Safety and Efficacy of PD0332991 (Palbociclib), a Cyclin-dependent Kinase 4 and 6 Inhibitor, in Patients With Oligodendroglioma or Recurrent Oligoastrocytoma Anaplastic With the Activity of the Protein RB Preserved

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

Official Title
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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

Conditions
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Oligodendroglioma, Oligoastrocytoma

Intervention / Treatment
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* Drug: Palbociclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and sign the informed consent approved by the Ethic Committee. Men or women aged greater than or equal to 18. Patients with oligodendroglioma anaplastic or oligoastrocytoma anaplastic according to WHO classification and histologically confirmed. Note: It can be included patients with oligoastrocytoma or oligodendroglioma G2 only if they have suffered a recurrence in which the diagnosis of the resection were G3. Patients in relapse after radiotherapy and one or two lines of chemotherapy. Note: Both previous radiotherapy and chemotherapy could be received in adjuvant therapy or previous recurrences. It is also accepted to be received concurrent chemoradiotherapy. In the secondary oligodendrogliomas or oligoastrocytomas anaplastic, the patients could have received chemotherapy and radiotherapy when the tumor was G2. All patients have to present positivity in immunohistochemical study for the RB protein in the tumor samples sent to the central lab. The cases must have 10 slides or a tumor block available from a biopsy or surgery. All patients have to show disease progression in a cerebral nuclear magnetic resonance. Interval of at least one week between the previous intracranial biopsy and the inclusion. Interval of at least 12 weeks between radiotherapy and the inclusion, unless: a) Recurrent tumor confirmed histologically b) recurrency showed in the NMR out of radiotherapy. Patients should have been recovered from previous therapies: 28 days since the end of any investigational product and since the end of any cytotoxic treatment. ECOG≤2 Stable or decreasing dose of corticoids during the five days prior to the inclusion patients who have been suffered from a tumor resection in the last recurrence are eligible if: A good surgery recover there is a measurable or evaluable disease after surgery Good bone marrow function: Neutrophils ≥ 1500/mm3 (1.5x10e9/L) Platelet ≥ 100.000/mm3 (100 x 10e9) Hemoglobin ≥ 9 g/dL Seric creatinine ≤ 1.5 x LSN of the site or estimated clearance ≥ 60 ml/min calculated. Bilirubin ≤ 1.5 x LSN (if Gilbert's syndrome ≤ 3 xLSN) AST (SGOT) and/or ALT ≤ 3 x LSN; alkaline phosphatase ≤ 2.5 x LSN. Nor pregnant women nor breast-feeding women. Women with heterosexual activity should have a negative pregnant test before the inclusion in the study. Both women and men should use an accepted contraceptive method during the study treatment and 1 month after treatment completed. Exclusion Criteria: Presence of meningeal carcinomatosis disseminated. Concomitant treatment with other investigational products Previous treatment wih an investigational product that could be active for CDK4/6 Any kind of surgery in the previous 2 weeks Presence of any clinically significant gastrointestinal abnormality that can affect oral administration, transit or absorption of study drug, such as the inability to take medication by mouth as tablets. Presence of any psychiatric or cognitive disorder that limits the understanding or the signature of informed consent and / or jeopardize the fulfillment of the requirements of this protocol. In the 7 days prior to the beginning of the treatment, to have received a treatment with: - Drugs inhibitor of the CYP3A4 - Drugs inductors of the CYP3A4 - Drugs that extends the QT interval QTc interval >480 msec, familiar history or personal of QT large Syndrome, QT short Syndrome, Brugada syndrome, QTc extension or Torsade de Pointes history Electrolyte disorder that may affect the QTc interval Significant or uncontrolled cardiovascular disease, including: Myocardial infarction within the previous 12 months Uncontrolled angina within the previous 6 months Congestive heart failure in the previous 6 months History of clinically significant ventricular arrhythmias of any type (as ventricular tachycardia, ventricular fibrillation or torsades de pointes) History of second or third grade heart block (these patients may be eligible if you currently have a pacemaker) Ictus Pulmonary embolism History of any cancer, except for the following circumstances: Patients with a history of other malignancies are eligible if they have been free of disease for at least the last 3 years, and at the discretion of the investigator, there is low risk of disease recurrence. Patients with the following cancers are eligible even if they are diagnosed and treated in the last 3 years: carcinoma in situ of the cervix and basal cell or basal cell skin carcinoma. Patients are ineligible if there is evidence of any neoplastic disease that required therapy other than surgery in the past 3 years. Patients positive for HIV Inflammatory bowel disease, chronic diarrhea, short gut syndrome or any upper gastrointestinal surgery including gastric resection. History of allergic reactions to Palbociclib Another acute or chronic serious medical condition, uncontrolled intercurrent illness or laboratory abnormality that may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of test results and that,investigator's discretion, make the patient inappropriate for entry into this trial. Uncontrolled intercurrent illness including, but are not limited to, ongoing or active infection or psychiatric illness / social situations that limit the compliance of study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib (PD0332991)<br>Palbociclib will be administrated orally at a dose of 125 mg/day during 21 days followed by a break of 7 days. All patients included will be treated in the same arm. Treatment will be administrated until disease progression, unacceptable adverse side effects or study end. | Drug: Palbociclib<br>* Palbociclib will be administered orally at a dose of 125 mg/day, until disease progression, unacceptable adverse side effects or study end.<br>* Other names: PD0332991;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) at six months (PFS6m) | Percentage of patients who have progressed / no progress after 6 months of treatment | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of oral administration of PD0332991 (reported adverse events, physical examinations and laboratory tests. Toxicity will be classified and tabulated by NCI-CTCAE v 4.0.) | Type, incidence, severity, frequency, severity and relationship with IMP of reported adverse events, physical examinations and laboratory tests. Toxicity will be classified and tabulated by NCI-CTCAE v 4.0. | Three years | 
| Anti-tumor response according to RANO criteria | According to RANO criteria, assessed by the PI of each center. There will be a central review. | 30 months | 
| Overall survival (OS) | Time from randomization to death by any cause. | 30 months | 
| Response duration | Time from first objective response up to disease progression according RANO (in patients with objective responses). | 30 months | 
| Changes in the use of glucocorticoids | Percentage of patients decreasing doses of corticosteroids during treatment. | 30 months | 
| Changes in neurological status. | By means of minimental test, it will be determined the changes in neurological status of patients. | 30 months | 
| Tumor biomarkers assessment | It will be evaluated whether some biomarkers are related with the Progression Free Survival/Overall survival and response rates. The following biomarkers will be assessed: Deletions in CDKN2A, CDKN2B, 1p, 19q; mutations in IDH, amplifications in CDK4, CDK6, cyclin D. | 30 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Palbociclib, oligodendroglioma, oligoastrocytoma anaplastic