Plerixafor After Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed High Grade Glioma

• Sponsor: Lawrence Recht (Other)
• Overall Status: Completed
• CT.gov ID: NCT01977677
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 30
• Location: 1
• Arm: 1
• Duration (Months): 46
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

This pilot phase I/II trial studies the side effects and best dose of plerixafor after radiation therapy and temozolomide and to see how well it works in treating patients with newly diagnosed high grade glioma. Plerixafor may stop the growth of tumor cells by blocking blood flow to the tumor. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x rays to kill tumor cells. Giving plerixafor after radiation therapy and temozolomide may be an effective treatment for high grade glioma.

Condition or Disease	Intervention/Treatment	Phase
Adult Ependymoblastoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Oligodendroglial Tumors; Adult Pineoblastoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET)	Radiation: radiation therapy; Drug: temozolomide; Drug: plerixafor; Other: laboratory biomarker analysis; Other: pharmacological study	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the safety of using continuous infusion Plerixafor subsequent to irradiation in patients with newly diagnosed glioblastoma multiforme (GBM).

2. To assess the efficacy of Plerixafor as measured by progression free survival at 6 months (PFS6) from the start of irradiation.

OUTLINE: This is a phase I, dose-escalation study of plerixafor followed by a phase II study.

Within 4 weeks of surgery, patients undergo radiation therapy and receive temozolomide orally (PO) over 42 days. Beginning 8 days prior to completion of chemoradiotherapy, patients receive plerixafor intravenously (IV) continuously for 2-4 weeks. Patients also receive temozolomide PO 5 days a month beginning 35 days after completion of radiation therapy.

After completion of study treatment, patients are followed up every 12 weeks for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of Local Field Irradiation and Temozolomide Followed by Continuous Infusion Plerixafor as an Upfront Therapy for Newly Diagnosed Glioblastoma GBM
• Study Start Date: Nov 1, 2014
• Actual Primary Completion Date: Nov 1, 2017
• Actual Study Completion Date: Sep 1, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (radiation therapy, temozolomide, plerixafor) Within 4 weeks of surgery, patients undergo radiation therapy and receive temozolomide PO over 42 days. Beginning 8 days prior to completion of chemoradiotherapy, patients receive plerixafor IV continuously for 2-4 weeks. Patients also receive temozolomide PO 5 days a month beginning 35 days after completion of radiation therapy.

Radiation: radiation therapy; Undergo radiation therapy; Other Names: irradiation radiotherapy therapy, radiation ; Drug: temozolomide; Given PO; Other Names: SCH 52365 Temodal Temodar TMZ ; Drug: plerixafor; Given IV; Other Names: AMD 3100 Mozobil ; Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies

Outcome Measures

Primary Outcome Measures

1. Dose-limiting Toxicity [Up to 30 days post plerixafor]

   Dose Limiting Toxicity is defined as defined as any hematologic or on-hematologic adverse events grade 3 or higher using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 with a suspected causal relationship to Plerixafor (including electrocardiogram changes indicative of ischemia, ventricular tachycardia)

2. Participants Alive and Without Disease Progression At 6 Months After the Start of the Irradiation [6 months from start of irradiation]

   Progression free survival based on the Response Assessment for Neuro-Oncology (RANO) criteria, using both clinical examinations and MRIs with and without contrast summarized with Kaplan Meier estimates.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have tissue confirmation of high grade (WHO Grade IV) glioma including but not limited to glioblastoma, gliosarcoma, glioblastoma with oligodendroglial features, glioblastoma with PNET features.

• The patient must have post-operative contrast enhanced imaging (CT or MRI) unless only biopsy performed (in which case post-operative imaging is not routinely obtained. In these patients, the preoperative study will serve as baseline.

• Patient should have surgery (biopsy, partial resection or gross total resection) and no additional anti-cancer therapy except the chemoradiation as specified in the protocol.

• For those patients in which steroids are clinically indicated, there must be a stable or decreasing dose of steroid medication for ≥ one week prior to the start of infusion.

• Patients must be between the ages of 18 and 75 years old.

• Patients must have Karnofsky Performance score ≥ 60.

• Adequate organ function is needed at time of screening visit including:

• ANC ≥ 1500

• Platelets ≥ 100,000 ml

• Serum Creatinine ≤ 1.5mg/dl; Cr Clearance should be >50 mL/min

• AST and ALT ≤ 3 times the upper limit of normal

• If female of childbearing potential, negative pregnancy test

• The patient or his/her legal representative must have the ability to understand and willingness to sign a written informed consent document.

• Patient agrees to use an effective method of contraception (hormonal or two barrier methods) while on study and for at least 3 months following the Plerixafor infusion

Exclusion Criteria:

• Prior or concurrent treatment with Avastin (bevacizumab)

• Prior exposure to Plerixafor

• Prior use of other investigational agents to treat the brain tumor

• Recent history of myocardial infarct (less than 3 months) or history of active angina or arrhythmia

• Prior malignancy except previously diagnosed and definitively treated more than 3 years prior to trial or whose prognosis is deemed good enough to not warrant surveillance

• Prior sensitivity to Plerixafor

• Pregnant or patients who are breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University, School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Lawrence Recht
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Lawrence Recht, Stanford University Hospitals and Clinics

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 29, 2015

More Information

Publications

None provided.

• Responsible Party: Lawrence Recht, Professor of Neurology, Stanford University
• ClinicalTrials.gov Identifier: NCT01977677
• Other Study ID Numbers: BRN0023; NCI-2013-02012; BRN0023; P30CA124435
• First Posted: Nov 7, 2013
• Last Update Posted: Oct 23, 2018
• Last Verified: Sep 1, 2018

• Additional relevant MeSH terms: Glioblastoma; Glioma; Gliosarcoma; Medulloblastoma; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Pinealoma; Sarcoma, Ewing; Neuroectodermal Tumors, Primitive, Peripheral; Plerixafor; Temozolomide

Study Results

Participant Flow

Recruitment Details	A total of 30 patients were enrolled at one study center.
Pre-assignment Detail	A total of 32 subjects were screened. One was a screen failure, one withdrew consent prior to initiating the infusion. Twenty-nine subjects enrolled and completed the 28 day Plerixafor infusion. One subject enrolled but did not complete the infusion due to an unrelated adverse event.

Arm/Group Title	Escalation: Plerixafor 200 mcg/kg/Day	Escalation: Plerixafor 400 mcg/kg/Day	Expansion: Plerixafor 400 mcg/kg/Day
Arm/Group Description	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 200 mcg/kg/day over 4 weeks.	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 400 mcg/kg/day over 4 weeks.	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 400 mcg/kg/day over 4 weeks.
Period Title: Overall Study
STARTED	3	6	21
COMPLETED	3	6	20
NOT COMPLETED	0	0	1

Baseline Characteristics

Arm/Group Title	Escalation: Plerixafor 200 mcg/kg/Day	Escalation: Plerixafor 400 mcg/kg/Day	Expansion: Plerixafor 400 mcg/kg/Day	Total
Arm/Group Description	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 200 mcg/kg/day over 4 weeks.	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 400 mcg/kg/day over 4 weeks.	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 400 mcg/kg/day over 4 weeks.	Total of all reporting groups
Overall Participants	3	6	20	29
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 66.7%	3 50%	15 75%	20 69%
>=65 years	1 33.3%	3 50%	5 25%	9 31%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64	62	60	60
Sex: Female, Male (Count of Participants)
Female	2 66.7%	2 33.3%	5 25%	9 31%
Male	1 33.3%	4 66.7%	15 75%	20 69%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	1 5%	1 3.4%
Not Hispanic or Latino	3 100%	6 100%	19 95%	28 96.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 16.7%	4 20%	5 17.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	2 10%	2 6.9%
White	3 100%	5 83.3%	14 70%	22 75.9%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%	6 100%	20 100%	29 100%

Outcome Measures

1. Primary Outcome

Title	Dose-limiting Toxicity
Description	Dose Limiting Toxicity is defined as defined as any hematologic or on-hematologic adverse events grade 3 or higher using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 with a suspected causal relationship to Plerixafor (including electrocardiogram changes indicative of ischemia, ventricular tachycardia)
Time Frame	Up to 30 days post plerixafor

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Escalation: Plerixafor 200 mcg/kg/Day	Escalation: Plerixafor 400 mcg/kg/Day	Expansion: Plerixafor 400 mcg/kg/Day
Arm/Group Description	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 200 mcg/kg/day over 4 weeks.	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 400 mcg/kg/day over 4 weeks.	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 400 mcg/kg/day over 4 weeks.
Measure Participants	3	6	21
Count of Participants [Participants]	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Participants Alive and Without Disease Progression At 6 Months After the Start of the Irradiation
Description	Progression free survival based on the Response Assessment for Neuro-Oncology (RANO) criteria, using both clinical examinations and MRIs with and without contrast summarized with Kaplan Meier estimates.
Time Frame	6 months from start of irradiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Escalation: Plerixafor 200 mcg/kg/Day	Escalation: Plerixafor 400 mcg/kg/Day	Expansion: Plerixafor 400 mcg/kg/Day
Arm/Group Description	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 200 mcg/kg/day over 4 weeks.	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 400 mcg/kg/day over 4 weeks.	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 400 mcg/kg/day over 4 weeks.
Measure Participants	3	6	20
Count of Participants [Participants]	3 100%	5 83.3%	19 95%

Adverse Events

Time Frame	Up to 30 days after Plerixafor Infusion
Arm/Group Title	Escalation: Plerixafor 200 mcg/kg/Day		Escalation: Plerixafor 400 mcg/kg/Day		Expansion: Plerixafor 400 mcg/kg/Day
Arm/Group Description	One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 200 mcg/kg/day over 4 weeks.		One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 400 mcg/kg/day over 4 weeks.		One week prior to the completion of radiotherapy with concurrent temozolomide, patients with newly diagnosed glioblastoma will receive continuous infusion of Plerixafor at a dose of 400 mcg/kg/day over 4 weeks.
All Cause Mortality
	Escalation: Plerixafor 200 mcg/kg/Day		Escalation: Plerixafor 400 mcg/kg/Day		Expansion: Plerixafor 400 mcg/kg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/6 (0%)		1/21 (4.8%)
Serious Adverse Events
	Escalation: Plerixafor 200 mcg/kg/Day		Escalation: Plerixafor 400 mcg/kg/Day		Expansion: Plerixafor 400 mcg/kg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		0/6 (0%)		3/21 (14.3%)
Gastrointestinal disorders
Abdominal Pain	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Disease Progression	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Pseudoprogression	1/3 (33.3%)	1	0/6 (0%)	0	0/21 (0%)	0
Hemorrhagic hepatic cyst	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Nervous system disorders
Encephalopathy	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	Escalation: Plerixafor 200 mcg/kg/Day		Escalation: Plerixafor 400 mcg/kg/Day		Expansion: Plerixafor 400 mcg/kg/Day
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		6/6 (100%)		21/21 (100%)
Blood and lymphatic system disorders
Anemia	0/3 (0%)	0	0/6 (0%)	0	2/21 (9.5%)	2
Cardiac disorders
Supraventricular Tachycardia	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Ear and labyrinth disorders
Tinnitus	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Eye disorders
Conjunctivitis	1/3 (33.3%)	1	3/6 (50%)	3	0/21 (0%)	0
Dry Eyes	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Eye Pain	0/3 (0%)	0	1/6 (16.7%)	1	0/21 (0%)	0
Floaters	1/3 (33.3%)	1	0/6 (0%)	0	0/21 (0%)	0
Watering Eyes	1/3 (33.3%)	1	0/6 (0%)	0	0/21 (0%)	0
Gastrointestinal disorders
Diarrhea	2/3 (66.7%)	2	2/6 (33.3%)	2	3/21 (14.3%)	3
Nausea	0/3 (0%)	0	3/6 (50%)	3	3/21 (14.3%)	3
Dyspepsia	1/3 (33.3%)	1	1/6 (16.7%)	1	1/21 (4.8%)	1
Abdominal Pain	0/3 (0%)	0	1/6 (16.7%)	1	0/21 (0%)	0
Vomiting	0/3 (0%)	0	1/6 (16.7%)	1	2/21 (9.5%)	2
Gastroesophageal reflux disease	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Gastrointestinal Pain	0/3 (0%)	0	1/6 (16.7%)	1	0/21 (0%)	0
Oral dysesthesia	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
General disorders
Fatigue	1/3 (33.3%)	1	1/6 (16.7%)	1	6/21 (28.6%)	6
Gait Disturbance	0/3 (0%)	0	0/6 (0%)	0	2/21 (9.5%)	2
Pain	0/3 (0%)	0	0/6 (0%)	0	2/21 (9.5%)	2
Fever	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Localized Edema	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Immune system disorders
Allergic Reaction	1/3 (33.3%)	1	1/6 (16.7%)	1	0/21 (0%)	0
Enhanced immune response	0/3 (0%)	0	1/6 (16.7%)	1	0/21 (0%)	0
Infections and infestations
Bone infection	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Thrush	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Skin Infection	0/3 (0%)	0	1/6 (16.7%)	1	0/21 (0%)	0
Upper respiratory tract infection	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Investigations
Platelet count decreased	0/3 (0%)	0	1/6 (16.7%)	1	2/21 (9.5%)	2
Cardiac Troponin 1 increased	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
INR increased	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Lymphocyte count decreased	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
White blood cell decreased	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Metabolism and nutrition disorders
Hypokalemia	1/3 (33.3%)	1	0/6 (0%)	0	1/21 (4.8%)	1
Hyperkalemia	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Hypocalcemia	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/3 (33.3%)	1	0/6 (0%)	0	0/21 (0%)	0
Nervous system disorders
Headache	1/3 (33.3%)	1	2/6 (33.3%)	2	4/21 (19%)	4
Dizziness	0/3 (0%)	0	0/6 (0%)	0	4/21 (19%)	4
Parasthesia	1/3 (33.3%)	1	1/6 (16.7%)	1	0/21 (0%)	0
Seizure	0/3 (0%)	0	0/6 (0%)	0	2/21 (9.5%)	2
Cognitive Disturbance	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Dysgeusia	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Facial Muscle Weakness	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Memory Impairment	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Tremor	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Psychiatric disorders
Insomnia	1/3 (33.3%)	1	4/6 (66.7%)	4	7/21 (33.3%)	7
Confusion	0/3 (0%)	0	1/6 (16.7%)	1	0/21 (0%)	0
Hallucinations	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Bad dreams	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Renal and urinary disorders
Hematuria	0/3 (0%)	0	1/6 (16.7%)	1	0/21 (0%)	0
Respiratory, thoracic and mediastinal disorders
allergic Rhinitis	0/3 (0%)	0	1/6 (16.7%)	1	0/21 (0%)	0
Skin and subcutaneous tissue disorders
wart like growth	1/3 (33.3%)	1	0/6 (0%)	0	0/21 (0%)	0
Rash maculopapular	0/3 (0%)	0	1/6 (16.7%)	1	1/21 (4.8%)	1
Bullous Dermatitis	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Allergic dermatitis	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Rash Spots on head	0/3 (0%)	0	0/6 (0%)	0	1/21 (4.8%)	1
Vascular disorders
Hot Flashes	1/3 (33.3%)	1	2/6 (33.3%)	2	5/21 (23.8%)	5
Hypertension	1/3 (33.3%)	1	0/6 (0%)	0	0/21 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.