Clinical trial NCT00923117: Sunitinib to Treat Recurrent Brain Cancer
Official title: A Phase II Trial of Sunitinib in the Treatment of Recurrent Malignant Gliomas
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Glioblastoma Multiforme
Malignant Gliomas
Anaplastic Gliomas
Keywords: Glioblastoma
Chemotherapy
Anti-Angiogenesis
Radiation
Brain Tumor
Malignant Glioma
Glioblastoma Multiforme
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2009-06-18
Enrollment: 87
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Background:

One way tumors are able to grow is by forming new blood vessels that supply them with nutrients and oxygen.

Sunitinib blocks certain proteins on the surface of tumor and blood vessel cells that are involved with the formation of new blood vessels.

Blocking these proteins may prevent the tumor cells or blood vessels from continuing to grow.

Objectives:

To determine whether sunitinib can cause tumors to shrink or stabilize in patients with recurrent brain cancer.

Eligibility:

Patients 18 years of age or older with brain cancer whose disease has worsened after standard treatment with surgery, radiation.

Design:

Patients take a sunitinib pill once a day in 4-week treatment cycles. Treatment may continue as long as the tumor remains stable or decreases in size and the side effects of treatment are tolerated.

Routine blood tests are done every 2 weeks during the first 8 weeks of treatment and then every 4 weeks after that.

Magnetic resonance imaging (MRI) scans are done before starting treatment (at baseline) and at the end of every 4-week cycle to monitor tumor growth.

Positron emission tomography (PET) scans are done at baseline and at the end of the first cycle.

Neurological and physical examinations are done at baseline, at week 2 of treatment and at the end of every treatment cycle.

Health-related quality of life is assessed every 4 weeks.

Pregnancy tests, electrocardiograms and echocardiograms are repeated as needed.

Detailed description: Background:

Solid tumors have multiple mechanisms for stimulating angiogenesis with the vascular endothelial growth factor (VEGF)-kinase insert domain receptor (KDR) axis being only one of them. Sunitinib, through its multiple tyrosine kinase receptor targets, represents an attempt to capitalize on the concept of targeting multiple mechanisms responsible for glioma-associated angiogenesis. Sunitinib inhibits platelet derived growth factor receptor (PDGFR) and c-kit (stem cell factor (SCF) receptor) at nanomolar concentrations. The combination blocks all three known major glioma-mediated angiogenic mechanisms (VEGF, c-kit, PDGF). Based on this scientific rationale, the promising anti-glioma activity of sunitinib in preclinical models, and the promising clinical data in patients with gliomas treated with other VEGF inhibitors, we are now proposing a phase II trial of sunitinib in patients with recurrent malignant gliomas.

Objectives:

To evaluate the anti-glioma activity of sunitinib in patients with recurrent malignant gliomas who are either naive or resistant to prior bevacizumab therapy.

Eligibility:

Patients with recurrent malignant glioma are eligible for this study.

Design:

This is a phase II study with a target enrollment of 64 (32 with glioblastoma multiforme (GBM) and 32 with anaplastic glioma (AG)) patients who have not progressed on prior treatment with anti-VEGF therapy, and 64 (32 with GBM and 32 with AG)patients who have progressed on prior bevacizumab therapy.

Sunitinib will be self-administered orally at 37.5 mg daily, with dose adjustments allowed for toxicity and concomitant drug interactions.

The primary endpoint is six-month progression free survival for both arms of the study.

We performed an interim analysis (see below) and after consulting with the pharmaceutical company (Pfizer) we believe that ending the study is the most appropriate course of action to take.

In the original design of the trial, for the AG stratum, the agent will be considered effective if at least 14 patients have not progressed by 6 months. Now, we have observed one out 10 Bev-naïve who haven't progressed by 6 months. Then given one patient in the first 10 patients whose PFS \>=6, the conditional probability of observing at least 14 out of 32 patients who are 6 month-PFS is only 43% even if the true 6 months-PFS is 55%. Since in the first 10 patients, we only observed one patient with PFS\>=6 months, it is unlikely that the true 6 month-PFS is 55%. The conditional power would be close to zero, if the true 6 month-PFS close to 10% as observed so far. Based on the conditional probability, the chance of a positive study is small, and hence the trial should be considered stopped for futility.

For Bev-resistant patients, because in the first 12 patients none had PFS \>= 6 months the conditional probability of declaring the agent being effective is even lower and equals 12%, if the true PFS at 6 months is 55%. Essentially there is little chance that the agent can be declared effective.

Eligibility criteria: * INCLUSION CRITERIA:

  1. Patients with histologically proven intracranial malignant glioma will be eligible for this protocol. Malignant gliomas include glioblastoma multiforme (GBM), gliosarcoma (GS), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant astrocytoma NOS (not otherwise specified).
  2. Patients may have received prior therapy with bevacizumab, but not within six weeks of starting treatment with sunitinib. Patients who received prior therapy with bevacizumab must have demonstrated radiographic disease progression while being treated with bevacizumab.
  3. Patients must have progressed after radiation and temozolomide therapy and have an interval of greater than or equal to 4 weeks from the completion of radiation therapy to study entry. If the patient has had prior stereotactic radio surgery, true tumor progression must be corroborated by fludeoxyglucose 18F (FDG)-positron emission tomography (PET) or magnetic resonance (MR) spectroscopy imaging.
  4. Patients must have evidence of tumor progression by contrast enhanced perfusion magnetic resonance imaging (MRI) or computed tomography (CT) scan. This scan should be performed within 14 days prior to registration and on a five-day stable dose of steroids. 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.
  5. 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.
* Residual disease following resection of recurrent tumor 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, and
  * within 14 days of registration, and
  * on a steroid dosage that has been stable for at least 5 days.

    f) Normal organ and marrow function defined as: total leukocyte count greater than or equal to 3000 cells/ul, absolute neutrophil count (ANC) greater than or equal to 1500 cells/ul, platelet count greater than or equal to 100,000 cells/ul, serum creatinine less than or equal to 2.0 times the upper limit of normal, and bilirubin less than or equal to 1.5 times the upper limit of normal, hemoglobin greater than or equal to 9.0 g/dL , serum calcium less than or equal to 12.0 mg/dL, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than or equal to 1.5 times the upper limit of normal, prothrombin time (PT) less than or equal to 1.5 upper limits of normal (ULN). Eligibility level for hemoglobin may be reached by transfusion.

    g) The effects of sunitinib on the developing human fetus at the recommended therapeutic dose are unknown. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

    h) All patients or their previously designated durable power of attorney (DPA) (if the patient is deemed by the treating physician to be impaired or questionably impaired in such a way that the ability of the patient to give informed consent is questionable) must sign an informed consent indicating that they are aware of the investigational nature of this study.

    i) Patients must be greater than or equal to 18 years old, and with a life expectancy greater than 8 weeks.

    j) Patients must have a Karnofsky performance status of greater than or equal to 60.

    k) Patients must have recovered from the toxic effects of prior therapy: 2 weeks from any investigational agent, two weeks from vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine, 1 week for non-cytotoxic agents, (e.g., interferon, tamoxifen, thalidomide, cis-retinoic acid, etc.), and 4 weeks from other cytotoxic therapy. Any questions related to the definition of non-cytotoxic agents should be directed to the Study Chair.

    l) 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 patients' ability to tolerate this therapy.

    m) This study was designed to include women and minorities, but was not designed to measure differences of intervention effects. Males and females will be recruited with no preference to gender. No exclusion to this study will be based on race. Minorities will actively be recruited to participate.

EXCLUSION CRITERIA:

1. Patients who, in the view of the treating physician, have significant active cardiac, hepatic, renal, or psychiatric diseases are ineligible.
2. Patients with a history of prior therapy directed against vascular endothelial growth factor (VEGF) (e.g. sorafenib, pazopanib, Zactima (ZD6474), AZD2171), with the exception of bevacizumab, will not be allowed to enroll.
3. Concurrent use of other standard chemotherapeutics or investigative agents.
4. Patients known to have a malignancy (other than their malignant glioma) that has required treatment in the last 12 months and/or are expected to require treatment in the next 12 months (except non-melanoma skin cancer or carcinoma in-situ in the cervix).
5. Patients who have an active infection.
6. Pregnant (positive pregnancy test) or nursing women. Both fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 3 months after the completion of sunitinib therapy.
7. Concurrent anti-coagulation or anti-platelet medication (including aspirin, non-steroidal anti-inflammatory agents, cyclooxygenase -2 (COX-2) inhibitors).
8. Serious or non-healing wound, ulcer or bone fracture
9. History of any of the following within 6 months of study entry: abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, stroke, myocardial infarction or unstable angina. Patients will not undergo diagnostic screening for any of these conditions.
10. Invasive procedures defined as follows:

    * Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy
    * Anticipation of need for major surgical procedures during the course of the study
    * Core biopsy within 7 days prior to start of therapy
11. Uncontrolled hypertension (greater than 150/100 mmHg) while on antihypertensive medications.
12. New York Heart Association class II or greater congestive heart failure.
13. Serious cardiac arrhythmia requiring medication.
14. Evidence of bleeding diathesis, coagulopathy, or international normalized ratio (INR) greater than 1.5.
15. History of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib.
16. Patients receiving any enzyme inducing anti-epileptic drugs (EIAEDs) and other potent cytochrome P450 3A4 (CYP3A4) modulators (per Appendixes B and C) within two weeks prior to treatment start are ineligible.
17. Baseline echocardiogram with ejection fraction less than 50% or greater than or equal to 20% decrease from a prior study
18. corrected QT interval(QTc) interval greater than 500 msec on baseline electrocardiogram (EKG).
19. Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with sunitinib.

Primary outcomes:
measure: 6-month Progression-free Survival.
timeFrame: 6 months
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 7/2/08 -12/6/13
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Teri N Kreisl, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43.
citation: Prados MD, Schold SC Jr, Fine HA, Jaeckle K, Hochberg F, Mechtler L, Fetell MR, Phuphanich S, Feun L, Janus TJ, Ford K, Graney W. A randomized, double-blind, placebo-controlled, phase 2 study of RMP-7 in combination with carboplatin administered intravenously for the treatment of recurrent malignant glioma. Neuro Oncol. 2003 Apr;5(2):96-103. doi: 10.1093/neuonc/5.2.96.
citation: Prados MD, Warnick RE, Mack EE, Chandler KL, Rabbitt J, Page M, Malec M. Intravenous carboplatin for recurrent gliomas. A dose-escalating phase II trial. Am J Clin Oncol. 1996 Dec;19(6):609-12. doi: 10.1097/00000421-199612000-00016.