A Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies

Study Overview
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Brief Summary
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This is an open label, single arm phase 1 dose escalation study and phase 2 study of BBI608 in combination with paclitaxel in patients with advanced malignancies.

Detailed Description
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This is an open label, multi-center, single arm phase 1 dose escalation study and phase 2 study of BBI608 in combination with paclitaxel in patients with advanced solid tumors for whom weekly paclitaxel is an acceptable option.

Official Title
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A Phase Ib/II Clinical Study of BBI608 Administered With Paclitaxel in Adult Patients With Advanced Malignancies

Conditions
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Cancer

Intervention / Treatment
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* Drug: BBI608
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent must be obtained and documented according to International Conference on Harmonization (ICH)- Good Clinical Practice (GCP), the local regulatory requirements, and permission to use private health information in accordance with the Health Insurance Portability and Accountability Act (HIPPA) prior to study-specific screening procedures A histologically or cytologically confirmed ovarian, breast, non-small cell lung, melanoma, gastric/GEJ/esophageal or other type of advanced cancer that is metastatic, unresectable, or recurrent and for which weekly paclitaxel is an acceptable therapeutic option. Patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer must also meet the following criteria: a. Must be either platinum-resistant or platinum-refractory according to the following definitions:(1)Platinum-resistant: a response to platinum therapy followed by progression within 6 months after completing therapy (2)Platinum-refractory: best response of stable disease or progression during platinum therapy; b. Must have had prior systemic treatment with a taxane; c. Must have received no more than 4 prior systemic cytotoxic regimens Patients with melanoma must also meet the following criteria: a. If melanoma is BRAF wild-type or has BRAF mutations that are not amenable to BRAF inhibitor therapy, and the patient is a candidate for immunotherapy, must have received ipilimumab; b. If melanoma is positive for the V600E or V600K BRAF mutation, must have received at least one line of prior therapy with a BRAF-specific inhibitor; either alone or in combination. Patients with triple negative breast cancer (estrogen receptor-negative (ER-), progesterone receptor-negative (PR-), and human epidermal growth factor receptor 2-negative (Her2-) must also meet the following criteria: a. Must have received at least one prior chemotherapy regimen for locally advanced or metastatic disease; b. Must have received prior taxane therapy. Patients with NSCLC (adenocarcinoma, squamous, or adenosquamous histopathology) must also meet the following criteria: a. Must have disease that is stage IIIB, not curable by surgery or radiotherapy, or stage IV; b. Must have received at least one prior chemotherapy regimen for locally advanced or metastatic disease; c. EGFR-positive or ALK-positive patients must have received at least one line of EGFR-directed or ALK-directed therapy, respectively; d. Must have received prior taxane therapy. Patients with adenocarcinoma arising from the esophagus, gastroesophageal junction, or stomach must also meet the following criteria: a. Must have received prior treatment with a platinum/fluoropyrimidine-based therapy with or without an anthracycline in the metastatic setting; or, in the adjuvant setting if recurrence occurred within 6 months of completing systemic adjuvant treatment; b. Patients with HER2 positive tumors must have had prior treatment with a Her2 inhibitor (e.g. trastuzumab or lapatinib); c. Patients who have received prior taxane therapy may be enrolled. Patients with thymic carcinoma must have received at least one prior systemic chemotherapy regiment for metastatic, recurrent, locally advanced or otherwise unresectable disease. ≥ 18 years of age Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1, see Section 9) Karnofsky performance Status ≥ 70% (Section 15) 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 the last BBI608 dose Females of childbearing potential must have a negative serum pregnancy test Aspartate transaminase (AST) and alanine transaminase (ALT) £1.5 × upper limit of normal (ULN), or ≤ 2.5 × ULN with metastatic liver disease Hemoglobin (Hgb) ≥ 10 g/dl Total bilirubin £ 1.5 × ULN Creatinine £ 1.5 ´ ULN or creatinine clearance > 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal Absolute neutrophil count ³ 1.5 x 109/L Platelets ≥ 100 x 109/L Life expectancy ≥ 3 months Exclusion Criteria: Anti-cancer chemotherapy, radiotherapy, immunotherapy, or investigational agents within 7 days of first dose provided all treatment-related adverse events have resolved or have been deemed irreversible, with the exception for a single dose radiation up to 8 Gray (equal to 800 RAD) with palliative intent for pain control up to 7 days before beginning the administration of BBI608. Surgery within 4 weeks prior to first dose Any known symptomatic brain metastases requiring steroids. Patients with treated brain metastases must be stable for 4 weeks after completion of that treatment, with image documentation required. Patients must have no clinical symptoms from brain metastases and must be either off steroids or on a stable dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with known leptomeningeal metastases are excluded, even if treated Pregnant or breastfeeding Significant gastrointestinal disorder(s), in the opinion of the Principal Investigator, (e.g., Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection) Unable or unwilling to swallow BBI608 capsules daily Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements Known severe hypersensitivity to paclitaxel Abnormal ECGs (ie, QT prolongation - QTc > 480 msec, signs of cardiac enlargement or hypertrophy, bundle branch block, signs of ischemia or necrosis and Wolff Parkinson White patterns)

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BBI608 and Paclitaxel 200mg BID<br>Patients will receive BBI608 orally continuously at 200mg BID. A treatment cycle will be 4 weeks (28 days). BBI608 will be administered twice daily. On days 3, 10, and 17 of each 28 day cycle, patients will receive a 1 hour infusion of paclitaxel. Cycles will be repeated until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, adjustment is permitted. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Paclitaxel<br> <br> * Other names: Abraxane;|
| Experimental: BBI608 and Paclitaxel 240mg BID<br>Patients will receive BBI608 orally continuously at 240mg BID. A treatment cycle will be 4 weeks (28 days). BBI608 will be administered twice daily. On days 3, 10, and 17 of each 28 day cycle, patients will receive a 1 hour infusion of paclitaxel. Cycles will be repeated until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, adjustment is permitted. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Paclitaxel<br> <br> * Other names: Abraxane;|
| Experimental: BBI608 and Paclitaxel 400mg BID<br>Patients will receive BBI608 orally continuously at 400mg BID. A treatment cycle will be 4 weeks (28 days). BBI608 will be administered twice daily. On days 3, 10, and 17 of each 28 day cycle, patients will receive a 1 hour infusion of paclitaxel. Cycles will be repeated until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, adjustment is permitted. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Paclitaxel<br> <br> * Other names: Abraxane;|
| Experimental: BBI608 and Paclitaxel 480mg BID<br>Patients will receive BBI608 orally continuously at 480mg BID. A treatment cycle will be 4 weeks (28 days). BBI608 will be administered twice daily. On days 3, 10, and 17 of each 28 day cycle, patients will receive a 1 hour infusion of paclitaxel. Cycles will be repeated until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, adjustment is permitted. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Paclitaxel<br> <br> * Other names: Abraxane;|
| Experimental: BBI608 and Paclitaxel 500mg BID<br>Patients will receive BBI608 orally continuously at 500mg BID. A treatment cycle will be 4 weeks (28 days). BBI608 will be administered twice daily. On days 3, 10, and 17 of each 28 day cycle, patients will receive a 1 hour infusion of paclitaxel. Cycles will be repeated until progression of disease, unacceptable toxicity, or another discontinuation criterion is met. In the case of toxicity, adjustment is permitted. | Drug: BBI608<br> <br> * Other names: BBI-608;Drug: Paclitaxel<br> <br> * Other names: Abraxane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events and Serious Adverse Events | Assessment of safety of napabucasin administered in participants with advanced malignancies for whom weekly paclitaxel was an acceptable option by reporting of adverse events and serious adverse events | The time from the date of first treatment, while the patient is taking napabucasin, and for 30 days after stopping therapy, an average of 4 months. | 
| Determination of the Recommended Phase 2 Dose by Assessing Dose-limiting Toxicities (DLTs) | Determination of the Recommended Phase 2 dose (RP2D) of napabucasin when administered with paclitaxel in patients with advanced malignancies. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determination of the Maximum Observed Concentration (Cmax) and Area Under the Plasma Concentration vs. Time Curve (AUClast) | To determine the maximum concentration of napabucasin and the area under the plasma concentration vs. time curve of napabucasin when administered in combination with weekly paclitaxel | Blood samples drawn on days 16 and 17 of the first study cycle | 
| Preliminary Anti-tumor Activity of BBI608 When Administered in Combination With Paclitaxel in Patients With Advanced Malignancies | To assess the preliminary anti-tumor activity, specifically the objective response rate (ORR) of napabucasin administered in combination with paclitaxel. The Objective Response Rate (ORR) is the proportion of participants with a complete response or partial response who have measurable disease at baseline imaging. | From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, for an anticipated average of six months | 
| The Objective Response Rate of Napabucasin Administered in Combination With Paclitaxel in Patients With Advanced Malignancies | Assessment of the objective response rate (ORR) of napabucasin administered in combination with paclitaxel in patients with advanced malignancies. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; The Objective Response Rate (ORR) is the proportion of participants with a complete response or partial response. | From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 60 months | 
| Disease Control Rate | To determine the disease control rate (CDR) of napabucasin administered in combination with paclitaxel in patients with advanced malignancies. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. The Disease Control Rate (DCR) is the proportion of patients whose best overall response is CR, PR or SD. | From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 60 months. | 
| Progression Free Survival of Patients With Advanced Malignancies | The effect of napabucasin given in combination with paclitaxel on Progression Free Survival (PFS) of patients with advanced malignancies. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions | The time from the date of first treatment to the date of first documentation of disease progression or death due to any cause, up to 60 months | 
| Overall Survival of Patients With Advanced Malignancies | The effect of napabucasin given in combination with paclitaxel on Overall Survival (OS) of patients with advanced malignancies | 4 weeks after the patient has been off study treatment, every 3 months up to 18 months, then every 6 months thereafter until death, up to 118 months | 
| Pharmacodynamics | To determine the response (increase or decrease) of biomarkers from biopsied tumors following the administration of napabucasin | Day 17 of cycle 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BBI608, thymic cancer