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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01931098
Recruitment Status : Completed
First Posted : August 29, 2013
Last Update Posted : April 21, 2020
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:


Glioblastoma is the most common and most aggressive type of malignant brain tumor. The drug pazopanib is used to treat people with a type of kidney cancer. Topotecan is used to treat lung cancer. Both topotecan and pazopanib have individually been used to treat patients with glioblastoma and some anti-tumor activity has been found. Researchers want to see if these two drugs together may be able to help people with glioblastoma.


To learn if pazopanib with topotecan can help control glioblastoma. Also, to study the safety of this drug combination.


Adults at least 18 years old whose glioblastoma has returned after treatment.


Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Brain computed tomography (CT) or magnetic resonance imaging (MRI) For these, participants lay in a machine that takes pictures.

Chest CT scan or x-ray

Heart electrocardiogram (EKG)

A questionnaire about quality of life

Participants will be assigned to a study group.

Participants will take the study drugs for 28-day cycles for up to 1 year. They will take capsules of topotecan by mouth once every day. They will take tablets of pazopanib by mouth once every day.

Participants will write in a diary the times they take the study drugs.

Participants will have several study visits during each cycle. These may include

Blood pressure measurement

Blood and urine tests


Physical exam and/or neurological exam

Brain MRI or CT scan to check the status of the disease

A symptom questionnaire

At the end of treatment, participants will have a physical exam. They may have blood drawn.

Participants will have follow-up calls once every 3 months to check.

Condition or disease Intervention/treatment Phase
Glioblastoma Glioblastoma Multiforme Gliosarcoma Brain Neoplasms Central Nervous System Neoplasms Drug: topotecan Drug: pazopanib Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 35 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (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
Study Start Date : December 10, 2015
Actual Primary Completion Date : September 12, 2019
Actual Study Completion Date : September 12, 2019

Arm Intervention/treatment
Experimental: 1
Topotecan and pazopanib are administered orallydaily
Drug: topotecan
Taken .25 mg orally, daily continuous until progression up to one year.

Drug: pazopanib
600 mg orally, daily until progression, up to one year.

Primary Outcome Measures :
  1. 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. [ Time Frame: six months and three months ]
    Proportion of patients that have progressive disease after 3 months and 6 months.

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
  • General Inclusion Criteria
  • 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. 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).
  • 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.

  • Patients must be greater than 12 weeks following completion of chemoradiation or any additional radiation to reduce the chance of pseudoprogression.
  • Measurable disease is required unless patient is post-operative and in that case patient can have no evidence of disease.
  • All patients must sign an informed consent indicating that they are aware of the investigational nature of this study.
  • Archived tumor tissue must be available for all subjects for confirmation of the diagnosis before or during treatment. Samples must be provided within 4 weeks of enrollment.
  • Patients must be greater than or equal to 18 years old.
  • Patients must have a Karnofsky performance status of greater than or equal to 60.
  • At the time of registration: Patients must have recovered from the toxic effects of prior therapy: greater than or equal to 28 days from any investigational agent, greater than or equal to 28 days from prior cytotoxic therapy, greater than or equal to 14 days from vincristine, greater than or equal to 42 days from nitrosoureas, greater than or equal to 21 days from procarbazine administration, >21 days from bevacizumab administration and greater than or equal to 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 noncytotoxic agents should be directed to Academic PI.
  • Patients must have adequate organ function:

    • Bone marrow function (WBC greater than or equal to 3,000/microl, ANC greater than or equal to 1,500/mm3, platelet count of greater than or equal to 100,000/mm3, and hemoglobin greater than or equal to 10 gm/dl).

      ---Eligibility level for hemoglobin may be reached by transfusion.

    • Liver function (alanine 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) less than or equal to 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.
    • Renal function (creatinine less than or equal to 1.5 mg/dL (133 micromol/L), or if > 1.5 mg/dL, calculated creatinine clearance greater than or equal to 50 cc/min), and urine protein to creatinine ratio of < 1 prior to registration.
  • Patients must have shown unequivocal radiographic evidence for tumor progression by MRI or CT scan as defined by Section 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.
  • Patients having undergone recent resection of recurrent or progressive tumor will be eligible as long as all of the following conditions apply:

    --They have recovered from the effects of surgery and be > 28 days from surgery.

  • 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.
  • 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.
  • 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.
  • A female is eligible to enter and participate in this study if she is of:

    • 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
      • Subjects not using hormone replacement therapy (HRT) must have experienced 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 >= 1year 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
    • 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. Novartis 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.

General Exclusion Criteria

  • 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.
  • 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.
  • 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.
  • 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.
    • Presence of uncontrolled infection.
    • Corrected QT interval (QTc) > 480 msecs using Bazett s formula. Bazett s Formula: QTc (Bazett)=QT/RR
  • 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
    • Symptomatic peripheral vascular disease
    • Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA), see appendix 13.7
    • Poorly controlled hypertension [defined as systolic blood pressure (SBP) of greater than or equal to 140 mmHg or diastolic blood pressure (DBP) of less than or equal to 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 less than or equal to 140/90 mmHg in order for a subject to be eligible for the study.
    • 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 anticoagulating

agents for at least 6 weeks are eligible.

  • 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).
  • Evidence of active bleeding or bleeding diathesis.
  • Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels
  • Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose of study drug.
  • 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.
  • Unable or unwilling to discontinue use of inducers and inhibitors of CYP450 listed in Appendix 13.4 and BCRP and PgP inducers and inhibitors 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.
  • Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing in severity, except alopecia.
  • Ongoing use of enzyme-inducing anti-epileptic agents (EIAEDs), unless 2 week washout has elapsed form last dose of EIAED.
  • 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.
  • Patients with a known hypersensitivity to pazopanib or topotecan or to their excipients.
  • Patients on total daily dose of dexamethasone greater than 16 mg/day.
  • 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.

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01931098

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Mark R Gilbert, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI) Identifier: NCT01931098    
Other Study ID Numbers: 160034
First Posted: August 29, 2013    Key Record Dates
Last Update Posted: April 21, 2020
Last Verified: December 5, 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Brain Tumors
Additional relevant MeSH terms:
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Brain Neoplasms
Nervous System Neoplasms
Central Nervous System Neoplasms
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents