Phase II Pilot, Prospective, Open Label, Multicenter CT, to Evaluate the Safety and Efficacy of Palbociclib (PD0332991), a Cyclin-dependent Kinase 4 and 6 (CDK4 and CDK6) Inhibitor, in Patients With Oligodendroglioma or Recurrent Oligoastrocytoma Anaplastic With the Activity of the Protein RB Preserved
Phase: PHASE2
Conditions: Oligodendroglioma, Oligoastrocytoma
Sponsor: Grupo Español de Investigación en Neurooncología

‭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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