patients‬‭and‬‭75%‬‭were‬‭methylated‬‭and‬‭IDH‬‭was‬‭analyzed‬‭in‬‭176‬‭patients‬‭and‬‭was‬
‭mutated‬‭in‬‭46%.‬‭For‬‭1p/19‬‭there‬‭is‬‭a‬‭benefit‬‭in‬‭PFS‬‭from‬‭50‬‭to‬‭157‬‭months‬‭and‬‭in‬‭OS‬‭from‬‭9‬‭years‬‭to‬‭a‬
‭median‬‭not‬‭yet‬‭reached‬‭(>12‬‭years)‬‭(p=0.059).‬‭However,‬‭in‬‭non-co-deleted‬‭patients,‬‭the‬‭differences‬‭do‬‭not‬
‭reach statistical significance.‬
‭In‬‭2012‬‭we‬‭also‬‭learned‬‭the‬‭final‬‭results‬‭of‬‭the‬‭RTOG‬‭9462‬‭study,‬‭which‬‭were‬‭very‬‭similar‬‭to‬‭those‬‭of‬‭the‬
‭EORTC‬ ‭study.‬‭16‬‭.‬ ‭Based‬ ‭on‬ ‭these‬ ‭data,‬ ‭post-surgical‬ ‭radiotherapy‬ ‭treatment‬‭will‬‭be‬‭complemented‬‭with‬
‭chemotherapy‬‭in‬‭the‬‭event‬‭that‬‭there‬‭is‬‭loss‬‭of‬‭1p/19q.‬‭In‬‭cases‬‭without‬‭chromosome‬‭loss,‬‭it‬‭is‬‭usual‬‭to‬‭use‬
‭radiotherapy exclusively.‬
‭In‬‭both‬‭the‬‭RTOG9462‬‭and‬‭EORTC‬‭26951‬‭studies,‬‭patients‬‭were‬‭treated‬‭with‬‭chemotherapy‬‭at‬‭relapse,‬‭still‬
‭achieving‬ ‭responses‬ ‭in‬ ‭some‬ ‭cases.‬ ‭Temozolomide‬ ‭was‬ ‭the‬ ‭most‬ ‭used‬ ‭alkylating‬ ‭agent‬ ‭in‬ ‭cases‬ ‭of‬
‭recurrence. However, there is currently no standard treatment for OA recurrence.‬
‭4.3. Implications of CDK4 and CDK6 in Oligodendroglial Tumors‬
‭4.3.1.CDK4/6 in Cancer‬
‭The‬‭proliferation‬‭of‬‭eukaryotic‬‭cells‬‭depends‬‭on‬‭an‬‭orderly‬‭progression‬‭through‬‭the‬‭different‬‭phases‬‭of‬‭the‬
‭cell‬‭cycle:‬‭G1,‬‭S,‬‭G2‬‭and‬‭M‬‭(mitosis).‬‭Cyclin-dependent‬‭kinases‬‭(CDKs)‬‭play‬‭an‬‭important‬‭role‬‭in‬‭regulating‬
‭these‬‭steps‬‭throughout‬‭the‬‭cell‬‭cycle‬‭and,‬‭especially‬‭in‬‭the‬‭step‬‭from‬‭G1‬‭to‬‭DNA‬‭replication‬‭(S)‬‭and‬‭in‬‭the‬
‭step‬‭between‬‭G2‬‭and‬‭mitosis‬‭(M).‬‭The‬‭regulation‬‭of‬‭the‬‭catalytic‬‭activity‬‭of‬‭CDKs‬‭occurs‬‭at‬‭multiple‬‭levels‬
‭such‬ ‭as‬ ‭their‬ ‭own‬ ‭phosphorylation/dephosphorylation;‬ ‭its‬ ‭synthesis‬ ‭and‬ ‭degradation‬ ‭rate;‬ ‭and‬ ‭the‬
‭expression or degradation of selective inhibitory proteins.‬
‭The‬‭transition‬‭from‬‭the‬‭G1‬‭phase‬‭to‬‭the‬‭S‬‭phase‬‭requires‬‭the‬‭phosphorylation‬‭of‬‭the‬‭retinoblastoma‬‭protein‬
‭(Rb)‬‭by‬‭CDK4‬‭and‬‭its‬‭analogous‬‭protein‬‭CDK6,‬‭forming‬‭a‬‭complex‬‭with‬‭their‬‭activating‬‭subunits,‬‭the‬‭D-type‬
‭cyclins,‬‭D1,‬‭D2‬‭and‬‭D3.‬‭Hyperphosphorylation‬‭of‬‭RB‬‭decreases‬‭its‬‭ability‬‭to‬‭repress‬‭E2F‬‭family‬‭transcription‬
‭factors‬ ‭and,‬ ‭consequently,‬ ‭the‬ ‭activation‬ ‭of‬ ‭multiple‬ ‭genes‬ ‭whose‬ ‭products‬ ‭are‬ ‭essential‬ ‭for‬ ‭DNA‬
‭replication.‬‭The‬‭p16‬‭and‬‭p18‬‭proteins,‬‭encoded‬‭by‬‭the‬‭CDKN2A/B‬‭gene,‬‭are‬‭responsible‬‭for‬‭inhibiting‬‭the‬
‭CDK4/6-Cyclin‬‭D‬‭complexes,‬‭preventing‬‭overactivity‬‭of‬‭the‬‭pathway.‬‭The‬‭loss‬‭of‬‭p16‬‭and‬‭p18‬‭are,‬‭therefore,‬
‭alterations frequently involved in neoplastic transformation.‬
‭Graph 1. Control of the cell cycle by the different Cyclin-CDK complexes.‬
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‭4.3.2. CDK4/6 in High Grade Gliomas‬
‭Genetic‬ ‭alterations‬ ‭affecting‬ ‭the‬ ‭CDK4/6-CyclinD-INK4-RB‬ ‭regulatory‬ ‭axis‬ ‭in‬ ‭gliomas‬ ‭are‬ ‭well‬
‭documented.‬‭17‬ ‭and‬ ‭have‬ ‭been‬ ‭corroborated‬ ‭in‬ ‭large-scale‬ ‭genetic‬ ‭analyzes‬‭18,19‬‭.‬ ‭The‬ ‭most‬ ‭frequent‬
‭alteration‬‭of‬‭this‬‭molecular‬‭pathway‬‭in‬‭glioblastomas‬‭is‬‭the‬‭homozygous‬‭deletion‬‭of‬‭the‬‭CDKN2A/B‬‭gene‬
‭that‬ ‭encodes‬ ‭the‬ ‭p16‬ ‭proteins.‬‭INK4a‬ ‭the‬ ‭p15‬‭INK4B‬‭,‬ ‭which‬ ‭affect‬ ‭more‬ ‭than‬ ‭50%‬ ‭of‬ ‭this‬ ‭tumor‬ ‭line.‬ ‭Other‬
‭alterations‬‭are‬‭amplification‬‭of‬‭CDK4‬‭(15-20%)‬‭and‬‭homozygous‬‭deletion‬‭of‬‭RB1‬‭(10%).‬‭Amplification‬‭of‬
‭CDK6 and cyclins D as well as homozygous deletion of p18‬‭INK4c‬‭They are less frequent.‬
‭Of‬‭all‬‭these‬‭alterations,‬‭only‬‭genetic‬‭inactivation‬‭of‬‭RB‬‭leads‬‭the‬‭tumor‬‭to‬‭be‬‭resistant‬‭to‬‭CDK4/6‬
‭inhibition.‬‭In‬‭fact,‬‭“in‬‭vitro”‬‭studies‬‭with‬‭PD0332991‬‭against‬‭a‬‭panel‬‭of‬‭glioblastoma‬‭showed‬‭that‬‭all‬‭those‬
‭with‬ ‭conservation‬ ‭of‬ ‭the‬ ‭RB‬ ‭protein‬ ‭were‬ ‭sensitive‬ ‭to‬ ‭the‬ ‭drug‬‭while‬‭the‬‭5‬‭cell‬‭lines‬‭with‬‭homozygous‬
‭inactivation of RB were resistant to PD0332991.‬
‭4.3.3. CDK4/6 in Oligodendrogliomas‬
‭As‬ ‭mentioned‬ ‭above,‬ ‭the‬ ‭most‬ ‭important‬ ‭genetic‬ ‭alteration‬ ‭in‬ ‭the‬ ‭transformation‬ ‭towards‬ ‭the‬ ‭grade‬‭of‬
‭anaplasia‬ ‭is‬ ‭the‬ ‭loss‬ ‭of‬ ‭the‬ ‭suppressor‬ ‭gene‬ ‭CDKN2A,‬ ‭which‬‭is‬‭located‬‭on‬‭chromosome‬‭9p21‬‭and‬‭its‬
‭alteration‬‭is‬‭very‬‭rare‬‭in‬‭low-grade‬‭gliomas.‬‭In‬‭most‬‭cases,‬‭there‬‭is‬‭loss‬‭of‬‭both‬‭copies‬‭of‬‭suppressor‬‭genes‬
‭adjacent‬‭to‬‭CDKN2A‬‭such‬‭as‬‭p14ARF‬‭and‬‭CDKN2B.‬‭CDKN2A‬‭and‬‭CDKN2B‬‭encode‬‭p16‬‭INK4a‬ ‭the‬‭p15‬‭INK4b‬
‭respectively‬‭whose‬‭function‬‭is‬‭to‬‭regulate‬‭the‬‭G1-S‬‭transition‬‭of‬‭the‬‭cell‬‭cycle‬‭through‬‭the‬‭inhibition‬‭of‬‭CDK4‬
‭and‬‭CDK6.‬‭As‬‭also‬‭previously‬‭reviewed,‬‭CDK4‬‭and‬‭CDK6‬‭cause‬‭phosphorylation‬‭of‬‭RB.‬‭In‬‭addition‬‭to‬‭the‬
‭loss‬‭of‬‭CDKN2A,‬‭OAs‬‭present‬‭other‬‭alterations‬‭in‬‭the‬‭RB‬‭pathway,‬‭so‬‭that‬‭practically‬‭all‬‭cases‬‭ultimately‬
‭present‬‭a‬‭severe‬‭dysfunction‬‭of‬‭this‬‭tumor‬‭suppressor‬‭pathway.‬‭Other‬‭alterations‬‭of‬‭this‬‭molecular‬‭pathway‬
‭are: hypermethylation of CDKN2A and CDKN2B, amplification and overexpression of CDK4.‬
‭4.4. Palbociclib (PD0332991)‬
‭Palbociclib‬‭is‬‭an‬‭oral‬‭CDK4‬‭and‬‭CDK6‬‭inhibitor‬‭that‬‭has‬‭been‬‭evaluated‬‭in‬‭various‬‭phase‬‭1‬‭and‬‭phase‬‭2‬
‭clinical‬‭trials‬‭in‬‭various‬‭indications.‬‭Palbociclib‬‭prevents‬‭the‬‭normal‬‭development‬‭of‬‭the‬‭cell‬‭cycle‬‭from‬‭the‬
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‭G1‬‭phase‬‭to‬‭the‬‭S‬‭phase‬‭and‬‭has‬‭demonstrated‬‭important‬‭antitumor‬‭activity‬‭in‬‭preclinical‬‭models‬‭such‬‭as‬
‭glioblastoma and also in human tumors such as metastatic breast cancer luminal phenotype‬‭1‬‭.‬
‭Treatment‬‭of‬‭cultured‬‭tumor‬‭cells‬‭with‬‭PD‬‭0332991‬‭causes‬‭growth‬‭arrest‬‭that‬‭is‬‭accompanied‬‭by‬‭inhibition‬
‭of‬‭specific‬‭phosphorylation‬‭of‬‭Rb‬‭by‬‭CDK4‬‭or‬‭CDK6‬‭at‬‭serine‬‭residues‬‭780‬‭and‬‭795‬‭of‬‭Rb.‬‭Consequently,‬
‭the‬ ‭phosphorylation‬ ‭status‬ ‭of‬ ‭these‬ ‭sites‬ ‭makes‬ ‭them‬ ‭specific‬ ‭biomarkers‬ ‭of‬ ‭CDK4/6‬ ‭inhibition‬ ‭by‬ ‭PD‬
‭0332991.‬‭IC50‬‭values‬‭​of‬‭reduced‬‭Rb‬‭phosphorylation‬‭at‬‭serine‬‭residues‬‭780‬‭and‬‭795‬‭in‬‭MDA‬‭mammary‬
‭carcinoma‬‭cells‬‭-MB-435‬‭were‬‭0.066‬‭and‬‭0.063‬‭μM,‬‭respectively.‬‭The‬‭IC50‬‭values‬‭​of‬‭the‬‭reduction‬‭of‬‭Rb‬
‭phosphorylation‬‭are‬‭similar‬‭to‬‭those‬‭of‬‭the‬‭inhibition‬‭of‬‭thymidine‬‭incorporation‬‭in‬‭various‬‭cultured‬‭normal‬
‭and tumor cells.‬
‭In‬‭a‬‭group‬‭of‬‭16‬‭RB+‬‭glioblastoma‬‭cell‬‭lines‬‭Palbociclib‬‭caused‬‭a‬‭potent‬‭cell‬‭cycle‬‭arrest‬‭effect‬‭in‬‭the‬‭G1‬
‭phase‬‭followed‬‭by‬‭senescence.‬‭However,‬‭5‬‭RB-‬‭Glioblastoma‬‭cell‬‭lines‬‭were‬‭resistant‬‭to‬‭treatment.‬‭20‬‭.‬‭The‬
‭selectivity‬‭of‬‭its‬‭mechanism‬‭of‬‭action‬‭is‬‭also‬‭proven‬‭by‬‭the‬‭fact‬‭that‬‭reducing‬‭the‬‭expression‬‭of‬‭RB‬‭RNA‬‭in‬
‭glioblastoma‬ ‭cell‬ ‭lines‬ ‭results‬ ‭in‬ ‭the‬ ‭cell‬ ‭lines‬ ‭becoming‬ ‭resistant‬ ‭to‬ ‭treatment.‬ ‭Also‬ ‭in‬ ‭intracerebral‬
‭glioblastoma‬‭xenografts‬‭it‬‭has‬‭been‬‭seen‬‭that‬‭Palbociclib‬‭can‬‭cross‬‭the‬‭blood-brain‬‭barrier‬‭by‬‭producing‬‭a‬
‭reduction‬‭in‬‭the‬‭implanted‬‭tumors.‬‭Also‬‭in‬‭glioblastoma‬‭xenografts‬‭it‬‭has‬‭been‬‭found‬‭that‬‭there‬‭may‬‭be‬‭an‬
‭enhancing‬‭action‬‭between‬‭Palbociclib‬‭and‬‭radiotherapy‬‭in‬‭this‬‭disease.‬‭Given‬‭these‬‭findings,‬‭a‬‭clinical‬‭trial‬
‭with Palbociclib in recurrent glioblastoma has been initiated (NCT01227434).‬
‭4.4.1. Background on preclinical pharmacokinetics and drug metabolism‬
‭Palbociclib‬‭inhibits‬‭RB‬‭phosphorylation‬‭by‬‭CDK4‬‭with‬‭an‬‭IC‬‭50‬‭of‬‭less‬‭than‬‭20nM‬‭and‬‭is‬‭capable‬‭of‬‭reducing‬
‭tumor‬‭growth‬‭of‬‭multiple‬‭tumor‬‭xenografts‬‭in‬‭immunodeficient‬‭mice.‬‭A‬‭stable‬‭plasma‬‭drug‬‭concentration‬‭of‬
‭1000‬‭mg/mL‬‭caused‬‭an‬‭80-90%‬‭inhibition‬‭in‬‭RB‬‭phosphorylation‬‭in‬‭addition‬‭to‬‭a‬‭50%‬‭reduction‬‭in‬‭tumor‬
‭growth.‬
‭In‬‭non-human‬‭species‬‭(dog,‬‭monkey‬‭and‬‭mouse),‬‭Palbociclib‬‭shows‬‭low‬‭to‬‭moderate‬‭plasma‬‭clearance,‬‭a‬
‭large‬‭volume‬‭of‬‭distribution‬‭and‬‭an‬‭oral‬‭bioavailability‬‭around‬‭23%-56%.‬‭Plasma‬‭protein‬‭binding‬‭is‬‭moderate‬
‭in mice, dogs and human plasma. In humans, Palbociclib is distributed more in erythrocytes than in plasma.‬
‭Radioequivalents‬ ‭of‬ ‭Palbociclib‬ ‭were‬ ‭widely‬ ‭distributed‬‭in‬‭most‬‭rat‬‭tissues‬‭after‬‭oral‬‭intake‬‭of‬‭the‬‭drug.‬
‭Palbociclib‬ ‭generates‬ ‭multiple‬ ‭metabolites‬ ‭detected‬ ‭in‬ ‭concentrations‬ ‭in‬ ‭all‬ ‭species‬ ‭studied,‬ ‭including‬
‭humans.‬ ‭It‬ ‭is‬ ‭metabolized‬ ‭by‬ ‭CYP3A‬ ‭enzymes,‬ ‭undergoing‬ ‭several‬ ‭steps‬ ‭including‬ ‭oxidation,‬
‭glucuronidation,‬ ‭sulfation‬ ‭and‬ ‭the‬ ‭combination‬ ‭of‬ ‭several‬ ‭of‬ ‭these‬ ‭processes.‬ ‭After‬ ‭administration‬ ‭of‬
‭radioisotope-labeled‬‭Palbociclib‬‭in‬‭rats,‬‭it‬‭was‬‭observed‬‭that‬‭the‬‭majority‬‭of‬‭the‬‭radiopharmaceutical‬‭was‬
‭eliminated‬ ‭via‬ ‭the‬ ‭fecal‬ ‭route.‬ ‭Neither‬ ‭Palbociclib‬ ‭nor‬ ‭its‬ ‭primary‬ ‭metabolism‬ ‭PF-05089326‬ ‭showed‬
‭significant‬ ‭inhibition‬‭of‬‭CYP1A2,‬‭CYP2B6,‬‭CYP2C8,‬‭CYP2C9,‬‭CYP2C19,‬‭or‬‭CYP2D6.‬‭It‬‭was‬‭found‬‭that‬
‭Palbociclib‬ ‭and‬ ‭PF-05089326‬ ‭produced‬ ‭an‬ ‭inhibition‬ ‭of‬ ‭CYP3A,‬ ‭so‬ ‭this‬ ‭drug‬ ‭potentially‬ ‭presents‬
‭pharmacokinetic‬‭interactions‬‭with‬‭other‬‭drugs‬‭metabolized‬‭by‬‭CYP3A.‬‭It‬‭has‬‭also‬‭been‬‭found‬‭in‬‭preclinical‬
‭studies‬‭that‬‭Palbociclib‬‭can‬‭inhibit‬‭the‬‭absorption‬‭and‬‭pharmacodynamics‬‭of‬‭drugs‬‭that‬‭are‬‭substrates‬‭of‬
‭P-glycoprotein and Breast Cancer Resistance Protein (BCRP).‬
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‭4.4.2. Background on the preclinical toxicology of the drug‬
‭Palbociclib‬‭had‬‭no‬‭effects‬‭on‬‭heart‬‭rate,‬‭heart‬‭rate,‬‭or‬‭blood‬‭pressure‬‭in‬‭dogs.‬‭However,‬‭an‬‭increase‬‭in‬‭the‬
‭QT interval was detected.‬
‭At‬‭the‬‭lung‬‭level,‬‭transient‬‭toxicity‬‭was‬‭found‬‭in‬‭dogs‬‭anesthetized‬‭with‬‭a‬‭dose‬‭of‬‭100‬‭mg/m2‬‭with‬‭a‬‭peak‬
‭concentration‬‭of‬‭2040‬‭ng/mL.‬‭With‬‭lower‬‭doses‬‭(20‬‭mg/m2,‬‭peak‬‭of‬‭414‬‭ng/mL)‬‭this‬‭type‬‭of‬‭toxicity‬‭was‬‭not‬
‭detected.‬
‭In‬‭animal‬‭studies,‬‭Palbociclib‬‭was‬‭lethal‬‭in‬‭rats‬‭when‬‭AUC‬‭values‬‭​were‬‭reached.‬‭(0-24)‬ ‭of‬‭46600‬‭and‬‭11100‬
‭ng/h/mL‬‭in‬‭males‬‭and‬‭females‬‭respectively.‬‭The‬‭cause‬‭of‬‭the‬‭greater‬‭susceptibility‬‭on‬‭the‬‭part‬‭of‬‭females‬‭is‬
‭not known.‬
‭Reversible‬‭pancytopenia‬‭occurred‬‭in‬‭both‬‭male‬‭and‬‭female‬‭rats‬‭at‬‭doses‬‭of‬‭300‬‭mg/m2‬‭and‬‭600‬‭mg/m2,‬
‭respectively.‬‭Testicular‬‭degeneration‬‭in‬‭rats‬‭occurred‬‭at‬‭doses‬‭of‬‭300‬‭mg/m2.‬‭The‬‭dose‬‭that‬‭produced‬‭the‬
‭decrease‬‭in‬‭hematological‬‭markers‬‭was‬‭12‬‭mg/m2‬‭in‬‭dogs,‬‭associating‬‭an‬‭AUC‬‭(0-24)‬ ‭at‬‭steady‬‭state‬‭of‬‭548‬
‭ng/h/mL.‬‭Monocytes‬‭and‬‭neutrophils‬‭were‬‭the‬‭most‬‭affected.‬‭The‬‭nadir‬‭was‬‭reached‬‭at‬‭the‬‭end‬‭of‬‭dosing‬
‭and all variations in these parameters were reversible.‬
‭In‬‭preclinical‬‭studies‬‭conducted‬‭in‬‭rats‬‭and‬‭dogs‬‭that‬‭took‬‭Palbociclib‬‭for‬‭a‬‭minimum‬‭of‬‭3‬‭weeks,‬‭effects‬‭on‬
‭the‬‭male‬‭reproductive‬‭organs‬‭were‬‭observed,‬‭such‬‭as‬‭disintegration‬‭of‬‭the‬‭structure‬‭of‬‭the‬‭seminiferous‬
‭tubules‬ ‭(tubes‬ ‭in‬ ‭the‬ ‭testicles‬ ‭where‬ ‭sperm‬ ‭are‬ ‭produced)‬ ‭as‬ ‭a‬ ‭decrease‬ ‭in‬ ‭semen‬ ‭secretion.‬
‭Dose-dependent‬‭effects,‬‭even‬‭in‬‭the‬‭4‬‭weeks‬‭after‬‭the‬‭last‬‭intake‬‭of‬‭palbociclib.‬‭None‬‭of‬‭these‬‭effects‬‭have‬
‭been observed at human dosages or in any clinical study.‬
‭4.4.3. Pharmacokinetics, Toxicity and Metabolism of the product in humans‬
‭PD‬‭0332991‬‭has‬‭been‬‭tested‬‭in‬‭a‬‭phase‬‭1‬‭dose-escalating‬‭study‬‭(A5481001)‬‭in‬‭74‬‭patients‬‭with‬‭advanced‬
‭cancer.‬‭Two‬‭dosing‬‭regimens‬‭were‬‭evaluated:‬‭regimen‬‭3/1‬‭(3‬‭weeks‬‭of‬‭treatment/1‬‭week‬‭off‬‭treatment)‬‭and‬
‭regimen 2/1 (2 weeks of treatment/1 week off treatment).‬
‭All‬‭DLTs‬‭observed‬‭in‬‭this‬‭study‬‭were‬‭related‬‭to‬‭myelosuppression,‬‭and‬‭were‬‭mainly‬‭grade‬‭3‬‭neutropenia‬
‭lasting‬‭more‬‭than‬‭7‬‭days‬‭after‬‭the‬‭end‬‭of‬‭the‬‭treatment‬‭cycle.‬‭However,‬‭the‬‭neutropenia‬‭was‬‭reversible‬‭and‬
‭not‬ ‭cumulative.‬ ‭The‬ ‭most‬ ‭frequent‬ ‭non-hematological‬ ‭adverse‬ ‭events‬ ‭were‬ ‭fatigue,‬ ‭anemia,‬ ‭diarrhea,‬
‭constipation,‬‭vomiting‬‭and‬‭dyspnea,‬‭all‬‭of‬‭which‬‭were‬‭mild‬‭or‬‭moderate‬‭in‬‭severity.‬‭A‬‭partial‬‭response‬‭was‬
‭reported‬‭in‬‭a‬‭patient‬‭with‬‭testicular‬‭cancer.‬‭Stable‬‭disease‬‭(SE)‬‭was‬‭seen‬‭in‬‭a‬‭total‬‭of‬‭13/37‬‭patients‬‭treated‬
‭with‬‭the‬‭3/1‬‭regimen‬‭evaluable‬‭for‬‭efficacy,‬‭including‬‭6‬‭patients‬‭with‬‭SE‬‭for‬‭40‬‭or‬‭more‬‭weeks.‬‭One‬‭of‬‭these‬
‭patients‬‭was‬‭a‬‭woman‬‭with‬‭ER+‬‭breast‬‭cancer‬‭who‬‭had‬‭previously‬‭received‬‭7‬‭lines‬‭of‬‭treatment‬‭for‬‭the‬
‭disease.‬‭This‬‭patient‬‭remained‬‭on‬‭treatment‬‭for‬‭80‬‭weeks‬‭(7‬‭cycles‬‭with‬‭50‬‭mg/day‬‭and‬‭13‬‭cycles‬‭with‬‭75‬
‭mg/day)‬‭and‬‭ended‬‭up‬‭abandoning‬‭it‬‭due‬‭to‬‭disease‬‭progression.‬‭Based‬‭on‬‭the‬‭efficacy‬‭results‬‭of‬‭this‬‭study,‬
‭the‬‭3/1‬‭regimen‬‭has‬‭been‬‭chosen‬‭for‬‭further‬‭clinical‬‭development.‬‭The‬‭DF2R‬‭for‬‭the‬‭3/2‬‭schedule‬‭is‬‭125‬
‭mg/day.‬
‭In‬ ‭the‬ ‭Phase‬ ‭1‬ ‭dose‬ ‭escalation‬ ‭study‬ ‭(A5481001),‬ ‭PD‬ ‭0332991‬ ‭was‬ ‭slowly‬ ‭absorbed.‬ ‭The‬ ‭median‬
‭maximum‬ ‭concentration‬ ‭appeared‬ ‭~4‬ ‭hours‬ ‭post-dose‬ ‭on‬ ‭day‬ ‭1,‬ ‭and‬ ‭exposure‬ ‭generally‬ ‭increased‬ ‭in‬
‭proportion‬‭to‬‭dose.‬‭The‬‭mean‬‭volume‬‭of‬‭distribution‬‭of‬‭PD‬‭0332991‬‭was‬‭3103‬‭L,‬‭significantly‬‭higher‬‭than‬
‭total‬‭body‬‭water‬‭(42‬‭L),‬‭indicating‬‭that‬‭PD‬‭0332991‬‭penetrates‬‭widely‬‭into‬‭peripheral‬‭tissues.‬‭PD‬‭0332991‬
‭was‬‭slowly‬‭removed;‬‭the‬‭mean‬‭terminal‬‭half-life‬‭was‬‭26.5‬‭hours,‬‭and‬‭the‬‭mean‬‭apparent‬‭oral‬‭clearance‬‭was‬
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‭86.1‬‭L/hour.‬‭Renal‬‭excretion‬‭is‬‭a‬‭minor‬‭route‬‭of‬‭elimination‬‭of‬‭PD‬‭0332991.‬‭The‬‭pilot‬‭evaluation‬‭of‬‭the‬‭effect‬
‭of‬ ‭food‬ ‭in‬ ‭this‬ ‭study‬‭observed‬‭higher‬‭exposures‬‭in‬‭fed‬‭than‬‭fasted‬‭subjects.‬‭Based‬‭on‬‭these‬‭data,‬‭and‬
‭because‬‭administration‬‭of‬‭PD‬‭0332991‬‭with‬‭a‬‭high-fat‬‭meal‬‭may‬‭increase‬‭exposure,‬‭patients‬‭should‬‭fast‬
‭from‬‭1‬‭hour‬‭before‬‭to‬‭2‬‭hours‬‭after‬‭administration.‬‭The‬‭effects‬‭of‬‭a‬‭non-fat‬‭meal‬‭on‬‭the‬‭pharmacokinetics‬‭of‬
‭PD‬ ‭0332991‬ ‭have‬ ‭not‬ ‭been‬ ‭evaluated.‬ ‭In‬ ‭clinical‬ ‭trials‬ ‭with‬ ‭palbociclib‬ ‭until‬ ‭December‬ ‭10,‬ ‭2014,‬ ‭two‬
‭different‬‭formulations‬‭of‬‭palbociclib‬‭have‬‭been‬‭provided:‬‭as‬‭isotethionate‬‭salt‬‭(PD-0332991)‬‭or‬‭as‬‭free‬‭base‬
‭(PD-0332991).‬‭Due‬‭to‬‭the‬‭inherent‬‭differences‬‭between‬‭the‬‭two‬‭in‬‭their‬‭solubility‬‭as‬‭a‬‭function‬‭of‬‭pH,‬‭the‬
‭administration‬‭recommendations‬‭in‬‭relation‬‭to‬‭meals‬‭and‬‭the‬‭potential‬‭effect‬‭of‬‭antacids‬‭on‬‭their‬‭absorption‬
‭differ between both formulations.‬
‭Patients‬ ‭receiving‬ ‭palbociclib‬ ‭isethionate‬ ‭capsules‬ ‭should‬ ‭take‬ ‭the‬ ‭drug‬ ‭on‬ ‭an‬ ‭empty‬ ‭stomach,‬ ‭while‬
‭palbociclib‬ ‭freebase‬ ‭capsules‬ ‭should‬ ‭be‬ ‭administered‬ ‭with‬ ‭food.‬ ‭Results‬ ‭from‬ ‭study‬ ‭A5481036‬
‭demonstrated‬‭that‬‭palbociclib‬‭freebase‬‭capsules‬‭administered‬‭with‬‭food‬‭were‬‭bioequivalent‬‭to‬‭isethionate‬
‭capsules‬‭administered‬‭under‬‭fasted‬‭conditions.‬‭In‬‭an‬‭interaction‬‭trial‬‭in‬‭healthy‬‭subjects,‬‭coadministration‬‭of‬
‭a‬‭single‬‭dose‬‭of‬‭125‬‭mg‬‭of‬‭palbociclib‬‭free‬‭base‬‭with‬‭food‬‭and‬‭multiple‬‭doses‬‭of‬‭the‬‭proton‬‭pump‬‭inhibitor‬
‭(PPI)‬ ‭rabeprazole‬ ‭reduced‬ ‭the‬ ‭Cmax‬ ‭of‬ ‭palbociclib‬ ‭by‬ ‭41%,‬ ‭but‬ ‭with‬ ‭limited‬ ‭impact‬ ‭on‬ ‭AUCinf‬ ‭(13%‬
‭decrease)‬‭when‬‭compared‬‭to‬‭a‬‭single‬‭dose‬‭of‬‭palbociclib‬‭free‬‭base.‬‭Given‬‭the‬‭small‬‭effect‬‭on‬‭gastric‬‭pH‬‭of‬
‭H2‬‭antagonists‬‭and‬‭locally‬‭acting‬‭antacids‬‭compared‬‭to‬‭PPIs,‬‭it‬‭is‬‭expected‬‭that‬‭the‬‭effect‬‭that‬‭these‬‭drugs‬
‭could have on the exposure to palbociclib when administered with food is expected to be minimal.‬
‭4.4.4. Clinical experience with Palbociclib in humans‬
‭In‬‭addition‬‭to‬‭the‬‭phase‬‭1‬‭study‬‭with‬‭increasing‬‭doses‬‭(A5481001),‬‭there‬‭are‬‭others‬‭evaluating‬‭tolerance‬
‭and‬‭activity‬‭of‬‭the‬‭compound‬‭in‬‭different‬‭tumors.‬‭The‬‭second‬‭study‬‭launched‬‭with‬‭Palbociclib‬‭(A5481002)‬‭is‬
‭evaluating‬ ‭the‬ ‭pharmacodynamics,‬‭clinical‬‭activity‬‭and‬‭safety‬‭of‬‭PD‬‭0332991‬‭in‬‭patients‬‭with‬‭previously‬
‭treated‬‭mantle‬‭cell‬‭lymphoma.‬‭PD‬‭0332991‬‭is‬‭being‬‭administered‬‭according‬‭to‬‭the‬‭3/1‬‭schedule‬‭at‬‭a‬‭dose‬
‭of‬‭125‬‭mg‬‭once‬‭daily.‬‭17‬‭patients‬‭have‬‭been‬‭included‬‭in‬‭the‬‭study.‬‭One‬‭complete‬‭response‬‭and‬‭two‬‭partial‬
‭responses‬‭were‬‭observed.‬‭The‬‭safety‬‭profile‬‭has‬‭been‬‭similar‬‭to‬‭that‬‭observed‬‭in‬‭the‬‭study‬‭with‬‭increasing‬
‭doses.‬
‭Another‬ ‭study‬ ‭(A5481004)‬ ‭is‬ ‭aimed‬ ‭at‬ ‭evaluating‬ ‭the‬ ‭safety‬ ‭and‬ ‭clinical‬ ‭activity‬ ‭of‬ ‭PD‬ ‭0332991‬ ‭in‬
‭combination with bortezomib and dexamethasone in patients with refractory multiple myeloma.‬
‭The‬‭A5481003‬‭clinical‬‭trial‬‭is‬‭the‬‭first‬‭phase‬‭2‬‭study‬‭in‬‭which‬‭we‬‭have‬‭information‬‭on‬‭the‬‭activity‬‭of‬‭the‬‭drug‬
‭in‬‭a‬‭specific‬‭tumor,‬‭in‬‭this‬‭case‬‭metastatic‬‭Her2-negative,‬‭hormone‬‭receptor-positive‬‭breast‬‭cancer.‬‭In‬‭these‬
‭patients,‬‭Palbociclib‬‭has‬‭shown‬‭an‬‭important‬‭and‬‭significant‬‭increase‬‭in‬‭Progression-Free‬‭Survival‬‭(PFS)‬
‭when‬‭associated‬‭with‬‭letrozole‬‭compared‬‭to‬‭treatment‬‭with‬‭letrozole‬‭as‬‭monotherapy‬‭(20.2‬‭months‬‭for‬‭the‬
‭combination‬‭versus‬‭10.2‬‭months).‬‭1‬‭.‬‭The‬‭combination‬‭was‬‭well‬‭tolerated‬‭when‬‭compared‬‭to‬‭treatment‬‭with‬
‭letrozole‬‭monotherapy.‬‭The‬‭most‬‭common‬‭side‬‭effects‬‭of‬‭the‬‭combination‬‭were‬‭uncomplicated‬‭neutropenia,‬
‭leukopenia‬‭and‬‭asthenia‬‭and‬‭the‬‭most‬‭common‬‭Grade‬‭3‬‭side‬‭effect‬‭was‬‭neutropenia‬‭(54%)‬‭and‬‭leukopenia‬
‭(21%).‬‭The‬‭most‬‭common‬‭Grade‬‭4‬‭side‬‭effect‬‭was‬‭neutropenia‬‭and‬‭asthenia,‬‭6%‬‭each.‬‭Only‬‭9%‬‭of‬‭patients‬
‭in‬‭this‬‭trial‬‭who‬‭received‬‭Palbocilclib‬‭had‬‭to‬‭stop‬‭treatment.‬‭Given‬‭the‬‭promising‬‭data‬‭from‬‭this‬‭phase‬‭II‬
‭clinical‬‭trial,‬‭study‬‭A5481008‬‭has‬‭recently‬‭been‬‭launched‬‭to‬‭compare‬‭the‬‭efficacy‬‭of‬‭letrozole‬‭+‬‭Palbociclib‬
‭versus letrozole in patients with ER+HER2- metastatic breast cancer in an extensive randomized phase III.‬
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‭In‬‭brain‬‭tumors,‬‭a‬‭study‬‭has‬‭already‬‭been‬‭launched‬‭(NCT01227434)‬‭that‬‭evaluates‬‭the‬‭activity‬‭and‬‭safety‬‭of‬
‭the‬‭drug‬‭in‬‭recurrent‬‭glioblastoma‬‭and‬‭also‬‭associates‬‭a‬‭pharmacokinetic‬‭and‬‭pharmacodynamic‬‭study‬‭in‬
‭samples of glioblastoma operated on days after the start of treatment with the drug.‬
‭After‬ ‭reviewing‬ ‭data‬ ‭accumulated‬ ‭from‬ ‭cases‬ ‭described‬ ‭in‬ ‭In‬ ‭clinical‬ ‭trials,‬ ‭interstitial‬ ‭lung‬ ‭disease‬
‭(ILD)/pneumonitis‬‭has‬‭been‬‭reported‬‭as‬‭a‬‭possible‬‭adverse‬‭reaction‬‭to‬‭palbociclib‬‭(IBRANCE®),‬‭with‬‭this‬
‭information reported in reference safety documents, the safety database, and in the literature. published.‬
‭Complete‬‭information‬‭on‬‭this‬‭compound‬‭can‬‭be‬‭obtained‬‭from‬‭the‬‭single‬‭safety‬‭reference‬‭document,‬‭which‬
‭in this study is the investigator's manual.‬
‭4.5. Justification‬
‭OA‬ ‭are‬ ‭rare‬ ‭tumors‬ ‭characterized‬ ‭by‬ ‭being‬ ‭chemosensitive‬ ‭and‬ ‭radiosensitive.‬ ‭In‬ ‭fact,‬ ‭although‬ ‭most‬
‭patients‬‭respond‬‭to‬‭a‬‭first‬‭line‬‭(temozolomide‬‭or‬‭PCV),‬‭the‬‭majority‬‭of‬‭patients‬‭suffer‬‭a‬‭relapse‬‭in‬‭less‬‭than‬‭2‬
‭years‬‭after‬‭treatment.‬‭Other‬‭cytotoxic‬‭agents‬‭such‬‭as‬‭irinotecan,‬‭paclitaxel,‬‭carboplatin‬‭and‬‭etoposic‬‭have‬
‭been‬‭evaluated‬‭in‬‭the‬‭second‬‭line‬‭but‬‭with‬‭very‬‭low‬‭response‬‭rates‬‭in‬‭this‬‭context.‬‭There‬‭is,‬‭therefore,‬‭a‬
‭need‬ ‭to‬ ‭find‬ ‭new‬ ‭drugs‬ ‭useful‬ ‭in‬ ‭these‬ ‭patients.‬ ‭In‬‭this‬‭sense,‬‭palbociclib‬‭has‬‭an‬‭interesting‬‭and‬‭solid‬
‭rationale for conducting an exploratory clinical trial in patients with OA.‬
‭Palbociclib‬ ‭could‬ ‭be‬ ‭especially‬ ‭active‬ ‭in‬ ‭patients‬ ‭with‬ ‭OA‬ ‭because‬ ‭these‬ ‭tumors‬ ‭frequently‬ ‭present‬
‭alterations‬ ‭in‬ ‭the‬ ‭RB‬ ‭pathway‬ ‭that‬ ‭could‬ ‭be‬ ‭reversible‬ ‭by‬ ‭blocking‬ ‭CDK4‬ ‭and‬ ‭CDK6.‬ ‭Furthermore,‬
‭alterations‬‭in‬‭this‬‭pathway,‬‭such‬‭as‬‭the‬‭loss‬‭of‬‭CDKN2A,‬‭seem‬‭to‬‭be‬‭fundamental‬‭in‬‭the‬‭transformation‬‭from‬
‭low‬‭to‬‭high‬‭grade‬‭since‬‭they‬‭are‬‭very‬‭rare‬‭in‬‭grade‬‭2‬‭oligodendrogliomas.‬‭Knowing‬‭that‬‭glioblastoma‬‭cell‬
‭lines‬‭with‬‭loss‬‭of‬‭the‬‭RB‬‭protein‬‭are‬‭resistant‬‭to‬‭treatment‬‭with‬‭Palbociclib,‬‭only‬‭patients‬‭who‬‭maintain‬‭RB‬
‭expression would be included in the present clinical trial.‬
‭Given‬‭the‬‭preclinical‬‭data‬‭in‬‭glioblastoma‬‭cell‬‭lines‬‭and‬‭xenografts,‬‭a‬‭clinical‬‭trial‬‭has‬‭been‬‭initiated‬‭with‬
‭Palbociclib‬‭in‬‭recurrent‬‭glioblastoma.‬‭However,‬‭we‬‭think‬‭that‬‭the‬‭RB‬‭pathway‬‭may‬‭be‬‭more‬‭decisive‬‭in‬‭the‬
‭oncogenesis‬‭of‬‭anaplastic‬‭oligodendrogliomas‬‭than‬‭in‬‭Glioblastomas‬‭where‬‭a‬‭very‬‭significant‬‭number‬‭of‬
‭cases have mutations in p53, EGFR and PDGFR, even coinciding with those that may exist in CDKN2A.‬
‭Data‬‭from‬‭phase‬‭1‬‭and‬‭2‬‭clinical‬‭trials‬‭with‬‭palbociclib‬‭indicate‬‭that‬‭it‬‭is‬‭an‬‭active‬‭drug‬‭in‬‭various‬‭types‬‭of‬
‭cancer‬ ‭and‬ ‭that‬ ‭it‬ ‭has‬ ‭a‬ ‭tolerable,‬ ‭known‬ ‭and‬ ‭controllable‬ ‭toxicity‬ ‭profile.‬‭The‬‭Palbociclib‬‭dose‬‭of‬‭125‬
‭mg/day‬‭on‬‭days‬‭1-21‬‭in‬‭28-day‬‭cycles‬‭has‬‭been‬‭chosen‬‭as‬‭it‬‭is‬‭the‬‭dose‬‭established‬‭as‬‭safe‬‭and‬‭effective‬
‭in‬‭the‬‭various‬‭phase‬‭1‬‭and‬‭2‬‭clinical‬‭trials‬‭already‬‭published.‬‭21‬ ‭and‬‭which‬‭is‬‭being‬‭used‬‭in‬‭phase‬‭3‬‭clinical‬
‭trials in patients with metastatic breast cancer.‬
‭In‬ ‭the‬ ‭previous‬ ‭classification‬ ‭of‬ ‭brain‬ ‭tumors,‬ ‭from‬ ‭2007,‬ ‭oligodendroglioma‬ ‭was‬ ‭defined‬ ‭based‬ ‭on‬ ‭its‬
‭morphological‬‭characteristics‬‭and‬‭cases‬‭in‬‭which‬‭there‬‭were‬‭cells‬‭resembling‬‭astrocytes‬‭were‬‭diagnosed‬‭as‬
‭Oligoastrocytomas‬ ‭or‬ ‭mixed‬ ‭gliomas.‬ ‭This‬ ‭led‬ ‭to‬ ‭significant‬ ‭interobserver‬ ‭variability‬ ‭when‬ ‭making‬ ‭the‬
‭diagnosis,‬‭which‬‭undermined‬‭the‬‭conclusions‬‭of‬‭any‬‭study‬‭or‬‭clinical‬‭trial‬‭carried‬‭out‬‭on‬‭oligodendroglial‬
‭tumors.‬ ‭The‬ ‭new‬ ‭2016‬ ‭WHO‬ ‭classification‬ ‭represents‬ ‭a‬ ‭significant‬ ‭advance‬ ‭as‬ ‭it‬ ‭requires‬ ‭that,‬ ‭to‬ ‭be‬
‭diagnosed‬ ‭as‬ ‭such,‬ ‭oligodendrogliomas‬ ‭must‬ ‭present‬ ‭mutations‬ ‭in‬ ‭the‬ ‭IDH1‬ ‭or‬ ‭IDH2‬ ‭genes‬ ‭and‬ ‭also‬
‭present‬ ‭codeletion‬ ‭of‬ ‭1p/19q.‬ ‭On‬ ‭the‬ ‭other‬ ‭hand,‬ ‭the‬ ‭new‬ ‭classification‬ ‭eliminates‬ ‭the‬ ‭diagnosis‬ ‭of‬
‭oligoastrocytoma‬ ‭and‬ ‭cases‬ ‭that‬ ‭have‬ ‭astrocyte‬ ‭populations‬ ‭mixed‬ ‭with‬ ‭oligodendrocytes‬ ‭will‬ ‭have‬ ‭to‬
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‭undergo‬ ‭a‬ ‭molecular‬ ‭study‬ ‭to‬ ‭classify‬ ‭them‬ ‭either‬ ‭as‬ ‭oligodendrogliomas‬ ‭(with‬ ‭loss‬ ‭of‬ ‭1p/19q)‬ ‭or‬ ‭as‬
‭astrocytomas (without loss of 1p/19q).‬‭23, 24,25‬
‭4.6. Goals‬
‭4.6.1. Main goal‬
‭To‬ ‭evaluate‬ ‭six-month‬ ‭progression-free‬ ‭survival‬ ‭(PFS)‬ ‭(6mPFS)‬ ‭in‬ ‭patients‬ ‭with‬ ‭recurrent‬ ‭anaplastic‬
‭oligodendrogliomas (Grade III).‬
‭4.6.2. Secondary objectives‬
‭●‬
‭To evaluate the safety and tolerability of oral administration of Palbociclib in patients with‬ ‭recurrent‬
‭anaplastic oligodendrogliomas.‬
‭●‬
‭Evaluate the antitumor response according to the RANO criteria‬
‭●‬
‭Assess Global Survival (GS)‬
‭●‬
‭To evaluate the duration of response in patients with an objective response.‬
‭●‬
‭Assess changes in glucocorticoid use.‬
‭●‬
‭Assess changes in neurological status‬
‭●‬
‭To‬‭evaluate‬‭whether‬‭the‬‭following‬‭biomarkers‬‭are‬‭related‬‭to‬‭PFS‬‭and‬‭OS:‬‭deletions‬‭in‬‭CDKN2A,‬
‭deletions in CDKN2B, CDK4 amplification, CDK6 amplification, cyclin D amplification.‬
‭●‬
‭To evaluate whether the following biomarkers are related to the response rate: deletions in‬
‭CDKN2A, CDKN2B deletions, CDK4 amplification, CDK6 amplification, Cyclin D amplification.‬
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‭5. DESIGN AND TYPE OF CLINICAL TRIALS‬
‭The‬‭GEINO-13‬‭study‬‭has‬‭been‬‭designed‬‭as‬‭a‬‭pilot,‬‭open-label,‬‭multicenter‬‭and‬‭prospective‬‭Phase‬‭II‬‭clinical‬
‭trial‬ ‭with‬ ‭a‬ ‭single‬ ‭treatment‬ ‭arm.‬ ‭The‬ ‭primary‬ ‭objective‬ ‭of‬ ‭the‬ ‭study‬ ‭is‬ ‭to‬ ‭evaluate‬ ‭six-month‬
‭progression-free survival (PFS) (6mPFS) in patients with recurrent anaplastic oligodendroglial tumors.‬
‭5.1. Tumor Screening Period‬
‭Informed‬ ‭consent‬ ‭will‬ ‭be‬‭obtained‬‭for‬‭the‬‭use‬‭of‬‭biological‬‭samples‬‭from‬‭the‬‭patient‬‭before‬‭starting‬‭the‬
‭selection period.‬
‭5.2. Centralized block review‬
‭A‬ ‭centralized‬ ‭pathological‬ ‭review‬ ‭will‬ ‭be‬ ‭carried‬ ‭out‬ ‭to‬ ‭confirm‬‭the‬‭anatomopathological‬‭and‬‭molecular‬
‭diagnosis‬ ‭of‬ ‭Anaplastic‬ ‭Oligodendroglioma‬ ‭(OA)‬ ‭in‬‭the‬‭Pathological‬‭Anatomy‬‭Service‬‭of‬‭Hospital‬‭12‬‭de‬
‭Octubre,‬‭a‬‭central‬‭neuropathology‬‭laboratory‬‭that‬‭will‬‭also‬‭determine‬‭if‬‭there‬‭is‬‭nuclear‬‭expression‬‭of‬‭the‬
‭RB protein through immunohistochemistry. .‬
‭As‬‭part‬‭of‬‭screening,‬‭all‬‭patients‬‭must‬‭have‬‭a‬‭paraffin-embedded‬‭tissue‬‭block‬‭available‬‭from‬‭a‬‭previous‬
‭biopsy‬‭or‬‭surgery‬‭(previously‬‭archived‬‭tumor‬‭samples).‬‭If‬‭there‬‭are‬‭several‬‭surgeries,‬‭samples‬‭from‬‭the‬‭last‬
‭intervention with areas of tumor must be sent.‬
‭In‬‭addition‬‭to‬‭determining‬‭the‬‭expression‬‭of‬‭the‬‭RB‬‭protein,‬‭the‬‭central‬‭laboratory‬‭will‬‭also‬‭carry‬‭out‬‭the‬
‭study‬ ‭of‬ ‭biomarkers‬ ‭in‬ ‭which‬ ‭fluorescent‬ ‭in‬ ‭situ‬ ‭hybridization‬ ‭(FISH)‬ ‭techniques‬ ‭and‬ ‭also‬ ‭sequencing‬
‭techniques‬ ‭will‬ ‭be‬ ‭required‬ ‭to‬ ‭determine‬ ‭the‬ ‭following‬ ‭genetic‬ ‭alterations:‬ ‭mutations‬ ‭in‬ ‭IDH1/2,‬‭1p/19q‬
‭losses,‬ ‭CDKN2A‬ ‭deletions,‬ ‭CDKN2B‬ ‭deletions,‬ ‭CDK4‬ ‭amplification,‬ ‭CDK6‬ ‭amplification,‬ ‭cyclin‬
‭amplification‬‭D‬‭.‬
‭For‬‭this‬‭trial,‬‭2‬‭informed‬‭consents‬‭have‬‭been‬‭prepared.‬‭In‬‭the‬‭first,‬‭authorization‬‭is‬‭obtained‬‭from‬‭the‬‭patient‬
‭to‬‭send‬‭the‬‭tumor‬‭sample‬‭and‬‭perform‬‭the‬‭centralized‬‭histological‬‭review.‬‭The‬‭second‬‭corresponds‬‭to‬‭the‬
‭clinical‬‭part‬‭of‬‭the‬‭trial‬‭and‬‭the‬‭molecular‬‭study.‬‭The‬‭informed‬‭consent‬‭for‬‭sample‬‭shipment‬‭can‬‭be‬‭signed‬
‭by‬‭the‬‭patient‬‭once‬‭the‬‭researcher‬‭identifies‬‭them‬‭as‬‭a‬‭potential‬‭patient‬‭for‬‭the‬‭trial,‬‭even‬‭if‬‭they‬‭have‬‭not‬
‭yet progressed to standard treatment.‬
‭No‬‭tumor‬‭sample‬‭can‬‭be‬‭mobilized‬‭from‬‭the‬‭hospital‬‭of‬‭origin‬‭until‬‭the‬‭patient‬‭has‬‭signed‬‭the‬‭first‬‭informed‬
‭consent.‬
‭The approximate response time to confirm if the patient is eligible will be 10 calendar days.‬
‭To send the tumor sample:‬
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‭The‬‭center‬‭must‬‭contact‬‭MFAR,‬‭S.L.‬‭-‬‭GEINO‬‭Technical‬‭Secretary,‬‭by‬‭sending‬‭the‬‭centralized‬‭review‬‭form‬
‭and‬‭sample‬‭collection‬‭form‬‭to‬‭FAX‬‭93‬‭253‬‭11‬‭68‬‭and‬‭she‬‭will‬‭send‬‭a‬‭courier‬‭to‬‭collect‬‭the‬‭samples.‬‭A‬‭copy‬
‭of the centralized review form must be submitted with the sample.‬
‭Central Laboratory Data:‬
‭Dr. A.S. Aurelio Hernandez Lain‬
‭Neuropathology Section.‬
‭Pathological Anatomy Service‬
‭12 de Octubre University Hospital‬
‭Main Building, basement 1‬
‭Avda. de Córdoba, s/n - 28041 Madrid‬
‭Madrid Spain‬
‭Tumor‬‭samples‬‭will‬‭be‬‭prepared‬‭according‬‭to‬‭the‬‭instructions‬‭detailed‬‭by‬‭the‬‭sponsor‬‭in‬‭the‬‭specific‬‭guide‬
‭and‬‭will‬‭be‬‭coded‬‭to‬‭preserve‬‭patient‬‭confidentiality.‬‭The‬‭central‬‭laboratory‬‭will‬‭send‬‭a‬‭report‬‭to‬‭each‬‭of‬‭the‬
‭principal‬ ‭investigators‬ ‭to‬ ‭inform‬ ‭them‬ ‭of‬ ‭the‬ ‭result‬ ‭of‬ ‭the‬ ‭histological‬ ‭review‬ ‭and‬‭immunohistochemical‬
‭analysis‬‭of‬‭RB.‬‭If‬‭there‬‭is‬‭leftover‬‭material‬‭once‬‭the‬‭initial‬‭determinations‬‭and‬‭the‬‭biomarker‬‭study‬‭have‬
‭been carried out, it will be returned to the hospital of origin at the end of the trial.‬
‭5.3. Patient Screening Period‬
‭The‬‭different‬‭procedures‬‭carried‬‭out‬‭as‬‭part‬‭of‬‭the‬‭patient's‬‭usual‬‭clinical‬‭management‬‭(for‬‭example,‬‭blood‬
‭tests,‬‭imaging‬‭tests,‬‭etc.)‬‭and‬‭performed‬‭before‬‭signing‬‭the‬‭general‬‭informed‬‭consent‬‭for‬‭the‬‭study‬‭can‬‭be‬
‭used‬‭for‬‭selection‬‭or‬‭as‬‭baseline‬‭results.‬‭as‬‭long‬‭as‬‭these‬‭tests‬‭have‬‭been‬‭carried‬‭out‬‭as‬‭specified‬‭in‬‭this‬
‭protocol.‬
‭5.4. Screening Failures‬
‭A‬‭patient‬‭will‬‭be‬‭considered‬‭a‬‭screening‬‭failure‬‭when‬‭they‬‭sign‬‭the‬‭informed‬‭consent‬‭but‬‭abandon‬‭the‬‭trial‬
‭for‬ ‭any‬ ‭reason‬ ‭before‬ ‭inclusion.‬ ‭All‬ ‭patients‬ ‭who‬ ‭are‬ ‭screening‬ ‭failures‬ ‭will‬ ‭be‬ ‭registered‬‭in‬‭the‬‭list‬‭of‬
‭patients‬‭undergoing‬‭screening‬‭but‬‭will‬‭not‬‭be‬‭included‬‭in‬‭the‬‭study‬‭database.‬‭The‬‭reasons‬‭for‬‭exclusion‬‭of‬
‭these patients who do not enter the trial must be recorded on the aforementioned forms.‬
‭An‬ ‭additional‬ ‭document‬ ‭will‬ ‭be‬ ‭added‬ ‭to‬ ‭the‬ ‭Center's‬ ‭Researcher‬‭File‬‭with‬‭detailed‬‭information‬‭on‬‭the‬
‭identification procedures for patient selection.‬
‭5.5. Patient inclusion procedure‬
‭Inclusion‬‭will‬‭be‬‭done‬‭online‬‭through‬‭the‬‭electronic‬‭CRD.‬‭The‬‭inclusion‬‭form‬‭must‬‭be‬‭completed‬‭in‬‭the‬‭CRD‬
‭and,‬‭once‬‭the‬‭center‬‭confirms‬‭that‬‭the‬‭patient‬‭meets‬‭all‬‭the‬‭inclusion‬‭criteria‬‭and‬‭none‬‭of‬‭the‬‭exclusion‬
‭criteria described in the protocol, the system will centrally assign a number to each patient. .‬
‭The‬ ‭system‬ ‭will‬ ‭send‬ ‭to‬ ‭the‬ ‭center,‬ ‭to‬ ‭the‬ ‭email‬ ‭registered‬ ‭in‬ ‭the‬ ‭eCRD,‬ ‭confirmation‬ ‭of‬‭the‬‭patient's‬
‭inclusion. Treatment will only begin if the center has received the email confirming the inclusion.‬
‭The patient's study number will identify subjects throughout participation in this study.‬
‭An additional document will be added to the Center's Investigator File with detailed information on patient‬
‭inclusion procedures.‬
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‭5.6. Start of treatment‬
‭Treatment‬‭will‬‭only‬‭begin‬‭if‬‭the‬‭center‬‭has‬‭received‬‭confirmation‬‭of‬‭inclusion‬‭as‬‭detailed‬‭in‬‭section‬‭5.4‬‭of‬‭this‬
‭protocol.‬
‭All‬‭patients‬‭included‬‭in‬‭the‬‭study‬‭will‬‭be‬‭treated‬‭with‬‭the‬‭experimental‬‭drug,‬‭Palbociclib,‬‭at‬‭a‬‭dose‬‭of‬‭125‬
‭mg/day‬ ‭on‬ ‭days‬ ‭1-21‬ ‭in‬ ‭28-day‬ ‭cycles.‬ ‭That‬ ‭is,‬ ‭administered‬ ‭21‬‭days‬‭followed‬‭by‬‭7‬‭days‬‭of‬‭rest.‬‭The‬
‭treatment‬‭cycles‬‭will‬‭continue‬‭until‬‭there‬‭is‬‭unacceptable‬‭toxicity,‬‭tumor‬‭progression,‬‭withdrawal‬‭of‬‭consent‬
‭or death of the patient. The visits and evaluations are detailed in section 8.1 of this protocol.‬
‭5.7. Associated Molecular Substudy‬
‭●‬
‭The molecular studies will be carried out at the Hospital 12 de Octubre, in the Section of‬
‭Neuropathology.‬
‭●‬
‭Translational‬‭assessment‬‭will‬‭be‬‭carried‬‭out‬‭to‬‭evaluate‬‭the‬‭association‬‭between‬‭drug‬‭activity‬‭and‬
‭different biomarkers such as p16 or CDK4/6 expression.‬
‭●‬
‭Additional tissue will be obtained from previous surgeries to study the presence of alterations‬
‭molecular in the tumor:‬
‭●‬
‭p16 expression will be evaluated retrospectively‬
‭●‬
‭The‬ ‭predictive‬ ‭role‬‭of‬‭potential‬‭biomarkers‬‭in‬‭basal‬‭samples‬‭will‬‭be‬‭explored‬‭retrospectively:‬‭for‬
‭example, among others, RNA pol II levels (effector of the CDK4/cyclin complex).‬
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‭6. PATIENT SELECTION CRITERIA‬
‭6.1. Inclusion criteria‬
‭1.‬
‭Ability to understand and sign the informed consent document approved by the‬
‭CEIC‬
‭2.‬
‭Men or women aged ≥ 18 years.‬
‭3.‬
‭Patients‬‭with‬‭anaplastic‬‭oligodendroglioma‬‭according‬‭to‬‭the‬‭new‬‭WHO‬‭(WHO)‬‭classification‬‭of‬‭2016‬
‭(In‬ ‭Press)‬‭23,24,25‬ ‭and‬ ‭confirmed‬ ‭histologically‬ ‭and‬ ‭molecularly‬ ‭at‬ ‭a‬ ‭central‬ ‭level.‬ ‭According‬ ‭to‬ ‭this‬
‭classification,‬ ‭oligodendrogliomas‬ ‭must‬ ‭present‬ ‭mutations‬ ‭in‬ ‭IDH1/2‬ ‭as‬ ‭well‬ ‭as‬ ‭a‬ ‭co-deletion‬ ‭of‬
‭chromosomes 1p/19q.‬
‭USE:‬‭Patients‬‭with‬‭the‬‭initial‬‭diagnosis‬‭of‬‭grade‬‭2‬‭oligodendroglioma‬‭may‬‭be‬‭included‬‭as‬‭long‬‭as‬‭they‬‭have‬
‭suffered a recurrence in which a new resection was performed whose diagnosis was grade 3.‬
‭USE‬ ‭2:‬ ‭Patients‬ ‭previously‬ ‭diagnosed‬ ‭with‬ ‭Oligoastrocytoma‬ ‭grade‬ ‭3‬ ‭according‬ ‭to‬ ‭the‬ ‭WHO‬ ‭2007‬
‭classification‬‭could‬‭be‬‭included‬‭if,‬‭in‬‭the‬‭centralized‬‭review,‬‭the‬‭criteria‬‭for‬‭Anaplastic‬‭Oligodendroglioma‬
‭according to the new classification are met.‬
‭4.‬
‭Patients‬ ‭in‬ ‭a‬ ‭relapse‬ ‭situation‬ ‭after‬ ‭having‬ ‭received‬ ‭radiotherapy‬ ‭and‬ ‭one‬ ‭or‬ ‭two‬ ‭lines‬ ‭of‬
‭chemotherapy.‬
‭USE:‬ ‭Both‬ ‭previous‬ ‭radiotherapy‬ ‭and‬ ‭previous‬ ‭chemotherapy‬ ‭may‬ ‭have‬ ‭been‬ ‭received‬ ‭in‬‭an‬‭adjuvant‬
‭situation‬‭or‬‭in‬‭previous‬‭recurrences.‬‭It‬‭is‬‭also‬‭admitted‬‭to‬‭have‬‭received‬‭concurrent‬‭chemoradiotherapy.‬‭In‬
‭anaplastic‬‭oligodendrogliomas,‬‭patients‬‭have‬‭been‬‭able‬‭to‬‭receive‬‭chemotherapy‬‭or‬‭radiotherapy‬‭when‬‭they‬
‭were still grade 2 tumors.‬
‭5.‬
‭All‬‭patients‬‭must‬‭present‬‭positivity‬‭in‬‭the‬‭immunohistochemical‬‭study‬‭for‬‭the‬‭Rb‬‭protein‬‭in‬‭the‬‭tumor‬
‭material‬ ‭analyzed‬ ‭by‬ ‭the‬ ‭central‬ ‭laboratory‬ ‭(Neuropathology‬ ‭Laboratory.‬ ‭Hospital‬ ‭Universitario‬ ‭12‬ ‭de‬
‭Octubre).‬
‭6.‬
‭Cases‬ ‭must‬‭have‬‭a‬‭paraffin-embedded‬‭tissue‬‭block‬‭available‬‭from‬‭a‬‭previous‬‭biopsy‬‭or‬‭surgery‬
‭(previously archived tumor samples) for central histological and molecular determinations.‬
‭7.‬
‭All patients must show disease progression on brain MRI as defined in the RANO Criteria.‬
‭8.‬
‭Interval‬ ‭of‬ ‭at‬ ‭least‬ ‭one‬ ‭week‬ ‭between‬ ‭previous‬ ‭intracranial‬ ‭biopsy,‬ ‭adequately‬ ‭healed,‬ ‭and‬
‭inclusion.‬
‭9.‬
‭Interval of at least 12 weeks between previous radiotherapy and inclusion, unless:‬
‭a.‬
‭Histopathological confirmation of recurrent tumor, the‬
‭b.‬
‭Recurrence on MRI outside the radiotherapy field.‬
‭10.‬
‭Patients‬‭must‬‭have‬‭recovered‬‭from‬‭prior‬‭therapies:‬‭28‬‭days‬‭from‬‭completion‬‭of‬‭any‬‭investigational‬
‭compound and/or from completion of any cytotoxic treatment.‬
‭11.‬
‭ECOG functional status ≤ 2.‬
‭12.‬
‭Stable or decreasing dose of corticosteroids during the five days prior to inclusion in the study.‬
‭13.‬
‭Patients‬‭who‬‭had‬‭tumor‬‭resection‬‭performed‬‭at‬‭the‬‭last‬‭recurrence‬‭are‬‭eligible‬‭if‬‭the‬‭following‬‭are‬
‭true:‬
‭a.‬
‭There is adequate recovery from surgery.‬
‭b.‬
‭There‬‭must‬‭be‬‭measurable‬‭or‬‭evaluable‬‭disease‬‭after‬‭surgery.‬‭For‬‭adequate‬‭radiological‬‭evaluation‬
‭of residual disease, MRI must have been performed within 72 hours after surgery or 4 weeks after surgery.‬
‭14.‬
‭Adequate spinal and organic function:‬
‭a.‬
‭Neutrophils ≥ 1500/mm‬‭3‬‭(1.5 X 10‬‭9‬‭/L)‬
‭b.‬
‭Platelets ≥ 100,000/mm‬‭3‬‭(100 X 10‬‭9‬‭)‬
‭c.‬
‭Hemoglobin ≥ 9 g/dL‬
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‭d.‬
‭Serum creatinine ≤ 1.5 X center ULN or estimated clearance ≥ 60 mL/min calculated.‬
‭e.‬
‭Bilirubin‬‭≤‬‭1.5‬‭times‬‭the‬‭ULN‬‭(in‬‭the‬‭case‬‭of‬‭Gilbert's‬‭Disease‬‭≤‬‭3‬‭times‬‭the‬‭ULN.‬‭AST‬‭(SGOT)‬
‭and/or ALT ≤ 3 x ULN;‬
‭f.‬
‭Alkaline phosphatase ≤ 2.5 X ULN.‬
‭15.‬
‭Women‬‭who‬‭are‬‭not‬‭pregnant‬‭or‬‭breastfeeding.‬‭Women‬‭of‬‭childbearing‬‭age,‬‭that‬‭is,‬‭of‬‭reproductive‬
‭age,‬ ‭between‬ ‭puberty‬ ‭and‬‭menopause,‬‭must‬‭have‬‭a‬‭negative‬‭pregnancy‬‭test‬‭(in‬‭blood‬‭or‬‭urine)‬‭before‬
‭inclusion‬ ‭in‬ ‭the‬ ‭study,‬ ‭both‬ ‭women‬ ‭of‬‭childbearing‬‭age‬‭and‬‭men.‬‭They‬‭must‬‭use‬‭a‬‭medically‬‭accepted‬
‭method‬ ‭of‬ ‭contraception‬ ‭while‬ ‭taking‬ ‭study‬ ‭medication‬ ‭and‬ ‭for‬ ‭1‬ ‭month‬ ‭after‬ ‭completion‬ ‭of‬‭treatment.‬
‭Appropriate‬ ‭methods‬ ‭(when‬‭used‬‭continuously‬‭and‬‭according‬‭to‬‭doctor‬‭and‬‭product‬‭instructions)‬‭are‬‭as‬
‭follows:‬
‭a.‬
‭Complete‬ ‭sexual‬ ‭abstinence‬‭that‬‭will‬‭begin‬‭during‬‭the‬‭14‬‭days‬‭prior‬‭to‬‭the‬‭first‬‭exposure‬‭to‬‭the‬
‭study‬‭drug,‬‭will‬‭continue‬‭throughout‬‭the‬‭treatment‬‭within‬‭the‬‭clinical‬‭trial‬‭and‬‭will‬‭be‬‭maintained‬‭until‬‭at‬‭least‬
‭21 days after the last dose of the drug.‬
‭b.‬
‭Oral contraceptives, both progestins in monotherapy and in combination with other agents.‬
‭c.‬
‭Injectable progesterone. Levonorgestrel implants.‬
‭d.‬
‭Vaginal‬ ‭ring‬ ‭with‬ ‭estrogen.‬ ‭Percutaneous‬ ‭contraceptive‬ ‭patches.‬ ‭Intrauterine‬ ‭device‬ ‭(IUD)‬ ‭or‬
‭intrauterine system (IUS) with a documented failure rate of less than 1% per year.‬
‭e.‬
‭Male‬‭partner‬‭sterilized‬‭(vasectomy‬‭with‬‭documented‬‭azoospermia)‬‭prior‬‭to‬‭his‬‭partner's‬‭entry‬‭into‬
‭the study (provided it is a monogamous couple).‬
‭f.‬
‭Double‬‭barrier‬‭method:‬‭Male‬‭condom‬‭and‬‭diaphragm/cervical‬‭cap‬‭with‬‭vaginal‬‭spermicidal‬‭agent‬
‭(foam/gel/film/cream/suppository).‬
‭g.‬
‭Breastfeeding‬‭women‬‭should‬‭discontinue‬‭natural‬‭feeding‬‭of‬‭the‬‭baby‬‭from‬‭before‬‭receiving‬‭the‬‭first‬
‭dose of the study drug until 14 days after the last dose of treatment.‬
‭6.2. Exclusion criteria‬
‭1.‬
‭Presence of disseminated meningeal carcinomatosis.‬
‭2.‬
‭Concomitant treatment with other investigational agents.‬
‭3.‬
‭Prior‬‭treatment‬‭with‬‭an‬‭investigational‬‭agent‬‭known‬‭or‬‭assumed‬‭to‬‭be‬‭active‬‭by‬‭the‬‭action‬‭of‬‭any‬‭of‬
‭the components against CDK4/6.‬
‭4.‬
‭Surgery‬‭of‬‭any‬‭type‬‭(does‬‭not‬‭include‬‭minor‬‭diagnostic‬‭procedures‬‭such‬‭as‬‭lymph‬‭node‬‭biopsy)‬
‭within‬ ‭2‬ ‭weeks‬ ‭prior‬ ‭to‬ ‭baseline‬ ‭disease‬ ‭assessments,‬ ‭or‬ ‭presence‬ ‭of‬ ‭side‬ ‭effects‬ ‭from‬ ‭previous‬
‭procedures.‬
‭5.‬
‭Presence‬‭of‬‭any‬‭clinically‬‭significant‬‭gastrointestinal‬‭abnormality‬‭that‬‭may‬‭affect‬‭the‬‭intake,‬‭transit‬
‭or absorption of the study drug, such as the inability to take oral tablet medication.‬
‭6.‬
‭Presence‬ ‭of‬ ‭any‬ ‭psychiatric‬ ‭or‬ ‭cognitive‬ ‭disorder‬ ‭that‬ ‭limits‬ ‭understanding‬ ‭or‬ ‭signing‬ ‭of‬ ‭the‬
‭informed consent and/or jeopardizes compliance with the requirements of this protocol.‬
‭7.‬
‭Having‬‭received‬‭any‬‭of‬‭the‬‭following‬‭pharmacological‬‭treatments‬‭in‬‭the‬‭7‬‭days‬‭prior‬‭to‬‭the‬‭start‬‭of‬
‭treatment:‬ ‭Strong‬ ‭CYP3A4‬ ‭inhibitor‬ ‭drugs‬ ‭(e.g.,‬ ‭amprenavir,‬ ‭atazanavir,‬ ‭boceprevir,‬ ‭clarithromycin,‬
‭conivaptan,‬ ‭delavirdine,‬ ‭diltiazem,‬ ‭erythromycin,‬ ‭fosamprenavir,‬ ‭indinavir,‬ ‭itraconazole,‬ ‭ketoconazole,‬
‭lopinavir,‬ ‭mibefradil,‬ ‭miconazole,‬ ‭nefazodone,‬ ‭nelfinavir,‬ ‭posaconazole,‬ ‭ritonavir,‬ ‭saquinavir,‬ ‭telaprevir,‬
‭telithromycin,‬ ‭verapamil,‬ ‭voriconazole‬ ‭and‬ ‭grapefruit‬ ‭or‬ ‭grapefruit‬ ‭juice).‬ ‭CYP3A4-inducing‬ ‭drugs‬ ‭(e.g.,‬
‭carbamazepine,‬ ‭felbamate,‬ ‭nevirapine,‬ ‭phenobarbital,‬‭phenytoin,‬‭pidone,‬‭rifabutin,‬‭rifampicin,‬‭rifapentin).‬
‭Drugs that increase the QT interval.‬
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‭8.‬
‭QTc‬‭interval‬‭>480‬‭msec‬‭(based‬‭on‬‭the‬‭average‬‭of‬‭the‬‭value‬‭taken‬‭in‬‭three‬‭ECG‬‭recordings),‬‭family‬
‭or‬ ‭personal‬ ‭history‬ ‭of‬ ‭long‬‭QT‬‭syndrome,‬‭short‬‭QT‬‭syndrome,‬‭Brugada‬‭syndrome,‬‭QTc‬‭prolongation‬‭or‬
‭history of Torsade de Pointes.‬
‭9.‬
‭Electrolyte‬ ‭disorder‬ ‭that‬ ‭may‬ ‭affect‬ ‭the‬ ‭QTc‬ ‭interval‬ ‭(e.g.‬ ‭hypocalcemia,‬ ‭hypokalemia‬ ‭and‬
‭hypomagnesemia).‬
‭10.‬
‭Significant or uncontrolled cardiovascular disease, including:‬
‭●‬
‭Myocardial infarction in the previous 12 months‬
‭●‬
‭Uncontrolled angina in the previous 6 months Congestive heart failure in the previous 6 months‬
‭●‬
‭History‬‭of‬‭clinically‬‭significant‬‭ventricular‬‭arrhythmias‬‭of‬‭any‬‭type‬‭(such‬‭as‬‭ventricular‬‭tachycardia,‬
‭ventricular fibrillation, or torsades de pointes)‬
‭●‬
‭History‬‭of‬‭second‬‭or‬‭third‬‭degree‬‭heart‬‭block‬‭(these‬‭patients‬‭may‬‭be‬‭eligible‬‭if‬‭they‬‭currently‬‭have‬‭a‬
‭pacemaker)‬
‭●‬
‭Stroke in the previous 3 months‬
‭●‬
‭Pulmonary thromboembolism in the previous 3 months‬
‭11.‬
‭History‬ ‭of‬ ‭any‬ ‭cancer‬ ‭except‬ ‭for‬ ‭the‬ ‭following‬ ‭circumstances:‬ ‭Patients‬ ‭with‬ ‭a‬ ‭history‬ ‭of‬ ‭other‬
‭malignancies‬‭are‬‭eligible‬‭if‬‭they‬‭have‬‭been‬‭disease-free‬‭for‬‭at‬‭least‬‭the‬‭last‬‭3‬‭years‬‭and‬‭in‬‭the‬‭investigator's‬
‭opinion‬‭there‬‭is‬‭a‬‭low‬‭risk‬‭of‬‭disease‬‭recurrence.‬‭People‬‭with‬‭the‬‭following‬‭cancers‬‭are‬‭eligible‬‭even‬‭if‬‭they‬
‭were‬‭diagnosed‬‭and‬‭treated‬‭within‬‭the‬‭last‬‭3‬‭years:‬‭cervical‬‭carcinoma‬‭in‬‭situ,‬‭cutaneous‬‭squamous‬‭cell‬
‭carcinoma‬‭and basal cell or basal cell cutaneous carcinoma.‬
‭12.‬
‭Human immunodeficiency virus infection.‬
‭13.‬
‭Inflammatory‬‭bowel‬‭disease,‬‭chronic‬‭diarrhea,‬‭short‬‭bowel‬‭syndrome‬‭or‬‭any‬‭upper‬‭gastrointestinal‬
‭surgery including gastric resection.‬
‭14.‬
‭Known sensitivity to Palbociclib.‬
‭15.‬
‭Other‬ ‭serious‬ ‭acute‬ ‭or‬ ‭chronic‬ ‭medical‬ ‭condition,‬‭uncontrolled‬‭intercurrent‬‭illness,‬‭or‬‭laboratory‬
‭abnormality‬ ‭that‬ ‭may‬ ‭increase‬ ‭the‬ ‭risk‬ ‭associated‬ ‭with‬ ‭participation‬ ‭in‬ ‭the‬‭trial‬‭or‬‭administration‬‭of‬‭the‬
‭investigational‬ ‭product‬ ‭or‬ ‭may‬ ‭interfere‬ ‭with‬ ‭the‬ ‭interpretation‬ ‭of‬ ‭trial‬ ‭results‬ ‭and‬ ‭that,‬ ‭Investigator's‬
‭discretion,‬‭make‬‭the‬‭patient‬‭unsuitable‬‭for‬‭entry‬‭into‬‭this‬‭trial.‬‭Uncontrolled‬‭intercurrent‬‭illness‬‭includes,‬‭but‬
‭is‬‭not‬‭limited‬‭to,‬‭ongoing‬‭or‬‭active‬‭infection‬‭or‬‭psychiatric‬‭illness/social‬‭situations‬‭that‬‭limit‬‭compliance‬‭with‬
‭study requirements.‬
‭6.3. Criteria provided for the permanent interruption of the IMP‬
‭Patients will receive the investigational product until one of the following occurs:‬
‭●‬
‭Progression according to RANO criteria.‬
‭●‬
‭Unacceptable‬ ‭toxicity‬ ‭or‬ ‭adverse‬ ‭events‬‭that‬‭could‬‭make‬‭the‬‭administration‬‭of‬‭the‬‭treatment‬‭an‬
‭unacceptable risk, in the opinion of the investigator.‬
‭●‬
‭Non-compliance‬ ‭by‬ ‭the‬ ‭patient,‬ ‭at‬ ‭the‬ ‭discretion‬ ‭of‬ ‭the‬ ‭researcher‬ ‭or‬ ‭the‬ ‭Sponsor,‬ ‭with‬ ‭the‬
‭requirements of the protocol.‬
‭●‬
‭Delay in administration of treatment of more than 4‬‭weeks.‬
‭●‬
‭Premature termination of the trial.‬
‭●‬
‭Investigator's Decision.‬
‭●‬
‭That the patient withdraws his consent to participate in the trial.‬
‭The reason why the investigational product has been discontinued must be clearly recorded in the‬
‭data collection notebook (CRD).‬
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‭Note:‬ ‭Temporary‬ ‭discontinuation‬ ‭of‬ ‭study‬ ‭medication‬ ‭due‬ ‭to‬ ‭an‬ ‭adverse‬ ‭event‬ ‭will‬ ‭not‬ ‭be‬ ‭considered‬
‭permanent discontinuation of the investigational product.‬
‭6.4. Criteria for withdrawal from the study‬
‭Patients‬‭will‬‭be‬‭encouraged‬‭to‬‭complete‬‭the‬‭trial,‬‭however,‬‭patients‬‭may‬‭voluntarily‬‭withdraw‬‭from‬‭the‬‭trial‬‭at‬
‭any‬‭time.‬‭The‬‭investigator‬‭may‬‭also,‬‭at‬‭his‬‭or‬‭her‬‭discretion,‬‭withdraw‬‭patients‬‭from‬‭this‬‭trial,‬‭or‬‭the‬‭Sponsor‬
‭may discontinue the trial.‬
‭The‬‭causes‬‭of‬‭premature‬‭abandonment‬‭of‬‭the‬‭trial‬‭must‬‭be‬‭documented‬‭in‬‭the‬‭data‬‭collection‬‭notebook‬
‭(CRD) as:‬
‭●‬
‭Closed/finished trial‬
‭●‬
‭Adverse event‬
‭●‬
‭Patient loss to follow-up‬
‭●‬
‭Investigator's Decision‬
‭●‬
‭Withdrawal of consent by the patient‬
‭●‬
‭Major protocol violation‬
‭●‬
‭Death‬
‭Both‬ ‭the‬ ‭date‬‭of‬‭withdrawal‬‭from‬‭the‬‭study‬‭and‬‭the‬‭reason‬‭for‬‭withdrawal‬‭will‬‭be‬‭recorded‬‭in‬‭the‬‭CRD.‬
‭Subsequent‬ ‭treatment‬ ‭and‬ ‭follow-up‬ ‭until‬ ‭death‬ ‭will‬ ‭be‬ ‭determined,‬ ‭guaranteeing‬ ‭the‬ ‭patient‬ ‭medical‬
‭assistance‬ ‭according‬ ‭to‬ ‭usual‬ ‭clinical‬ ‭practice.‬ ‭In‬ ‭the‬ ‭event‬ ‭of‬ ‭death,‬ ‭the‬ ‭autopsy‬ ‭certificate‬ ‭with‬ ‭the‬
‭documented cause of death should be obtained, if possible.‬
‭Note: Patients who abandon the trial for any reason will not be able to be included again.‬
‭7. DESCRIPTION OF THE TREATMENT‬
‭All‬‭patients‬‭included‬‭in‬‭the‬‭study‬‭will‬‭be‬‭treated‬‭with‬‭the‬‭experimental‬‭drug,‬‭Palbociclib,‬‭at‬‭a‬‭dose‬‭of‬‭125‬‭mg‬
‭once‬‭daily‬‭continuously‬‭for‬‭three‬‭weeks‬‭followed‬‭by‬‭1‬‭week‬‭of‬‭rest.‬‭The‬‭100‬‭mg‬‭and‬‭75‬‭mg‬‭presentations‬
‭are‬‭planned‬‭in‬‭case‬‭of‬‭dose‬‭reductions.‬‭For‬‭the‬‭scheduling‬‭of‬‭visits‬‭and‬‭evaluations,‬‭28-day‬‭cycles‬‭will‬‭be‬
‭considered.‬
‭7.1. Preparation and dispensing‬
‭Palbociclib‬‭capsules‬‭will‬‭be‬‭dispensed‬‭for‬‭21-day‬‭treatment‬‭periods.‬‭The‬‭formulation‬‭of‬‭palbociclib‬‭that‬‭will‬
‭be‬‭administered‬‭to‬‭study‬‭patients‬‭is‬‭the‬‭free‬‭base.‬‭Palbociclib‬‭comes‬‭as‬‭yellow/caramel-colored‬‭capsules‬
‭containing 75, 100, or 125 mg of study medication. The capsules can be distinguished by size and color.‬
‭The‬‭patient‬‭and‬‭protocol‬‭numbers‬‭will‬‭be‬‭noted‬‭in‬‭the‬‭spaces‬‭reserved‬‭for‬‭this‬‭purpose‬‭on‬‭the‬‭bottle‬‭label.‬
‭Facility‬‭staff‬‭should‬‭ensure‬‭that‬‭patients‬‭clearly‬‭understand‬‭the‬‭instructions‬‭for‬‭self-medication,‬‭especially‬
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‭the‬‭need‬‭to‬‭take‬‭the‬‭drug‬‭with‬‭food.‬‭Unused‬‭drug‬‭or‬‭empty‬‭vials‬‭must‬‭be‬‭returned‬‭to‬‭the‬‭facility‬‭at‬‭the‬‭next‬
‭study visit.‬
‭Palbociclib‬‭is‬‭an‬‭agent‬‭that‬‭has‬‭to‬‭be‬‭handled‬‭and‬‭administered‬‭with‬‭care.‬‭The‬‭patient‬‭should‬‭be‬‭instructed‬
‭to‬ ‭store‬ ‭the‬ ‭study‬ ‭drug‬ ‭out‬ ‭of‬ ‭the‬ ‭reach‬ ‭of‬‭children,‬‭at‬‭a‬‭temperature‬‭of‬‭between‬‭15-30ºC‬‭in‬‭case‬‭the‬
‭investigational‬ ‭product‬ ‭delivered‬ ‭to‬ ‭the‬ ‭patient‬ ‭corresponds‬ ‭to‬ ‭the‬ ‭'investigational‬ ‭presentation'‬ ‭in‬ ‭the‬
‭bottle/canister,‬‭while‬‭that‬‭if‬‭the‬‭re-labeled‬‭commercial‬‭presentation‬‭for‬‭testing‬‭(box‬‭of‬‭3‬‭blister‬‭packs)‬‭has‬
‭been‬‭dispensed‬‭to‬‭the‬‭patient,‬‭no‬‭special‬‭measures‬‭will‬‭be‬‭required‬‭for‬‭its‬‭conservation.‬‭Patients‬‭should‬‭be‬
‭instructed‬‭to‬‭keep‬‭the‬‭medication‬‭in‬‭the‬‭bottles‬‭provided‬‭and‬‭not‬‭transfer‬‭them‬‭to‬‭any‬‭other‬‭container.‬‭Due‬
‭to‬‭potential‬‭unknown‬‭risks‬‭associated‬‭with‬‭topical‬‭and‬‭environmental‬‭exposure‬‭to‬‭experimental‬‭compounds,‬
‭capsules should not be opened or emptied into any vehicle for oral intake; They should be swallowed intact.‬
‭7.2. Administration‬
‭Patients‬‭should‬‭be‬‭instructed‬‭to‬‭swallow‬‭Palbociclib‬‭capsules‬‭whole,‬‭without‬‭chewing,‬‭before‬‭swallowing.‬‭A‬
‭capsule‬‭should‬‭not‬‭be‬‭swallowed‬‭if‬‭it‬‭is‬‭broken,‬‭cracked,‬‭or‬‭not‬‭intact‬‭for‬‭any‬‭other‬‭reason.‬‭Patients‬‭must‬
‭take‬‭the‬‭drug‬‭with‬‭food‬‭and‬‭they‬‭should‬‭be‬‭encouraged‬‭to‬‭take‬‭each‬‭dose‬‭at‬‭approximately‬‭the‬‭same‬‭time‬
‭each day. The treatment will be administered for 21 days followed by 7 days of rest.‬
‭7.3. Therapeutic compliance‬
‭Patients‬‭will‬‭keep‬‭diaries‬‭noting‬‭doses‬‭administered,‬‭missed,‬‭or‬‭modified,‬‭as‬‭well‬‭as‬‭significant‬‭delays‬‭in‬
‭administration‬ ‭(i.e.,‬ ‭>‬ ‭6‬ ‭hours‬ ‭from‬ ‭the‬ ‭planned‬ ‭administration‬ ‭time).‬ ‭There‬ ‭are‬ ‭no‬ ‭predetermined‬
‭compliance criteria to be included in the study endpoint analyses.‬
‭Patients‬‭will‬‭bring‬‭unused‬‭study‬‭medication‬‭and‬‭empty‬‭containers‬‭to‬‭all‬‭study‬‭visits.‬‭Treatment‬‭compliance‬
‭will‬ ‭be‬ ‭evaluated‬ ‭by‬ ‭counting‬ ‭the‬ ‭number‬ ‭of‬ ‭tablets‬ ‭and‬ ‭reflecting‬ ‭in‬ ‭the‬ ‭clinical‬ ‭history‬ ‭any‬ ‭possible‬
‭discrepancies‬‭between‬‭the‬‭theoretical‬‭number‬‭of‬‭tablets‬‭left‬‭and‬‭the‬‭actual‬‭one.‬‭Study‬‭site‬‭staff‬‭will‬‭monitor‬
‭potential‬ ‭reasons‬ ‭for‬ ‭noncompliance‬ ‭(e.g.,‬ ‭adverse‬ ‭event,‬ ‭loss‬ ‭of‬ ‭medication),‬ ‭and‬ ‭take‬ ‭measures‬ ‭to‬
‭improve this.‬
‭General rules:‬
‭●‬
‭Patients who miss a full dose on one day should NOT “make up” on the next day.‬
‭●‬
‭Patients‬‭who‬‭vomit‬‭at‬‭any‬‭time‬‭after‬‭taking‬‭the‬‭dose‬‭should‬‭NOT‬‭“make‬‭up”‬‭for‬‭it‬‭and‬‭will‬‭continue‬
‭treatment the next day as prescribed.‬
‭●‬
‭Patients who inadvertently take an extra dose on the same day should skip the next day's dose.‬
‭7.4. Dose modifications‬
‭Every‬‭effort‬‭should‬‭be‬‭made‬‭to‬‭administer‬‭the‬‭study‬‭treatment‬‭at‬‭the‬‭dose‬‭and‬‭schedule‬‭established‬‭in‬‭the‬
‭protocol.‬‭However,‬‭in‬‭the‬‭event‬‭of‬‭significant‬‭treatment-related‬‭toxicity,‬‭an‬‭adjustment‬‭in‬‭the‬‭administration‬
‭of the study medication (palbociclib) may be necessary as described in the following sections.‬
‭Depending‬‭on‬‭the‬‭nature‬‭of‬‭the‬‭toxicity‬‭observed,‬‭it‬‭may‬‭be‬‭necessary‬‭to‬‭adjust‬‭the‬‭dose‬‭of‬‭study‬‭drugs‬‭or‬
‭discontinue treatment.‬
‭In‬ ‭the‬ ‭event‬ ‭of‬ ‭significant‬ ‭treatment-related‬ ‭toxicity,‬ ‭administration‬ ‭of‬ ‭PD-0332991‬‭(palbociclib)‬‭may‬‭be‬
‭interrupted‬‭or‬‭postponed‬‭and/or‬‭the‬‭dose‬‭may‬‭be‬‭decreased‬‭as‬‭explained‬‭below.‬‭If‬‭multiple‬‭types‬‭of‬‭toxicity‬
‭occur,‬‭dose‬‭modification‬‭should‬‭be‬‭based‬‭on‬‭the‬‭worst‬‭toxicity‬‭observed.‬‭Patients‬‭will‬‭be‬‭instructed‬‭to‬‭notify‬
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‭the investigator of any adverse signs or symptoms.‬
‭Dose modifications can be made in three ways:‬
‭●‬
‭Within‬‭a‬‭cycle:‬‭Administration‬‭will‬‭be‬‭stopped‬‭until‬‭adequate‬‭recovery‬‭occurs‬‭and‬‭the‬‭dose‬‭will‬‭be‬
‭reduced (if necessary) during a given treatment cycle.‬
‭●‬
‭Between‬ ‭one‬ ‭cycle‬ ‭and‬ ‭the‬ ‭next:‬ ‭the‬ ‭next‬ ‭cycle‬ ‭can‬ ‭be‬ ‭postponed‬ ‭when‬ ‭persistent‬ ‭toxicity‬ ‭is‬
‭observed at the time when a new cycle should be started.‬
‭●‬
‭In‬ ‭the‬ ‭next‬ ‭cycle:‬ ‭it‬ ‭may‬ ‭be‬ ‭necessary‬ ‭to‬ ‭decrease‬ ‭the‬ ‭dose‬ ‭in‬ ‭the‬ ‭next‬ ‭cycle‬ ‭due‬ ‭to‬‭toxicity‬
‭observed during the previous cycle.‬
‭7.4.1. Treatment interruptions‬
‭Treatment should be postponed/interrupted in patients who experience the following events:‬
‭●‬
‭Grade 3 uncomplicated neutropenia (ANC<1,000/mm‬‭3‬‭).‬
‭●‬
‭Grade 3 Neutropenia (ANC<1,000/mm‬‭3‬‭) associated with‬‭documented infection or fever ≥ 38.5ºC.‬
‭●‬
‭Grade 4 Neutropenia (ANC<500/mm‬‭3‬‭).‬
‭●‬
‭Grade 4 thrombopenia (platelet count <25,000/mm‬‭3‬‭).‬
‭●‬
‭Non-hematological‬ ‭toxicity‬ ‭of‬ ‭Grade‬ ‭≥3‬ ‭(including‬ ‭nausea,‬ ‭vomiting,‬ ‭diarrhea‬ ‭and‬ ‭high‬ ‭blood‬
‭pressure, only if they persist despite optimal medical treatment).‬
‭●‬
‭Grade 3 QTc prolongation (QTc ≥501 msec) on at least two different ECGs.‬
‭Follow-up‬‭evaluations‬‭should‬‭be‬‭performed‬‭until‬‭recovery‬‭occurs‬‭according‬‭to‬‭the‬‭investigator's‬‭criteria.‬‭The‬
‭requirements that must be met to restart treatment are listed in Section 7.4.2 (“Delays in administration”)‬
‭Administration‬ ‭may‬ ‭be‬ ‭postponed‬ ‭as‬‭necessary‬‭until‬‭toxicity‬‭resolves.‬‭Depending‬‭on‬‭when‬‭the‬‭adverse‬
‭event‬‭resolves,‬‭discontinuation‬‭of‬‭treatment‬‭may‬‭result‬‭in‬‭the‬‭patient‬‭having‬‭to‬‭skip‬‭all‬‭subsequent‬‭planned‬
‭doses within that same cycle or even having to postpone the start of the next cycle.‬
‭If‬‭recovery‬‭from‬‭the‬‭adverse‬‭event‬‭that‬‭led‬‭to‬‭discontinuation‬‭of‬‭treatment‬‭occurs‬‭within‬‭the‬‭same‬‭cycle,‬
‭restarting‬‭administration‬‭of‬‭the‬‭medication‬‭is‬‭permitted‬‭in‬‭that‬‭cycle.‬‭Doses‬‭missed‬‭due‬‭to‬‭toxicity‬‭will‬‭not‬‭be‬
‭replaced‬‭within‬‭the‬‭same‬‭cycle.‬‭The‬‭need‬‭to‬‭reduce‬‭the‬‭dose‬‭at‬‭the‬‭time‬‭of‬‭restarting‬‭treatment‬‭should‬‭be‬
‭based‬‭on‬‭the‬‭criteria‬‭in‬‭Section‬‭7.4.3‬‭(Dose‬‭reductions)‬‭unless‬‭otherwise‬‭agreed‬‭after‬‭the‬‭case‬‭is‬‭discussed‬
‭between‬‭the‬‭investigator‬‭and‬‭the‬‭promoter‬‭of‬‭the‬‭clinical‬‭trial.‬‭If‬‭a‬‭dose‬‭reduction‬‭is‬‭finally‬‭applied‬‭in‬‭the‬
‭same cycle, the patient will have to go to the center again for a new dispensation of the medication.‬
‭In‬‭the‬‭event‬‭that‬‭the‬‭interruption‬‭of‬‭treatment‬‭is‬‭due‬‭for‬‭reasons‬‭other‬‭than‬‭toxicity‬‭related‬‭to‬‭treatment‬‭(e.g.,‬
‭non-cancer‬‭surgical‬‭intervention)‬‭and‬‭the‬‭interruption‬‭lasts‬‭>2‬‭weeks,‬‭the‬‭sponsor‬‭will‬‭be‬‭consulted‬‭before‬
‭restarting treatment after interruption.‬
‭7.4.2. Administration delays‬
‭Restart‬‭of‬‭treatment‬‭after‬‭discontinuation‬‭due‬‭to‬‭the‬‭development‬‭of‬‭treatment-related‬‭toxicity‬‭or‬‭the‬‭start‬‭of‬
‭a new cycle cannot be carried out until all of the following criteria are met:‬
‭−‬
‭Platelet count ≥50,000/mm‬‭3‬
‭−‬
‭RAN ≥1.000/mm‬‭3‬ ‭and absence of fever.‬
‭−‬
‭Recovery‬ ‭to‬ ‭Grade‬ ‭≤‬ ‭1‬ ‭or‬ ‭baseline‬ ‭(or,‬ ‭at‬ ‭the‬‭discretion‬‭of‬‭the‬‭investigator,‬‭to‬‭Grade‬‭≤2‬‭if‬‭not‬
‭considered‬ ‭a‬ ‭risk‬ ‭to‬ ‭patient‬ ‭safety)‬ ‭of‬‭Grade‬‭3‬‭or‬‭higher‬‭non-hematologic‬‭AEs‬‭related‬‭to‬‭the‬‭treatment‬
‭(including‬‭nausea,‬‭nausea,‬‭vomiting,‬‭diarrhea‬‭and‬‭high‬‭blood‬‭pressure‬‭only‬‭if‬‭they‬‭persist‬‭despite‬‭optimal‬
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‭medical‬‭treatment‬‭having‬‭been‬‭instituted),‬‭with‬‭the‬‭exception‬‭of‬‭alopecia.‬‭QTc‬‭<501‬‭msec‬‭and‬‭potentially‬
‭reversible‬‭causes‬‭(eg,‬‭electrolyte‬‭imbalance,‬‭concomitant‬‭medications‬‭known‬‭to‬‭prolong‬‭QTc)‬‭have‬‭been‬
‭corrected.‬ ‭If‬ ‭QTc‬ ‭remains‬ ‭above‬ ‭480‬ ‭msec,‬ ‭the‬ ‭ECG‬ ‭should‬ ‭be‬ ‭monitored‬ ‭more‬ ‭frequently,‬ ‭at‬ ‭the‬
‭investigator's discretion, until QTc ≤480 msec.‬
‭If‬‭treatment‬‭is‬‭postponed‬‭due‬‭to‬‭a‬‭decrease‬‭in‬‭hematologic‬‭parameters,‬‭the‬‭frequency‬‭with‬‭which‬‭blood‬‭cell‬
‭count determination is performed should be increased as clinically indicated.‬
‭If‬‭these‬‭parameters‬‭reach‬‭normal‬‭within‬‭2‬‭weeks‬‭of‬‭stopping‬‭treatment‬‭or‬‭delaying‬‭the‬‭start‬‭of‬‭the‬‭cycle,‬
‭treatment‬‭with‬‭PD-0332991/palbociclib‬‭can‬‭be‬‭restarted.‬‭For‬‭adverse‬‭events‬‭requiring‬‭a‬‭dose‬‭reduction‬‭at‬
‭the time of restarting treatment, see Section 7.4.3 Dose reductions.‬
‭If‬ ‭the‬ ‭above‬ ‭parameters‬ ‭have‬ ‭not‬ ‭returned‬ ‭to‬ ‭normal‬ ‭within‬ ‭the‬ ‭first‬ ‭2‬ ‭weeks‬‭after‬‭stopping‬‭treatment‬
‭administration‬ ‭(including‬‭the‬‭planned‬‭1-week‬‭treatment-free‬‭period)‬‭or‬‭within‬‭2‬‭weeks‬‭after‬‭delaying‬‭the‬
‭start‬ ‭of‬ ‭the‬ ‭cycle,‬ ‭you‬ ‭should‬ ‭Consider‬ ‭the‬ ‭possibility‬ ‭of‬ ‭permanently‬ ‭discontinuing‬ ‭treatment‬ ‭with‬
‭PD-0332991/palbociclib.‬‭Restarting‬‭treatment‬‭for‬‭patients‬‭who‬‭recover‬‭from‬‭treatment-related‬‭toxicity‬‭after‬
‭>‬‭2‬‭weeks‬‭of‬‭treatment‬‭interruption‬‭or‬‭delay‬‭in‬‭cycle‬‭initiation,‬‭but‬‭for‬‭whom‬‭the‬‭investigator‬‭believes‬‭that‬
‭benefit is occurring clinically obvious, it is left to the discretion of the investigator.‬
‭A‬‭new‬‭cycle‬‭will‬‭only‬‭be‬‭started‬‭when‬‭the‬‭previously‬‭indicated‬‭criteria‬‭are‬‭met‬‭and‬‭the‬‭treatment‬‭can‬‭be‬
‭administered; Otherwise, the beginning of the new cycle will be postponed until said criteria are met.‬
‭In‬ ‭the‬ ‭event‬ ‭that‬ ‭the‬ ‭start‬ ‭of‬ ‭a‬ ‭new‬ ‭cycle‬ ‭is‬ ‭delayed‬ ‭due‬ ‭to‬ ‭treatment-related‬ ‭toxicity,‬ ‭the‬‭procedures‬
‭required‬‭on‬‭Day‬‭1‬‭of‬‭that‬‭cycle‬‭will‬‭be‬‭performed‬‭when‬‭PD-0332991/palbociclib‬‭therapy‬‭is‬‭reinstated.‬‭It‬‭will‬
‭not‬ ‭be‬ ‭necessary‬ ‭to‬ ‭repeat‬ ‭the‬ ‭procedures‬ ‭on‬ ‭Day‬ ‭1‬ ‭of‬ ‭the‬ ‭new‬ ‭cycle‬ ‭(physical‬ ‭examination,‬ ‭ECOG‬
‭functional‬‭status,‬‭ECG,‬‭blood‬‭biochemistry,‬‭blood‬‭count)‬‭that‬‭had‬‭been‬‭performed‬‭before‬‭knowing‬‭the‬‭need‬
‭to‬‭delay‬‭the‬‭start‬‭of‬‭the‬‭cycle‬‭(1)‬‭if‬‭they‬‭are‬‭not‬‭required.‬‭to‬‭determine‬‭if‬‭the‬‭study‬‭drug‬‭can‬‭be‬‭reintroduced‬
‭and (2) whether they have been carried out within 7 days prior to the reintroduction of the study drug.‬
‭7.4.3. Dose reductions‬
‭After‬‭discontinuation‬‭of‬‭PD-0332991/palbociclib‬‭or‬‭delay‬‭in‬‭starting‬‭a‬‭new‬‭cycle,‬‭a‬‭dose‬‭reduction‬‭may‬‭be‬
‭necessary when restarting treatment.‬
‭No‬‭specific‬‭dose‬‭adjustment‬‭is‬‭recommended‬‭when‬‭discontinuation‬‭of‬‭treatment‬‭or‬‭delay‬‭in‬‭starting‬‭a‬‭new‬
‭cycle‬‭is‬‭due‬‭to‬‭the‬‭occurrence‬‭of‬‭treatment-related‬‭Grade‬‭1/2‬‭toxicity.‬‭However,‬‭the‬‭researcher‬‭must‬‭always‬
‭treat‬‭patients‬‭according‬‭to‬‭his‬‭or‬‭her‬‭discretion‬‭and‬‭in‬‭accordance‬‭with‬‭the‬‭specific‬‭clinical‬‭circumstances‬‭of‬
‭each case.‬
‭PD0332991/‬ ‭palbociclib‬ ‭dose‬ ‭reduction‬ ‭is‬ ‭allowed‬ ‭by‬ ‭1‬ ‭and,‬ ‭if‬ ‭necessary,‬ ‭2‬ ‭dose‬ ‭levels‬ ‭(‬‭Table‬ ‭1‬‭),‬
‭depending‬‭on‬‭the‬‭type‬‭and‬‭intensity‬‭of‬‭the‬‭toxicity‬‭observed.‬‭Patients‬‭requiring‬‭more‬‭than‬‭2‬‭dose‬‭reductions‬
‭will‬‭be‬‭removed‬‭from‬‭study‬‭treatment‬‭and‬‭enter‬‭the‬‭follow-up‬‭phase.‬‭All‬‭dose‬‭modifications/adjustments‬
‭must‬ ‭be‬ ‭clearly‬ ‭documented‬ ‭in‬ ‭the‬ ‭patient's‬ ‭source‬ ‭documents‬ ‭and‬ ‭in‬ ‭the‬ ‭investigational‬ ‭product‬
‭administration section of the CRD.‬
‭Once‬‭the‬‭dose‬‭has‬‭been‬‭reduced‬‭in‬‭a‬‭given‬‭patient,‬‭the‬‭new‬‭dose‬‭will‬‭be‬‭used‬‭in‬‭all‬‭subsequent‬‭cycles,‬
‭unless it is necessary to reduce it again. Re-escalation of doses is not allowed.‬
‭Table 1. Available dose levels‬
‭Dose level‬
‭PD-0332991/palbociclib for 3 out of every 4 weeks‬
‭(3/1 treatment regimen)‬
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‭Starting dose‬
‭125 mg/day‬
‭-1‬
‭100 mg/day‬
‭-2‬
‭75 mg/day*‬
‭Discontinue study treatment‬
‭*Dose reduction of PD-0332991/palbociclib below 75 mg/day is not permitted.‬
‭Recommended‬ ‭PD-0332991/palbociclib‬ ‭dose‬ ‭modifications‬ ‭for‬ ‭treatment-related‬ ‭toxicity‬ ‭that‬ ‭requires‬
‭treatment‬‭interruption‬‭or‬‭delay‬‭or‬‭that‬‭persists‬‭despite‬‭initiation‬‭of‬‭optimal‬‭medical‬‭therapy‬‭are‬‭described‬‭in‬
‭the‬‭Table 2‬‭.‬
‭Table‬ ‭2.‬ ‭PD-0332991/palbociclib‬ ‭dose‬ ‭modifications‬ ‭for‬ ‭treatment-related‬ ‭toxicity‬ ‭that‬ ‭requires‬ ‭treatment‬
‭interruption or delay or that persists despite optimal medical treatment.‬
‭Toxicity‬
‭Restart treatment with‬
‭PD-0332991/‬
‭palbociclib con:‬
‭Grade 3 uncomplicated neutropenia‬‭(RAN<1.000/mm3)‬
‭The same dose level‬
‭Grade 3 Neutropenia‬‭(RAN<1.000/mm3)‬‭associated with‬‭a documented‬
‭infection or fever ≥38.5°C‬
‭↓ 1 Dose level‬
‭Grade 4 Neutropenia‬‭(RAN<500/mm3)‬
‭↓ 1 Dose level‬
‭Grade 4 thrombopenia‬‭(Platelet count <25,000/mm3)‬
‭↓ 1 Dose level‬
‭Grade ≥3 non-hematological toxicity‬‭(includes nausea,‬‭vomiting, diarrhea‬
‭and high blood pressure, only if they persist despite optimal medical treatment)‬
‭↓ 1 Dose level‬
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‭Management of QTc prolongation‬
‭In‬‭case‬‭of‬‭QTc‬‭prolongation,‬‭possible‬‭alternative‬‭potentially‬‭reversible‬‭causes‬‭should‬‭be‬‭investigated,‬‭such‬
‭as alterations in serum electrolytes or use of concomitant medication that may cause QTc prolongation.‬
‭If‬‭any‬‭reversible‬‭cause‬‭is‬‭identified,‬‭it‬‭should‬‭be‬‭corrected‬‭in‬‭a‬‭medically‬‭appropriate‬‭manner‬‭(i.e.,‬‭correction‬
‭of‬ ‭electrolyte‬ ‭disturbances‬ ‭with‬ ‭nutritional‬ ‭supplements‬ ‭until‬ ‭values‬ ‭​are‬ ‭within‬ ‭normal‬ ‭limits‬ ‭and/or‬
‭discontinuation, if possible, of concomitant medication. which is known to cause QT prolongation).‬
‭Recommendations on dose modification in case of QTc prolongation are presented in Table 3:‬
‭Toxicity (NCI CTC Grade, Version 4.0)‬
‭Grade 2 QTc prolongation‬
‭Grade 3 QTc‬
‭prolongation‬
‭Grade 4 QTc‬
‭prolongation‬
‭Reversible cause‬
‭identified‬
‭Treat the reversible cause.‬
‭Initiate more frequent ECG‬
‭monitoring according to‬
‭investigator's clinical‬
‭judgment until QTc ≤480‬
‭msec.‬
‭Continue with the‬‭same dose‬
‭level‬‭(1)‬
‭Treat the reversible cause.‬
‭Discontinue study‬
‭treatment until QTc < 501‬
‭msec.‬
‭Restart study treatment‬
‭with‬‭same dose level.‬
‭Initiate more frequent ECG‬
‭monitoring according to‬
‭investigator's clinical‬
‭judgment until QTc ≤ 480‬
‭msec‬
‭Permanently‬
‭discontinue study‬
‭treatment‬
‭Unidentified reversible‬
‭cause‬
‭Initiate more frequent ECG‬
‭monitoring according to‬
‭investigator's clinical‬
‭judgment until QTc ≤480‬
‭msec.‬
‭Continue with the‬‭same dose‬
‭level‬‭(1)‬
‭Interrupt study treatment‬
‭until QTc < 501 msec.‬
‭Restart treatment at the‬
‭next lower dose level.‬‭(2)‬
‭Initiate more frequent ECG‬
‭monitoring according to‬
‭investigator's clinical‬
‭judgment until QTc ≤ 480‬
‭msec‬
‭Permanently‬
‭discontinue study‬
‭treatment‬
‭1.‬
‭If‬‭the‬‭QTc‬‭interval‬‭persists‬‭above‬‭480‬‭msec‬‭for‬‭more‬‭than‬‭2‬‭cycles,‬‭or‬‭if‬‭Grade‬‭2‬‭QTc‬‭prolongation‬‭recurs‬‭in‬‭the‬‭absence‬‭of‬
‭other‬ ‭alternative‬ ‭causes‬ ‭or‬ ‭despite‬ ‭correction‬‭of‬‭the‬‭alternative‬‭causes,‬‭treatment‬‭should‬‭be‬‭considered.‬‭possibility‬‭of‬‭adjusting‬‭the‬
‭dose‬‭and/or‬‭definitively‬‭discontinuing‬‭study‬‭treatment‬‭after‬‭consulting‬‭with‬‭a‬‭cardiologist‬‭and‬‭the‬‭clinical‬‭trial‬‭medical‬‭monitor,‬‭taking‬
‭into‬‭account‬‭the‬‭safety‬‭data‬‭that‬‭have‬‭been‬‭obtained‬‭up‬‭to‬‭that‬‭point‬‭in‬‭the‬‭clinical‬‭development‬‭program‬‭of‬‭PD-0332991‬‭and‬‭based‬‭on‬
‭the investigator's clinical judgment.‬
‭2.‬
‭If‬‭Grade‬‭3‬‭QTc‬‭prolongation‬‭occurs‬‭again‬‭after‬‭a‬‭dose‬‭reduction,‬‭consideration‬‭should‬‭be‬‭given‬‭to‬‭further‬‭dose‬‭adjustment‬
‭and/or‬‭definitive‬‭discontinuation‬‭of‬‭study‬‭treatment‬‭after‬‭consultation‬‭with‬‭a‬‭physician.‬‭cardiologist‬‭and‬‭with‬‭the‬‭medical‬‭monitor‬‭of‬‭the‬
‭clinical‬ ‭trial,‬ ‭taking‬ ‭into‬ ‭account‬ ‭the‬ ‭safety‬ ‭data‬ ‭that‬ ‭have‬ ‭been‬ ‭obtained‬ ‭to‬ ‭that‬ ‭point‬ ‭in‬ ‭the‬ ‭clinical‬ ‭development‬ ‭program‬ ‭of‬
‭PD-0332991 and based on the clinical judgment of the investigator.‬
‭7.5. Medication errors and overdoses‬
‭In‬‭this‬‭clinical‬‭trial,‬‭medication‬‭errors‬‭may‬‭consist‬‭of‬‭administering‬‭or‬‭taking‬‭the‬‭wrong‬‭drug,‬‭by‬‭the‬‭wrong‬
‭patient,‬‭at‬‭the‬‭wrong‬‭time,‬‭or‬‭with‬‭the‬‭wrong‬‭drug‬‭dose.‬‭Any‬‭medication‬‭error‬‭must‬‭be‬‭recorded‬‭in‬‭the‬‭data‬
‭collection‬ ‭notebook‬ ‭(CRD),‬‭and,‬‭when‬‭applicable,‬‭in‬‭the‬‭serious‬‭adverse‬‭events‬‭form‬‭(SAE).‬‭If‬‭an‬‭error‬
‭occurs in the medication dosage, the clinical trial sponsor must be notified immediately.‬
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‭Medication‬ ‭errors‬ ‭should‬‭be‬‭reported‬‭regardless‬‭of‬‭the‬‭presence‬‭or‬‭absence‬‭of‬‭an‬‭associated‬‭AE/SAE,‬
‭including:‬
‭●‬
‭Medication errors that affect the patient's exposure to the investigational product;‬
‭●‬
‭Possible‬‭errors‬‭with‬‭medication‬‭or‬‭its‬‭use‬‭outside‬‭of‬‭what‬‭is‬‭foreseen‬‭in‬‭the‬‭protocol,‬‭regardless‬‭of‬
‭whether or not they affect the patients participating in the clinical trial.‬
‭Regardless‬‭of‬‭whether‬‭the‬‭medication‬‭error‬‭is‬‭accompanied‬‭by‬‭an‬‭AE,‬‭as‬‭determined‬‭by‬‭the‬‭investigator,‬
‭the‬‭error‬‭should‬‭be‬‭recorded‬‭on‬‭the‬‭adverse‬‭event‬‭(AE)‬‭page‬‭and,‬‭if‬‭applicable,‬‭the‬‭associated‬‭AE(s)‬‭will‬‭be‬
‭recorded on the adverse events (AEs) section of the CRD.‬
‭7.6. Conservation and accounting of medication‬
‭The‬ ‭Promoter‬ ‭will‬ ‭supply‬ ‭the‬ ‭study‬ ‭treatment‬ ‭(Palbociclib).‬ ‭Special‬ ‭storage‬ ‭conditions‬ ‭(15-30ºC)‬ ‭are‬
‭required‬ ‭for‬ ‭“presentation‬ ‭as‬ ‭an‬ ‭investigational‬ ‭drug”‬ ‭(cans/flasks)‬ ‭within‬ ‭its‬ ‭original‬ ‭container.‬ ‭For‬ ‭the‬
‭re-labeled‬‭commercial‬‭presentation‬‭(box‬‭of‬‭3‬‭blister‬‭packs),‬‭no‬‭special‬‭conservation‬‭measures‬‭are‬‭required‬
‭as‬‭long‬‭as‬‭it‬‭is‬‭kept‬‭in‬‭its‬‭original‬‭packaging.‬‭The‬‭pharmacy‬‭service‬‭must‬‭keep‬‭a‬‭detailed‬‭inventory‬‭of‬‭this‬
‭drug‬‭in‬‭the‬‭center.‬‭Medication‬‭must‬‭be‬‭kept‬‭in‬‭a‬‭secure‬‭closed‬‭area‬‭of‬‭​the‬‭study‬‭center‬‭in‬‭accordance‬‭with‬
‭applicable‬ ‭legal‬ ‭requirements.‬ ‭Returned‬ ‭medication‬ ‭must‬ ‭be‬ ‭kept‬ ‭separate‬ ‭from‬ ‭medication‬ ‭to‬ ‭be‬
‭dispensed.‬ ‭Subjects‬ ‭included‬ ‭in‬ ‭the‬ ‭trial‬ ‭will‬ ‭be‬ ‭provided‬ ‭with‬ ‭instructions‬ ‭for‬‭self-administration‬‭and‬‭a‬
‭sufficient amount of drug for their treatment until the next scheduled visit.‬
‭In‬‭addition,‬‭a‬‭patient‬‭diary‬‭will‬‭also‬‭be‬‭provided‬‭to‬‭each‬‭of‬‭the‬‭study‬‭participants‬‭to‬‭record‬‭the‬‭taking‬‭of‬‭the‬
‭scheduled‬ ‭doses.‬ ‭Compliance‬ ‭with‬ ‭study‬‭treatment‬‭regimens‬‭by‬‭subjects‬‭will‬‭be‬‭documented‬‭using‬‭the‬
‭patient‬‭diary,‬‭dispensing‬‭log,‬‭and‬‭pharmacy‬‭service‬‭returns‬‭log.‬‭Any‬‭study‬‭treatment‬‭not‬‭used‬‭by‬‭the‬‭patient‬
‭must‬‭be‬‭returned‬‭to‬‭the‬‭pharmacy‬‭service‬‭for‬‭inventory‬‭and‬‭subsequent‬‭disposal.‬‭The‬‭pharmacy‬‭service‬‭will‬
‭keep the registration of the investigational product updated.‬
‭7.7. Concomitant medication‬
‭All‬‭medication,‬‭including‬‭herbal‬‭supplements‬‭and‬‭vitamins,‬‭or‬‭treatment‬‭received‬‭by‬‭the‬‭patient‬‭during‬‭the‬
‭trial and the reason for its administration must be recorded in the CRD.‬
‭Because‬ ‭inhibition‬‭of‬‭CYP3A‬‭isoenzymes‬‭may‬‭increase‬‭exposure‬‭to‬‭PD‬‭0332991,‬‭potentially‬‭increasing‬
‭toxicity,‬ ‭the‬ ‭use‬ ‭of‬ ‭known‬ ‭strong‬ ‭CYP3A‬ ‭inhibitors‬ ‭(such‬ ‭as‬ ‭ketoconazole,‬ ‭miconazole,‬ ‭itraconazole,‬
‭posaconazole,‬ ‭clarithromycin,‬ ‭erythromycin)‬ ‭is‬ ‭not‬ ‭permitted.‬ ‭,‬ ‭tilithromycin,‬ ‭nefazodone,‬ ‭diltiazem,‬
‭verapamil,‬ ‭indinavir,‬ ‭saquinavir,‬ ‭ritonavir,‬ ‭nelfinavir,‬ ‭lopinavir,‬ ‭atazanavir,‬ ‭amprenavir,‬ ‭fosamprenavir,‬
‭delavirdine and grapefruit juice).‬
‭Additionally,‬ ‭drugs‬ ‭that‬ ‭are‬ ‭known‬ ‭strong‬ ‭CYP3A‬ ‭inducers‬ ‭(such‬ ‭as‬ ‭carbamazepine,‬ ‭dexamethasone,‬
‭felbamate,‬ ‭omeprazole,‬ ‭Primodone,‬ ‭phenobarbital,‬ ‭rifampicin,‬ ‭phenytoin,‬ ‭rifabutin,‬ ‭rifapentine,‬ ‭and‬ ‭St.‬
‭John's‬‭wort)‬‭are‬‭not‬‭recommended‬‭for‬‭use.‬‭While‬‭receiving‬‭study‬‭treatment,‬‭patients‬‭will‬‭not‬‭be‬‭allowed‬‭to‬
‭receive‬ ‭other‬ ‭antitumor‬ ‭treatment.‬ ‭Medications‬ ‭intended‬ ‭exclusively‬ ‭for‬ ‭supportive‬ ‭care‬ ‭(e.g.,‬
‭corticosteroids,‬ ‭anticonvulsants,‬ ‭analgesics,‬ ‭antidiarrheals,‬ ‭antidepressants)‬ ‭may‬ ‭be‬ ‭used‬ ‭at‬ ‭the‬
‭investigator's discretion.‬
‭Primary‬‭prophylactic‬‭use‬‭of‬‭granulocyte‬‭colony-stimulating‬‭factors‬‭is‬‭not‬‭permitted,‬‭but‬‭may‬‭be‬‭used‬‭to‬‭treat‬
‭treatment-onset‬ ‭neutropenia‬ ‭in‬ ‭accordance‬ ‭with‬ ‭current‬ ‭WHO‬ ‭guidelines.‬‭American‬ ‭Society‬ ‭of‬ ‭Clinical‬
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‭Oncology‬ ‭(ASCO)‬‭22‬‭.‬ ‭Colony-stimulating‬ ‭factors‬ ‭(CSFs)‬ ‭should‬ ‭not‬‭be‬‭used‬‭for‬‭prophylactic‬‭purposes‬‭in‬
‭cycle‬‭1.‬‭If‬‭neutropenic‬‭complications‬‭are‬‭observed‬‭in‬‭a‬‭cycle‬‭in‬‭which‬‭primary‬‭CSF‬‭prophylaxis‬‭has‬‭not‬
‭been‬‭received,‬‭secondary‬‭prophylaxis‬‭may‬‭be‬‭administered‬‭at‬‭the‬‭discretion‬‭of‬‭the‬‭investigator,‬‭but‬‭only‬‭if‬
‭dose reduction or deferral is not considered a reasonable alternative.‬
‭Erythropoietin may be used for supportive treatment of anemia at the investigator's discretion.‬
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‭8. DEVELOPMENT OF THE TEST AND EVALUATION OF THE RESPONSE‬
‭​‬‭8.1. Study procedures‬
‭​‬
‭Selection‬
‭(within 14‬
‭days prior‬
‭to‬
‭inclusion)‬
‭C1‬
‭D1‬
‭C1‬
‭D15‬
‭C2‬
‭D1‬
‭C2‬
‭D15‬
‭Each‬
‭4‬
‭weeks‬
‭Each‬
‭8‬
‭weeks‬
‭Each‬
‭12‬
‭weeks‬
‭End of‬
‭treatment‬
‭(after 4‬
‭weeks)‬
‭Follow-up if‬
‭treatment‬
‭ends‬
‭without‬
‭progressio‬
‭n (every 6‬
‭weeks)‬
‭Follow-up‬
‭after‬
‭progression‬
‭(every 4‬
‭weeks until‬
‭death)‬
‭Informed consent‬
‭X‬
‭Eligibility‬
‭X‬
‭Anamnesis‬
‭X‬
‭Demographics‬
‭X‬
‭Physical exam‬‭4‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭ECOG‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Barthel index‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Test minimental‬
‭X‬
‭X‬
‭X‬‭5‬
‭X‬
‭X‬
‭Concomitant‬
‭medication‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Complete‬
‭hematology‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Complete‬
‭biochemistry‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Urine analysis‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Coagulation tests‬
‭X‬
‭X‬
‭X‬
‭ECG‬
‭X‬
‭X‬
‭pregnancy test‬
‭X‬‭1‬
‭X‬
‭Magnetic‬
‭resonance‬
‭X‬‭2‬
‭X‬‭6‬
‭X‬‭6‬
‭Sending tumor‬
‭sample‬
‭X‬‭7‬
‭Palbociclib‬
‭Dispensing‬
‭X‬
‭X‬
‭X‬
‭Therapeutic‬
‭compliance‬
‭X‬
‭X‬
‭Corticosteroid‬
‭dosage‬
‭X‬‭3‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Toxicities registry‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭X‬
‭Survival‬
‭X‬
‭1- The serum or urine pregnancy test for women of childbearing age must be performed ≤ 72 hours before the start of the study treatment and at the‬
‭end of treatment visit.‬
‭2- Cranial Magnetic Resonance is admitted in a period of ≤ 28 days‬
‭3- Dose of corticosteroids in the 5 days prior to inclusion‬
‭4- Physical examination, measurements of pulse at rest, blood pressure, respiratory rate, temperature, weight, height and ophthalmic examination‬
‭Those patients undergoing treatment who report new symptoms or worsening of visual symptoms should be immediately referred to an ophthalmology‬
‭specialist for examination. complementary.‬
‭5- The Mini Mental test will be carried out on C1D1 and also on day 1 of each even cycle, that is, every 8 weeks from C2D1‬
‭6-‬‭MRI‬‭imaging‬‭tests‬‭will‬‭be‬‭performed‬‭every‬‭12‬‭weeks‬‭until‬‭disease‬‭progression,‬‭responses‬‭to‬‭treatment‬‭(PR,‬‭CR)‬‭must‬‭be‬‭confirmed‬‭at‬‭4‬‭weeks‬
‭using‬‭the‬‭same‬‭method,‬‭if‬‭the‬‭patient‬‭abandons‬‭treatment‬‭for‬‭any‬‭reason‬‭before‬‭progression,‬‭MRIs‬‭should‬‭continue‬‭to‬‭be‬‭performed‬‭every‬‭12‬‭weeks‬
‭as part of the follow-up until progression.‬
‭7-‬ ‭The‬ ‭sending‬‭of‬‭the‬‭tumor‬‭sample‬‭may‬‭be‬‭carried‬‭out‬‭after‬‭obtaining‬‭the‬‭informed‬‭consent‬‭of‬‭the‬‭tumor‬‭sample‬‭from‬‭the‬‭candidate‬‭patient.‬‭The‬
‭tumor‬ ‭tissue‬ ‭from‬ ‭the‬ ‭original‬ ‭diagnostic‬ ‭biopsy‬ ‭or‬ ‭a‬‭recently‬‭obtained‬‭biopsy‬‭will‬‭be‬‭sent‬‭to‬‭the‬‭Neuropathology‬‭laboratory‬‭of‬‭the‬‭12‬‭de‬‭Octubre‬
‭University Hospital.‬
‭Description of procedures:‬
‭Informed‬‭consent:‬‭For‬‭this‬‭trial,‬‭two‬‭informed‬‭consents‬‭have‬‭been‬‭prepared,‬‭one‬‭for‬‭sending‬‭the‬‭tumor‬‭sample‬
‭for‬‭centralized‬‭review‬‭and‬‭confirming‬‭the‬‭diagnosis‬‭and‬‭another‬‭informed‬‭consent‬‭for‬‭the‬‭clinical‬‭part‬‭of‬‭the‬‭trial‬
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‭and‬‭carrying‬‭out‬‭the‬‭molecular‬‭analysis.‬‭No‬‭sample‬‭can‬‭be‬‭mobilized‬‭from‬‭the‬‭hospital‬‭of‬‭origin‬‭until‬‭the‬‭patient‬
‭has signed the informed consent for the tumor sample.‬
‭Eligibility:‬‭Verification that the patient meets all‬‭the inclusion criteria and none of the exclusion criteria.‬
‭History:‬‭During‬ ‭the‬ ‭baseline‬ ‭period‬ ‭in‬ ‭the‬ ‭2‬ ‭weeks‬ ‭prior‬ ‭to‬ ‭inclusion,‬ ‭a‬ ‭general‬ ‭anamnesis‬ ‭with‬ ‭details‬ ‭of‬
‭coexisting‬‭diseases,‬‭oncological‬‭history‬‭(specific‬‭history‬‭of‬‭cancer,‬‭date‬‭of‬‭diagnosis,‬‭type‬‭of‬‭primary‬‭tumor‬‭with‬
‭histological‬ ‭diagnosis,‬ ‭previous‬ ‭surgical‬ ‭processes‬ ‭with‬ ‭dates,‬‭and‬‭any‬‭other‬‭relevant‬‭medical‬‭history‬‭in‬‭the‬
‭previous‬‭6‬‭months),‬‭smoking‬‭habit‬‭and‬‭history‬‭of‬‭weight‬‭loss‬‭in‬‭the‬‭last‬‭6‬‭months,‬‭previous‬‭systemic‬‭treatments‬
‭(in the previous 4 weeks), dates of administration, as well as reason for discontinuation.‬
‭Demographics:‬‭Date of birth, race and sex.‬
‭Physical‬ ‭exam:‬ ‭Physical‬ ‭examination,‬ ‭measurements‬ ‭of‬ ‭resting‬ ‭pulse,‬ ‭blood‬ ‭pressure,‬ ‭respiratory‬ ‭rate,‬
‭temperature,‬‭weight,‬‭height,‬‭and‬‭an‬‭ophthalmic‬‭examination‬‭.‬‭Those‬‭patients‬‭undergoing‬‭treatment‬‭who‬‭report‬
‭new‬‭symptoms‬‭or‬‭worsening‬‭of‬‭visual‬‭symptoms‬‭should‬‭be‬‭immediately‬‭referred‬‭to‬‭an‬‭ophthalmology‬‭specialist‬
‭for complementary examination.‬
‭ECOG:‬‭Functional status will be assessed using the‬‭ECOG (Eastern Cooperative Oncology Group) scale.‬
‭Barthel‬‭Index‬‭and‬‭Minimental‬‭Test:‬‭The‬‭neurological‬‭and‬‭functional‬‭examination‬‭will‬‭be‬‭assessed‬‭using‬‭the‬
‭Barthel index and the Minimental Test.‬
‭Concomitant‬‭medication:‬‭All‬‭drugs‬‭taken‬‭in‬‭the‬‭last‬‭4‬‭weeks‬‭prior‬‭to‬‭inclusion‬‭and‬‭concomitantly‬‭during‬‭the‬
‭study‬‭will‬‭be‬‭recorded‬‭in‬‭the‬‭medical‬‭record‬‭and‬‭in‬‭the‬‭data‬‭collection‬‭notebook‬‭with‬‭the‬‭indication,‬‭information‬
‭on the dose and dates of administration.‬
‭Complete‬ ‭hematology:‬ ‭Complete‬ ‭blood‬ ‭count‬ ‭including‬ ‭a‬ ‭total‬ ‭white‬ ‭blood‬ ‭cell‬ ‭count‬ ‭with‬ ‭differential,‬
‭hemoglobin, and platelet count.‬
‭Complete‬‭biochemistry:‬‭Serum‬‭chemistry‬‭including‬‭glucose,‬‭creatinine,‬‭total‬‭bilirubin,‬‭alkaline‬‭phosphatase,‬
‭aspartate aminotransferase (AST) or SGOT, alanine aminotransferase (ALT) or SGPT.‬
‭Urine‬ ‭analysis:‬‭In‬ ‭the‬ ‭baseline‬ ‭period,‬ ‭every‬ ‭4‬‭weeks‬‭during‬‭treatment,‬‭at‬‭the‬‭end‬‭of‬‭treatment‬‭visit‬‭and‬‭in‬
‭follow-ups if treatment ends without progression.‬
‭Coagulation‬ ‭tests:‬‭Coagulation‬ ‭studies‬‭will‬‭include‬‭prothrombin‬‭time‬‭(PT),‬‭partial‬‭thromboplastin‬‭time‬‭(PTT),‬
‭and fibrinogen.‬
‭ECG:‬ ‭An‬‭electrocardiogram‬‭(ECG)‬‭value‬‭must‬‭be‬‭obtained‬‭at‬‭baseline,‬‭within‬‭28‬‭days‬‭before‬‭inclusion,‬‭and‬
‭every 8 weeks thereafter.‬
‭Pregnancy test:‬‭Serum or urine pregnancy test for‬‭women of childbearing age.‬
‭Cranial‬ ‭Magnetic‬ ‭Resonance:‬‭Cranial‬ ‭MRI‬ ‭that‬ ‭will‬ ‭be‬ ‭taken‬ ‭as‬ ‭a‬ ‭base‬ ‭examination‬ ‭in‬ ‭terms‬ ‭of‬‭response‬
‭evaluation‬‭(it‬‭is‬‭allowed‬‭to‬‭be‬‭performed‬‭in‬‭a‬‭period‬‭≤‬‭28‬‭days).‬‭The‬‭response‬‭should‬‭always‬‭be‬‭assessed‬‭with‬
‭the‬‭same‬‭equipment‬‭as‬‭the‬‭initial‬‭examination.‬‭If‬‭the‬‭corticosteroid‬‭dose‬‭increases‬‭after‬‭the‬‭cranial‬‭MRI‬‭and‬‭the‬
‭start‬‭of‬‭treatment,‬‭a‬‭new‬‭baseline‬‭MRI‬‭should‬‭be‬‭performed.‬‭That‬‭is,‬‭at‬‭the‬‭time‬‭of‬‭starting‬‭treatment,‬‭the‬‭dose‬‭of‬
‭corticosteroids‬‭must‬‭be‬‭equal‬‭to‬‭or‬‭less‬‭than‬‭the‬‭dose‬‭that‬‭the‬‭patient‬‭was‬‭taking‬‭at‬‭the‬‭time‬‭of‬‭the‬‭MRI‬‭used‬‭as‬
‭baseline.‬
‭Response evaluation will follow the RANO and McDonald criteria for brain lesions visualized on MRI.‬
‭Send‬ ‭tumor‬ ‭sample:‬‭Submission‬ ‭of‬ ‭tumor‬ ‭for‬ ‭centralized‬ ‭review‬ ‭to‬ ‭confirm‬ ‭the‬ ‭diagnosis‬ ‭of‬ ‭Anaplastic‬
‭Oligodendroglioma‬ ‭(OA)‬ ‭in‬ ‭a‬ ‭central‬ ‭neuropathology‬‭laboratory.‬‭It‬‭will‬‭also‬‭be‬‭determined‬‭if‬‭there‬‭is‬‭nuclear‬
‭expression of the RB protein by Immunohistochemistry.‬
‭Palbociclib Dispensing:‬‭Palbociclib capsules will be‬‭dispensed for 21-day treatment periods.‬
‭Therapeutic‬‭compliance:‬‭Any‬‭missed‬‭dose‬‭or‬‭loss‬‭due‬‭to‬‭vomiting‬‭should‬‭be‬‭indicated‬‭in‬‭the‬‭patient's‬‭diary,‬
‭medical history and CRD, in the same way as all doses administered.‬
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‭Corticosteroid‬‭dosage:‬‭Record‬‭in‬‭the‬‭patient's‬‭medical‬‭history‬‭and‬‭in‬‭the‬‭CRD‬‭the‬‭doses‬‭of‬‭corticosteroids‬‭for‬
‭the‬‭5‬‭days‬‭prior‬‭to‬‭inclusion.‬‭At‬‭each‬‭visit,‬‭the‬‭dose‬‭of‬‭corticosteroid‬‭received‬‭by‬‭the‬‭patient‬‭must‬‭be‬‭recorded‬‭in‬
‭the clinical history and in the CRD.‬
‭Toxicities‬ ‭record:‬‭Safety‬ ‭assessments‬ ‭and‬ ‭adverse‬ ‭events‬ ‭include‬ ‭tumor-related,‬ ‭treatment-related,‬ ‭and‬
‭unrelated‬‭signs‬‭and‬‭symptoms.‬‭Adverse‬‭events‬‭will‬‭be‬‭documented‬‭and‬‭recorded‬‭in‬‭the‬‭CRD‬‭upon‬‭notification‬
‭by‬ ‭patients.‬ ‭Specific‬‭questions‬‭will‬‭be‬‭asked‬‭about‬‭adverse‬‭events.‬‭Adverse‬‭events‬‭will‬‭be‬‭monitored‬‭at‬‭the‬
‭post-treatment‬ ‭follow-up‬ ‭visit‬ ‭30+/-3‬ ‭days‬ ‭after‬ ‭the‬ ‭end‬ ‭of‬ ‭treatment‬ ‭or‬ ‭until‬ ‭all‬ ‭drug-related‬ ‭toxicities‬‭have‬
‭resolved‬‭or‬‭are‬‭considered‬‭irreversible,‬‭whichever‬‭occurs.‬‭later.‬‭Toxicity‬‭grading‬‭will‬‭be‬‭based‬‭on‬‭the‬‭National‬
‭Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0).‬
‭Survival:‬‭All‬‭patients‬‭will‬‭be‬‭followed‬‭for‬‭subsequent‬‭antineoplastic‬‭treatments‬‭and‬‭survival,‬‭regardless‬‭of‬‭the‬
‭reasons‬‭for‬‭withdrawal‬‭of‬‭study‬‭treatment.‬‭It‬‭is‬‭recommended‬‭to‬‭maintain‬‭telephone/face-to-face‬‭contacts‬‭every‬
‭4‬ ‭weeks‬ ‭in‬ ‭order‬ ‭to‬ ‭carry‬ ‭out‬‭timely‬‭periodic‬‭follow-up.‬‭Information‬‭regarding‬‭subsequent‬‭treatments‬‭should‬
‭include‬‭the‬‭list‬‭of‬‭post-study‬‭treatments,‬‭drugs‬‭administered,‬‭and‬‭the‬‭start‬‭and‬‭stop‬‭date‬‭of‬‭administration‬‭of‬
‭each drug; All of this will be noted in the medical history and in the CRD.‬
‭Follow-up‬ ‭for‬ ‭overall‬ ‭survival‬ ‭will‬ ‭be‬ ‭carried‬ ‭out‬ ‭until‬ ‭death.‬ ‭The‬‭date‬‭of‬‭death‬‭will‬‭be‬‭verified‬‭to‬‭determine‬
‭survival.‬
‭​‬‭8.2. Determinations in the selection phase (baseline determinations)‬
‭Before‬‭carrying‬‭out‬‭any‬‭study-specific‬‭procedure,‬‭dated‬‭and‬‭signed‬‭CEIC-approved‬‭informed‬‭consent‬‭must‬‭be‬
‭obtained.‬‭All‬‭urine,‬‭hematological‬‭and‬‭biochemical‬‭tests,‬‭pregnancy‬‭tests‬‭will‬‭be‬‭analyzed‬‭at‬‭a‬‭local‬‭laboratory.‬
‭Procedures‬‭that‬‭are‬‭part‬‭of‬‭usual‬‭treatment‬‭are‬‭not‬‭considered‬‭study-specific‬‭procedures.‬‭Procedures‬‭that‬‭are‬
‭part‬ ‭of‬ ‭regular‬ ‭care‬ ‭may‬ ‭be‬ ‭used‬ ‭as‬ ‭screening‬ ‭procedures‬ ‭to‬ ‭determine‬ ‭eligibility.‬ ‭Before‬ ‭starting‬ ‭study‬
‭treatment,‬‭all‬‭subjects‬‭will‬‭be‬‭assessed‬‭for‬‭eligibility.‬‭The‬‭selection‬‭process‬‭begins‬‭on‬‭the‬‭day‬‭the‬‭subject‬‭signs‬
‭the‬ ‭informed‬ ‭consent‬ ‭approved‬ ‭by‬ ‭the‬ ‭CEIC‬ ‭and‬ ‭continues‬ ‭until‬ ‭the‬ ‭patient's‬ ‭inclusion‬ ‭in‬ ‭the‬ ‭trial‬ ‭and‬
‭subsequent initiation of the study treatment. In this study, only eligible subjects will receive the study treatment.‬
‭All‬‭subjects‬‭must‬‭have‬‭completed‬‭the‬‭following‬‭procedures‬‭≤‬‭14‬‭days‬‭(unless‬‭otherwise‬‭specified)‬‭prior‬‭to‬‭the‬
‭start of study treatment:‬
‭●‬
‭Review of the inclusion and exclusion criteria.‬
‭●‬
‭Clinical and medication history.‬
‭●‬
‭Physical examination, measurements of resting pulse, blood pressure, respiratory rate,‬
‭temperature,‬
‭weight and height.‬
‭●‬
‭ECOG (Eastern Cooperative Oncology Group) performance status (≤ 14 days before study inclusion).‬
‭●‬
‭Analytical tests (≤ 14 days before inclusion in the study):‬
‭- Complete blood count including a total white blood cell count with differential, hemoglobin, and platelet count.‬
‭-‬ ‭Serum‬ ‭biochemistry‬ ‭including‬ ‭creatinine,‬ ‭total‬ ‭bilirubin,‬ ‭alkaline‬ ‭phosphatase,‬ ‭aspartate‬ ‭aminotransferase‬
‭(AST) or SGOT, alanine aminotransferase (ALT) or SGPT.‬
‭●‬
‭Coagulation studies will include prothrombin time (PT), partial thromboplastin time (PTT), and fibrinogen.‬
‭●‬
‭Systematic urine analysis.‬
‭●‬
‭Serum‬‭or‬‭urine‬‭pregnancy‬‭test‬‭for‬‭women‬‭of‬‭childbearing‬‭potential‬‭(≤72‬‭hours‬‭before‬‭onset‬
‭of‬ ‭the‬
‭treatment under study).‬
‭●‬
‭ECG (investigator will clinically evaluate all reports)‬
‭●‬
‭Cranial‬‭MRI‬‭that‬‭will‬‭be‬‭taken‬‭as‬‭a‬‭base‬‭examination‬‭in‬‭terms‬‭of‬‭response‬‭evaluation‬‭(it‬‭is‬‭allowed‬‭to‬‭be‬
‭performed‬‭in‬‭a‬‭period‬‭≤‬‭28‬‭days).‬‭The‬‭response‬‭should‬‭always‬‭be‬‭assessed‬‭with‬‭the‬‭same‬‭equipment‬‭as‬‭the‬
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‭initial‬‭examination.‬‭If‬‭the‬‭corticosteroid‬‭dose‬‭increases‬‭after‬‭the‬‭cranial‬‭MRI‬‭and‬‭the‬‭start‬‭of‬‭treatment,‬‭a‬‭new‬
‭baseline‬‭MRI‬‭should‬‭be‬‭performed.‬‭That‬‭is,‬‭at‬‭the‬‭time‬‭of‬‭starting‬‭treatment,‬‭the‬‭dose‬‭of‬‭corticosteroids‬‭must‬‭be‬
‭equal to or less than the dose that the patient was taking at the time of the MRI used as baseline.‬
‭●‬
‭Dose of corticosteroids in the 5 days prior to inclusion.‬
‭●‬
‭The‬ ‭paraffin-embedded‬ ‭tumor‬ ‭block‬ ‭must‬ ‭be‬ ‭identified,‬ ‭prepared‬ ‭and‬ ‭sent‬ ‭to‬ ‭the‬ ‭central‬‭laboratory‬
‭(Hospital‬ ‭12‬ ‭de‬ ‭Octubre)‬ ‭and‬ ‭have‬ ‭received‬ ‭confirmation‬ ‭of‬‭diagnosis‬‭and‬‭molecular‬‭analysis.‬‭FISH‬‭will‬‭be‬
‭performed‬‭to‬‭study‬‭the‬‭deletions‬‭in‬‭chromosomes‬‭1p‬‭and‬‭19q‬‭in‬‭addition‬‭to‬‭DNA‬‭extraction‬‭and‬‭High‬‭Resolution‬
‭Melting‬‭(HRM)‬‭to‬‭determine‬‭mutations‬‭in‬‭the‬‭IDH1‬‭and‬‭IDH2‬‭genes.‬‭The‬‭sample‬‭may‬‭be‬‭submitted‬‭at‬‭any‬‭time‬
‭prior to inclusion, even if the patient is still receiving active treatment for the oligodendroglial tumor.‬
‭Treatment‬ ‭should‬ ‭begin‬ ‭as‬ ‭soon‬ ‭as‬ ‭possible‬ ‭and‬ ‭no‬ ‭later‬ ‭than‬ ‭4‬ ‭weeks‬ ‭after‬ ‭the‬ ‭baseline‬ ‭radiological‬
‭examination.‬
‭​‬‭8.3. Tests during treatment‬
‭Patients‬‭will‬‭be‬‭visited‬‭on‬‭days‬‭1‬‭and‬‭14‬‭of‬‭the‬‭first‬‭2‬‭cycles‬‭and‬‭on‬‭days‬‭1‬‭of‬‭the‬‭subsequent‬‭cycles,‬‭during‬
‭which time the following will be performed:‬
‭●‬
‭Physical‬ ‭examination,‬ ‭resting‬ ‭pulse‬ ‭measurements,‬ ‭blood‬ ‭pressure,‬ ‭respiratory‬ ‭rate,‬ ‭temperature,‬
‭weight‬
‭●‬
‭Concomitant medication‬
‭●‬
‭Analytical tests:‬
‭-‬
‭Complete‬‭blood‬‭count‬‭including‬‭a‬‭total‬‭white‬‭blood‬‭cell‬‭count‬‭with‬‭differential,‬‭hemoglobin,‬‭and‬‭platelet‬
‭count.‬
‭-‬
‭Serum‬‭chemistry‬‭including‬‭creatinine,‬‭total‬‭bilirubin,‬‭alkaline‬‭phosphatase,‬‭aspartate‬‭aminotransferase‬
‭(AST) or SGOT, alanine aminotransferase (ALT) or SGPT.‬
‭●‬
‭Therapeutic compliance.‬
‭●‬
‭Coagulation tests (only in C2D1 and every 4 weeks thereafter).‬
‭●‬
‭Corticosteroid dosage.‬
‭●‬
‭Registry of adverse events.‬
‭If‬‭the‬‭patient‬‭needs‬‭to‬‭increase‬‭the‬‭doses‬‭of‬‭dexamethasone‬‭or‬‭worsens‬‭neurologically,‬‭it‬‭is‬‭advisable‬‭to‬‭repeat‬
‭the initial radiology to rule out progression.‬
‭Response evaluation will follow the RANO and McDonald criteria for brain lesions visualized on MRI.‬
‭On‬ ‭day‬ ‭1‬ ‭of‬ ‭each‬‭cycle,‬‭the‬‭patient‬‭will‬‭be‬‭given‬‭the‬‭trial‬‭medication,‬‭in‬‭addition,‬‭systematic‬‭urine‬‭analysis,‬
‭Barthel‬‭Index‬‭and‬‭ECOG‬‭performance‬‭status‬‭will‬‭be‬‭performed.‬‭The‬‭Minimental‬‭Test‬‭will‬‭be‬‭carried‬‭out‬‭on‬‭C1D1‬
‭and also on day 1 of each even cycle, that is, every 8 weeks from C2D1.‬
‭MRI‬‭imaging‬‭tests‬‭will‬‭be‬‭performed‬‭every‬‭12‬‭weeks‬‭until‬‭disease‬‭progression,‬‭responses‬‭to‬‭treatment‬‭(PR,‬‭CR)‬
‭must‬‭be‬‭confirmed‬‭at‬‭4‬‭weeks‬‭using‬‭the‬‭same‬‭method,‬‭if‬‭the‬‭patient‬‭abandons‬‭treatment‬‭for‬‭any‬‭reason‬‭before‬
‭progression. , MRIs should continue to be performed every 12 weeks as part of the follow-up until progression.‬
‭Heart function will be monitored with an ECG every 8 weeks.‬
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‭​‬‭8.4. Security Visit‬
‭4‬‭weeks‬‭after‬‭the‬‭end‬‭of‬‭treatment‬‭for‬‭any‬‭reason,‬‭the‬‭safety‬‭visit‬‭will‬‭be‬‭carried‬‭out,‬‭during‬‭which‬‭the‬‭following‬
‭will be carried out:‬
‭●‬
‭Physical‬ ‭examination,‬ ‭and‬ ‭vital‬ ‭signs‬ ‭(resting‬‭pulse‬‭measurements,‬‭blood‬‭pressure,‬‭respiratory‬‭rate,‬
‭temperature, weight, and height).‬
‭●‬
‭ECOG (Eastern Cooperative Oncology Group) functional status‬
‭●‬
‭Barthel index‬
‭●‬
‭Minimental Test‬
‭●‬
‭Analytical tests:‬
‭- Complete blood count including a total white blood cell count with differential, hemoglobin, and platelet count.‬
‭-‬ ‭Serum‬ ‭biochemistry‬ ‭including‬ ‭creatinine,‬ ‭total‬ ‭bilirubin,‬ ‭alkaline‬ ‭phosphatase,‬ ‭aspartate‬ ‭aminotransferase‬
‭(AST) or SGOT, alanine aminotransferase (ALT) or SGPT.‬
‭●‬
‭Systematic urine analysis‬
‭●‬
‭Registry of adverse events‬
‭MRI‬‭imaging‬‭tests‬‭will‬‭be‬‭performed‬‭every‬‭12‬‭weeks‬‭until‬‭disease‬‭progression,‬‭responses‬‭to‬‭treatment‬‭(PR,‬‭CR)‬
‭must‬‭be‬‭confirmed‬‭at‬‭4‬‭weeks‬‭using‬‭the‬‭same‬‭method,‬‭if‬‭the‬‭patient‬‭abandons‬‭treatment‬‭for‬‭any‬‭reason‬‭before‬
‭progression. , MRIs should continue to be performed every 12 weeks as part of the follow-up until progression.‬
‭​‬‭8.5. Follow-up visits from the end of treatment without progression to PE‬
‭Once‬ ‭treatment‬‭is‬‭completed‬‭for‬‭any‬‭cause‬‭other‬‭than‬‭disease‬‭progression,‬‭the‬‭following‬‭procedures‬‭will‬‭be‬
‭performed every 6 weeks until disease progression:‬
‭●‬
‭Physical examination, and vital signs (resting pulse measurements, blood pressure,‬
‭respiratory‬
‭rate, temperature).‬
‭●‬
‭ECOG (Eastern Cooperative Oncology Group) functional status‬
‭●‬
‭Barthel index‬
‭●‬
‭Minimental Test‬
‭●‬
‭Analytical tests:‬
‭- Complete blood count including a total white blood cell count with differential, hemoglobin, and platelet count.‬
‭- Serum biochemistry including creatinine, total bilirubin, alkaline phosphatase, aspartate aminotransferase‬
‭(AST) or SGOT, alanine aminotransferase (ALT) or SGPT‬
‭●‬
‭Systematic urine analysis‬
‭●‬
‭Radiological‬‭images‬‭in‬‭localization‬‭of‬‭the‬‭disease‬‭using‬‭MRI.‬‭Cranial‬‭MRI‬‭that‬‭will‬‭be‬‭taken‬‭as‬‭a‬‭base‬
‭scan‬‭in‬‭terms‬‭of‬‭response‬‭scan.‬‭The‬‭response‬‭should‬‭always‬‭be‬‭assessed‬‭with‬‭the‬‭same‬‭equipment‬‭as‬‭the‬
‭baseline MRI.‬
‭​‬‭8.6. Post-progression follow-up‬
‭Once‬‭the‬‭patient‬‭progresses,‬‭follow-up‬‭for‬‭overall‬‭survival‬‭until‬‭death‬‭every‬‭4‬‭weeks,‬‭which‬‭can‬‭be‬‭either‬‭visits‬‭to‬
‭the‬‭oncology‬‭service‬‭or‬‭telephone‬‭calls.‬‭The‬‭patient's‬‭current‬‭status‬‭and‬‭registration‬‭of‬‭new‬‭cancer‬‭treatments‬
‭will be determined.‬
‭The date of death will be verified to determine survival.‬
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‭​‬‭8.7. Response evaluation‬
‭The‬ ‭evaluation‬ ‭of‬‭the‬‭response‬‭will‬‭be‬‭carried‬‭out‬‭in‬‭each‬‭center‬‭using‬‭the‬‭radiological‬‭results,‬‭the‬‭patient's‬
‭symptoms‬‭and‬‭the‬‭doses‬‭of‬‭dexamethasone‬‭required.‬‭It‬‭will‬‭be‬‭based‬‭on‬‭the‬‭recently‬‭modified‬‭RANO‬‭response‬
‭criteria.‬‭The‬‭RANO‬‭criteria‬‭will‬‭be‬‭followed‬‭for‬‭the‬‭global‬‭assessment‬‭of‬‭response.‬‭In‬‭the‬‭progression‬‭due‬‭to‬
‭sudden‬ ‭neurological‬ ‭deterioration,‬ ‭it‬ ‭is‬ ‭advisable‬ ‭to‬ ‭perform‬ ‭a‬ ‭radiological‬ ‭examination.‬ ‭If‬ ‭the‬ ‭radiological‬
‭examination cannot be performed, progression of brain disease will be considered.‬
‭Imaging‬‭tests‬‭(MRIs)‬‭will‬‭be‬‭performed‬‭every‬‭12‬‭weeks‬‭until‬‭disease‬‭progression.‬‭Responses‬‭to‬‭treatment‬‭(PR,‬
‭CR)‬‭must‬‭be‬‭confirmed‬‭at‬‭4‬‭weeks‬‭using‬‭the‬‭same‬‭method,‬‭as‬‭required‬‭by‬‭the‬‭RANO‬‭criteria.‬‭If‬‭the‬‭patient‬
‭discontinues‬ ‭treatment‬ ‭for‬ ‭any‬ ‭reason‬ ‭before‬ ‭progression,‬ ‭MRIs‬ ‭should‬ ‭continue‬ ‭to‬‭be‬‭performed‬‭every‬‭12‬
‭weeks as part of the follow-up until progression.‬
‭Once‬‭the‬‭patient‬‭progresses,‬‭follow-up‬‭for‬‭overall‬‭survival‬‭will‬‭be‬‭done‬‭until‬‭death,‬‭every‬‭4‬‭weeks.‬‭It‬‭can‬‭be‬‭both‬
‭visits‬‭to‬‭the‬‭oncology‬‭service‬‭and‬‭telephone‬‭calls.‬‭The‬‭patient's‬‭current‬‭status‬‭and‬‭registration‬‭of‬‭new‬‭cancer‬
‭treatments will be determined.‬
‭​‬‭8.8. Centralized image review‬
‭A‬‭centralized‬‭review‬‭of‬‭the‬‭MRIs‬‭performed‬‭on‬‭all‬‭patients‬‭will‬‭be‬‭carried‬‭out‬‭on‬‭October‬‭12.‬‭The‬‭responsible‬
‭radiologist will be Dr. Ana Ramos González.‬
‭12 de Octubre University Hospital‬
‭Radiology Service. Neuroradiology Section‬
‭Mail: ramosana3@yahoo.es‬
‭Loss: 913908000‬
‭The‬ ‭MRIs‬ ‭will‬ ‭be‬ ‭sent‬ ‭to‬‭the‬‭external‬‭reviewer‬‭in‬‭electronic‬‭format,‬‭conveniently‬‭anonymized,‬‭indicating‬‭the‬
‭inclusion number assigned to the patient and the date of the determination.‬
‭An‬ ‭additional‬ ‭document‬ ‭will‬ ‭be‬ ‭added‬ ‭to‬ ‭the‬ ‭Center's‬ ‭Investigator‬ ‭File‬ ‭with‬ ‭detailed‬ ‭information‬ ‭on‬ ‭the‬
‭centralized image review procedures.‬
‭​‬
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‭​‬‭9. ADVERSE EVENTS‬
‭Timely,‬‭accurate‬‭and‬‭complete‬‭communication‬‭and‬‭analysis‬‭of‬‭safety‬‭information‬‭from‬‭clinical‬‭studies‬‭is‬‭crucial‬
‭for‬ ‭the‬ ‭protection‬ ‭of‬ ‭patients,‬ ‭investigators‬ ‭and‬ ‭the‬ ‭sponsor,‬ ‭and‬ ‭is‬ ‭a‬ ‭requirement‬ ‭enforced‬ ‭by‬ ‭regulatory‬
‭agencies‬‭around‬‭the‬‭world.‬‭The‬‭sponsor‬‭has‬‭established‬‭standard‬‭operating‬‭procedures‬‭(SOPs)‬‭in‬‭accordance‬
‭with‬‭international‬‭regulatory‬‭provisions‬‭to‬‭ensure‬‭proper‬‭communication‬‭of‬‭safety‬‭information;‬‭All‬‭clinical‬‭studies‬
‭conducted by the sponsor or its affiliates will be conducted in accordance with these procedures.‬
‭​‬‭9.1. Definition‬
‭Adverse event (AA):‬
‭An‬‭AE‬‭is‬‭any‬‭unfavorable‬‭medical‬‭incident‬‭in‬‭a‬‭patient‬‭or‬‭subject‬‭of‬‭a‬‭clinical‬‭investigation,‬‭even‬‭if‬‭it‬‭does‬‭not‬
‭necessarily‬‭have‬‭a‬‭causal‬‭relationship‬‭with‬‭the‬‭study‬‭treatment.‬‭Any‬‭event‬‭involving‬‭adverse‬‭reactions‬‭to‬‭the‬
‭drug, illnesses that begin during the study, or exacerbations of preexisting illnesses should be recorded.‬
‭In‬‭addition,‬‭clinically‬‭important‬‭abnormalities‬‭found‬‭on‬‭physical‬‭examination‬‭and‬‭abnormal‬‭findings‬‭on‬‭objective‬
‭tests (e.g., x-rays or ECG) should also be recorded as AEs. The‬
‭Criteria for determining whether an abnormal objective test finding should be reported as an AE are as follows:‬
‭• the test result is associated with clinically important symptoms, and/or‬
‭• the test result leads to a change in study treatment or withdrawal of the patient from the study, significant‬
‭additional concomitant drug or other treatment, and/or‬
‭• the test result leads to one of the outcomes indicated in the definition of AAG, and/or‬
‭• the investigator considers the test result to be an AA.‬
‭Serious adverse event (SAE):‬
‭An SAE is any adverse event occurring with any dose that:‬
‭• produces death (is fatal),‬
‭• threatens the patient's life,‬
‭• makes hospitalization or prolonged hospitalization necessary,‬
‭• produces persistent or significant disability or disability,‬
‭• is a congenital anomaly or birth defect, or‬
‭• is medically important.‬
‭Medical‬‭and‬‭scientific‬‭judgment‬‭should‬‭be‬‭exercised‬‭to‬‭decide‬‭whether‬‭urgent‬‭communication‬‭is‬‭appropriate‬‭in‬
‭other‬‭situations,‬‭such‬‭as‬‭important‬‭medical‬‭events‬‭that‬‭do‬‭not‬‭immediately‬‭threaten‬‭the‬‭patient's‬‭life‬‭or‬‭lead‬‭to‬
‭hospitalization‬‭but‬‭may‬‭endanger‬‭the‬‭patient‬‭or‬‭may‬‭require‬‭intervention‬‭to‬‭prevent‬‭one‬‭of‬‭the‬‭outcomes‬‭listed‬‭in‬
‭the definition above.‬
‭Any‬‭suspected‬‭transmission‬‭of‬‭an‬‭infectious‬‭agent‬‭through‬‭a‬‭medication‬‭is‬‭also‬‭considered‬‭a‬‭serious‬‭adverse‬
‭reaction.‬
‭Life-threatening event:‬
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‭Any‬‭event‬‭in‬‭which‬‭the‬‭patient‬‭is‬‭at‬‭risk‬‭of‬‭death‬‭at‬‭the‬‭time‬‭of‬‭the‬‭event;‬‭It‬‭does‬‭not‬‭refer‬‭to‬‭an‬‭event‬‭that‬
‭hypothetically could have caused death if it had been more severe.‬
‭Hospitalization/prolongation of hospitalization:‬
‭Any‬ ‭event‬ ‭requiring‬ ‭hospitalization‬ ‭(or‬ ‭prolonged‬ ‭hospitalization)‬ ‭that‬ ‭occurs‬ ‭or‬ ‭worsens‬ ‭during‬ ‭a‬ ‭patient's‬
‭participation‬‭in‬‭a‬‭clinical‬‭study‬‭should‬‭be‬‭reported‬‭as‬‭an‬‭SAE.‬‭Prolongation‬‭of‬‭hospitalization‬‭is‬‭defined‬‭as‬‭any‬
‭extension‬‭of‬‭a‬‭patient's‬‭hospitalization‬‭beyond‬‭the‬‭planned/required‬‭stay‬‭at‬‭initial‬‭admission,‬‭in‬‭the‬‭judgment‬‭of‬
‭the investigator or the doctor responsible for the patient.‬
‭The following hospitalization cases do not meet the SAE reporting criteria:‬
‭a)‬‭Reasons‬‭described‬‭in‬‭the‬‭protocol‬‭(for‬‭example,‬‭drug‬‭administration,‬‭complementary‬‭tests‬‭required‬‭by‬‭the‬
‭protocol).‬ ‭Hospitalizations‬ ‭or‬ ‭prolongations‬ ‭of‬ ‭hospitalization‬ ‭due‬ ‭to‬ ‭a‬ ‭complication‬ ‭of‬ ‭the‬ ‭administration‬ ‭of‬
‭treatment or procedures will be reported as SAEs.‬
‭b)‬‭Hospitalizations‬‭or‬‭extensions‬‭of‬‭hospitalization‬‭for‬‭technical,‬‭practical‬‭or‬‭social‬‭reasons,‬‭in‬‭the‬‭absence‬‭of‬‭an‬
‭AA.‬
‭c)‬‭Previously‬‭scheduled‬‭hospitalizations‬‭(that‬‭is,‬‭scheduled‬‭before‬‭entry‬‭into‬‭the‬‭study).‬‭Any‬‭surgical‬‭intervention‬
‭or procedure scheduled prior to study entry must be documented in the CRD.‬
‭Unexpected adverse event (not listed):‬
‭An unexpected AE, the nature or severity of which does not correspond to the information regarding the product.‬
‭The‬ ‭reference‬ ‭document‬ ‭to‬ ‭establish‬‭expectability‬‭will‬‭be‬‭the‬‭current‬‭version‬‭of‬‭the‬‭palbociclib‬‭investigator's‬
‭manual.‬
‭Associated with drug use‬
‭An‬‭AE‬‭is‬‭considered‬‭associated‬‭with‬‭the‬‭use‬‭of‬‭the‬‭investigational‬‭medicinal‬‭product‬‭if‬‭the‬‭causality‬‭assessment‬
‭is related to one of the investigational medicinal products or is unknown according to the definitions below.‬
‭Causality assessment‬
‭The‬ ‭investigator‬ ‭must‬ ‭provide‬ ‭a‬ ‭causality‬ ‭assessment‬ ‭for‬ ‭each‬ ‭investigational‬ ‭medicinal‬ ‭product‬ ‭(including‬
‭combination products and comparators) according to the following criteria:‬
‭AND There is a reasonable possibility that the study medication(s) will cause the serious adverse event.‬
‭N‬‭There‬‭is‬‭no‬‭reasonable‬‭possibility‬‭that‬‭the‬‭study‬‭medication(s)‬‭will‬‭cause‬‭the‬‭serious‬‭adverse‬‭event‬‭and‬‭other‬
‭causes are more likely.‬
‭UK‬‭Unknown.‬‭It‬‭should‬‭only‬‭be‬‭used‬‭in‬‭special‬‭situations‬‭where‬‭the‬‭researcher‬‭has‬‭insufficient‬‭information‬‭(for‬
‭example, the patient has not been treated at your center), and if none of the previous options can be used.‬
‭Urgent communication‬
‭The‬‭promoter‬‭will‬‭assume‬‭responsibility‬‭for‬‭the‬‭proper‬‭communication‬‭of‬‭AAs‬‭to‬‭the‬‭regulatory‬‭authorities.‬‭The‬
‭sponsor‬‭will‬‭also‬‭report‬‭all‬‭unexpected‬‭SAEs‬‭associated‬‭with‬‭the‬‭use‬‭of‬‭the‬‭study‬‭treatment‬‭to‬‭the‬‭investigators‬
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‭and‬‭clinical‬‭research‬‭ethics‬‭committees‬‭(CEIC)‬‭in‬‭accordance‬‭with‬‭current‬‭regulations,‬‭unless‬‭other‬‭measures‬
‭are required and documented by the CEIC. .‬
‭​‬‭9.2. Notification and Documentation of Adverse Events‬
‭AEs will be collected by the sponsor up to 30 days after administration of the last dose of study treatment.‬
‭All‬ ‭AEs‬ ‭must‬ ‭be‬ ‭recorded‬ ‭in‬‭the‬‭source‬‭document‬‭and‬‭in‬‭the‬‭CRD‬‭using‬‭medical‬‭terminology.‬‭Investigators‬
‭should‬‭assess‬‭the‬‭severity‬‭(grade)‬‭of‬‭the‬‭event‬‭according‬‭to‬‭NCI-CTC‬‭AE‬‭V‬‭4.0,‬‭assign‬‭a‬‭relationship‬‭to‬‭the‬‭trial‬
‭drug,‬‭and‬‭seek‬‭and‬‭obtain‬‭appropriate‬‭information‬‭to‬‭determine‬‭the‬‭outcome‬‭and‬‭to‬‭evaluate‬‭whether‬‭it‬‭meets‬
‭the‬‭criteria‬‭for‬‭classification‬‭as‬‭AAG‬‭that‬‭requires‬‭immediate‬‭communication.‬‭The‬‭researcher‬‭must‬‭provide‬‭any‬
‭information requested by the promoter, in addition to that collected in the CRD.‬
‭All SAEs (as defined above) that occur during the clinical trial or within 30‬
‭days‬‭after‬‭the‬‭last‬‭dose‬‭of‬‭the‬‭study‬‭medication,‬‭regardless‬‭of‬‭the‬‭treatment‬‭group‬‭or‬‭the‬‭suspected‬‭relationship‬
‭with‬‭the‬‭study‬‭treatment,‬‭must‬‭be‬‭reported‬‭by‬‭the‬‭investigator.‬‭Additionally,‬‭any‬‭SAEs‬‭that‬‭occur‬‭as‬‭a‬‭result‬‭of‬
‭diagnostic‬‭procedures‬‭or‬‭interventions‬‭specific‬‭to‬‭this‬‭protocol‬‭must‬‭also‬‭be‬‭reported.‬‭Beyond‬‭this‬‭time‬‭period,‬
‭only SAEs suspected to be related to the study drug should be reported.‬
‭The‬ ‭AAG‬ ‭report‬ ‭must‬ ‭contain‬ ‭a‬ ‭complete‬‭written‬‭summary‬‭detailing‬‭the‬‭important‬‭aspects‬‭of‬‭the‬‭applicable‬
‭adverse‬‭events.‬‭Where‬‭applicable,‬‭information‬‭about‬‭relevant‬‭medical‬‭records‬‭and‬‭autopsy‬‭reports‬‭should‬‭be‬
‭included. Tracking information must be sent to MFAR, S.L. in the next 24 hours.‬
‭All‬‭SAEs‬‭suspected‬‭to‬‭be‬‭related‬‭to‬‭study‬‭treatment‬‭should‬‭be‬‭followed‬‭after‬‭withdrawal‬‭until‬‭the‬‭event‬‭or‬‭its‬
‭sequelae have resolved or stabilized at a level acceptable to the investigator or designee.‬
‭9.3. Pregnancy notification‬
‭The‬‭pregnancy‬‭of‬‭a‬‭female‬‭patient‬‭or‬‭the‬‭partner‬‭of‬‭a‬‭male‬‭patient,‬‭not‬‭being‬‭a‬‭serious‬‭adverse‬‭event‬‭in‬‭itself,‬
‭should also be managed expeditiously just like an SAE.‬
‭It‬‭must‬‭be‬‭registered‬‭on‬‭a‬‭specific‬‭pregnancy‬‭notification‬‭form,‬‭notified‬‭expeditiously‬‭(within‬‭24‬‭hours)‬‭from‬‭when‬
‭it‬‭is‬‭known‬‭and‬‭followed‬‭until‬‭the‬‭end,‬‭even‬‭if‬‭a‬‭voluntary‬‭or‬‭spontaneous‬‭interruption‬‭occurs,‬‭describing‬‭the‬
‭details of the birth and the presence or absence of any defect in the fetus or any congenital anomaly.‬
‭Potential‬ ‭effects‬ ‭of‬ ‭spermatogenesis:‬ ‭pregnancies‬ ‭that‬ ‭occur‬ ‭in‬ ‭the‬ ‭partner‬ ‭of‬ ‭a‬ ‭male‬‭patient‬‭must‬‭also‬‭be‬
‭notified‬ ‭within‬ ‭24‬ ‭hours‬ ‭using‬‭the‬‭specific‬‭pregnancy‬‭form‬‭and‬‭followed‬‭until‬‭the‬‭end,‬‭even‬‭if‬‭a‬‭voluntary‬‭or‬
‭spontaneous‬‭interruption‬‭occurs,‬‭describing‬‭the‬‭details‬‭of‬‭the‬‭pregnancy.‬‭birth‬‭and‬‭the‬‭presence‬‭or‬‭absence‬‭of‬
‭any‬‭defect‬‭in‬‭the‬‭fetus‬‭or‬‭any‬‭congenital‬‭anomaly.‬‭Likewise,‬‭your‬‭pregnant‬‭partner‬‭would‬‭be‬‭instructed‬‭to‬‭contact‬
‭his or her doctor immediately.‬
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‭​‬
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‭​‬‭10. STATISTICAL CONSIDERATIONS‬
‭​‬‭10.1. Study variables‬
‭Percentage of patients who have relapsed/not relapsed to the study treatment 6 months after starting it.‬
‭​‬‭10.2. Primary objective‬
‭To determine whether palbociclib could delay disease progression in patients with anaplastic oligodendroglioma.‬
‭​‬‭10.3. Hypothesis‬
‭Clinical‬‭basis:‬‭historical‬‭data‬‭for‬‭the‬‭elaboration‬‭of‬‭the‬‭study‬‭hypothesis‬‭have‬‭been‬‭obtained‬‭from‬‭the‬‭analysis‬‭of‬
‭a‬ ‭database‬ ‭containing‬ ‭350‬ ‭patients‬ ‭with‬ ‭recurrent‬ ‭high-grade‬ ‭gliomas‬ ‭(125‬ ‭anaplastic‬ ‭gliomas)‬ ‭who‬ ‭were‬
‭prospectively‬ ‭treated‬ ‭in‬ ‭phase‬ ‭II‬ ‭studies.‬ ‭The‬ ‭6-month‬ ‭progression-free‬ ‭survival‬ ‭(PFS-6m)‬ ‭was‬ ‭31%‬ ‭for‬
‭anaplastic‬‭gliomas‬‭(Wong‬‭et‬‭al.‬‭J‬‭Clin‬‭Oncol‬‭17:2572-2578).‬‭The‬‭authors‬‭acknowledge‬‭the‬‭limitation‬‭because‬‭in‬
‭this‬ ‭study‬ ‭the‬ ‭results‬ ‭were‬ ‭analyzed‬ ‭for‬ ‭all‬ ‭anaplastic‬ ‭gliomas‬ ‭and‬ ‭not‬ ‭only‬‭anaplastic‬‭oligodendrogliomas.‬
‭However,‬ ‭no‬ ‭further‬ ‭published‬ ‭data‬ ‭are‬ ‭available‬ ‭regarding‬ ‭the‬ ‭results‬ ‭in‬ ‭recurrent‬ ‭anaplastic‬
‭oligodendrogliomas.‬
‭Null hypothesis (H0): P≤P0‬
‭Alternative hypothesis to test (H1): P≥P1‬
‭Assumptions:‬
‭P: probability of remaining alive and progression-free at 6 months‬
‭P0: 25%‬
‭P1: 45%‬
‭Expected profit: 20% (25% vs. 45%)‬
‭Type I error, α≤0.05‬
‭Type II error, β≥0.20‬
‭Sample size: 40 patients‬
‭A benefit will be considered if 18/40 patients are alive and progression-free at 6 months.‬
‭​‬‭10.4. Statistic analysis‬
‭Associations‬‭between‬‭overall‬‭survival‬‭and‬‭progression-free‬‭survival‬‭with‬‭patients'‬‭baseline‬‭characteristics‬‭will‬‭be‬
‭evaluated using the log-rank test.‬
‭The‬‭maximum‬‭relative‬‭risk‬‭value‬‭based‬‭on‬‭the‬‭log-rank‬‭test‬‭will‬‭be‬‭used‬‭to‬‭provide‬‭a‬‭quantitative‬‭summary‬‭of‬‭the‬
‭data,‬ ‭with‬ ‭95%‬ ‭confidence‬ ‭intervals.‬ ‭Median‬ ‭survival,‬ ‭time‬ ‭to‬ ‭progression,‬ ‭and‬ ‭associated‬ ‭95%‬ ‭confidence‬
‭intervals‬‭will‬‭be‬‭calculated.‬‭Kaplan-Meier‬‭curves‬‭will‬‭be‬‭constructed‬‭to‬‭show‬‭the‬‭estimated‬‭probabilities‬‭of‬‭overall‬
‭survival and time to progression.‬
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‭​‬‭11. ETHICAL AND LEGAL CONSIDERATIONS‬
‭​‬‭11.1. Ethics Committee‬
‭The‬‭study‬‭will‬‭be‬‭carried‬‭out‬‭in‬‭accordance‬‭with‬‭the‬‭principles‬‭of‬‭the‬‭Declaration‬‭of‬‭Helsinki‬‭Adopted‬‭by‬‭the‬‭18th‬
‭World‬‭Medical‬‭Assembly,‬‭Helsinki,‬‭Finland,‬‭June‬‭1964‬‭updated‬‭to‬‭its‬‭latest‬‭version‬‭Fortaleza,‬‭Brazil,‬‭October‬
‭2013.‬
‭With‬‭the‬‭standards‬‭of‬‭Good‬‭Clinical‬‭Practice‬‭(GCP)‬‭issued‬‭by‬‭the‬‭working‬‭group‬‭on‬‭the‬‭Efficacy‬‭of‬‭Medicinal‬
‭Substances of the European Economic Community (1990) (CPMP/ICH/135/95).‬
‭And the Laws and Regulations in force in Spain:‬
‭●‬
‭Royal‬ ‭Decree‬ ‭1090/2015,‬ ‭of‬ ‭December‬ ‭4,‬ ‭which‬ ‭regulates‬ ‭clinical‬ ‭trials‬ ‭with‬ ‭medicines,‬ ‭the‬ ‭Ethics‬
‭Committees for Research with medicines and the Spanish Registry of Clinical Studies.‬
‭●‬
‭The‬‭Oviedo‬‭Convention‬‭of‬‭April‬‭4,‬‭1997‬‭on‬‭human‬‭rights‬‭and‬‭biomedicine,‬‭ratified‬‭in‬‭the‬‭BOE‬‭in‬‭October‬
‭1999.‬
‭●‬
‭In‬‭the‬‭rules‬‭for‬‭the‬‭adequate‬‭protection‬‭of‬‭personal‬‭data,‬‭as‬‭provided‬‭in‬‭Regulation‬‭(EU)‬‭2016/679‬‭of‬‭the‬
‭European‬‭Parliament‬‭and‬‭of‬‭the‬‭Council‬‭of‬‭April‬‭27,‬‭2016‬‭regarding‬‭the‬‭protection‬‭of‬‭natural‬‭persons‬‭with‬‭regard‬
‭to‬‭processing‬‭of‬‭personal‬‭data‬‭and‬‭the‬‭free‬‭circulation‬‭of‬‭these‬‭data‬‭and‬‭repealing‬‭the‬‭European‬‭Parliament‬
‭Directive‬ ‭95/46/EC‬ ‭of‬ ‭October‬ ‭24,‬ ‭1995‬ ‭on‬ ‭the‬ ‭protection‬ ‭of‬ ‭individuals‬ ‭with‬ ‭respect‬ ‭to‬ ‭the‬ ‭processing‬ ‭of‬
‭personal‬‭data‬‭and‬‭Organic‬‭Law‬‭3‬‭/2018‬‭on‬‭Protection‬‭of‬‭Personal‬‭Data‬‭and‬‭guarantee‬‭of‬‭digital‬‭rights.‬‭The‬‭rights‬
‭and‬‭obligations‬‭regarding‬‭clinical‬‭information‬‭and‬‭documentation,‬‭as‬‭provided‬‭in‬‭Law‬‭41/2002,‬‭of‬‭November‬‭14,‬
‭the basic regulator of patient autonomy.‬
‭●‬
‭Law 14/2007, of July 3, on Biomedical Research.‬
‭​‬‭11.2. Authorities‬
‭The‬‭study‬‭protocol‬‭and/or‬‭documents‬‭inherent‬‭to‬‭it‬‭will‬‭be‬‭sent‬‭to‬‭them‬‭before‬‭starting‬‭the‬‭trial,‬‭as‬‭established‬‭by‬
‭national authorities.‬
‭​‬‭11.3. Informed consent‬
‭The patient must sign two separate informed consents: one for the clinical trial, another for biological samples.‬
‭The‬‭doctor‬‭will‬‭have‬‭to‬‭explain‬‭the‬‭nature,‬‭purposes‬‭and‬‭possible‬‭consequences‬‭of‬‭the‬‭clinical‬‭trial,‬‭in‬‭a‬‭way‬‭that‬
‭is understandable to the patient.‬
‭The‬‭subject‬‭of‬‭the‬‭study‬‭will‬‭give‬‭his‬‭or‬‭her‬‭consent‬‭by‬‭signing‬‭the‬‭corresponding‬‭model‬‭in‬‭duplicate.‬‭For‬‭this‬
‭purpose, each model must bear the signature of the researcher and the patient.‬
‭The‬‭investigator‬‭will‬‭not‬‭initiate‬‭any‬‭determination‬‭corresponding‬‭to‬‭the‬‭trial‬‭until‬‭the‬‭patient's‬‭consent‬‭has‬‭been‬
‭obtained.‬
‭The‬‭informed‬‭consent‬‭used‬‭in‬‭the‬‭trial‬‭and‬‭any‬‭changes‬‭made‬‭during‬‭the‬‭study‬‭must‬‭be‬‭approved‬‭by‬‭the‬‭Ethics‬
‭Committee.‬
‭​‬‭11.4. Confidentiality‬
‭In‬‭order‬‭to‬‭guarantee‬‭the‬‭confidentiality‬‭of‬‭the‬‭trial‬‭data‬‭in‬‭accordance‬‭with‬‭the‬‭provisions‬‭of‬‭Organic‬‭Law‬‭3/2018‬
‭on‬ ‭the‬ ‭Protection‬ ‭of‬ ‭Personal‬ ‭Data‬ ‭and‬ ‭guarantee‬ ‭of‬ ‭digital‬ ‭rights‬ ‭and‬ ‭Regulation‬ ‭(EU)‬ ‭2016/679‬ ‭of‬ ‭the‬
‭European‬‭Parliament‬‭and‬‭of‬‭the‬‭Council‬‭of‬‭27‬‭of‬‭April‬‭2016‬‭relating‬‭to‬‭the‬‭protection‬‭of‬‭natural‬‭persons‬‭with‬
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‭regard‬‭to‬‭the‬‭processing‬‭of‬‭personal‬‭data‬‭and‬‭the‬‭free‬‭circulation‬‭of‬‭these‬‭data‬‭and‬‭repealing‬‭the‬‭European‬
‭Parliament‬‭Directive‬‭95/46/EC‬‭of‬‭October‬‭24,‬‭1995‬‭on‬‭the‬‭protection‬‭of‬‭people‬‭with‬‭respect‬‭to‬‭the‬‭processing‬‭of‬
‭personal‬‭data,‬‭only‬‭the‬‭personnel‬‭designated‬‭by‬‭the‬‭Promoter,‬‭for‬‭monitoring/auditing‬‭tasks,‬‭the‬‭researcher‬‭and‬
‭his‬‭team‬‭of‬‭collaborators,‬‭the‬‭Clinical‬‭Research‬‭Ethics‬‭Committee‬‭of‬‭the‬‭corresponding‬‭center‬‭will‬‭have‬‭access‬
‭to them. or the one who oversees the trial and the relevant health authorities.‬
‭In‬ ‭the‬ ‭aforementioned‬ ‭case‬ ‭of‬ ‭Monitoring/Audits,‬ ‭the‬ ‭researcher‬ ‭must‬ ‭provide‬ ‭direct‬ ‭access‬ ‭to‬ ‭the‬ ‭source‬
‭documents and data.‬
‭The‬‭content‬‭of‬‭the‬‭data‬‭collection‬‭notebooks‬‭(CRD)‬‭as‬‭well‬‭as‬‭the‬‭documents‬‭generated‬‭during‬‭the‬‭study‬‭will‬‭be‬
‭protected‬ ‭from‬ ‭unauthorized‬ ‭uses‬ ‭by‬ ‭people‬ ‭outside‬ ‭the‬ ‭research‬ ‭and,‬ ‭therefore,‬‭will‬‭be‬‭considered‬‭strictly‬
‭confidential and will not be revealed to third parties except those specified in the previous section.‬
‭​‬‭11.5. Safe‬
‭All‬‭patients‬‭in‬‭this‬‭clinical‬‭study‬‭will‬‭be‬‭insured‬‭through‬‭an‬‭insurance‬‭policy,‬‭in‬‭compliance‬‭with‬‭the‬‭conditions‬
‭stipulated‬‭by‬‭the‬‭R.D.‬‭1090/2015‬‭of‬‭December‬‭4‬‭and‬‭European‬‭Regulation‬‭536/2014‬‭of‬‭April‬‭16,‬‭which‬‭regulate‬
‭clinical trials with medicines.‬
‭​‬‭11.6. End of study‬
‭The‬‭trial‬‭will‬‭be‬‭considered‬‭regulatory‬‭closed‬‭after‬‭the‬‭primary‬‭and‬‭secondary‬‭endpoints‬‭are‬‭sufficiently‬‭prepared‬
‭for initial publication. Follow-up observations of patients included in the trial can be maintained indefinitely.‬
‭​‬‭11.7. Premature end of study‬
‭This‬‭study‬‭may‬‭be‬‭stopped‬‭prematurely‬‭if,‬‭in‬‭the‬‭opinion‬‭of‬‭the‬‭sponsor,‬‭there‬‭is‬‭sufficient‬‭reasonable‬‭cause.‬‭The‬
‭investigator‬‭will‬‭receive‬‭written‬‭notification‬‭in‬‭which‬‭the‬‭terminated‬‭party‬‭documents‬‭the‬‭reason‬‭for‬‭discontinuing‬
‭the study.‬
‭Circumstances justifying study discontinuation include, but are not limited to:‬
‭• Determination of unforeseen, considerable or unacceptable risks to patients‬
‭• Impossibility of including an acceptable number of patients‬
‭• Insufficient compliance with protocol requirements‬
‭• Plans to modify, suspend or discontinue the development of the study drug.‬
‭In‬‭the‬‭event‬‭of‬‭premature‬‭termination‬‭of‬‭the‬‭study,‬‭all‬‭materials‬‭(fully‬‭or‬‭partially‬‭completed‬‭and‬‭blank‬‭CRDs,‬
‭study drug, etc.) must be returned to the Sponsor.‬
‭​‬‭12. PRACTICAL CONSIDERATIONS‬
‭​‬‭12.1. Diagnostic Criteria for the Pathology Under Study‬
‭Patients‬‭with‬‭confirmation‬‭of‬‭the‬‭diagnosis‬‭of‬‭Anaplastic‬‭Oligodendroglioma‬‭(OA)‬‭in‬‭the‬‭Pathological‬‭Anatomy‬
‭Service‬‭of‬‭the‬‭12‬‭de‬‭Octubre‬‭University‬‭Hospital,‬‭a‬‭central‬‭neuropathology‬‭laboratory‬‭that‬‭will‬‭also‬‭determine‬‭if‬
‭there‬‭is‬‭nuclear‬‭expression‬‭of‬‭the‬‭RB‬‭protein‬‭through‬‭immunohistochemistry,‬‭and‬‭who‬‭comply‬‭with‬‭the‬‭criteria,‬
‭may be included in this study. the eligibility criteria detailed in point 6 of this protocol.‬
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‭​‬‭12.2. Researcher Responsibilities According to Good Clinical Practices‬
‭The responsibilities of the principal investigator in each participating Center will be:‬
‭1. Sign the essay project.‬
‭2. Know in depth the properties of medications.‬
‭3. Obtain informed consent from subjects prior to inclusion in the trial.‬
‭4. Ensure that patients will receive appropriate medical care in case of adverse events,‬
‭including significant laboratory values ​related to the assay.‬
‭5. Collect, record and report data correctly.‬
‭6. Immediately report serious or unexpected adverse events to the sponsor.‬
‭7. Guarantee that all people involved will respect the confidentiality of any information‬
‭about the test subjects.‬
‭8. Regularly inform the Clinical Research Ethics Committee of the progress of the trial.‬
‭9. Be responsible for preparing the final report of the test, giving your agreement to it with your signature.‬
‭​‬‭12.3. Instructions for completing the CRD‬
‭The CRD completion guide is located in the center's researcher file.‬
‭​‬‭12.4. Supply of study medication‬
‭Palbociclib will be supplied by the Promoter through the Pfizer SLU laboratory.‬
‭​‬‭12.5. Conditioning and Labeling‬
‭Labels of study drugs will contain information that complies with applicable regulatory requirements.‬
‭​‬‭12.6. Articles and Publications‬
‭As‬‭indicated‬‭in‬‭Royal‬‭Decree‬‭1090/2015‬‭of‬‭December‬‭4‬‭and‬‭European‬‭Regulation‬‭536/2014‬‭of‬‭April‬‭16,‬‭which‬
‭regulate‬ ‭clinical‬ ‭trials‬ ‭with‬ ‭medicines,‬ ‭the‬ ‭promoter‬ ‭is‬ ‭obliged‬ ‭to‬ ‭publish‬ ‭both‬‭positive‬‭and‬‭negative‬‭results.‬
‭negative‬‭results,‬‭from‬‭clinical‬‭trials‬‭authorized‬‭in‬‭scientific‬‭journals‬‭and‬‭with‬‭mention‬‭of‬‭the‬‭Clinical‬‭Research‬
‭Ethics Committee that approved the study.‬
‭The‬‭Responsible‬‭Investigators‬‭of‬‭the‬‭study‬‭and‬‭the‬‭researchers‬‭who‬‭contribute‬‭at‬‭least‬‭3%‬‭of‬‭the‬‭patients‬‭will‬
‭appear as authors.‬
‭The order of authors will be strictly based on the number of patients included by the different researchers.‬
‭The clinical publication will be carried out by those responsible for the clinical study and the clinical researchers.‬
‭It‬‭will‬‭be‬‭the‬‭responsibility‬‭of‬‭the‬‭first‬‭author,‬‭the‬‭Principal‬‭Investigators‬‭of‬‭the‬‭study,‬‭and‬‭the‬‭study‬‭designer‬‭to‬
‭write the final publications.‬
‭The‬‭anonymity‬‭of‬‭the‬‭subjects‬‭who‬‭are‬‭the‬‭source‬‭of‬‭the‬‭study‬‭samples‬‭will‬‭be‬‭maintained‬‭at‬‭all‬‭times.‬‭The‬
‭results‬ ‭or‬ ‭conclusions‬ ‭of‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭communicated‬ ‭primarily‬ ‭in‬ ‭scientific‬ ‭publications‬ ‭before‬ ‭being‬
‭disclosed‬‭to‬‭the‬‭non-health‬‭public.‬‭Procedures‬‭of‬‭as‬‭yet‬‭undetermined‬‭effectiveness‬‭will‬‭not‬‭be‬‭made‬‭known‬‭in‬‭a‬
‭premature or sensational manner.‬
‭Participating‬‭investigators‬‭should‬‭not‬‭publish‬‭any‬‭data‬‭about‬‭patients‬‭that‬‭are‬‭directly‬‭related‬‭to‬‭the‬‭objectives‬‭of‬
‭the study until the trial report is published.‬
‭The‬‭trial‬‭will‬‭be‬‭registered‬‭in‬‭the‬‭public‬‭access‬‭database,‬‭www.clinicaltrials.gov‬‭and,‬‭according‬‭to‬‭the‬‭provisions‬
‭of‬ ‭Royal‬ ‭Decree‬ ‭1090/2015‬ ‭of‬ ‭December‬ ‭4‬ ‭and‬ ‭European‬ ‭Regulation‬ ‭536/2014‬‭of‬‭April‬‭16,‬‭which‬‭regulate‬
‭clinical trials with medicines, in the Spanish Registry of Clinical Studies (REec)‬‭.‬
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‭​‬‭12.7. Monitoring‬
‭The study will be monitored through local visits, telephone calls and periodic inspection of the‬
‭CRD frequently enough to verify the following in monitored patients:‬
‭●‬
‭Study‬‭Medication:‬‭storage‬‭conditions,‬‭that‬‭supplies‬‭are‬‭adequate‬‭throughout‬‭the‬‭clinical‬‭trial,‬‭that‬‭the‬
‭Principal‬‭Investigators‬‭only‬‭administer‬‭the‬‭trial‬‭medication‬‭to‬‭patients‬‭included‬‭in‬‭the‬‭clinical‬‭trial,‬‭that‬‭the‬‭receipt,‬
‭use‬‭and‬‭return‬‭of‬‭the‬‭study‬‭medication‬‭trial‬‭is‬‭adequately‬‭controlled‬‭and‬‭documented‬‭and‬‭that‬‭the‬‭disposal‬‭of‬
‭unused medication complies with applicable regulatory requirements.‬
‭●‬
‭Patient recruitment rate‬
‭●‬
‭That written informed consent has been obtained prior to inclusion in the trial‬
‭●‬
‭Compliance with approved protocol and amendments, if applicable‬
‭●‬
‭That‬ ‭the‬ ‭researcher‬ ‭has‬ ‭the‬ ‭latest‬ ‭version‬ ‭of‬ ‭the‬ ‭Investigator's‬ ‭manual‬ ‭or‬ ‭the‬ ‭summary‬ ‭of‬ ‭product‬
‭characteristics,‬‭all‬‭the‬‭supplies‬‭necessary‬‭for‬‭the‬‭correct‬‭development‬‭of‬‭the‬‭trial‬‭to‬‭comply‬‭with‬‭the‬‭applicable‬
‭regulatory requirements.‬
‭●‬
‭That the Investigator and his team are adequately informed about the trial‬
‭●‬
‭Integrity and correctness of the data entered in the CRD, 100% SDV of the monitored patients‬
‭●‬
‭CI/HIP: Signature/date and name of patient/investigator‬
‭●‬
‭Eligibility criteria and selection tests‬
‭●‬
‭Recording of adverse events, SAEs and SAE reports‬
‭●‬
‭Main variable of the trial‬
‭●‬
‭Dispensing/stock of IMP in the pharmacy service, traceability (brand, units, lot, etc.)‬
‭●‬
‭Protocol deviations‬
‭●‬
‭Collection, storage and shipping of biological samples/images‬
‭●‬
‭Communicate‬ ‭deviations‬ ‭from‬ ‭the‬ ‭protocol,‬ ‭standard‬ ‭work‬ ‭procedures,‬ ‭good‬ ‭clinical‬ ‭practices‬ ‭and‬
‭regulatory‬‭requirements‬‭applicable‬‭to‬‭the‬‭researcher‬‭and‬‭taking‬‭necessary‬‭actions‬‭to‬‭prevent‬‭the‬‭recurrence‬‭of‬
‭detected deviations.‬
‭Monitoring‬‭visits‬‭will‬‭be‬‭carried‬‭out‬‭by‬‭the‬‭study‬‭monitors.‬‭It‬‭is‬‭understood‬‭that‬‭these‬‭monitors‬‭will‬‭be‬‭able‬‭to‬
‭access‬ ‭the‬ ‭patients'‬ ‭medical‬ ‭records‬ ‭after‬ ‭requesting‬ ‭it‬ ‭from‬ ‭the‬ ‭researcher.‬ ‭The‬ ‭researcher‬ ‭will‬ ‭dedicate‬
‭sufficient time to these visits and will facilitate access to all documentation to authorized persons.‬
‭The‬‭study‬‭may‬‭be‬‭audited‬‭by‬‭an‬‭independent‬‭body.‬‭Likewise,‬‭members‬‭of‬‭the‬‭CEIC‬‭of‬‭the‬‭Hospital‬‭where‬‭the‬
‭trial is being carried out may make “follow-up visits” to it.‬
‭​‬‭12.8. Amendments to the Protocol‬
‭Supplements‬‭or‬‭changes‬‭to‬‭the‬‭protocol‬‭can‬‭be‬‭made‬‭exclusively‬‭by‬‭the‬‭Promoter,‬‭who‬‭must‬‭send‬‭them‬‭to‬‭the‬
‭Ethics Committee and the Regulatory Authorities (in Spain AEMPS) as amendments to the protocol.‬
‭​‬‭12.9. Data processing‬
‭All‬ ‭data‬ ‭(personal,‬ ‭clinical,‬ ‭economic‬‭and‬‭from‬‭studies‬‭of‬‭biological‬‭material)‬‭obtained‬‭about‬‭patients‬‭will‬‭be‬
‭processed‬‭in‬‭accordance‬‭with‬‭Regulation‬‭(EU)‬‭2016/679‬‭of‬‭the‬‭European‬‭Parliament‬‭and‬‭of‬‭the‬‭Council‬‭of‬‭April‬
‭27,‬‭2016‬‭regarding‬‭the‬‭protection‬‭of‬‭natural‬‭persons‬‭with‬‭regard‬‭to‬‭the‬‭processing‬‭of‬‭personal‬‭data‬‭and‬‭the‬‭free‬
‭circulation‬‭of‬‭these‬‭data‬‭and‬‭repealing‬‭the‬‭European‬‭Parliament‬‭Directive‬‭95/46/EC‬‭of‬‭October‬‭24,‬‭1995‬‭on‬‭the‬
‭protection of individuals with respect to processing of personal data.‬
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‭This‬‭study‬‭will‬‭also‬‭be‬‭carried‬‭out‬‭in‬‭accordance‬‭with‬‭Organic‬‭Law‬‭15/1999,‬‭of‬‭December‬‭13,‬‭on‬‭the‬‭protection‬‭of‬
‭personal data.‬
‭In‬‭accordance‬‭with‬‭the‬‭provisions‬‭of‬‭the‬‭aforementioned‬‭legislation,‬‭patients‬‭may‬‭exercise‬‭the‬‭rights‬‭of‬‭access,‬
‭modification, opposition and cancellation of data, for which they must contact the clinical trial doctor.‬
‭The‬ ‭content‬ ‭of‬ ‭the‬ ‭CRD‬ ‭as‬ ‭well‬ ‭as‬ ‭the‬ ‭documents‬ ‭generated‬ ‭during‬ ‭the‬ ‭study‬ ‭will‬ ‭be‬ ‭considered‬ ‭strictly‬
‭confidential and will not be revealed to third parties.‬
‭​‬‭12.10. Documentation‬
‭The‬‭investigator/institution‬‭shall‬‭maintain‬‭the‬‭trial‬‭documents‬‭in‬‭accordance‬‭with‬‭ICH‬‭Topic‬‭E6‬‭Section‬‭8,‬‭and‬‭in‬
‭accordance with relevant regulatory requirements.‬
‭Essential‬‭documents‬‭should‬‭be‬‭archived‬‭in‬‭accordance‬‭with‬‭BPC‬‭guidelines‬‭or‬‭for‬‭a‬‭longer‬‭period‬‭of‬‭time,‬‭if‬
‭required by relevant regulations.‬
‭The‬‭original‬‭data‬‭of‬‭study‬‭patients‬‭(medical‬‭records)‬‭should‬‭be‬‭stored‬‭according‬‭to‬‭the‬‭archival‬‭period‬‭applicable‬
‭at the study centers, but not for a period shorter than 25 years.‬
‭​‬
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‭​‬‭13. BIBLIOGRAPHY‬
‭1.‬
‭Finn‬‭R.‬‭Results‬‭of‬‭a‬‭randomized‬‭phase‬‭2‬‭study‬‭of‬‭PD‬‭0332991,‬‭a‬‭cyclin-dependent‬‭kinase‬‭(CDK)‬‭4/6‬
‭inhibitor,‬‭in‬‭combination‬‭with‬‭letrozole‬‭vs‬‭letrozole‬‭alone‬‭for‬‭first-line‬‭treatment‬‭of‬‭ER+/HER2-‬‭advanced‬‭breast‬
‭cancer‬‭(BC).‬‭Abstract.‬‭Publication‬‭Number‬ ‭CT-101.‬‭Presented‬‭at‬‭AACR‬‭2014;‬‭April‬‭6,‬‭2014;‬‭San‬‭Diego,‬‭CA‬
‭USA‬‭.‬
‭2.‬
‭Louis‬‭DN,‬‭Ohgaki‬‭H,‬‭Wiestler‬‭OD,‬‭Cavenee‬‭WK‬‭(eds)‬‭(2007).‬‭World‬‭Health‬‭Organization‬‭Classification‬
‭of Tumours of the Central Nervous System‬‭. IARC,‬‭Lyon‬‭ISBN 92-832-2430-2‬‭.‬
‭3.‬
‭Central Brain Tumor Registry of the United States. First Annual Report (1995).‬
‭4.‬
‭Mork‬‭SJ,‬‭Lindegaard‬‭KF,‬‭Halvorsen‬‭TB,‬‭Lehmann‬‭EH,‬‭Solgaard‬‭T,‬‭Hatlevoll‬‭R,‬‭et‬‭al.‬‭Oligodendroglioma:‬
‭incidence and biological behavior in a defined population. J Neurosurg 1985;63:881-9.‬
‭5.‬
‭Reifenberger‬‭G.‬‭Kros‬‭JM,‬‭Burger‬‭PC,‬‭Louis‬‭DN,‬‭Collins‬‭VP.‬‭Chapter‬‭2:‬‭Oligodendroglial‬‭tumours‬‭and‬
‭mixed‬‭gliomas.‬‭En‬‭Kleihues‬‭P,‬‭Cavenne‬‭WK‬‭eds.‬‭Pathology‬‭and‬‭genetics‬‭of‬‭tumours‬‭of‬‭the‬‭nervous‬‭system.‬
‭WHO Classification of tumours. Lyon: IARC Press, 2000:55-70.‬
‭6.‬
‭Celli‬‭P,‬‭Nofrone‬‭I,‬‭Palma‬‭L,‬‭Cantore‬‭G,‬‭Fortuna‬‭A.‬‭Cerebral‬‭oligodendroglioma:‬‭prognostic‬‭factors‬‭and‬
‭life history. Neurosurgery 1994;35:1018-34.‬
‭7.‬
‭Nijjar‬‭TS,‬‭Simpson‬‭WJ,‬‭Gadalla‬‭T,‬‭McCartney‬‭M.‬‭Oligodendroglioma.‬‭The‬‭princess‬‭Margaret‬‭Hospital‬
‭experience (1958-1984). Cancer 1993;71:4002-6.‬
‭8.‬
‭Shaw‬‭EG,‬‭Scheithauer‬‭BW,‬‭O’Fallon‬‭JR,‬‭Tazelaar‬‭HD,‬‭Davis‬‭DH.‬‭Oligodendrogliomas:‬‭The‬‭Mayo‬‭Clinic‬
‭experience. J Neurosurg 1992;76:428–34.‬
‭9.‬
‭Bigner‬‭SH,‬‭Matthews‬‭MR,‬‭Rasheed‬‭BK,‬‭et‬‭al.‬‭Molecular‬‭genetic‬‭aspects‬‭of‬‭oligodendrogliomas‬‭including‬
‭analysis by comparative genomic hybridization. Am J Pathol 1999;155:375-86.‬
‭10.‬
‭Bortolotto‬‭S,‬‭Chiado-Piat‬‭L,‬‭Cavalla‬‭P,‬‭Bosone‬‭I,Chio‬‭A,‬‭Mauro‬‭A,‬‭et‬‭al.‬‭CDKN2A/p16‬‭inactivation‬‭in‬‭the‬
‭prognosis of oligodendrogliomas. Int J Cancer 2000;88:554–88.‬
‭11.‬
‭Watanabe‬‭T,‬‭Yokoo‬‭LL,‬‭Yokoo‬‭M,‬‭Yonekawa‬‭Y,‬‭Kleihues‬‭P,‬‭Ogaki‬‭H.Concurrent‬‭inactivation‬‭of‬‭RB1‬‭and‬
‭TP53 pathways in anaplastic oligodendrogliomas. J Neuropathol Exp Neurol 2001;60:1181-9.‬
‭12.‬
‭Cairncross‬‭JG,‬‭Ueki‬‭K,‬‭Zlatescu‬‭MC‬‭et‬‭al.‬‭Specific‬‭genetic‬‭predictors‬‭of‬‭chemotherapeutic‬‭response‬‭and‬
‭survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998; 90:1473-1479.‬
‭13.‬
‭Cairncross‬‭G,‬‭Berckey‬‭B,‬‭shaw‬‭E‬‭et‬‭al.‬‭Phase‬‭III‬‭trial‬‭of‬‭chemotherapy‬‭plus‬‭radiotherapy‬‭compared‬‭with‬
‭radiotherapy‬‭alone‬‭for‬‭pure‬‭and‬‭mixed‬‭anaplastic‬‭oligodendroglioma:‬‭Intergroup‬‭Radiation‬‭Therapy‬‭Oncology‬
‭Group Trial 9402. JCO 2006; 24:2707‬‭.‬
‭14.‬
‭Van‬ ‭den‬ ‭Bent‬ ‭,‬ ‭Carpentier‬ ‭A,‬ ‭Brandes‬ ‭A‬ ‭et‬ ‭al.‬ ‭Adjuvant‬ ‭procarbazine,‬ ‭Lomustine‬ ‭and‬ ‭Vincristine‬
‭improves‬‭progresión-free‬‭survival‬‭but‬‭nor‬‭overall‬‭survival‬‭in‬‭newly‬‭diagnosed‬‭anaplastic‬‭oligodendrogliomas‬‭and‬
‭oligoastrocytomas:‬‭A‬‭randomized‬‭European‬‭Organisation‬‭for‬‭Research‬‭and‬‭Treatment‬‭of‬‭cancer‬‭phase‬‭II‬‭trial.‬
‭JCO 2006; 24:2715.‬
‭15.‬
‭Van‬ ‭den‬ ‭Bent‬ ‭M,‬ ‭Brandes‬ ‭A,‬ ‭Taphroorn‬ ‭M,‬ ‭et‬ ‭al.‬ ‭Adjuvant‬ ‭procarbazine,‬ ‭lomustine‬ ‭and‬ ‭vincristine‬
‭chemotherapy‬‭in‬‭newly‬‭diagnosed‬‭anaplastic‬‭oligodendroglioma:‬‭long-term‬‭follow-wp‬‭of‬‭EORTC‬‭Brain‬‭Tumor‬
‭Study 26951. J Clin Oncol. 2013: 344-350.‬
‭16.‬
‭Cairncross‬‭G,‬‭wang‬‭M,‬‭shaw‬‭E‬‭et‬‭al.‬‭Phase‬‭III‬‭of‬‭chemoradiotherapy‬‭for‬‭anaplastic‬‭oligodendroglioma:‬
‭long term results of RTOG 9402.‬‭J Clin Oncol.‬‭2013‬‭Jan 20;31(3):337-43.‬
‭17.‬
‭Wiedemeyer‬ ‭R,‬ ‭Brennan‬ ‭C,‬ ‭Heffernan‬ ‭TP,‬ ‭et‬ ‭al.‬ ‭Feedback‬ ‭circuit‬ ‭among‬ ‭INK4‬ ‭tumor‬ ‭suppressors‬
‭constrains human glioblastoma development.‬‭Cancer‬‭Cell 2008;13:355–64‬‭.‬
‭18.‬
‭The‬ ‭Cancer‬ ‭Genome‬ ‭Atlas‬ ‭(TCGA)‬ ‭Research‬ ‭Network.‬ ‭Comprehensive‬ ‭genomic‬ ‭characterization‬
‭defines human glioblastoma genes and core pathways. Nature 2008;455:1061–8.‬
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‭19.‬
‭Parsons‬ ‭DW,‬ ‭Jones‬ ‭S,‬ ‭Zhang‬ ‭X,‬ ‭et‬ ‭al.‬ ‭An‬ ‭integrated‬ ‭genomic‬ ‭analysis‬ ‭of‬ ‭human‬ ‭glioblastoma‬
‭multiforme. Science 2008;321:1807–12‬‭.‬
‭20.‬
‭Michaud‬‭K,‬‭Solomon‬‭DA,‬‭Oermann‬‭E,‬‭et‬‭al.‬‭Pharmacologic‬‭inhibition‬‭of‬‭cyclin-dependent‬‭kinases‬‭4‬‭and‬
‭6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res. 2010; 70: 3228-38.‬
‭21.‬
‭Keith‬‭T.‬‭Flaherty,‬‭Patricia‬‭M.‬‭LoRusso,‬‭Angela‬‭DeMichele,‬‭et‬‭al.‬‭Phase‬‭I,‬‭Dose-Escalation‬‭Trial‬‭of‬‭the‬
‭Oral‬‭Cyclin-Dependent‬‭Kinase‬‭4/6‬‭Inhibitor‬‭PD‬‭0332991,‬‭Administered‬‭Using‬‭a‬‭21-Day‬‭Schedule‬‭in‬‭Patients‬‭with‬
‭Advanced Cancer. Clin Cancer Res 2012;18:568-576‬‭.‬
‭22.‬
‭Smith‬ ‭TJ,‬ ‭Khatcheressian‬ ‭J,‬ ‭Lyman‬ ‭GH,‬ ‭Ozer‬ ‭H,‬ ‭Armitage‬ ‭JO,‬ ‭Balducci‬‭L,‬‭Benner‬‭CL,‬‭Cantor‬‭SB,‬
‭Crawford‬‭J,‬‭Cross‬‭SJ,‬‭Demetri‬‭G,‬‭Desch‬‭CE,‬‭Pizzo‬‭PA,‬‭Schiffer‬‭CA,‬‭Schwartzberg‬‭L,‬‭Somerfield‬‭MR,‬‭Somlo‬‭G,‬
‭Wade‬‭JC,‬‭Wade‬‭JL,‬‭Winn‬‭RJ,‬‭Wozniak‬‭AJ,‬‭Wolff‬‭AC.‬‭2006‬‭Update‬‭of‬‭Recommendations‬‭for‬‭the‬‭Use‬‭of‬‭White‬
‭Blood‬‭Cell‬‭Growth‬‭Factors:‬‭An‬‭Evidence-Based‬‭Clinical‬‭Practice‬‭Guideline.‬‭Journal‬‭of‬‭Clinical‬‭Oncology‬‭2006;‬
‭24, 19: 3187-3205.‬
‭23.‬
‭Rushing‬‭Elisabeth‬‭J.‬‭and‬‭Wesseling‬‭Pieter.‬‭Towards‬‭an‬‭integrated‬‭morphological‬‭and‬‭molecular‬‭WHO‬
‭diagnosis‬ ‭of‬ ‭central‬ ‭nervous‬ ‭system‬ ‭tumors:‬ ‭a‬ ‭paradigm‬ ‭shift.‬ ‭Current‬ ‭opinion‬ ‭in‬ ‭neurology‬‭.‬ ‭2015‬ ‭Sep‬‭19;‬
‭28:000–000‬‭.‬
‭24.‬
‭Louis‬ ‭David‬ ‭N.,‬ ‭von‬ ‭Deimling‬ ‭Andreas,‬ ‭Aldape‬ ‭Kenneth,‬ ‭Figarella-Branger‬ ‭Dominique,‬ ‭et‬ ‭al.‬
‭International‬ ‭Society‬ ‭of‬ ‭Neuropathology-Haarlem‬ ‭Consensus‬ ‭Guidelines‬ ‭for‬ ‭Nervous‬ ‭System‬ ‭Tumor‬
‭Classification and Grading. Brain Pathology 24 (2014) 429–435‬‭.‬
‭25.‬
‭D. Capper, G. Reifenberger. Classification of gliomas. Neurologist. 2015; 86:672–683‬
‭​‬
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‭ANNEX I - PATIENT INFORMATION SHEET AND INFORMED CONSENT‬
‭Separate document‬
‭​‬
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‭​‬‭ANNEX II - BARTHEL INDEX‬
‭Item‬
‭Patient Situation‬
‭Points‬
‭Eat‬
‭Totally independent‬
‭10‬
‭Need help cutting meat, bread, etc.‬
‭5‬
‭Dependent‬
‭0‬
‭wash up‬
‭Independent: enters and leaves the bathroom alone‬
‭5‬
‭Dependent‬
‭0‬
‭Get dressed‬
‭Independent: Able to put on and take off clothes, button, tie shoes‬
‭10‬
‭Need help‬
‭5‬
‭Dependent‬
‭0‬
‭To get ready‬
‭Independent for washing your face, hands, combing your hair, shaving,‬
‭putting on makeup, etc.‬
‭5‬
‭Dependent‬
‭0‬
‭Depositions‬
‭(assess the‬
‭previous week)‬
‭Normal continence‬
‭10‬
‭Occasionally an episode of incontinence, or need help administering‬
‭suppositories or lavatinas‬
‭5‬
‭Incontinence‬
‭0‬
‭Urination‬
‭(assess the‬
‭previous week)‬
‭Normal continence, or able to care for the catheter if it is inserted‬
‭10‬
‭At most one episode of incontinence per day, or needs help caring for the‬
‭catheter‬
‭5‬
‭Incontinence‬
‭0‬
‭Use the toilet‬
‭Independent to go to the toilet room, take off and put on clothes‬
‭10‬
‭He needs help to go to the toilet but he cleans himself‬
‭5‬
‭Dependent‬
‭0‬
‭Move‬
‭Independent to go from the chair to the bed‬
‭15‬
‭Minimal physical help or supervision to do it‬
‭10‬
‭Needs a lot of help, but is able to sit alone‬
‭5‬
‭Dependent‬
‭0‬
‭Wander‬
‭Independent, walks only a distance of 50 meters‬
‭15‬
‭Needs physical assistance or supervision to walk a distance of 50 meters‬
‭10‬
‭Independent in a wheelchair without assistance‬
‭5‬
‭Dependent‬
‭0‬
‭Steps‬
‭Independent for going down and up stairs‬
‭10‬
‭Need physical help or supervision to do it‬
‭5‬
‭Dependent‬
‭0‬
‭Total:‬
‭Maximum score: 100 points (90 if you are in a wheelchair)‬
‭Result and degree of dependency‬
‭<20‬
‭Total‬
‭20-35‬
‭Grave‬
‭40-55‬
‭Moderate‬
‭>= 60‬
‭Light‬
‭100‬
‭Independent‬
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‭ANNEX III - MINI MENTAL STATE EXAMINATION (MMSE) - Adapted ESPAÑA‬
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‭​‬‭ANNEX IV - RANO RESPONSE CRITERIA‬
‭COMPLETE ANSWER:‬
‭Disappearance of signal in T1Gd MRI‬
‭Stability or reduction in Flair/T2 images‬
‭No new radiological lesions‬
‭Stability or clinical improvement‬
‭Absence of corticosteroids or minimum stable dose‬
‭PARTIAL ANSWER:‬
‭MRI image reduction by 50% in T1Gd‬
‭Stability or reduction in Flair/T2 images‬
‭No new radiological lesions‬
‭Stability or clinical improvement‬
‭With reduced or stable steroids‬
‭PROGRESSION:‬‭Any of the following‬
‭25% growth of the tumor in T1Gd MRI‬
‭Significant increase in Flair/T2 images*‬
‭Appearance of new lesions‬
‭Irreversible clinical neurological worsening, even in the absence of radiological worsening.‬
‭Need to increase dexamethasone (>2 weeks) to prevent progressive neurological deterioration.‬
‭USE:‬‭Only progression criteria 1,2 and 3 are applicable‬‭for the purposes of patient inclusion in the clinical trial.‬
‭STABLE DISEASE:‬
‭T1Gd image with an increase of less than 25% or a decrease of less than 50%‬
‭Flair/T2 Image Stability‬
‭No new radiological lesions‬
‭clinically stable‬
‭Stable cortisone doses (which should not be increased to maintain neurological deterioration)‬
‭*not attributable to radiotherapy, demyelination, ischemia, infection, seizures, postoperative changes or other‬
‭treatment effects.‬
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SAP_001.pdf: 
 GEINO-13 
 FINAL STATISTICAL REPORT 
 TABLES, LISTS AND FIGURES 
 xx  th  of xxxxxxx de xxxx (version xx) 


 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 SPONSOR 
 STUDY CHIEF INVESTIGATOR 
 MONITORING ORGANISATION (CRO) 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
 Page  2  of  38 


 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 INDEX 
 1.  RESULTS (TABLES, LISTS AND FIGURES) 
 6 
 1.1.  STUDY POPULATION 
 6 
 1.1.1.  SCREENED PATIENTS 
 6 
 1.2.  DEMOGRAPHIC AND CLINICAL BASELINE CHARACTERISTICS 
 8 
 1.2.1.  CLINICAL BASELINE CHARACTERISTICS 
 8 
 1.2.2.  CLINICAL TUMOUR CHARACTERISTICS 
 9 
 1.2.3.  PREVIOUS PATHOLOGIES 
 13 
 1.3.  EFFICACY ANALYSES 
 17 
 1.3.1.  PRIMARY EFFICACY ANALYSES: PFS 
 17 
 1.3.2.  SECONDARY EFFICACY ANALYSES 
 19 
 1.4.  SAFETY ANALYSES 
 32 
 1.4.1.  ADEVERSE EVENTS 
 32 
 1.4.2.  TOXICITIES 
 35 
 1.4.3.  SERIOUS ADVERSE EVENTS 
 37 
 1.5.  ANNEX I: LIST OF ALL TOXICITIES 
 38 
 1.6.  ANNEX II: ADDITIONAL RESULTS 
 41 
 1.6.1.  LONG SURVIVORS 
 41 
 1.6.2.  BASELINE AND TUMOUR CHARACTERISTICS VS LONG  SURVIVORS  42 
 1.6.3.  ADDITIONAL FIGURES 
 43 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
 Page  3  of  38 


 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Tables: 
 Table 1. Screened patients 
 6 
 Table 2. Evaluable patients 
 6 
 Table 3. Patients included and excluded from each hospital 
 6 
 Table 4. List of patients excluded from the analysis 
 7 
 Table 5. Age 
 8 
 Table 6. Gender and race 
 8 
 Table 7. Clinical data 
 8 
 Table 8. Analytical data 
 8 
 Table 9. Biochemistry data 
 8 
 Table 10. Coagulation data 
 9 
 Table 11. Thyroid function 
 9 
 Table 12. ECG 
 9 
 Table 13. First surgery characteristics 
 9 
 Table 14. List of patients with diagnosisin first surgery 
 10 
 Table 15. Last surgery characteristics 
 11 
 Table 16. Deletion 
 11 
 Table 17. Surgery compliance 
 12 
 Table 18. Baseline Barthel Index and Minimental test 
 12 
 Table 19. Previous pathologies 
 13 
 Table 20. List of previous pathologies 
 15 
 Table 21. Time since diagnosis 
 16 
 Table 22. Progression Free Survival 
 17 
 Table 23. Time until PD/exitus (only pts with event) 
 18 
 Table 24. Overall Survival 
 19 
 Table 25. Time until exitus (only deaths) 
 20 
 Table 26. Time of follow-up (all patients) 
 20 
 Table 27. Best response and Clinical benefit rate 
 21 
 Table 28. Status at end of study 
 21 
 Table 29. RANO Evaluation (I) 
 22 
 Table 30. RANO Evaluation (II) 
 23 
 Table 31. List of patients with RANO progressions with deatils 
 24 
 Table 32. Use of Corticoids 
 25 
 Table 33. List of patients receiving corticoids and Follow-up of dosage 
 25 
 Table 34. Minimental Test: Results for each patient 
 26 
 Table 35. Minimental Test: Summary in each visit 
 26 
 Table 36. Minimental Test: Comparison between visits and baseline 
 27 
 Table 37. Barthel Index: Results for each patient 
 29 
 Table 38. Barthel Index: Summary in each visit 
 29 
 Table 39. Barthel Index: Comparison between visits and baseline 
 30 
 Table 40. Satey results summary 
 32 
 Table 41. Frequencies of all adverse events 
 32 
 Table 42. Most frequent adverse events 
 33 
 Table 43. Most frequent adverse events with grades 
 34 
 Table 44. Frequency of Toxicities 
 35 
 Table 45. Most frequent Toxicities 
 35 
 Table 46. Most frequent Toxicities with grades 
 36 
 Table 47. List of SAEs 
 37 
 Table 48. List of all toxicities 
 38 
 Table 49. Long survivors 
 41 
 Table 50. Long survivors 
 41 
 Table 51. Baseline and tumour characteristic vs long survivors 
 42 
 Figures: 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Figure 1. Progression Free Survival 
 18 
 Figure 2. Overall Survival 
 20 
 Figure 3. Use of corticoids 
 25 
 Figure 4. Minimental Test evolution 
 28 
 Figure 5. Barthel Index evolution 
 31 
 Figure 6. Progression Free Survival (R format) 
 43 
 Figure 7. Overall Survival (R format) 
 43 
 Figure 8. Swimmer plot: patient’s follow-up 
 44 
 Figure 9. Spider plot: % change in lessions measurements from baseline 
 45 
 Figure  10.  Spider  plot:  %  change  in  lessions  measurements  from  baseline  (excluding 
 outlier value) 
 45 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
 Page  5  of  38 


 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.  RESULTS (TABLES, LISTS AND FIGURES) 
 The database of the study was closed on the 10-10-2019. 
 1.1.  STUDY POPULATION 
 1.1.1.  SCREENED PATIENTS 
 A  total  of  xx  patients  were  screened  and  eventually  xx  patients  fulfilled  all  the 
 inclusion and exclusion criteria. 
 Table 1. Screened patients 
 N 
 % 
Hospital 
Name 
Total 
Fulfils every 
inclusion and 
none of the 
exclusion 
criteria 
Patient fulfils all the inclusion criteria and none of exclusion according to the 
protocol 
Patient does not fulfil the eligibility criteria 
Total 
 xx  patients  were  considered  evaluable  for  the  study  and  the  reason  for 
 non-evaluability was screening failure in all the cases. 
 Table 2. Evaluable patients 
 N 
 % 
Evaluable patients 
No 
Yes 
Total 
Non evaluable reason 
Screening failure 
Total 
 Table 3. Patients included and excluded from each hospital 
 Evaluable patients 
 No 
 Yes 
 Total 
 N 
 % 
 N 
 % 
 N 
 % 
Hospital Name 
…. 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Those patients excluded from the analysis are listed in the following table. 
 Table 4.  List of patients  excluded from the analysis 
 Patient 
 number 
 Hospital 
 Non evaluable 
 reason 
 Fulfils every inclusion and none of the 
 exclusion criteria 
 1 
 2 
 3 
 4 
 .. 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
 Page  7  of  38 


 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 DEMOGRAPHIC AND CLINICAL BASELINE CHARACTERISTICS 
 The median of the age was xx years and xx % were males. 
 Table 5. Age 
 N 
 Mean 
 SD 
 Median 
 Min 
 Max 
Age in years (at informed consent signature) 
 Table 6. Gender and race 
 N 
 % 
 Gender 
 Men 
 Female 
 Total 
 Race 
 White 
 Hispanic 
 Total 
 1.1.2.  CLINICAL BASELINE CHARACTERISTICS 
 Table 7. Clinical data 
 N 
 % 
Performance Status (PS) 
0 
1 
2 
Total 
 N 
 Mean 
 SD 
 Media 
 n 
 Min 
 Max 
Systolic blood pressure 
Diastolic blood pressure 
Weight 
Height 
 Table 8. Analytical data 
 N 
 Mean 
 SD 
 Median 
 Min 
 Max 
Haemoglobin (g/dl) 
Platelets (x 10e9/L) 
Leukocytes (x 10e9/L) 
Neutrophils (x 10e9/L) 
Lymphocytes (x 10e9/L) 
 Table 9. Biochemistry data 
 N 
 Mean 
 SD 
 Median 
 Min 
 Max 
Sodium (mmol/L) 
Potassium (mmol/L) 
Calcium (mg/dL) 
Magnesium (mg/dL) 
Glucose (mg/dL) 
Creatinine (mg/dL) 
AST (U/L) 
ALT (U/L) 
Total bilirubin (mg/dL) 
GGT (U/L) 
Alkaline Phosphatase (U/L) 
Albumin (g/dL) 
LDH (U/L) 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
 Page  8  of  38 


 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Table 10. Coagulation data 
 N 
 Mean 
 SD 
 Median 
 Min 
 Max 
TP value 
TTPA value 
Fib (mg/dL) 
 Table 11. Thyroid function 
 N 
 Mean 
 SD 
 Median 
 Min 
 Max 
TSH value 
T3 value 
 Table 12. ECG 
 N 
 % 
Qtc 
 Unknown 
 <450 mseg 
 450-480 mseg 
 Total 
 1.1.3.  CLINICAL TUMOUR CHARACTERISTICS 
 In  the  first  surgery  16  patients  (47.1%)  had  a  tumour  of  grade  2  while  13 
 (38.2%) had a grade 3 tumour. 
 Table 13. First surgery characteristics 
 N 
 % 
Diagnosis with grade (First 
surgery) 
Oligoastrocytoma grade 2 
Oligoastrocytoma grade 3 
Oligodendroglioma grade 2 
Oligodendroglioma grade 3 
Oligodendroglioma grade unknown 
Diagnosis and grade unknown 
Total 
Grade (First surgery) 
Grade 2 
Grade 3 
Unknown 
Total 
Anaplasia (First surgery) 
0 
1 
2 
4 
Unknown 
Total 
High cellularity (First surgery) No 
Yes 
Total 
Endothelial proliferation (First 
surgery) 
No 
Yes 
Total 
Necrosis (First surgery) 
No 
Yes 
Total 
Mitosis (First surgery) 
No 
Yes 
Total 
Nuclear anomalies (First 
surgery) 
No 
Yes 
Total 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
 Page  9  of  38 


 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Table 14. List of patients with diagnosis in first surgery 
 Patient 
 number 
 Hospital 
 Diagnosis with grade (First surgery) 
 Grade (First surgery) 
 1 
 2 
 3 
 4 
 5 
 … 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 In  the  last  surgery,  every  patient  (100%)  was  diagnosed  with  an 
 oligodendroglioma grade 3. 
 Table 15. Last surgery characteristics 
 N 
 % 
Diagnosis with grade (Last surgery) 
Oligodendroglioma grade 3 
Total 
Grade (Last surgery) 
Grade 3 
Total 
Anaplasia (Last surgery) 
0 
1 
2 
3 
4 
5 
Total 
High cellularity (Last surgery) 
No 
Yes 
Total 
Endothelial proliferation (Last 
surgery) 
No 
Yes 
Total 
Necrosis (Last surgery) 
No 
Yes 
Total 
Mitosis (Last surgery) 
No 
Yes 
Total 
Nuclear anomalies (Last surgery) 
No 
Yes 
Total 
 Table 16. Deletion 
 N 
 % 
Deletion 1p 
Yes 
Total 
Deletion 19q 
Yes 
Total 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 In  x  patients  (xx%)  the  surgery  was  not  completed.  Biopsy  was  performed  in  x 
 patients (xx%) and craniotomy in XX patients (xx%). 
 Table 17. Surgery compliance 
 N 
 % 
Surgery 
No 
Yes 
Total 
Type of surgery 
Biopsy 
Craniotomy 
No applicable (Surgery not done) 
Total 
Relapse location Bihemispheric 
Cingulate (right) 
…. ( Indicate locations) 
Total 
 The  baseline  barthel  index  mean  was  xx  and  the  baseline  minimental  test  mean 
 was xx (data was available in xx patients). 
 Table 18. Baseline Barthel Index and Minimental test 
 N 
 Mean 
 SD 
 Median 
 Min 
 Max 
Barthel index (baseline) 
Mini mental test (baseline) 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.2.3.  PREVIOUS PATHOLOGIES 
 For  9  patients  (26.5%)  previous  pathologies  were  not  reported.  In  those  patients 
 with  previous  pathologies,  seizures  were  the  most  common  (n=7,  17.6%) 
 previous pathology. 
 Table 19. Previous pathologies 
 N 
 % 
Previous 
pathologies 
No 
Yes 
Total 
 N 
 % 
Previous 
pathologies 
.(Indicate previous pathologies. Exemples: 
Fatigue 
Cognitive disturbance 
Muscle weakness left-sided 
…. 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
 Page  13  of  38 


 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Table 20. List of previous pathologies 
 Pat. n. 
 Hospital 
 Previous pathology 
 Intensity 
 Action 
 1 
 01-003 
 2 
 01-004 
 3 
 01-006 
 … 
 01-006 
 Table 21. Time since diagnosis 
 N 
 Mean 
 SD 
 Median 
 Min 
 Max 
Time since 1st diagnosis until 1st cycle (months) 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.2.  EFFICACY ANALYSES 
 1.2.1.  PRIMARY EFFICACY ANALYSES: PFS 
 At  6  and  9  months  the  estimated  PFS  was  21.23%  (with  95%  CI  11-40.97),  at 
 12  months  it  was  16.99%  (with  95%  CI  7.71-37.43)  and  from  18  to  48  months  it 
 was 11.32% (with 95% CI 3.68-34.86). 
 The median of PFS was 2.84 months (with 95% CI 2.71-5.39). 
 Table 22. PFS estimated survival ratio 
 Progression Free Survival 
 Events (%, total N) 
 Patients at risk 
 % estimated cumulative 
 survival ratio 
 CI 95% 
 At 6 months 
 At 9 months 
 At 12 months 
 At 18 months 
 At 24 months 
 At 30 months 
 At 36 months 
 At 42 months 
 At 48 months 
 Note:  Estimated using Kaplan-Meier product-limit method 
 Table 23. Median/mean PFS (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Progression Free Survival 
 Note:  Estimated using Kaplan-Meier product-limit method 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Figure 1. Progression Free Survival 
 In the 28 patients with PD, the median until progression was 2.8 months. 
 Table 24. Time until PD/exitus (only pts with event) 
 Overall 
 Overall 
 (N=xx) 
 Time until PD/Exitus 
    N 
    Mean (95%CI) 
    SD 
    Median (95%CI) 
    Range 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.3.2.  SECONDARY EFFICACY ANALYSES 
 1.2.2.1 
 OS 
 At  6  months  the  estimated  OS  was  xx  %  (with  xx%  CI  xx-xx),  at  9  months  it  was 
 xx % (with xx% CI xx-xx), at xx months it was …. 
 The median of OS was xxx months (with xx% CI xx-xx) 
 Table 25. OS estimated survival ratio 
 Overall Survival  Events (%, total N)  Patients at risk 
 % estimated cumulative 
 survival ratio 
 CI 95% 
 At 6 months 
 At 9 months 
 At 12 months 
 At 18 months 
 …… 
 Note:  Estimated using Kaplan-Meier product-limit method 
 Table 26. Median/mean OS (estimated by Kaplan-Meier) 
 Median (months) 
 CI 95% 
 Mean 
 CI 95% 
 Overall Survival 
 Note:  Estimated using Kaplan-Meier product-limit method 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Figure 2. Overall Survival 
 In those patients who died (n=xx), the median of follow-up was xx months. 
 Table 27. Time until exitus (only deaths) 
 Overall 
 Overall 
 (N=xx) 
 Time until Exitus 
    N 
    Mean (95%CI) 
    SD 
    Median 
 (95%CI) 
    Range 
 In  overall,  the  median  of  follow-up  was  xx  months  (minimum  xx  months  and 
 maximum of xx months). 
 Table 28. Time of follow-up (all patients) 
 Overall 
 Overall (N=xx) 
 Time until Exitus 
    N 
    Mean (95%CI) 
    SD 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Overall 
 Overall (N=xx) 
    Median 
 (95%CI) 
    Range 
 1.2.2.2  RESPONSES 
 13  patients  (38.2%,  with  95%  CI  21.9-54.6),  reached  clinical  benefit  (all  were 
 Stable Disease). 
 Table 29. Best response and Clinical benefit rate 
 N (%, 95% CI) 
Best response 
rate 
CR 
SD 
PD 
No evaluated 
Total 
Clinical benefit 
rate 
No 
Yes (CR or PR or SD) 
No evaluable 
Total 
 In  xx  patients  (xx%)  the  reason  to  end  of  treatment  was  PD;  xx  patients  (xx%) 
 were alive at the end of follow-up. 
 Table 30. Status at end of study 
 N (%) 
Current 
status 
End of treatment due to patient decision and patient is alive at end of follow-up 
End of treatment due to PD and patient is alive at end of follow-up 
End of treatment due to PD and patient is exitus 
End of treatment but reason not reported and patient is exitus 
End of treatment due to lack of clinical benefit and patient is alive at end of follow-up 
On treatment 
Total 
End of 
treatment 
reason 
PD 
Toxicity (with PD) 
Patient decision 
On treatment 
No clinical benefit 
Total 
Status at 
end of 
follow-up 
Alive 
Exitus 
Total 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.2.2.3  RANO EVALUATION 
 xx  patients  (xx%)  presented  PD  in  RANO  evaluations,  xx  (xx%)  of  them  in  the  2nd  RANO,  x  (xx%)  the  3rd,  x  (xx%)  in  the  5th  and  x 
 (xx%) in the 6th. 
 Table 31. RANO Evaluation (I) 
 N 
 % 
RANO 
evaluation 
with PD 
Without PD in RANO 
2 
3 
5 
6 
Total 
Reason of 
PD with 
RANO 
Example: 
T1-Gd+:/ T2-FLAIR: / New lesions: New appearance/ Corticoids evolution (last 5 days): Stable/ Clinical evaluation (neurological): Stable 
… 
Total 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Table 32. RANO Evaluation (II) 
 N 
 % 
T1Gd+ (PD 
RANO) 
NA or not reported 
Decrease <5% or Increase < 25% 
Increase >/= 25%* 
Total 
T2/FLAIR 
(PD RANO) 
NA or not reported 
Increase 
Stable 
Total 
New lesions 
(PD RANO) 
NA or not reported 
New appearance 
No 
Total 
Corticoids 
evolution 
(PD RANO) 
NA or not reported 
Decrease 
Increase 
No corticoids 
Stable 
Total 
Clinical 
evaluation 
(PD RANO) 
NA or not reported 
Stable 
Worsening 
Total 
 DATE :  29/11/2022 (version 1.3) 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Table 33. List of patients with RANO progressions with details 
 Patient 
 number 
 Evaluation 
 RANO con 
 PD 
 Reason of PD with RANO 
1 
 Example: T1-Gd+:Increase >/= 25%*/ T2-FLAIR: Stable/ New lesions: No/ Corticoids evolution (last 5 days): No corticoids/ Clinical evaluation (neurological): Stable 
2 
… 
 DATE :  29/11/2022 (version 1.3) 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.2.2.4  USE OF CORTICOIDS 
 x patients (xx%) reported use of corticoids. 
 Table 34. Use of Corticoids 
 N 
 % 
Receive corticoids during 
treatment (cycles) 
No 
Yes 
Total 
Changes in corticoids 
doses from baseline 
(during treatment cycles) 
No 
Increased 
Increased with posterior decrease 
Decreased 
Stable 
Total 
 Table 35. List of patients receiving corticoids and Follow-up of dosage 
 Patient 
 number 
 Receive 
 corticoids during 
 treatment (cycles) 
 Changes in corticoids doses 
 from baseline (during treatment 
 cycles) 
 C1 
 D1 
 C1 
 D15 
 C2 
 D1 
 C2 
 D15 
 C3 
 D1 
 C4 
 D1 
 C5 
 D1 
 C6 
 D1 
 C7 
 D1 
 C8 
 D1 
 C9 
 D1 
 C10 
 D1 
 C11 
 D1 
 1 
 Yes 
 Example: 
 Decreased/Increased/Stable 
 2 
 3 
 ……. 
 Figure 3. Use of corticoids 
 DATE :  29/11/2022 (version 1.3) 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.1.1.1  EVOLUTION OF MINIMENTAL TEST 
 The  results  of  the  minimental  test  for  each  patient  (when  available),  is  reported 
 in the following table. 
 Table 36. Minimental Test: Results for each patient 
 Patient 
 number 
 Baseline  C2 
 d1 
 C3 
 d1 
 C4 
 d1 
 C5 
 d1 
 C6 
 d1 
 C7 
 d1 
 C8 
 d1 
 C9 
 d1 
 C10 
 d1 
 C12 
 d1 
 C13 
 d1 
 C14 
 d1 
 C15 
 d1 
 C16 
 d1 
 C17 
 d1 
 C18 
 d1 
 C19 
 d1 
 C20 
 d1 
 C21 
 d1 
 C22 
 d1 
 C23 
 d1 
 End of 
 treatment 
   
   
   
   
   
   
   
   
   
   
   
   
 …. 
   
   
   
   
   
   
   
   
   
   
   
   
   
   
 Table 37. Minimental Test: Summary in each visit 
 N 
 Mean (SD) 
 Median (Min-Max) 
 Test Minimental (baseline) 
 Test Minimental (cycle 2 d1) 
 Test Minimental (cycle 3 d1) 
 Test Minimental (cycle 4 d1) 
 Test Minimental (cycle 5 d1) 
 Test Minimental (cycle 6 d1) 
 Test Minimental (cycle 7 d1) 
 Test Minimental (cycle 8 d1) 
 Test Minimental (cycle 9 d1) 
 Test Minimental (cycle 10 d1) 
 Test Minimental (cycle 12 d1) 
 Test Minimental (cycle 13 d1) 
 Test Minimental (cycle 14 d1) 
 Test Minimental (cycle 15 d1) 
 Test Minimental (cycle 16 d1) 
 Test Minimental (cycle 17 d1) 
 Test Minimental (cycle 18 d1) 
 Test Minimental (cycle 19 d1) 
 Test Minimental (cycle 20 d1) 
 Test Minimental (cycle 21 d1) 
 Test Minimental (cycle 22 d1) 
 Test Minimental (cycle 23 d1) 
 Test Minimental (end of treatment) 
 . 
 Table 38. Minimental Test: Comparison between visits and baseline 
 N 
 Mean (SD) 
 Median (Min-Max) 
 p-valor  1 
 Test Minimental (baseline) 
 Test Minimental (cycle 2 d1) 
 Test Minimental (baseline) 
 Test Minimental (cycle 3 d1) 
 Test Minimental (baseline) 
 Test Minimental (cycle 4 d1) 
 Test Minimental (baseline) 
 Test Minimental (cycle 5 d1) 
 Test Minimental (baseline) 
 Test Minimental (cycle 6 d1) 
 Test Minimental (baseline) 
 Test Minimental (cycle 7 d1) 
 Test Minimental (baseline) 
 Test Minimental (cycle 8 d1) 
 Test Minimental (baseline) 
 DATE :  29/11/2022 (version 1.3) 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Test Minimental (cycle 9 d1) 
 Test Minimental (baseline) 
 Test Minimental (cycle 10 d1) 
 Test Minimental (baseline) 
 Test Minimental (end of treatment) 
 1: Wilcoxon test 
 Figure 4. Minimental Test evolution 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.1.1.2  EVOLUTION OF BARTHEL INDEX 
 The  results  of  the  Barthel  Index  for  each  patient  (when  available),  is  reported  in 
 the following table. 
 Table 39. Barthel Index: Results for each patient 
 Patient 
 number 
 Baseline 
 C2 
 d1 
 C3 
 d1 
 C4 
 d1 
 C5 
 d1 
 C6 
 d1 
 C7 
 d1 
 C8 
 d1 
 C9 
 d1 
 C10 
 d1 
 C11 
 d1 
 C12 
 d1 
 C13 
 d1 
 C14 
 d1 
 C15 
 d1 
 C16 
 d1 
 C17 
 d1 
 C18 
 d1 
 C19 
 d1 
 C20 
 d1 
 C21 
 d1 
 C22 
 d1 
 C23 
 d1 
 End of 
 treatment 
 …. 
   
   
   
   
   
   
   
   
   
   
 Table 40. Barthel Index: Summary in each visit 
 N 
 Mean (SD) 
 Median (Min-Max) 
 Barthel Index (baseline) 
 Barthel Index (cycle 2 d1) 
 Barthel Index (cycle 3 d1) 
 Barthel Index (cycle 4 d1) 
 Barthel Index (cycle 5 d1) 
 Barthel Index (cycle 6 d1) 
 Barthel Index (cycle 7 d1) 
 Barthel Index (cycle 8 d1) 
 Barthel Index (cycle 9 d1) 
 Barthel Index (cycle 10 d1) 
 Barthel Index (cycle 11 d1) 
 Barthel Index (cycle 12 d1) 
 Barthel Index (cycle 13 d1) 
 Barthel Index (cycle 14 d1) 
 Barthel Index (cycle 15 d1) 
 Barthel Index (cycle 16 d1) 
 Barthel Index (cycle 17 d1) 
 Barthel Index (cycle 18 d1) 
 Barthel Index (cycle 19 d1) 
 Barthel Index (cycle 20 d1) 
 Barthel Index (cycle 21 d1) 
 Barthel Index (cycle 22 d1) 
 Barthel Index (cycle 23 d1) 
 Barthel Index (end of treatment) 
 The  Barthel  Index  result  in  each  visit  was  compared  with  the  baseline  result  in 
 those  cases  with  results  for  at  least  4  patients  (for  each  pairwise  comparison 
 only  those  patients  with  measures  in  both  visits  could  be  compared).  No 
 statistically  significant  differences  were  found  in  any  of  the  comparisons  with 
 baseline. 
 Table 41. Barthel Index: Comparison between visits and baseline 
 N 
 Mean (SD) 
 Median (Min-Max) 
 p-valor  1 
 Barthel Index(baseline) 
 Barthel Index(cycle 2 d1) 
 Barthel Index(baseline) 
 Barthel Index(cycle 3 d1) 
 Barthel Index(baseline) 
 Barthel Index(cycle 4 d1) 
 Barthel Index(baseline) 
 Barthel Index(cycle 5 d1) 
 Barthel Index(baseline) 
 Barthel Index(cycle 6 d1) 
 Barthel Index(baseline) 
 Barthel Index(cycle 7 d1) 
 Barthel Index(baseline) 
 DATE :  29/11/2022 (version 1.3) 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Barthel Index(cycle 8 d1) 
 Barthel Index(baseline) 
 Barthel Index(cycle 9 d1) 
 Barthel Index(baseline) 
 Barthel Index(cycle 10 d1) 
 Barthel Index(baseline) 
 Barthel Index(end of treatment) 
 1: Wilcoxon test 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Figure 5. Barthel Index evolution 
 DATE :  29/11/2022 (version 1.3) 
 CONFIDENTIAL 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.2.  SAFETY ANALYSES 
 Every  patient  but  one  presented  at  least  one  adverse  event  during  follow-up 
 (n=xx,  xx%).  xx  patients  (xx%)  presented  at  least  one  adverse  event  grade≥3 
 during  follow-up.  xx  patients  (x%)  presented  at  least  one  toxicity  (related  AE) 
 during  follow-up.  xx  patients  (xx%)  presented  at  least  one  toxicity  grade≥3 
 (related  AE)  during  follow-up.  xx  patients  (xx%)  presented  at  least  one  SAE 
 during follow-up, and none was reported as related to the treatment. 
 Table 42. Safety results summary 
 N 
 % 
AE 
No 
Yes 
Total 
Adverse event grade≥3 
No 
Yes 
Total 
Toxicity (any) 
No 
Yes 
Total 
Toxicity grade≥3 
No 
Yes 
Total 
SAE (any) 
No 
Yes 
Total 
SAE related 
No 
Total 
 1.2.1. 
 1.2.2.  ADEVERSE EVENTS 
 The most frequent adverse event (any grade) were xxxxx (xx%, n=xx).... 
 Table 43. Frequencies of all adverse events 
 N 
 % 
Adverse 
event 
EXAMPLES: 
Neutrophil count decreased 
Fatigue 
Platelet count decreased 
Anaemia 
…… 
 %: calculated respect the total number of patients (N=34) 
 The  most  frequent  adverse  events,  (at  least  in  10%  of  the  patients,  n=xx),  are 
 reported in the following table: 
 Table 44. Most frequent adverse events 
 N 
 % 
Specify Adverse events. 
EXAMPLE:  Fatigue 
No 
 10 
 29.4% 
Yes 
 24 
 70.6% 
Total 
 34 
 100.0% 
…… 
No 
 14 
 41.2% 
Yes 
 20 
 58.8% 
 DATE :  29/11/2022 (version 1.3) 
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Total 
 34 
 100.0% 
 The  most  frequent  adverse  events  with  their  respective  grades  are  reported  in 
 the following table: 
 Table 45. Most frequent adverse events with grades 
 No 
 G1 
 G2 
 G3 
 G4 
 Total 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 
Specify Adverse events. 
EXAMPLE:  Fatigue 
…… 
 DATE :  29/11/2022 (version 1.3) 
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 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
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 1.2.2.  TOXICITIES 
 The  most  frequent  toxicities  (related  AE  of  any  grade)  were  xxx  decreased 
 (xx%, n=xx).... 
 Table 46. Frequency of Toxicities 
 N 
 % 
Adverse 
event 
 Specify Advert event. EXAMPLE: Neutrophil count decreased 
 …. 
 %: calculated respect the total number of patients (N=xx) 
 The  most  frequent  toxicities  (at  least  in  10%  of  the  patients,  n=x),  are  reported 
 in the following table: 
 Table 47. Most frequent Toxicities 
 N 
 % 
 Specify Advert event 
 EXAMPLE: Neutrophil count 
 decreased 
No 
Yes 
Total 
… 
No 
Yes 
Total 
 The  most  frequent  toxicities  with  their  respective  grades  are  reported  in  the 
 following table: 
 Table 48. Most frequent Toxicities with grades 
 No 
 G1 
 G2 
 G3 
 G4 
 Total 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 
 N 
 % 
 Specify Advert event 
 EXAMPLE: Neutrophil count 
 decreased 
…. 
 DATE :  29/11/2022 (version 1.3) 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.2.3.  SERIOUS ADVERSE EVENTS 
 Table 49. List of SAEs 
 Patient 
 number 
 Hospital 
 AE grade 
 Relation 
 Intensity 
 Action 
 SAE 
 (any) 
1 
2 
 … 
3 
 …. 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.3.  ANNEX I: LIST OF ALL TOXICITIES 
 Table 50. List of all toxicities 
 Patient 
 number 
 Hospital 
 AE grade 
 Relation 
 Intensity 
 Action 
 SAE (any) 
1 
2 
3 
4 
… 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.4.  ANNEX II: ADDITIONAL RESULTS 
 In  the  event  that  the  study  coordinator  considered  evaluating  the  variables  of  a 
 subgroup  of  patients  (those  of  interest  for  the  article), 
 for  example  patients  with 
 progression  free  survival  longer  than  9  months  (low  survivors ),  some  tables  and 
 graphs (PFS and OS)  could be required 
 1.4.1.  LONG SURVIVORS 
 Table 51. Long survivors 
   
 N 
 % 
 Long 
 survivor 
 (PFS≥9m) 
 No 
 Yes 
 Total 
 x patients were considered long survivors and are listed below: 
 List of long survivor patients (PFS≥9 months) 
 Table 52. Long survivors 
 Patient 
 number 
 Time until 
 PD/Exitus 
 Progression Free 
 Survival 
 Time until 
 Exitus 
 Overall 
 survival 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
 DATE :  29/11/2022 (version 1.3) 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.4.2.  BASELINE 
 AND 
 TUMOUR  CHARACTERISTICS  VS  LONG 
 SURVIVORS 
 Those  variables  reported  in  table  1  of  the  article  are  reported  below  stratified  by 
 long survivors. 
 Table 53. Baseline and tumour characteristic vs. long survivors 
 Long survivor (PFS≥9m) 
 p-value 
 No (n=27) 
 Yes (n=7) 
 Total (n=34) 
 Age, mean +/-SD 
 years 
 median (range) 
 mean (SD) 
 Gender, n (%) 
 Male 
 Female 
 KPS, n (%) 
 0 
 1 
 2 
 Barthel Index, n=31 
 median (range) 
 mean (SD) 
 MMSE, n=31 
 median (range) 
 mean (SD) 
 Prior treatments, n 
 (%) 
 Temozolomide 
 Nitrosoureas 
 Radiotherapy 
 Tumor characteristics at first surgery 
 Diagnosis, n (%) 
 Oligoastrocytoma 
 Grade 2 
 Grade 3 
 Oligodendroglioma 
 Grade 2 
 Grade 3 
 Unknown 
 Not reported 
 Time from first AO 
 diagnosis to first 
 cycle, median 
 (range) months 
 median (range) 
 mean (SD) 
 Corticoids use during treatment, n (%) 
 1: T-test for independent samples; 2: Mann-Whitney U test; 3: Fisher exact test. 
 DATE :  29/11/2022 (version 1.3) 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 1.4.3.  ADDITIONAL FIGURES 
 Figure 6. Progression Free Survival (R format) 
 Figure 7. Overall Survival (R format) 
 DATE :  29/11/2022 (version 1.3) 
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 Study GEINO 13 
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 Figure 8. Swimmer plot: patient’s follow-up 
 DATE :  29/11/2022 (version 1.3) 
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 Study GEINO 13 
 STATISTICAL REPORT: TABLES, LISTS AND FIGURES 
 Sponsor: GRUPO ESPAÑOL DE INVESTIGACIÓN EN NEUROONCOLOGÍA 
 Figure 9. Spider plot: % change in lesions’ measurements from baseline 
 Patient  04-001  had  measurements  that  are  considered  outliers  (too  extreme) 
 and  the  spider  graph  has  been  repeated  excluding  that  patient  to  prevent 
 skewing the results. 
 Figure 10. Spider plot: % change in lesions’ measurements from baseline (excluding 
 outlier value) 
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