MDACC Study Summary 2007-0816

Study Summary
No. 2007-0816:.......Brain; CNS......John DeGroot......Neuro Oncology

Study Summary Title



Study Summary Number:	2007-0816

Study Title:	A Phase 2 Study of XL184 in Subjects with Progressive or Recurrent Glioblastoma Multiforme in First or Second Relapse

Physician

New Patient Referral



Name:	John DeGroot	Patients Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Dept:	Neuro Oncology	Referring MD Call:	800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)

Phone:	713-792-2883 Contact us about clinical trials

General Information



Disease Group:	Brain CNS	Supported By:	Exelixis, Inc.

Phase of Study:	Phase II	Return Visit:	Every 2 weeks for first 2 cycles, then every 4 weeks for cycles 3 and beyond. (Groups A&B) Every 2 weeks for first cycle, then every 3 weeks for cycles 2 and beyond. (Group C)

Treatment Agents:	XL184	Home Care:	Patient will take the study drug at home

Treatment Loc:	Both at MDACC & outside MDACC at one or more Collaborating Sites or Institutions

Estimated Length of Stay in Houston:	N/A


Description/ Intervention:	The goal of this clinical research study is to learn if XL184 can help to slow or stop the growth of glioblastoma. The safety of XL184 will also be studied.

Study Objectives / Outcomes

Primary objectives

To evaluate objective response rate (ORR) for subjects with recurrent or progressive glioblastoma multiforme(GBM) following treatment with XL184

To evaluate the safety and tolerability of XL184 in this population

Secondary objectives

To assess duration of response, 6-month and median PFS, and overall survival

To further characterize the PK and pharmacodynamic parameters of XL184

To correlate the pathway dysfunction of GBM-relevant genes such
as MET and of relevant downstream signaling molecules with clinical outcome

To correlate changes in serial vascular magnetic resonance imaging (vascular MRI)
with clinical outcome

To analyze tumor volumetrics based on MRI

To evaluate the glucocorticoid-sparing effect of XL184

Exploratory objective

To evaluate the effect of XL184 on the radiologic pattern of disease progression (eg, local vs multifocal/gliomatosis as determined by independent radiology review)

To correlate the apparent diffusion coefficient (ADC) values with clinical benefit following treatment with XL184

Study Status Information



Study Activation / Registration Date:	09/04/2008

IRB Review and Approval Date:	09/04/2008

Study Type:	Phase Ii Or Phase I/Ii

Recruitment Status:	Open

Projected Accrual:	225

Enrollment Eligibility

If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

Inclusion Criteria:

1) The subject has progressive or recurrent GBM in the first or second relapse based on the criteria below: A) For subjects in Treatment Group A: The subject has radiographic evidence of progressive or recurrent GBM by MRI scan (performed within the past 14 days and while on a fixed or decreasing dose of glucocorticoids for at least 5 days). • Subjects with an initial diagnosis of Grade 3 glioma that relapsed as GBM are eligible, provided that the Grade 3 glioma was treated with external beam radiation therapy and systemic chemotherapy. (Groups A & B)

2) (1. continued) B) For subjects in Treatment Group B: The subject has progressive or recurrent GBM, with prospectively confirmed measurable disease by MRI performed within 14 days of the first dose of XL184 . Prospective confirmation of measurable disease will require a minimal lesion size of 1 cm, and will be performed by the central independent review committee (IRC). (Groups A & B)

3) (2. continued) • MRI sequences documenting progressive or recurrent GBM must be identified before study entry • Subjects with an initial diagnosis of Grades 1-3 glioma that relapsed as GBM are eligible, provided that the subjects' treatment has included both radiation therapy and temozolomide • Subjects on glucocorticoids must be on a stable dose for at least 5 days before their MRI scan. (Groups A & B)

4) The subject has received radiation therapy and temozolomide therapy for treatment of GBM (for subjects in Treatment Group B only).

5) Subjects having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply: A) For subjects in Treatment Group A: The first dose of XL184 occurs at least 14 days after surgery and the subject has recovered from the effects of surgery (residual disease following resection of recurrent tumor is not mandated for eligibility into the study. (Groups A & B)

6) (5. continued) To best assess the extent of residual disease post-operatively, a baseline MRI should be done within 14 days before the first dose of XL184. If the glucocorticoid dose is increased between the date of imaging and registration, a new baseline MRI is required on a stable or decreasing glucocorticoid dose for at least 5 days). B) For subjects in Treatment Group B: The first dose of XL184 occurs at least 14 days after surgery, the subject has recovered from the effects of surgery, and measurable residual disease is identified per inclusion criterion #1. (Groups A & B)

7) The subject is at least 18 years old.

8) The subject has a KPS (Karnofsky Performance Scale) of >/=60%. (Groups A & B)

9) The subject is capable of understanding the protocol and has signed the informed consent document.

10) The subject has organ and marrow function as follows: absolute neutrophil count >/=1500/mm3, platelet count >/= 100,000/mm3, hemoglobin >/= 9 g/dL, bilirubin </= 1.5 mg/dL, serum creatinine </= 1.5 mg/dL (or glomerular filtration rate [GFR] >/= 30 mL/min using Modification of Diet in Renal Disease [MDRD] Study Equation method if serum creatinine > 1.5 mg/dL), and ALT and AST </= 2.5 times the upper limit of normal, and (for Group C) urine protein/creatinine ratio </= 1

11) Sexually active subjects (male and female) must agree to use medically accepted methods of contraception during the course of the study and for 3 months following discontinuation of study drug (excluding women who are not of childbearing potential and men who have been sterilized).

12) Female subjects of childbearing potential must have a negative pregnancy test at screening. Females of childbearing potential are defined as sexually mature women without prior hysterectomy or who have had evidence of menses in the past 12 months. Amenorrhea for 12 months must be in the absence of chemotherapy, anti-estrogens, or ovarian suppression.

13) The subject has locally determined histologically confirmed diagnosis of Grade 4 astrocytic tumor (WHO criteria 2007) (Group C)

14) The subject has received prior standard radiation for Grade 3 or 4 astrocytic tumor, as defined by a minimum cumulative dose of 40 Gy administered.(Group C)

15) The subject has received prior temozolomide therapy for Grade 3 or 4 astrocytic tumor: a) If in first relapse (as defined in Inclusion # 16), subjects must have received temozolomide until progression, intolerance, or completion of planned therapy. b) If in second relapse (as defined in Inclusion # 16), subjects must have received temozolomide until progression, intolerance, or completion of planned therapy either for first-line treatment or for treatment after first relapse. (Group C)

16) The subject is in first or second Grade 4 relapse, defined as having one or two progressions as Grade 4 astrocytic tumor, as determined by investigator, since the original diagnosis of any grade glioma. Original Diagnosis: Grade 1-3, Grade 4. Relapse Status at Study Enrollment*: 1st or 2nd relapse as Grade 4. *Subjects may have had additional prior progressions/relapses of lower-grade glioma. (Group C)

17) (16. continued) The criteria for determining progression depending on time from radiotherapy are: (a) Subjects <12 weeks from completion of radiation for astrocytic tumor must demonstrate: (1) progression as demonstrated by new enhancement on T1 post-contrast imaging outside of the radiation field, or (2) new or increasing lesions within the radiation field and unequivocal histopathologic evidence of viable Grade 4 astrocytic tumor at the time of recurrence (eg, sheets of solid tumor or increased Ki67/MIB-1 labeling). (Group C)

18) (17 continued) (b) Subjects >/= 12 weeks from completion of radiation for astrocytic tumor must demonstrate unequivocal radiographic demonstration of disease progression on brain MRI: (1) Increase in enhancing disease or appearance of a new lesion on T1 post contrast images and/or (2) Increase in volume on T2 weighted images attributed to Grade 4 astrocytic tumor. (Group C)

19) (18 continued) Summary of Eligibility Requirements for Histopathology, Prior Radiation, and Prior Temozolomide: Subject must have histopathologic evidence of Grade 4 astrocytic tumor and Prior Standard Radiation for Grade 3 or 4 astrocytoma and Prior Temozolomide for Grade 3 or 4 astrocytoma.(Group C)

20) The subject must have a baseline brain MRI scan within 14 days prior to first dose of study treatment while either not receiving glucocorticoids during the 5 days prior to the baseline MRI scan or on a stable dose of glucocorticoids during the 5 days prior to the baseline MRI scan. (Group C)

21) ( 20. continued) The following conditions also apply: A stable dose of steroids is defined as the same daily dose of steroids for 5 consecutive days prior to the MRI scan. Historic scans have been identified and must be available for central review. As determined by investigator, subjects must have measurable disease at baseline with a minimal lesion size of 10 � 5 mm. (Group C)

22) Subjects having undergone recent resection or biopsy of tumor will be eligible as long as all of the following conditions apply: the first dose of XL184 occurs at least 28 days after surgery; the subject has recovered from the effects of surgery; measurable residual disease is identified per inclusion criterion # 20. (Group C)

23) 8. The subject has a Karnofsky Performance Status (KPS) >/= 70% and has the ability to swallow whole capsules. (Group C)

24) Archival or fresh (BOTH preferred) Grade 4 astrocytic tumor tissue (unstained consecutive slides, frozen tumor tissue or a paraffin block) has been identified and is available for shipment to the central laboratory, where allowed by local regulatory bodies (including Institutional Review Board [IRB]/Independent Ethics Committee [IEC] policies). (Group C)

25) Sexually active subjects (male and female) must agree to use medically accepted methods of contraception during the course of the study and for 3 months following discontinuation of study drug (excluding women who are not of childbearing potential and men who have been sterilized). (Group C)

Exclusion Criteria:

1) The subject has received any of the following: a. Anti-cancer therapy (including investigational agents and biologic agents [antibodies, immune modulators, cytokines] within 28 days (except for bevacizuma), or nitrosoureas or mitomycin C within 42 days before the first dose of XL184. b.Bevacizumab withing 14 days of first dose of XL184. c. A small-molecule kinase inhibitor (including investigational small-molecule kinase inhibitors) or non-cytotoxic hormonal agent within 7 days prior to the first dose of XL184, whichever is shorter. (Groups A&B)

2) (1. continued) d.Other investigational therapy, including any agents not specified, within 21 days of the first dose of XL184. f. Radiation therapy within 90 days before the first dose of XL184. g. Carmustine wafer within 42 days of the first dose of XL184. (Groups A&B)

3) The subject has received more than two prior systemic antitumor therapies, including initial treatment for GBM and treatment for one prior relapse. Surgical resection is not considered a prior systemic antitumor therapy. (Groups A&B)

4) The subject has evidence of acute intracranial or intratumoral hemorrhage either by MRI or computerized tomography (CT) scan. (Groups A&B)

5) The subject is unable to undergo MRI scan (e.g has pacemaker).

6) The subject has received enzyme-inducing anti-epileptic agents within 14 days before the first dose of XL184 (eg, carbamazepine, phenytoin, phenobarbital, primidone).

7) The subject has not recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Grade </=1 from AEs due to antineoplastic agents, investigational drugs, or other medications that were administered before study enrollment. (Groups A&B)

8) The subject is pregnant or breast-feeding.

9) The subject has an infection requiring systemic treatment. (Groups A&B)

10) The subject has a known allergy or hypersensitivity to any of the components of the XL184 formulation (XL184 Drug Substance, silicified microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate,fumed silica, Glidant Stearic acid, iron oxide,Titanium dioxide, Gelatin). (Groups A&B)

11) The subject has serious intercurrent illness, such as uncontrolled hypertension(sustained blood pressure readings of > 140 mmHg systolic or > 90 mmHg diastolic not controlled with anti-hypertensive medication), unhealed wounds from recent surgery or clinically significant cardiac arrhythmias or a recent history of significant disease such as either symptomatic congestive heart failure or unstable angina pectoris within 3 months, myocardial infarction within the past 6 months or myocardial infarction within 6 months before the first dose of XL184. (Groups A&B)

12) The subject has had another diagnosis of malignancy (unless non-melanoma skin cancer, in situ carcinoma of the cervix, or a malignancy diagnosed >/= 12 years previously) or currently has evidence of malignancy (unless non-melanoma skin cancer or in situ carcinoma of the cervix). (Groups A&B)

13) The subject has received any of the following: (a) Non-standard radiation therapy for glioblastoma such as brachytherapy, systemic radioisotope therapy (RIT), or intra-operative radiotherapy (IORT). (b) Non-anti-angiogenic therapy (including investigational agents, small-molecule kinase inhibitors, and biologic agents [antibodies, immune modulators, vaccines, cytokines]) or non-cytotoxic hormonal agent within 28 days or mitomycin C within 42 days prior to the first dose of XL184. (Group C)

14) (13. continued) (c) Other investigational therapy, including any agents not specified above, within 28 days prior to the first dose of XL184, whichever is shorter. (d) Prior treatment with nitrosoureas (including carmustine wafer) at any time. (e) For Group C1, any prior VEGF or VEGFR2 based anti-angiogenic therapy. Agents in this category include, but are not limited to, bevacizumab, cediranib, pazopanib, vandetanib, sorafenib, and VEGF-trap. (f) For Group C2, bevacizumab within 14 days of first dose of XL184. (Group C)

15) The subject is receiving warfarin (or other coumarin derivatives) at study entry and unable to switch to low molecular weight heparin. (Group C)

16) The subject has evidence of intracranial or intratumoral hemorrhage >/= Grade 1 either by MRI or computerized tomography (CT) scan. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin may enter the study. (Group C)

17) The subject has received treatment with XL184. (Group C)

18) The subject has not recovered to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0 Grade </= 1 from AEs (except alopecia) due to surgery, antineoplastic agents, investigational drugs, or other medications that were administered before study enrollment. (Group C)

19) The subject has evidence of wound dehiscence. (Group C)

20) The subject has serious intercurrent illness - hypertension (two or more blood pressure (BP) readings performed at screening of > 140 mmHg systolic or > 90 mmHg diastolic) despite optimal treatment,unhealed wounds from recent surgery,significant cardiac arrhythmias; or a recent history of serious disease - symptomatic congestive heart failure or unstable angina pectoris within 3 months, myocardial infarction, stroke, transient ischemic attack within 6 months, active infection requiring systemic treatment or hospitalization within 2 weeks prior to the first dose of study treatment.(Group C)

21) The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding. (Group C)

22) The subject has received any live virus vaccine within 28 days or any inactivated vaccine within 7 days prior to first dose of study treatment. (Group C)

23) The subject has had another diagnosis of malignancy (unless non-melanoma skin cancer, in situ carcinoma of the cervix, or a malignancy diagnosed ≥ 2 years previously) or currently has evidence of malignancy (unless non-melanoma skin cancer or in situ carcinoma of the cervix). (Group C)

24) The subject has a known allergy or hypersensitivity to any of the components of the XL184 formulations. (Group C)

Links

Registration Number: NCT00704288
Study Information on Clinical Trials Registry (clinicaltrials.gov)