BTTC12-01: 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

Summary

Group a: Patient must have failed prior chemoradiation with temozolomide and any other therapies except BeV (have not received bevacizumab in the past)
Group B: Patient must have failed primary chemoradiation and a BeV-incorporating treatment (have received bevacizumab in the past)
up to 34 participants will be enrolled in Group a and up to 32 participants will be enrolled in Group 2.

Patients will be treated with the combination of topotecan and pazopanib at the following doses:
Pazopanib: Starting dose is 600 mg (3x200mg) per day to be taken orally, daily, continuous, without food at least one hour before or two hours after a meal.
Topotecan: Starting dose of topotecan is 0.25 mg orally, daily, continuous.

Recurrent glioblastoma with no prior exposure to bevacizumab cohort (Group a):
a maximum of 34 patients will be observed in a two-stage Simon optimum design. in the first stage, 9 patients will be accrued. if two or more patients are progression-free at 6 months (PFS6), an additional 25 patients will be accrued. We halt registering patients after 9 patients until we have at least 2 patients are progression free at six months. if 9 or more out of 34 have PFS6, then the study will be declared promising. This study has a 5% chance of declaring promise if the PFS6 rate is at most 15%. it has an 80% chance of declaring promise if the PFS rate is at least 35%.

Recurrent glioblastoma with prior exposure to bevacizumab cohort (Group B):
in the group that failed bevacizumab, a maximum of 32 patients will be observed in a two-stage Simon optimum design. in the first stage, 14 patients will be accrued. if one or more patients is progression-free at 3 months (PFS3), an additional 18 patients will be accrued. We will halt registration after 14 patients until at least 1 patient is progression free at 3-months. if 2 or more out of 32 have PFS3, then the study will be declared promising. This study has a 5% chance of declaring promise if the PFS3 rate is at most 1%. it has an 80% chance of declaring promise if
the PFS rate is at least 12%.

The primary efficacy endpoint is progression free survival (PFS) at six months from patient registration for bevacizumab naive patients and PFS at 3 months for patients with prior bevacizumab treatment. However, objective response status should be measured and recorded.

Participant Eligibility

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 OMCR database prior to treatment with study drugs.
7. Archived tumor tissue must be available for all subjects for biomarker analysis 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 (ON-HOLD).
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).
12. Patients must have adequate organ function:
a. Bone marrow function (WBC > 3,000/[MICRO-SYMBOL]l, ANC > 1,500/mm3, platelet count of >
100,000/mm3, and hemoglobin > 10 gm/dl) (Eligibility level for hemoglobin may be reached by transfusion.)
b. Liver function (alaninie amino transferase (ALT) and aspartate aminotransferase (AST) < 2.5 X ULN, and total bilirubin < 1.5 X ULN), prothrombin time (PT) or international normalized ratio (INR), and activated partial thromboplastin time (aPTT) <= 1.2 X ULN (Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted). Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation.
c. Renal function (creatinine <=1.5 mg/dL (133 [MICRO-SYMBOL]mol/L), or if > 1.5 mg/dL, calculated creatinine clearance > 50 cc/min), and urine protein to creatinine ratio of < 1 before starting therapy.
d. These tests must be performed within 14 days prior to registration.
13. Patients must have shown unequivocal radiographic evidence for tumor progression by
MRI or CT scan as defined by Section 9.2.4.5. 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:
a. They have recovered from the effects of surgery and be > 28 days from surgery.
b. 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 postoperatively, 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 entry.
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:
a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had:
λA hysterectomy
λA bilateral oophorectomy (ovariectomy)
λA bilateral tubal ligation
λIs post-menopausal (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). 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).
λChildbearing 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:
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.
Injectable progestogen.
Implants of levonorgestrel.
Estrogenic vaginal ring.
Percutaneous contraceptive patches.
Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year.
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.
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.