Study of Tesevatinib Monotherapy in Patients With Recurrent Glioblastoma

Study Description

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Brief Summary:

This is a multicenter, Phase 2 study to assess the activity of tesevatinib in patients with recurrent glioblastoma.

Condition or disease	Intervention/treatment	Phase
Glioblastoma; Recurrent Glioblastoma; Brain Tumor	Drug: Tesevatinib	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	40 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 2, Multicenter Study of Tesevatinib Monotherapy in Patients With Recurrent Glioblastoma
Study Start Date :	June 2016
Estimated Primary Completion Date :	December 2018
Estimated Study Completion Date :	December 2018

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Glioblastoma; The single arm design assessing PFS-6 in the overall population with the ability to detect a rate of 25% is appropriate as a preliminary test of activity in patients with glioblastoma, based on PFS-6 rates seen in randomized studies with bevacizumab [Weathers 2015; Taal 2014; Galanis 2015]. The sample size of this study is also designed to permit the comparison of results with EGFR amplified and non-amplified tumors, as well as EGFRvIII mutated versus wild-type. The sample size is adequate to characterize the safety profile in patients with glioblastoma.

Drug: Tesevatinib; Other Name: KD019, XL647

Outcome Measures

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Primary Outcome Measures :

1. Median Progression-Free Survival (PFS) [ Time Frame: 6 months ]
   The primary objective is to determine the median progression-free survival (PFS-6) by assessing the median number of days from Cycle 1, Day 1 through 6 months of treatment or until disease progression or death.

Secondary Outcome Measures :

1. Progression-Free Survival (PFS) at 6 months- EGFRvIIIpos [ Time Frame: 6 months ]
   To determine the progression-free survival at 6 months (PFS-6) by assessing the percentage of patients with EGFRvIIIpos glioblastoma who are without disease progression or death at 6 months.
2. Progression-Free Survival (PFS) at 6 months - EGFR gene amplified [ Time Frame: 6 months ]
   To determine the median progression-free survival at 6 months (PFS-6) by assessing the percentage of patients with EGFR gene amplified who are without disease progression or death at 6 months.
3. Overall Survival at 9 months [ Time Frame: 9 months ]
   To determine the overall survival (OS) by measuring the percentage of patients alive at 9 months.
4. Overall Survival at 9 months - EGFRvIIIpos [ Time Frame: 9 months ]
   To determine the median overall survival (OS) in the subgroup of patients with EGFRvIIIpos by measuring the percentage of patients alive at 9 months.
5. Median Overall Survival at 9 months - EGFR gene amplified [ Time Frame: 9 months ]
   To determine the overall survival (OS) in the subgroup of patients with EGFR gene amplified tumors by measuring the percentage of patients with EGFR gene amplified tumors alive at 9 months.
6. Evaluate the concentration of tesevatinib in patients with and without systemic steroid treatment. [ Time Frame: 12 months ]
7. Quality of Life in Patient Receiving tesevatinib [ Time Frame: 12 months ]
   To evaluate changes in the neurocognitive function in patients receiving tesevatinib using the M.D. Anderson Symptom Inventory - Brain Tumor questionnaire (MDASI-BT) questionnaires.
8. Quality of Life in Patient Receiving tesevatinib in sub-group [ Time Frame: 12 months ]
   To evaluate changes in the neurocognitive function in the sub-group of patients with EGFRvIIIneg and EGFR gene amplificationneg tumors as compared to those in patients with EGFRvIIIpos and EGFR gene amplificationpos tumors using the M.D. Anderson Symptom Inventory - Brain Tumor questionnaire (MDASI-BT) questionnaires.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

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Locations

United States, Arizona
Center for Neurosciences
Tucson, Arizona, United States, 85718
United States, California
City of Hope
Duarte, California, United States, 91010
University of California, San Francisco (UCSF)
San Francisco, California, United States, 94143
United States, Colorado
University of Colorado Cancer Center
Aurora, Colorado, United States, 80045
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Michigan
Henry Ford Hospital
Detroit, Michigan, United States, 48202
United States, New York
Columbia University, Herbert Irving Comprehensive Cancer Center
New York, New York, United States, 10032
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Texas
UT MD Anderson Cancer Center
Houston, Texas, United States, 77030
United States, Utah
Huntsman Cancer Institute
Salt Lake City, Utah, United States, 84112

Sponsors and Collaborators

Kadmon Corporation, LLC

More Information

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Responsible Party:	Kadmon Corporation, LLC
ClinicalTrials.gov Identifier:	NCT02844439 History of Changes
Other Study ID Numbers:	KD019-208
First Posted:	July 26, 2016
Last Update Posted:	August 7, 2018
Last Verified:	August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors	Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue