A Study of PD 0332991 in Patients With Recurrent Rb Positive Glioblastoma

Study Overview
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Brief Summary
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This study will determine the efficacy of the small molecule CDK4/6 inhibitor PD 0332991 (as measured by progression free survival at 6 months) in patients with recurrent glioblastoma multiforme or gliosarcoma who are Rb positive. A total of 30 patients will be treated; 15 will undergo a planned surgical resection and receive drug for 7 days prior to surgery, followed by drug after recovery from surgery, and the other 15 patients will receive drug without a planned surgical procedure.

Detailed Description
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A total of 30 patients with recurrent Glioblastoma or Gliosarcoma will be treated with PD 0332991 at a dose of 125 mg daily for 21 consecutive days followed by a 7 day break off therapy (cycle length is 28 days). Of these 30 patients, 15 will receive drug for 7 days prior to an indicated, intended surgical resection for progression, and will then resume drug at the same dose after recovery from surgery. Treatment will be repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients will be given the option to continue on study past 12 cycles, up to a maximum of 24 cycles. Following registration, available blocks or slides from a previous surgery must be submitted for diagnosis review (confirmation of Glioblastoma multiforme or Gliosarcoma) and Rb status determination. Only patients with Rb positive tumors can be treated, and Rb tumor status must be known prior to any treatment. Additional tissue from previous surgeries will also be obtained to evaluate molecular abnormalities in the tumor. These studies will be done retrospectively and are not required to be performed prior to registration. Monitoring will include a clinical and neurological exam before the beginning of each cycle (every 4 weeks). Complete blood counts with differential will be examined on days 1 and 15 of each cycle. Liver and renal function will be performed every 4 weeks. Toxicity and dose modifications will be based on the NCI CTCAE Version 4. Disease status will be assessed clinically each cycle (every 4 weeks) and radiographically after each second cycle (every 8 weeks).

Official Title
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A Phase II Study of PD 0332991 in Patients With Recurrent Rb Positive Glioblastoma

Conditions
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Glioblastoma, Gliosarcoma, Anaplastic Astrocytoma

Intervention / Treatment
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* Drug: PD 0332991 (pre-surgery)
* Drug: PD 0332991
* Procedure: Resection as clinical care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18 years or older with KPS > 60, with life expectancy of > 8 weeks with radiographically proven recurrent, intracranial Glioblastoma multiforme or Gliosarcoma; patients must have documentation of Rb positive disease. All patients must sign an informed consent and must have signed an authorization for the release of their protected health information. Patients must have had prior external beam radiation and temozolomide chemotherapy; there is no limit to the number of prior chemotherapies used; patients may be treated in their first, second or third relapse Patients must have recovered from the toxic effects of prior therapy Patients must have adequate bone marrow function and renal function before starting therapy. A pre-study EKG with a normal QT interval is required for all patients Patients must have shown unequivocal evidence for tumor progression by MRI scan and on a steroid dose that has been stable for at least 7 days. Patients must have an interval of greater than or equal to 42 days from the completion of radiation therapy to study entry. A subset of 15 patients will be enrolled prior to a planned, indicated surgical resection. Patients can be enrolled pre-operatively only if they are surgical candidates, do not have evidence of an acute intracranial hemorrhage and are able to start protocol treatment in a window of 7 days before surgery. Male and female patients with reproductive potential must use an approved contraceptive method. Women of childbearing potential must have a negative beta-HCG pregnancy test Blocks or slides of tumor tissue from a previous surgery must be available to do IHC Rb staining. Patients with negative tumors (Rb negative) will be excluded from the study. Exclusion Criteria: Patients must not have any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy. Patients with a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are ineligible. Patients on enzyme-inducing anti-epileptic drugs or other drugs that cause CYP3A enzyme induction or inhibition will not be eligible

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Surgical Group<br>PD 0332991 125 mg daily for 7 days prior to an indicated, intended surgical resection as clinical care for progression, and then resume drug at the same dose after recovery from surgery on a repeating schedule of 21 consecutive days of drug followed by a 7 day break off therapy (cycle length is 28 days). Treatment will be repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients will be given the option to continue on study past 12 cycles, up to a maximum of 24 cycles. | Drug: PD 0332991 (pre-surgery)<br>* PD 0332991 for 7 days prior to an indicated, intended surgical resection for progression<br>* Other names: IBRANCE, Pfizer, Inc.;Drug: PD 0332991<br>* PD 0332991 daily for 21 consecutive days followed by a 7 day break off therapy, repeating cycles<br>* Other names: IBRANCE, Pfizer, Inc.;Procedure: Resection as clinical care<br>* Indicated, intended, surgical resection as clinical care<br>|
| Experimental: Non-surgical group<br>Patients not in need of surgery treated with PD 0332991 125 mg daily for 21 consecutive days followed by a 7 day break off therapy (cycle length is 28 days). Treatment will be repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients will be given the option to continue on study past 12 cycles, up to a maximum of 24 cycles. | Drug: PD 0332991<br>* PD 0332991 daily for 21 consecutive days followed by a 7 day break off therapy, repeating cycles<br>* Other names: IBRANCE, Pfizer, Inc.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Efficacy of the small molecule CDK4/6 inhibitor PD 0332991 in patients with recurrent glioblastoma multiforme or gliosarcoma who are Rb positive was measured by progression free survival. A total of 30 patients was intended to be treated; up to 15 patients were to undergo a planned, intended surgical resection and receive drug for 7 days prior to surgery, followed by drug after recovery from surgery; and up to 15 patients were to receive drug without a planned surgical procedure. | up to 142 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | The number of participants with protocol related toxicity described by CTCAE version 4.0 | 1-2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma, Gliosarcoma, Anaplastic astrocytoma, Malignant astrocytoma NOS, Malignant glioma, GBM