A Study of BBI608 in Adult Patients With Advanced, Refractory Hematologic Malignancies

Study Overview
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Brief Summary
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This is a multicenter, open label, Phase 1 dose-escalation study of BBI608 administered to patients with relapsed, refractory hematologic malignancies, including multiple myeloma, lymphoma, and others.

Official Title
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A Phase Ib Clinical Study of BBI608 for Adult Patients With Advanced, Refractory Hematologic Malignancies

Conditions
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Hematologic Malignancy

Intervention / Treatment
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* Drug: BBI608
* Drug: Dexamethasone
* Drug: Bortezomib
* Drug: Imatinib
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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Major Inclusion Criteria: Signed written informed consent must be obtained and documented according to the International Conference on Harmonisation (ICH) and be in accordance with local regulatory requirements A histologically confirmed hematologic malignancy that is advanced, relapsed, or refractory to standard, currently available anti-cancer treatment options ≥ 18 years of age Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 at dose escalation phase and of ≤ 2 at dose expansion phase Male or female patients of child-producing potential must agree to use contraception or avoidance of pregnancy measures during the study and for 30 days after their last dose Females of childbearing potential must have a negative serum pregnancy test Aspartate transaminase (AST) ≤ 2.5 x upper limit of normal (ULN) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN). Patients whose disease involves the liver and who have laboratory values of AST ≤ 3.5 ULN, AST ≤ 3.5 ULN, and albumin ≥ 35g/L may be enrolled if agreed upon by the Principal Investigator and Medical Monitor for the Sponsor Total bilirubin < 1.5 x ULN, except for cases in which elevation of total bilirubin is due to elevated levels of unconjugated bilirubin consistent with a diagnosis of Gilbert's Syndrome Life expectancy ≥ 3 months

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 1<br>Patients with multiple myeloma treated with BBI608 | Drug: BBI608<br>* Patients will receive BBI608 orally twice daily, with doses separated by approximately 12 hours. The starting dose for all cohorts will be 240 mg twice daily. Subsequently, cohorts at alternate dose-levels (480 mg twice daily) may be enrolled as determined by the criteria for dose-escalation.<br>* Other names: BBI-608;|
| Experimental: Arm 2<br>Patients with lymphoma treated with BBI608 | Drug: BBI608<br>* Patients will receive BBI608 orally twice daily, with doses separated by approximately 12 hours. The starting dose for all cohorts will be 240 mg twice daily. Subsequently, cohorts at alternate dose-levels (480 mg twice daily) may be enrolled as determined by the criteria for dose-escalation.<br>* Other names: BBI-608;|
| Experimental: Arm 3<br>Patients with acute myeloid leukemia or myelo-dysplastic syndrome treated with BBI608 | Drug: BBI608<br>* Patients will receive BBI608 orally twice daily, with doses separated by approximately 12 hours. The starting dose for all cohorts will be 240 mg twice daily. Subsequently, cohorts at alternate dose-levels (480 mg twice daily) may be enrolled as determined by the criteria for dose-escalation.<br>* Other names: BBI-608;|
| Experimental: Arm 4<br>Patients with chronic myeloid leukemia treated with BBI608 | Drug: BBI608<br>* Patients will receive BBI608 orally twice daily, with doses separated by approximately 12 hours. The starting dose for all cohorts will be 240 mg twice daily. Subsequently, cohorts at alternate dose-levels (480 mg twice daily) may be enrolled as determined by the criteria for dose-escalation.<br>* Other names: BBI-608;|
| Experimental: Arm 5<br>Patients with multiple myeloma treated with BBI608 and dexamethasone | Drug: BBI608<br>* Patients will receive BBI608 orally twice daily, with doses separated by approximately 12 hours. The starting dose for all cohorts will be 240 mg twice daily. Subsequently, cohorts at alternate dose-levels (480 mg twice daily) may be enrolled as determined by the criteria for dose-escalation.<br>* Other names: BBI-608;Drug: Dexamethasone<br>* Dexamethasone will be taken orally at a dose level of 40 mg once weekly, on Days 1, 8, 15, and 22 of each Cycle. Patients over the age of 75 years are allowed to begin dexamethasone at a dose of 20 mg once weekly, on Days 1, 8, 15, and 22 of each Cycle. Dexamethasone should be taken with food or milk, and a minimum of 2 hours should separate a dose of dexamethasone from a dose of BBI608.<br>|
| Experimental: Arm 6<br>Patients with multiple myeloma treated with BBI608 and bortezomib | Drug: BBI608<br>* Patients will receive BBI608 orally twice daily, with doses separated by approximately 12 hours. The starting dose for all cohorts will be 240 mg twice daily. Subsequently, cohorts at alternate dose-levels (480 mg twice daily) may be enrolled as determined by the criteria for dose-escalation.<br>* Other names: BBI-608;Drug: Bortezomib<br>* Bortezomib will be administered at 1.3 mg/m2/dose as a 3-5 second bolus intravenous (IV) injection or subcutaneous injection twice weekly for 2 weeks (Day 1, 4, 8, and 11) followed by a 10-day rest period (Day 12-21).<br>* Other names: Velcade;|
| Experimental: Arm 7<br>Patients with chronic myeloid leukemia treated with BBI608 and imatinib | Drug: BBI608<br>* Patients will receive BBI608 orally twice daily, with doses separated by approximately 12 hours. The starting dose for all cohorts will be 240 mg twice daily. Subsequently, cohorts at alternate dose-levels (480 mg twice daily) may be enrolled as determined by the criteria for dose-escalation.<br>* Other names: BBI-608;Drug: Imatinib<br>* Imatinib will be taken orally once daily with a meal and a large glass of water. For patients having difficulty swallowing, imatinib can be dissolved in water or apple juice for intake. The dose of imatinib is 400 mg for CML patients in the chronic phase and 600 mg for CML patients in the accelerated phase or in blast crisis. A minimum of 2 hours should separate a dose of imatinib from a dose of BBI608.<br>* Other names: Gleevec;|
| Experimental: Arm 8<br>Patients with chronic lymphocytic leukemia treated with BBI608 | Drug: BBI608<br>* Patients will receive BBI608 orally twice daily, with doses separated by approximately 12 hours. The starting dose for all cohorts will be 240 mg twice daily. Subsequently, cohorts at alternate dose-levels (480 mg twice daily) may be enrolled as determined by the criteria for dose-escalation.<br>* Other names: BBI-608;|
| Experimental: Arm 9<br>Patients with chronic lymphocytic leukemia treated with BBI608 and ibrutinib | Drug: BBI608<br>* Patients will receive BBI608 orally twice daily, with doses separated by approximately 12 hours. The starting dose for all cohorts will be 240 mg twice daily. Subsequently, cohorts at alternate dose-levels (480 mg twice daily) may be enrolled as determined by the criteria for dose-escalation.<br>* Other names: BBI-608;Drug: Ibrutinib<br>* Ibrutinib will be taken orally once daily with water. Do not open, break, or chew the capsules. The dose of ibrutinib is 420 mg for patients with normal liver function and is 140 mg for patients with mild liver impairment (Child-Pugh class A). A minimum of 2 hours should separate a dose of ibrutinib from a dose of BBI608.<br>* Other names: Imbruvica;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the safety and tolerability of BBI608 administered as monotherapy and in combination with dexamethasone, bortezomib, imatinib or ibrutinib by assessing dose-limiting toxicities (DLTs) |  | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile of BBI608 when administered in monotherapy and in combination with dexamethasone, bortezomib, imatinib or ibrutinib as assessed by maximum plasma concentration and area under the curve |  | -5min, 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 8, 11, 12 hours on day 1, cycles 1 and 2 | 
| Pharmacodynamic activity of BBI608 when administered in monotherapy and in combination with dexamethasone, bortezomib, imatinib or ibrutinib as assessed by biomarker analysis | Histopathology and Cancer Stem Cell assays will be performed to provide information of the biomarkers on patient blood samples collected on-study, as well as on (if available) bone marrow, other biopsied patient tumor tissue, and archival samples. | 20 weeks | 
| Assessment of the preliminary anti-tumor activity by performing tumor assessments |  | 20 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Lymphoma, Acute Myeloid Leukemia, Myelo-Dysplastic Syndrome, Chronic Myeloid Leukemia, Chronic Lymphocytic Leukemia