A Study of BBI608 in Combination With Temozolomide in Adult Patients With Recurrent or Progressed Glioblastoma

Study Overview
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Brief Summary
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This is an open label, multi-center, phase 1 safety run-in and phase 2 study of BBI608 in combination with temozolomide in patients with recurrent or progressive glioblastoma who have not received prior bevacizumab therapy.

Detailed Description
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In arm A, patients who are candidates for surgical resection will receive BBI608 as monotherapy prior to resection, followed by post-operative BBI608 administered in combination with temozolomide. In arm B, patients who are not candidates for surgical resection will receive BBI608 administered orally, daily, in combination with temozolomide. In the phase 1/dose-limiting toxicity (DLT) cohort portion of this study, pharmacokinetics will be evaluated for both arms A and B. Pharmacodynamics will be evaluated in all patients who undergo surgical resection.

Official Title
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A Phase Ib/II Clinical Study of BBI608 in Combination With Temozolomide for Adult Patients With Recurrent or Progressed Glioblastoma

Conditions
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Glioblastoma

Intervention / Treatment
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* Drug: BBI608
* Drug: Temozolomide


Participation Criteria
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Eligibility Criteria
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Major Eligibility Criteria Signed written informed consent must be obtained and documented according to International Conference on Harmonisation (ICH) and local regulatory requirements. A histologically confirmed supratentorial glioblastoma (GBM) at first recurrence/progression (except for transformation from previous low grade glioma) following standard front-line therapy, for which treatment with temozolomide (TMZ) would be acceptable as determined by the Investigator Previously received standard front-line GBM treatment including maximal surgical resection followed by external beam radiation therapy. Patients may or may not be candidates for repeat surgical resection of the recurrent/progressed GBM. Patients must have unequivocal evidence of tumor recurrence/progression by MRI at a minimum of 12 weeks following completion of chemoradiation or radiation therapy. Patients must have measurable or non-measurable disease by response assessment in neuro-oncology Response Assessment in Neuro-oncology (RANO) criteria

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Patients for whom surgery is recommended as part of treatment for recurrent Glioblastoma. | Drug: BBI608<br>* In arm A, BBI608 will be administered at the recommended Phase 2 dose (RP2D) twice daily for 7(±2) days prior to planned surgical resection or biopsy of recurrent GBM. Upon the clinical recovery of the patient and at a time between 15-28 days after surgery, BBI608 will be administered orally, daily, each day of a 28 day cycle in combination with temozolomide. In arm B, patients who are not candidates for surgical resection will receive BBI608 administered orally, daily, each day of a 28 day cycle at the RP2D in combination with temozolomide.<br>* Other names: BBI-608;Drug: Temozolomide<br>* Temozolomide (TMZ) will be administered orally, once daily, at a dose of 150 mg/m^2 daily on days 1 through 5 of each 28-day study cycle. The dose of temozolomide can be increased to 200 mg/m^2 as per standard TMZ dosing guidelines for patients who complete at least one cycle at 150 mg/m^2.<br>* Other names: Temodar;|
| Experimental: Arm B<br>Patients for whom surgery is not recommended as part of the treatment for recurrent Glioblastoma. | Drug: BBI608<br>* In arm A, BBI608 will be administered at the recommended Phase 2 dose (RP2D) twice daily for 7(±2) days prior to planned surgical resection or biopsy of recurrent GBM. Upon the clinical recovery of the patient and at a time between 15-28 days after surgery, BBI608 will be administered orally, daily, each day of a 28 day cycle in combination with temozolomide. In arm B, patients who are not candidates for surgical resection will receive BBI608 administered orally, daily, each day of a 28 day cycle at the RP2D in combination with temozolomide.<br>* Other names: BBI-608;Drug: Temozolomide<br>* Temozolomide (TMZ) will be administered orally, once daily, at a dose of 150 mg/m^2 daily on days 1 through 5 of each 28-day study cycle. The dose of temozolomide can be increased to 200 mg/m^2 as per standard TMZ dosing guidelines for patients who complete at least one cycle at 150 mg/m^2.<br>* Other names: Temodar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting Toxicities (DLTs) | Number of patients who experienced a dose limiting toxicity following a dosing of BBI608 | 28 days after first administration of combination treatment (BBI608+TMZ) | 
| Progression Free Survival (PFS)-6 | To assess the effect of BBI608 + temozolomide (TMZ) therapy defined as the percentage of patients who have survived without objective disease progression for at least 6 months after treatment per neuro-oncology (RANO) criteria who had evaluable disease at baseline. PFS-6 is defined as the percentage of patients who survived without objective disease progression per RANO criteria for at least 6 months after treatment. | From the time of exposure to study drug to first objective documentation of disease progression or death due to any cause, assessed up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS)-12 | To assess the effect of BBI608 + temozolomide (TMZ) therapy defined as the percentage of patients who have survived without objective disease progression for at least 12 months after treatment per neuro-oncology (RANO) criteria who had evaluable disease at baseline. PFS-12 is defined as the percentage of patients who survived without objective disease progression per RANO criteria for at least 12 months after treatment. | From the time of exposure to study drug to first objective documentation of disease progression or death due to any cause, up to 12 months | 
| Overall Survival (OS) | To assess the effect of BBI608 + temozolomide (TMZ) on the overall survival of patients with recurrent or progressive glioblastoma multiforme (GBM) who had not received prior treatment with bevacizumab or other anti-vascular endothelial growth factor agents who either were eligible or not eligible for surgical resection. | From the time of exposure to study drug to death from any cause. If patient discontinued study drug, they were assessed the first 3 months after discontinuation, then every 3 months up to 1 year, then every 6 months thereafter until death. | 
| Disease Control Rate (DCR) | To assess the percentage of patients that had evaluable disease at baseline with a documented complete response, partial response, and stable disease (CR + PR + SD) based on the Response Assessment in Neuro-Oncology (RANO) criteria out of all patients who received at least one dose of any study drug and had evaluable disease at baseline. | 4 weeks | 
| Overall Response Rate (ORR) | The proportion of patients with a documented complete response and partial response (CR + PR) based on RANO criteria. | 4 weeks | 
| Pharmacokinetic Profile of BBI608 and Temozolomide When Administered in Combination With Temozolomide as Assessed by the Area Under the Curve | The area under the curve of BBI608, from time 0 to the last quantifiable concentration, calculated by a combination of linear and logarithmic trapezoidal methods (linear up/log down method) | On Day 1 and Day 5 after the first dosing, prior to dosing and 1, 2, 3, 5, 5h40m (day 1 only), 6, 7, 8 and 24 hours after first dose of BBI608 | 
| Pharmacodynamic Activity of BBI608 When Administered in Combination With Temozolomide as Assessed by Tumor Biopsy and Cancer Stem Cell Assays as Well as the Concentration of Study Drug in Tumors | Tumor samples to provide information of the biomarkers by histopathology and Cancer Stem Cell assays as well as the concentration of study drug in tumors. | At the time of surgical resection | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GBM, Malignant Glioma