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

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).

Inclusion Criteria:

- Patients with radiographically proven recurrent, intracranial Glioblastoma multiforme
or Gliosarcoma will be eligible for this protocol. Patients must have documentation
of Rb positive disease.

- All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study. Patients must have signed an authorization for
the release of their protected health information. Patients must be registered prior
to treatment with study drug. Treatment must take place within 7 days of
registration; if treatment is delayed more than 7 days, the laboratory tests for
eligibility and history and physical exam must be repeated.

- 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 be > 18 years old, and with a life expectancy > 8 weeks.

- Patients must have a Karnofsky Performance Status of > 60.

- At the time of registration: Patients must have recovered from the toxic effects of
prior therapy: > 28 days from any investigational agent [NOTE: off-label use of FDA
approved agents are not considered investigational for the purposes of this
protocol], >28 days from prior cytotoxic therapy, >42 days from nitrosoureas, > 28
days from bevacizumab, and >7 days for non-cytotoxic agents, e.g., interferon,
tamoxifen, thalidomide, cis-retinoic acid, and erlotinib, for example. Any questions
related to the definition of non-cytotoxic agents should be directed to the Study
Chair.

- Patients must have adequate bone marrow function (WBC > 3,000/µl, ANC > 1,500/mm3,
platelet count of > 100,000/mm3, and hemoglobin > 10 gm/dl), adequate liver function
(SGOT and bilirubin < 2 times ULN), and adequate renal function (creatinine < 1.5
mg/dL) before starting therapy. A pre-study EKG is required for all patients, and
patients must have a normal QT interval. These tests must be performed within 14
days prior to registration. Eligibility level for hemoglobin may be reached by
transfusion.

- Patients must have shown unequivocal radiographic evidence for tumor progression by
MRI scan. A scan should be performed within 14 days prior to registration and on a
steroid dose that has been stable for at least 7 days. If the steroid dose is
increased between the date of imaging and registration a new baseline MRI is
required. The same type of scan, i.e., MRI must be used throughout the period of
protocol treatment for tumor measurement. Patients unable to undergo MR imaging will
not be eligible.

- Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply:

- They have recovered from the effects of surgery.

- Residual disease following resection of recurrent intracranial Glioblastoma
Multiforme or Gliosarcoma is not mandated for eligibility into the study. To
best assess the extent of residual disease post-operatively, an MRI should be
done no later than 96 hours in the immediate post-operative period or at least 4
weeks post-operatively, within 14 days prior to registration. If the 96-hour
scan is more than 14 days before registration, the scan needs to be repeated.
If the steroid dose is increased between the date of imaging and registration, a
new baseline MRI is required on a stable steroid dosage for at least 7 days.

- Patients must have failed prior radiation therapy and temozolomide and must have an
interval of greater than or equal to 42 days from the completion of radiation therapy
to study entry.

- Patients with prior therapy that included interstitial brachytherapy, stereotactic
radiosurgery, or Gliadel wafers must have confirmation of true progressive disease
rather than radiation necrosis based upon PET scanning, MR spectroscopy or surgical
documentation of disease.

- 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, if appropriate (for example, intrauterine device [IUD], birth
control pills, or barrier device) during and for 3 months after discontinuation of
study treatment. Women of childbearing potential must have a negative beta-HCG
pregnancy test documented within 14 days prior to registration.

- 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 must not have an active infection or serious intercurrent medical illness.
Patients with a history of acute intracranial hemorrhage will also be excluded.

- Patients must not be pregnant/breast feeding and must agree to practice adequate
contraception.

- Patients must not have any disease that will obscure toxicity or dangerously alter
drug metabolism.

- Because of the potential for drug interactions, patients on enzyme-inducing
anti-epileptic drugs or other drugs that cause CYP3A enzyme induction or inhibition
will not be eligible unless they are off therapy for at least 14 days

- Patients with congenital or other reasons for prolongation of the QT interval on
EKG will be excluded