Inclusion Criteria:
1. Willingness and ability to provide written informed consent and to comply with the
study protocol as judged by the investigator. 2. Age ≥ 18 years old. 3. Kamofsky performance status ≥70%
4. Stable or decreasing dose of corticosteroids within 5 days prior to study 5.
enrollment.
5. For women who are not postmenopausal (i.e., < 12 months after last menstruation) or
surgically sterile (absence of ovaries and/or uterus) and who are sexually active:
agreement to use an adequate method of contraception (oral contraceptives,
intrauterine contraceptive device, barrier method of contraception in conjunction
with spermicidal jelly) during the treatment period and for at least 6 months after
the last dose of study drug.
6. For male patients who are sexually active and who are partners of premenopausal
women: agreement to use a barrier method of contraception during the treatment
period and for at least 6 months after the last dose of study drug.
7. Histologically confirmed glioblastoma. A local pathology report constitutes adequate
documentation of histology for study inclusion. Patients with an initial diagnosis
of a lower-grade glioma are eligible if a subsequent biopsy was determined to be
glioblastoma.
8. First recurrence after concurrent or adjuvant chemoradiotherapy. Imaging
confirmation of first tumor progression or regrowth as defined by the RANO criteria
. A minimum of 12 weeks must have elapsed from the completion of radiotherapy to
study entry to minimize the potential for MRI changes related to radiation necrosis
that might be misdiagnosed as progression of disease, unless there is a new lesion
outside the radiation field or unequivocal evidence of viable tumor on
histopathological sampling.
9. Prior treatment with TMZ for low grade glioma or glioblastoma.
10. No more than one prior line of systemic treatment for glioblastoma. Concurrent and
adjuvant TMZ-based chemotherapy, including the combination of TMZ with an
investigational agent, is considered one line of therapy.
11. Prior therapy with gamma knife or other focal high-dose radiotherapy is allowed, but
the patient must have subsequent histologic documentation of recurrence, unless the
recurrence is a new lesion outside the irradiated field.
12. Recovery from the toxic effects of prior therapy, with a minimum time of:
1. ≥ 28 days elapsed from the administration of any prior cytotoxic agents, except
≥ 14 days from vincristine, ≥ 21 days from procarbazine, and ≥ 42 days from
nitrosureas. 2. ≥ 28 days elapsed from the administration of any investigational agent. 3. ≥ 14 days elapsed from administration of any non-cytotoxic agent (e.g.,
interferon, tamoxifen, thalidomide, cis-retinoic acid)
13. Patients who have undergone recent surgery for recurrent or progressive tumor are
eligible provided that:
1. Surgery must have confirmed the recurrence. 2. There must be residual disease. 3. A minimum of 28 days must have elapsed from the day of surgery to first dose of
the study drug. For core or needle biopsy, a minimum of 7 days must have
elapsed prior to study entry. 14. Availability of formalin-fixed paraffin-embedded tumor tissue diagnostic of
glioblastoma.
Exclusion Criteria:
1. Concurrent therapeutic intervention (including radiation therapy and NovoTTF).
2. Prior exposure to EGFR inhibitors.
3. Prior exposure to bevacizumab or other VEGF- or VEGF-receptor-targeted agent within
8 weeks of study start.
4. Prior treatment with prolifeprospan 20 with carmustine wafer.
5. Prior intracerebral agent.
6. Evidence of recent hemorrhage on baseline MRI of the brain. However, patients with
clinically asymptomatic presence of hemosiderin, resolving hemorrhagic changes
related to surgery, or presence of punctuate hemorrhage in the tumor are eligible.
7. Need for urgent palliative intervention for primary disease (e.g., rapidly
increasing intracranial pressure, impending herniation, uncontrolled seizures).
8. Hematology:
ANC < 1.5 x109/L; Plt < 100 x109/L Hgb < 9.0 g/dL within 7 days prior to enrollment.
The use of transfusion or other intervention to achieve Hb ≥ 9 g/dL is acceptable.
9. T.Bili. ≥ 1.5 x ULN (except in patients diagnosed with Gilbert's disease).
10. AST(SGOT), ALT(SGPT), or alkaline phosphatase (ALP) ≥ 2.5 x ULN.
11. S. Creat. > 1.5 x ULN.
12. K+ or Mg+ < LLN.
13. In the absence of therapeutic intent to anticoagulate the patient: INR > 1.5 or PT >
1.5 xULN or aPTT > 1.5 xULN Therapeutic anticoagulation.
14. Known contraindication to MRI, such as cardiac pacemaker, shrapnel or ocular foreign
body.
15. Used any prescription medication during the prior 2 weeks that the investigator
judges is likely to interfere with the study or to pose an additional risk to the
patient in participating, specifically inhibitors or inducers of cytochrome P450
(CYP)3A4 (refer to Appendix 5). A stable regimen (≥ 4 weeks) of antidepressants of
the selective serotonin re-uptake inhibitor (SSRI) class is allowed (common SSRIs
include escitalopram oxalate, citalopram, fluvoxamine, paroxetine, sertraline, and
fluoxetine).
16. Taking any drugs associated with torsades de pointes or known to moderately or
severely prolong the QTc(F) interval. 17. History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic
sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR
interval only), or congenital long QT syndrome. Patients with a history of atrial
arrhythmias should be discussed with the Medical Monitor.
18. Uncontrolled diabetes, as evidenced by fasting serum glucose level >200 mg/dL. 19. New York Heart Association (NYHA) Grade II or greater congestive cardiac failure.
20. Has marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval
> 470 msec) using the Fridericia method of correction for heart rate.
21. History of myocardial infarction (within 12 months) or unstable angina (within 6
months) prior to study enrolment.
22. History of stroke or transient ischemic attacks within 6 months prior to study
enrolment.
23. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to study enrolment.
24. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic
anticoagulation).
25. History of intracranial abscess within 6 months prior to study enrolment.
26. History of another malignancy in the previous 3 years, with a disease-free interval
of < 3 years. Patients with prior history of in situ cancer or basal or squamous
cell skin cancer are eligible.
27. Evidence of any active infection requiring hospitalization or IV antibiotics within
2 weeks prior to study enrolment.
28. Known hypersensitivity to any excipients of tesevatinib.
29. Inability to swallow or absorb orally-administered medication.
