Phase II Pazopanib Plus Topotecan for Recurrent Glioblastoma Multiforme (GBM)

Study ID

Cancer Related

Healthy Volunteers

Study Sites

  • Clements University Hospital
  • UT Southwestern Ambulatory Services
  • Zale Lipshy University Hospital

Penny Currykosky

Principal Investigator
Edward Pan, M.D.

Official Title

A Phase II Trial of Oral Pazopanib Plus Oral Topotecan Metronomic Antiangiogenic Therapy for Recurrent Glioblastoma Multiforme (A) Without Prior Bevacizumab Exposure and (B) After Failing Prior Bevacizumab

Brief Overview

The goal of this clinical research study is to learn if pazopanib when given in combination
with topotecan can help to control glioblastoma. The safety of this drug combination will
also be studied.

The study doctor can explain how the study drugs are designed to work.


Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study
group based on if you have received bevacizumab or not:

- You will be in Group A if you have not received bevacizumab in the past.

- You will be in Group B if you have received bevacizumab in the past.

Both groups will receive pazopanib and topotecan at the same dose level and on the same
schedule. Up to 34 participants will be enrolled in Group 1 and up to 32 participants will
be enrolled in Group 2.

Study Drug Administration:

Each cycle is 28 days.

You will take capsules of topotecan by mouth 1 time everyday at about the same time each
day. You should swallow the capsules whole with at least 1 cup (8 ounces) of water, with or
without food.

You will take tablets of pazopanib by mouth 1 time every day at about the same time each
day. They should be taken on an empty stomach (at least 1 hour before and 2 hour after
eating) with about 1 cup (8 ounces) of water.

Pazopanib should be taken whole with water and must not be broken or crushed.

If a dose of pazopanib is missed, it should not be taken if it is less than 12 hours until
the next dose.

If you vomit after taking the study drugs, you should not take a replacement dose on that
day. You should resume taking the study drugs at the next scheduled dose on the following
day. If vomiting continues, you should tell your doctor.

You will be given a study drug diary to record the times that you take the study drugs and
if you vomit. You should bring the diary to each study visit.

Study Visits:

At Week 1, your blood pressure will be measured.

At Week 2, your blood pressure will be measured and blood (about 1 teaspoon) will be drawn
for routine tests.

At Week 4, you will have an EKG.

Every 4 weeks:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine and biomarker testing.

- Urine will be collected to check your kidney function.

Every 8 weeks:

- You will have a neurological exam.

- Blood (about 1 teaspoon) will be drawn to check thyroid function.

- You will have an EKG.

If you are in Group A, you will have a brain MRI or CT scan at Week 4 of Cycle 2, and then
every other cycle after that (Cycles 4, 6, 8 and so on) to check the status of the disease.
You will also complete the symptom questionnaire at these visits.

If you are in Group B, you will have a brain MRI or CT scan at Week 4 of Cycles 1, 2, 3, and
then every other cycle after that (Cycles 5, 7, 9 and so on) to check the status of the
disease. You will also complete the symptom questionnaire at these visits.

At any time during the study, extra tests may be performed if the doctor thinks they are
needed for your safety. The study doctor will tell you more about any extra tests.

End-of-Treatment Visit:

Within 14 days after your last dose of the study drugs, you will have an end-of-treatment
visit. The following tests and procedures will be performed:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine and biomarker testing. This blood
draw will also include a pregnancy test if you can become pregnant.

Length of Treatment:

You may take the study drugs for up to 1 year. You will no longer be able to take the study
drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to
follow study directions.

Your participation on the study will be over after the long-term follow-up phone calls.

Long-Term Follow-Up Calls:

After you have stopped taking the study drugs and completed your end-of-treatment visit, the
study staff will call you 1 time every 3 months from then on to check on how you are doing.
Each phone call should last about 5 minutes.

This is an investigational study. Pazopanib is FDA approved and commercially available for
the treatment of renal cell cancer. Topotecan is FDA approved and commercially available for
the treatment of lung cancer. In this study, the combination of pazopanib and topotecan is
being used for research purposes only.

Up to 66 participants will be enrolled in this multicenter study. Up to 15 will take part at
MD Anderson.

Participant Eligibility

Inclusion Criteria:

1. Patients with histologically proven intracranial glioblastoma multiforme (GBM) or
gliosarcoma (GS). Patients will be eligible if the original histology was low-grade
glioma and a subsequent histological diagnosis of a GBM or GS is made. Patients must
have evidence of progression of the GBM or GS on MRI or CT scan.

2. Patient must have failed prior chemoradiation with temozolomide and any other
therapies except BEV (group A), or must have failed primary chemoradiation and a
BEV-incorporating treatment (group B).

3. Patients may have had treatment for no more than 2 prior relapses. Relapse is defined
as progression following initial therapy (i.e. radiation+/- chemo if that was used as
initial therapy). The intent therefore is that patients had no more than 3 prior
therapies (initial and treatment for 2 relapses). If the patient had a surgical
resection for relapsed disease and no anti-cancer therapy was instituted for up to 12
weeks, and the patient undergoes another surgical resection, this is considered as 1
relapse. For patients who had prior therapy for a low-grade glioma, the surgical
diagnosis of a high-grade glioma will be considered the first relapse

4. Patients must be greater than 12 weeks following completion of chemoradiation or any
additional radiation to reduce the chance of pseudoprogression.

5. Measurable disease is required unless patient is post-operative and in that case
patient can have no evidence of disease.

6. 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 in the
MD ANDERSON CANCER CENTER Office of Multicenter Clinical Research (OMCR) database
prior to treatment with study drugs.

7. Archived tumor tissue must be available for all subjects for biomarker analysis and
confirmation of the diagnosis before or during treatment. Samples must be provided
within 4 weeks of enrollment.

8. Tissue to be analyzed for MGMT (if not already performed) and additional analyses
noted in correlative biomarker section.

9. Patients must be >/= 18 years old.

10. Patients must have a Karnofsky performance status of >/= 60.

11. At the time of registration: Patients must have recovered from the toxic effects of
prior therapy: >/= 28 days from any investigational agent, >/=28 days from prior
cytotoxic therapy, >/=14 days from vincristine, >/=42 days from nitrosoureas, >/=21
days from procarbazine administration, >21 days from bevacizumab administration and
>/=7 days for non-cytotoxic agents, e.g., interferon, tamoxifen, thalidomide,
cis-retinoic acid, etc. (radiosensitizer does not count). Any questions related to
the definition of non-cytotoxic agents should be directed to the Study Chair.

12. Patients must have adequate organ function: 1) Bone marrow function (WBC >/=3,000/µl,
ANC >/=1,500/mm3, platelet count of >/=100,000/mm3, and hemoglobin >/=10 gm/dl).
Eligibility level for hemoglobin may be reached by transfusion. 2) Liver function
(alanine amino transferase (ALT) and aspartate aminotransferase (AST) <2.5XULN(upper
limit of normal), and total bilirubin <1.5XULN), prothrombin time (PT) or
international normalized ratio (INR), and activated partial thromboplastin time
(aPTT) not permitted. Subjects receiving anticoagulant therapy are eligible if their INR is
stable and within the recommended range for the desired level of anticoagulation. 3)
Renal function (creatinine 1.5mg/dL, calculated
creatinine clearance >/=50cc/min), and urine protein to creatinine ratio of <1 prior
to registration. 4) These tests must be performed within 14 days prior to

13. Patients must have shown unequivocal radiographic evidence for tumor progression by
MRI or CT scan. A scan should be performed within 14 days prior to registration and
on a steroid dose that has been stable or decreasing for at least 5 days. If the
steroid dose is increased between the date of imaging and registration a new baseline
MR/CT is required. The same type of scan, i.e., MRI or CT must be used throughout the
period of protocol treatment for tumor measurement.

14. Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply: 1) They have recovered
from the effects of surgery and be > 28 days from surgery. 2) Residual disease
following resection of recurrent GBM or GS is not mandated for eligibility into the
study. To best assess the extent of residual disease post-operatively, a CT/ 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/CT is required on a stable steroid dosage for at least 5 days.

15. Patients must have failed prior radiation therapy and must have an interval of
greater than or equal to 12 weeks from the completion of radiation therapy to study

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

17. A female is eligible to enter and participate in this study if she is of: 1)
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
including any female who has had: A hysterectomy; A bilateral oophorectomy
(ovariectomy); A bilateral tubal ligation; Is post-menopausal: a) Subjects not using
hormone replacement therapy (HRT) must have experienced total cessation of menses for
>/= 1 year and be greater than 45 years in age, OR, in questionable cases, have a
follicle stimulating hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL
(<140 pmol/L).b) Subjects using HRT must have experienced total cessation of menses
for >= 1 year and be greater than 45 years of age OR have had documented evidence of
menopause based on FSH and estradiol concentrations prior to initiation of HRT.

18. ( 17. continued) 2) Childbearing potential, including any female who has had a
negative serum pregnancy test within 2 weeks prior to the first dose of study
treatment, preferably as close to the first dose as possible, and agrees to use
adequate contraception. GSK acceptable contraceptive methods, when used consistently
and in accordance with both the product label and the instructions of the physician,
are as follows: a) Complete abstinence from sexual intercourse for 14 days before
exposure to investigational product, through the dosing period, and for at least 21
days after the last dose of investigational product. Oral contraceptive, either
combined or progestogen alone. b) Injectable progestogen. c) Implants of
levonorgestrel. d) Estrogenic vaginal ring.

19. (18. continued) e) Percutaneous contraceptive patches. f) Intrauterine device (IUD)
or intrauterine system (IUS) with a documented failure rate of less than 1% per year.
g) Male partner sterilization (vasectomy with documentation of azoospermia) prior to
the female subject's entry into the study, and this male is the sole partner for that
subject. h) Double barrier method: condom and an occlusive cap (diaphragm or
cervical/vault caps) with a vaginal spermicidal agent
(foam/gel/film/cream/suppository). Female subjects who are lactating should
discontinue nursing prior to the first dose of study drug and should refrain from
nursing throughout the treatment period and for 14 days following the last dose of
study drug

Exclusion Criteria:

1. 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.

2. 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.

3. Clinically significant gastrointestinal abnormalities that may increase the risk for
gastrointestinal bleeding including, but not limited to: Active peptic ulcer disease;
Known intraluminal metastatic lesion/s with risk of bleeding; Inflammatory bowel
disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal
conditions with increased risk of perforation; History of abdominal fistula,
gastrointestinal perforation, or intra abdominal abscess within 28 days prior to
beginning study treatment.

4. Clinically significant gastrointestinal abnormalities that may affect absorption of
investigational product including, but not limited to: Malabsorption syndrome; Major
resection of the stomach or small bowel.

5. Presence of uncontrolled infection.

6. Corrected QT interval (QTc) > 480 msecs using Bazett's formula.

7. History of any one or more of the following cardiovascular conditions within the past
6 months: Cardiac angioplasty or stenting; Myocardial infarction; Unstable angina;
Coronary artery bypass graft surgery; 4Symptomatic peripheral vascular disease..

8. Class III or IV congestive heart failure, as defined by the New York Heart
Association (NYHA).

9. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of >/=140
mmHg or diastolic blood pressure (DBP) of >/= 90mmHg]. Note: Initiation or adjustment
of antihypertensive medication(s) is permitted prior to study entry. BP must be
re-assessed on two occasions that are separated by a minimum of 1 hour; on each of
these occasions, the mean (of 3 readings) SBP / DBP values from each BP assessment
must be
10. History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6
months. Note: Subjects with recent DVT who have been treated with therapeutic
anti-coagulating agents for at least 6 weeks are eligible.

11. Prior major surgery or trauma within 28 days and/or presence of any non-healing
wound, fracture, or ulcer (procedures such as catheter placement not considered to be

12. Evidence of active bleeding or bleeding diathesis.

13. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.

14. Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of
study drug.

15. Any serious and/or unstable pre-existing medical, psychiatric, or other condition
that could interfere with subject's safety, provision of informed consent, or
compliance to study procedures.

16. Unable or unwilling to discontinue use of inducers and inhibitors of CYP450 and BCRP
and PgP inducers and inhibitors listed in the protocol for at least 14 days or five
half-lives of a drug (whichever is longer) prior to the first dose of study drug and
for the duration of the study. CYP3A4 substrates can be administered, but
investigators will need to be aware of possible increased or decreased effectiveness
of the non-study drug and this should be recorded in concomitant medications.
Dexamethasone is acceptable although listed as a CYP3A4 inducers/inhibitors as long
as the dose is 16 mg/day or lesser.

17. Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is
progressing in severity, except alopecia.

18. Ongoing use of enzyme-inducing anti-epileptic agents (EIAEDs), unless 2 week washout
has elapsed form last dose of EIAED.

19. 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

20. Patients with a known hypersensitivity to pazopanib or topotecan or to their

21. Patients on total daily dose of dexamethasone greater than 16 mg/day.

22. Patients must not have received prior therapy with topotecan, pazopanib, or related
drugs such as tyrosine kinase inhibitors, VEGF inhibitors (except bevacizumab). Prior
treatment with TKIs that do not impact VEGFR -1, -2, or -3, PDGFR -a, -b of cKIT
could be allowed.

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