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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by M.D. Anderson Cancer Center
Sponsor:
Collaborators:
Brain Tumor Trials Collaborative
GlaxoSmithKline
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01931098
First received: August 23, 2013
Last updated: July 23, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Brain Neoplasms
Central Nervous System Neoplasms
Drug: Pazopanib
Drug: Topotecan
Behavioral: Symptom Questionnaire
Behavioral: Phone Calls
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Progression Free Survival Rate for Recurrent Glioblastoma (rGBM) Patients with No Prior Bevacizumab (BEV) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    A maximum of 34 patients observed in a two-stage Simon optimum design. In the first stage, 9 patients accrued. If two or more patients are progression-free at 6 months (PFS6), an additional 25 patients accrued. Registration halted after 9 patients until at least 2 patients are progression free at six months. If 9 or more out of 34 have PFS6, then the study declared promising. 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%.

  • Progression Free Survival Rate for Recurrent Glioblastoma (rGBM) Patients with Prior Bevacizumab [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
    In the group that failed bevacizumab, a maximum of 32 patients observed in a two-stage Simon optimum design. In the first stage, 14 patients accrued. If one or more patients is progression-free at 3 months (PFS3), an additional 18 patients accrued. Registration halted after 14 patients until at least 1 patient is progression free at 3-months. If 2 or more out of 32 have PFS3, then 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%.


Estimated Enrollment: 66
Study Start Date: November 2013
Estimated Primary Completion Date: November 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A - Recurrent Glioblastoma - No Prior Bevacizumab

Patients 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.

Drug: Pazopanib
Starting dose: 600 mg by mouth daily for a 28 day cycle.
Other Name: GW786034
Drug: Topotecan
Starting dose: 0.25 mg by mouth daily for a 28 day cycle.
Other Name: Hycamtin
Behavioral: Symptom Questionnaire
Symptom questionnaire completed at baseline for both Groups. Group A: Completion at week 4 of cycle 2, then every odd cycle after that. Group B: Completion at week 4 of cycle 1, 2, 3, then every other cycle after that.
Behavioral: Phone Calls
After study drugs stopped and end-of-treatment visit completed, study staff will call patient 1 time every 3 months. Each phone call should last about 5 minutes.
Experimental: Group B - Recurrent Glioblastoma with Prior Bevacizumab

Patients 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.

Drug: Pazopanib
Starting dose: 600 mg by mouth daily for a 28 day cycle.
Other Name: GW786034
Drug: Topotecan
Starting dose: 0.25 mg by mouth daily for a 28 day cycle.
Other Name: Hycamtin
Behavioral: Symptom Questionnaire
Symptom questionnaire completed at baseline for both Groups. Group A: Completion at week 4 of cycle 2, then every odd cycle after that. Group B: Completion at week 4 of cycle 1, 2, 3, then every other cycle after that.
Behavioral: Phone Calls
After study drugs stopped and end-of-treatment visit completed, study staff will call patient 1 time every 3 months. Each phone call should last about 5 minutes.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 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). 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) </=1.2XULN. Concomitant elevations in bilirubin and AST/ALT above 1.0xULN 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. 3) Renal function (creatinine </=1.5mg/dL (133 µmol/L), or if >1.5mg/dL, calculated creatinine clearance >/=50cc/min), and urine protein to creatinine ratio of <1 before starting therapy. 4) 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. 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 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: 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 ≤ 140/90 mmHg in order for a subject to be eligible for the study.
  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 major).
  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 listed 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. BCRP and PgP inducers and inhibitors will be also prohibited.
  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 excipients.
  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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01931098

Contacts
Contact: Marta Penas-Prado, MD 713-792-2883

Locations
United States, California
Cedar-Sinai Medical Center Not yet recruiting
West Hollywood, California, United States, 90048
United States, Florida
MD Anderson Cancer Center - Orlando Not yet recruiting
Orlando, Florida, United States, 32806
United States, Illinois
Northwestern University, Feinberg School of Medicine Not yet recruiting
Chicago, Illinois, United States, 60611
Rush University Medical Center Not yet recruiting
Chicago, Illinois, United States, 60612
United States, Massachusetts
Dana Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
United States, Michigan
Henry Ford Health System Not yet recruiting
Detroit, Michigan, United States, 48202
United States, Missouri
Washington University School of Medicine Not yet recruiting
St Louis, Missouri, United States, 63110
United States, North Carolina
University of North Carolina Chapel Hill Not yet recruiting
Chapel Hill, North Carolina, United States, 27523
United States, Ohio
Cleveland Clinic Foundation Not yet recruiting
Cleveland, Ohio, United States, 44195
United States, South Carolina
MUSC Hollings Cancer Center Not yet recruiting
Charleston, South Carolina, United States, 29425
United States, Texas
Texas Oncology Austin Brain Tumor Center Not yet recruiting
Austin, Texas, United States, 78705
U.T. Southwestern Medical Center at Dallas Not yet recruiting
Dallas, Texas, United States, 75235
Baylor University Medical Center Not yet recruiting
Dallas, Texas, United States, 75246
The Methodist Hospital System Not yet recruiting
Houston, Texas, United States, 77030
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
United States, Utah
University of Utah Health Network Not yet recruiting
Salt Lake City, Utah, United States, 84102-1959
United States, Wisconsin
Aurora Sinai Medical Center Not yet recruiting
Milwaukee, Wisconsin, United States, 53233
Sponsors and Collaborators
M.D. Anderson Cancer Center
Brain Tumor Trials Collaborative
GlaxoSmithKline
Investigators
Principal Investigator: Marta Penas-Prado, MD M.D. Anderson Cancer Center
Study Director: Morris Groves, MD Texas Oncology - Austin Brain Tumor Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01931098     History of Changes
Other Study ID Numbers: BTTC12-01
Study First Received: August 23, 2013
Last Updated: July 23, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Recurrent glioblastoma
Intracranial glioblastoma multiforme
Brain Neoplasms
Central Nervous System Neoplasms
CNS
rGBM
Brain tumor
GBM
Gliosarcoma
GS
Pazopanib
GW786034
Topotecan
Hycamtin
Symptom questionnaire
Phone calls

Additional relevant MeSH terms:
Glioblastoma
Brain Neoplasms
Neoplasms
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Topotecan
Bevacizumab
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 01, 2014