PD0332991: A Study of PD 0332991 in Patients With Recurrent Rb Positive Glioblastoma

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01227434
• Collaborator: Pfizer (Industry)
• Enrollment: 23
• Location: 1
• Arms: 2
• Duration (Months): 39
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma; Gliosarcoma; Anaplastic Astrocytoma	Drug: PD 0332991 (pre-surgery); Drug: PD 0332991; Procedure: Resection as clinical care	Phase 2

Detailed Description

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of PD 0332991 in Patients With Recurrent Rb Positive Glioblastoma
• Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Surgical Group 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); PD 0332991 for 7 days prior to an indicated, intended surgical resection for progression; Other Names: Pfizer PD 0332991 palbociclib IBRANCE, Pfizer, Inc. ; Drug: PD 0332991; PD 0332991 daily for 21 consecutive days followed by a 7 day break off therapy, repeating cycles; Other Names: Pfizer PD 0332991 palbociclib IBRANCE, Pfizer, Inc. ; Procedure: Resection as clinical care; Indicated, intended, surgical resection as clinical care
Experimental: Non-surgical group 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; PD 0332991 daily for 21 consecutive days followed by a 7 day break off therapy, repeating cycles; Other Names: Pfizer PD 0332991 palbociclib IBRANCE, Pfizer, Inc.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival [up to 142 weeks]

   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.

Secondary Outcome Measures

1. Number of Participants With Adverse Events as a Measure of Safety and Tolerability [1-2 years]

   The number of participants with protocol related toxicity described by CTCAE version 4.0

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143

Sponsors and Collaborators

• University of California, San Francisco
• Pfizer

Investigators

• Principal Investigator: Michael D Prados, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01227434
• Other Study ID Numbers: 10105
• First Posted: Oct 25, 2010
• Last Update Posted: Jul 17, 2015
• Last Verified: Jun 1, 2015

• Keywords provided by University of California, San Francisco: Glioblastoma; Gliosarcoma; Anaplastic astrocytoma; Malignant astrocytoma NOS; Malignant glioma; GBM
• Additional relevant MeSH terms: Glioblastoma; Astrocytoma; Gliosarcoma; Palbociclib

Study Results

Participant Flow

Pre-assignment Detail	Of 23 participants consented, 1 was found ineligible prior to randomization

Arm/Group Title	Surgical Group	Non-surgical Group
Arm/Group Description	PD 0332991 125 mg daily for 7 days prior to an indicated, surgical resection for progression, and 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 repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients given the option to continue on study past 12 cycles, up to a maximum of 24 cycles.	Patients not in need of surgery 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). Treatment repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients given the option to continue on study past 12 cycles, up to a maximum of 24 cycles.
Period Title: Overall Study
STARTED	6	16
COMPLETED	6	16
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Surgical Group	Non-surgical Group	Total
Arm/Group Description	PD 0332991 125 mg daily for 7 days prior to an indicated, intended surgical resection 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 repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients given the option to continue on study past 12 cycles, up to a maximum of 24 cycles.	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 repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients given the option to continue on study past 12 cycles, up to a maximum of 24 cycles.	Total of all reporting groups
Overall Participants	6	16	22
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	5 83.3%	14 87.5%	19 86.4%
>=65 years	1 16.7%	2 12.5%	3 13.6%
Sex: Female, Male (Count of Participants)
Female	3 50%	7 43.8%	10 45.5%
Male	3 50%	9 56.3%	12 54.5%
Region of Enrollment (participants) [Number]
United States	6 100%	16 100%	22 100%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival
Description	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.
Time Frame	up to 142 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Surgical Group	Non-surgical Group
Arm/Group Description	PD 0332991 125 mg daily for 7 days prior to an indicated, intended surgical resection 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 repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients given the option to continue on study past 12 cycles, up to a maximum of 24 cycles.	Patients not requiring 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 repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients given the option to continue on study past 12 cycles, up to a maximum of 24 cycles.
Measure Participants	6	16
Mean (Full Range) [weeks]	4	14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Surgical Group, Non-surgical Group
	Comments	Compared to historical estimates of PFS-6 months. With 30 patients, there would be 90% power to detect an improvement in the PFS-6 months rate from 10% (historical estimate) to 30% based on a one-sided exact test with alpha=0.1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.10
	Comments
	Method	Exact binomial distribution
	Comments
Method of Estimation	Estimation Parameter	Exact binomial distribution
	Estimated Value	0.10
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Surgical Group	Non-surgical Group
Arm/Group Description	PD 0332991 at a dose of 125 mg daily for 7 days prior to an indicated, intended surgical resection 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 repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients given the option to continue on study past 12 cycles, up to a maximum of 24 cycles.	Patients not requiring 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 repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients given the option to continue on study past 12 cycles, up to a maximum of 24 cycles.
Measure Participants	6	16
Number [participants]	6 100%	16 100%

Adverse Events

Time Frame	3 years
Adverse Event Reporting Description	Adverse events were collected from date of first drug, until 30 days following completion of study treatment
Arm/Group Title	Surgical Group		Non-surgical Group
Arm/Group Description	PD 0332991 125 mg daily for 7 days prior to an indicated, intended surgical resection 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 repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients given the option to continue on study past 12 cycles, up to a maximum of 24 cycles.		Patients not requiring 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 repeated every 28 days, and in the absence of disease progression patients may receive treatment for 12 cycles. At that time patients given the option to continue on study past 12 cycles, up to a maximum of 24 cycles.
All Cause Mortality
	Surgical Group		Non-surgical Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Surgical Group		Non-surgical Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		4/16 (25%)
Gastrointestinal disorders
Abdominal Pain	0/6 (0%)	0	1/16 (6.3%)	1
Mucositis	0/6 (0%)	0	1/16 (6.3%)	1
General disorders
Death NOS	1/6 (16.7%)	1	2/16 (12.5%)	2
Infections and infestations
Meningitis	1/6 (16.7%)	1	0/16 (0%)	0
Wound Infection	1/6 (16.7%)	2	0/16 (0%)	0
Lung Infection	0/6 (0%)	0	1/16 (6.3%)	1
Musculoskeletal and connective tissue disorders
Muscle Weakness	1/6 (16.7%)	1	0/16 (0%)	0
Nervous system disorders
Cerebral Spinal Fluid Leakage	1/6 (16.7%)	1	0/16 (0%)	0
Cognitive disturbance	1/6 (16.7%)	1	0/16 (0%)	0
Headache	2/6 (33.3%)	2	1/16 (6.3%)	1
Seizure	2/6 (33.3%)	2	0/16 (0%)	0
Peripheral Motor Neuropathy	0/6 (0%)	0	1/16 (6.3%)	1
Other (Not Including Serious) Adverse Events
	Surgical Group		Non-surgical Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)		15/16 (93.8%)
Cardiac disorders
Atrial fibrillation	0/6 (0%)		1/16 (6.3%)
Sinus tachycardia	1/6 (16.7%)		2/16 (12.5%)
Ear and labyrinth disorders
Tinnitus	1/6 (16.7%)		0/16 (0%)
Endocrine disorders
Cushingoid	0/6 (0%)		1/16 (6.3%)
Eye disorders
Blurred vision	1/6 (16.7%)		0/16 (0%)
Right upper quadrant defect	1/6 (16.7%)		0/16 (0%)
Gastrointestinal disorders
Abdominal pain	0/6 (0%)		1/16 (6.3%)
Constipation	0/6 (0%)		3/16 (18.8%)
Diarrhea	1/6 (16.7%)		0/16 (0%)
Dyspepsia	0/6 (0%)		1/16 (6.3%)
Stool urgency	0/6 (0%)		1/16 (6.3%)
Food craving	0/6 (0%)		1/16 (6.3%)
Stomach discomfort	1/6 (16.7%)		0/16 (0%)
Hemorrhoidal hemorrhage	0/6 (0%)		1/16 (6.3%)
Mucositis Oral	0/6 (0%)		4/16 (25%)
Nausea	1/6 (16.7%)		3/16 (18.8%)
Vomiting	0/6 (0%)		2/16 (12.5%)
General disorders
Death NOS	1/6 (16.7%)		2/16 (12.5%)
Edema limbs	1/6 (16.7%)		1/16 (6.3%)
Fatigue	2/6 (33.3%)		7/16 (43.8%)
Flu like symptoms	0/6 (0%)		1/16 (6.3%)
Gait disturbance	0/6 (0%)		2/16 (12.5%)
Groin pain	0/6 (0%)		2/16 (12.5%)
Infections and infestations
Bronchial infection	0/6 (0%)		1/16 (6.3%)
Eye infection	0/6 (0%)		1/16 (6.3%)
Lung infection	0/6 (0%)		1/16 (6.3%)
Meningitis	1/6 (16.7%)		0/16 (0%)
Skin infection	0/6 (0%)		1/16 (6.3%)
Upper respiratory infection	0/6 (0%)		1/16 (6.3%)
Wound infection	0/6 (0%)		1/16 (6.3%)
Injury, poisoning and procedural complications
Bruising	0/6 (0%)		1/16 (6.3%)
Investigations
Alanine aminotransferase increased	2/6 (33.3%)		0/16 (0%)
Aspartate aminotransferase increased	1/6 (16.7%)		0/16 (0%)
Lymphocyte count decreased	2/6 (33.3%)		7/16 (43.8%)
Neutrophil count decreased	0/6 (0%)		8/16 (50%)
Platelet count decreased	1/6 (16.7%)		5/16 (31.3%)
Weight gain	0/6 (0%)		2/16 (12.5%)
White blood cell decreased	0/6 (0%)		5/16 (31.3%)
Metabolism and nutrition disorders
Anorexia	0/6 (0%)		1/16 (6.3%)
Dehydration	0/6 (0%)		1/16 (6.3%)
Hyperglycemia	0/6 (0%)		1/16 (6.3%)
Hyponatremia	1/6 (16.7%)		0/16 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/6 (0%)		1/16 (6.3%)
Generalized muscle weakness	1/6 (16.7%)		2/16 (12.5%)
Muscle weakness-left sided	1/6 (16.7%)		2/16 (12.5%)
Muscle weakness lower limb	0/6 (0%)		1/16 (6.3%)
Muscle weakness right-sided	1/6 (16.7%)		0/16 (0%)
Muscle weakness upper limb	1/6 (16.7%)		2/16 (12.5%)
Hip and shoulder pain	0/6 (0%)		1/16 (6.3%)
Pain in chest and shoulder-from fall	0/6 (0%)		1/16 (6.3%)
Myalgia	1/6 (16.7%)		1/16 (6.3%)
Pain in extremity	0/6 (0%)		1/16 (6.3%)
Nervous system disorders
Ataxia	0/6 (0%)		2/16 (12.5%)
Cerebrospinal fluid leakage	1/6 (16.7%)		0/16 (0%)
Cognitive disturbance	2/6 (33.3%)		1/16 (6.3%)
Dysarthria	0/6 (0%)		1/16 (6.3%)
Dysphasia	1/6 (16.7%)		3/16 (18.8%)
Facial nerve disorder	0/6 (0%)		2/16 (12.5%)
Headache	2/6 (33.3%)		8/16 (50%)
Hydrocephalus	1/6 (16.7%)		0/16 (0%)
Intracranial hemorrhage	1/6 (16.7%)		0/16 (0%)
Memory impairment	0/6 (0%)		3/16 (18.8%)
Trouble reading	0/6 (0%)		1/16 (6.3%)
Neglect	0/6 (0%)		1/16 (6.3%)
Decreased coordination	0/6 (0%)		1/16 (6.3%)
L UQ VF neglect	0/6 (0%)		1/16 (6.3%)
Intraventricular hemorrhage	1/6 (16.7%)		0/16 (0%)
Peripheral motor neuropathy	1/6 (16.7%)		0/16 (0%)
Peripheral sensory neuropathy	0/6 (0%)		1/16 (6.3%)
Seizure	2/6 (33.3%)		0/16 (0%)
Spasticity	0/6 (0%)		1/16 (6.3%)
Tremor	0/6 (0%)		1/16 (6.3%)
Psychiatric disorders
Agitation	1/6 (16.7%)		0/16 (0%)
Anxiety	1/6 (16.7%)		3/16 (18.8%)
Confusion	0/6 (0%)		1/16 (6.3%)
Depression	0/6 (0%)		2/16 (12.5%)
Insomnia	1/6 (16.7%)		3/16 (18.8%)
Renal and urinary disorders
Urinary frequency	0/6 (0%)		1/16 (6.3%)
Urinary incontinence	0/6 (0%)		3/16 (18.8%)
Urinary urgency	0/6 (0%)		1/16 (6.3%)
Reproductive system and breast disorders
Painful lump	0/6 (0%)		1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/6 (16.7%)		1/16 (6.3%)
Atelectasis	0/6 (0%)		1/16 (6.3%)
Cough	0/6 (0%)		2/16 (12.5%)
Dyspnea	0/6 (0%)		1/16 (6.3%)
Epistaxis	0/6 (0%)		3/16 (18.8%)
Hoarseness	0/6 (0%)		1/16 (6.3%)
Nasal congestion	0/6 (0%)		1/16 (6.3%)
Productive cough	0/6 (0%)		1/16 (6.3%)
Sore throat	0/6 (0%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Alopecia	0/6 (0%)		1/16 (6.3%)
Dry skin	0/6 (0%)		1/16 (6.3%)
Erythema multiforme	0/6 (0%)		1/16 (6.3%)
Pain of skin	1/6 (16.7%)		0/16 (0%)
Rash maculo-papular	0/6 (0%)		1/16 (6.3%)
Strial rash	0/6 (0%)		1/16 (6.3%)
Minor skin changes	0/6 (0%)		1/16 (6.3%)
Skin hyperpigmentation	0/6 (0%)		1/16 (6.3%)
Vascular disorders
Hematoma	0/6 (0%)		1/16 (6.3%)
Thromboembolic event	1/6 (16.7%)		0/16 (0%)
Deep vein thrombosis (DVT)	0/6 (0%)		1/16 (6.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.