Cancer
Conditions
Keywords
BBI608, thymic cancer
Brief summary
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
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.
Interventions
DRUGBBI608
DRUGPaclitaxel
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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 2. 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. 3. 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 4. 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. 5. 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. 6. 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. 7. 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. 8. Patients with thymic carcinoma must have received at least one prior systemic chemotherapy regiment for metastatic, recurrent, locally advanced or otherwise unresectable disease. 9. ≥ 18 years of age 10. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST 1.1, see Section 9) 11. Karnofsky performance Status ≥ 70% (Section 15) 12. 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 13. Females of childbearing potential must have a negative serum pregnancy test 14. Aspartate transaminase (AST) and alanine transaminase (ALT) £1.5 × upper limit of normal (ULN), or ≤ 2.5 × ULN with metastatic liver disease 15. Hemoglobin (Hgb) ≥ 10 g/dl 16. Total bilirubin £ 1.5 × ULN 17. Creatinine £ 1.5 ´ ULN or creatinine clearance \> 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal 18. Absolute neutrophil count ³ 1.5 x 109/L 19. Platelets ≥ 100 x 109/L 20. Life expectancy ≥ 3 months
Exclusion criteria
1. 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. 2. Surgery within 4 weeks prior to first dose 3. 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 4. Pregnant or breastfeeding 5. Significant gastrointestinal disorder(s), in the opinion of the Principal Investigator, (e.g., Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection) 6. Unable or unwilling to swallow BBI608 capsules daily 7. 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 8. Known severe hypersensitivity to paclitaxel 9. 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With 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. | 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 |
| Determination of the Recommended Phase 2 Dose by Assessing Dose-limiting Toxicities (DLTs) | 28 days | Determination of the Recommended Phase 2 dose (RP2D) of napabucasin when administered with paclitaxel in patients with advanced malignancies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Objective Response Rate of Napabucasin Administered in Combination With Paclitaxel in Patients With Advanced Malignancies | From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 60 months | 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. |
| Disease Control Rate | From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 60 months. | 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. |
| Determination of the Maximum Observed Concentration (Cmax) and Area Under the Plasma Concentration vs. Time Curve (AUClast) | Blood samples drawn on days 16 and 17 of the first study cycle | 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 |
| Overall Survival 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 | The effect of napabucasin given in combination with paclitaxel on Overall Survival (OS) of patients with advanced malignancies |
| Pharmacodynamics | Day 17 of cycle 1 | To determine the response (increase or decrease) of biomarkers from biopsied tumors following the administration of napabucasin |
| Progression Free Survival of Patients With Advanced Malignancies | 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 | 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 |
| Preliminary Anti-tumor Activity of BBI608 When Administered in Combination With Paclitaxel in Patients With Advanced Malignancies | 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 | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
565 participants were enrolled between April 2011 and March 2020.
Pre-assignment details
Participants who died, withdrew consent to survival follow up or were lost to follow up were considered to have completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Napabucasin 200mg BID Plus Paclitaxel Participants received napabucasin 200mg BID administered orally, twice daily, in combination with a fixed dose of paclitaxel administered IV weekly on day 3, 10 and 17 of each 28 day cycle. | 2 |
| Napabucasin 240mg BID Plus Paclitaxel Participants received napabucasin 240mg BID administered orally, twice daily, in combination with a fixed dose of paclitaxel administered IV weekly on day 3, 10 and 17 of each 28 day cycle. | 185 |
| Napabucasin 400mg BID Plus Paclitaxel Participants received napabucasin 400mg BID administered orally, twice daily, in combination with a fixed dose of paclitaxel administered IV weekly on day 3, 10 and 17 of each 28 day cycle. | 4 |
| Napabucasin 480mg BID Plus Paclitaxel Participants received napabucasin 480mg BID administered orally, twice daily, in combination with a fixed dose of paclitaxel administered IV weekly on day 3, 10 and 17 of each 28 day cycle. | 317 |
| Napabucasin 500mg BID Plus Paclitaxel Participants received napabucasin 500mg BID administered orally, twice daily, in combination with a fixed dose of paclitaxel administered IV weekly on day 3, 10 and 17 of each 28 day cycle. | 57 |
| Total | 565 |
Baseline characteristics
| Characteristic | Napabucasin 200mg BID Plus Paclitaxel | Napabucasin 240mg BID Plus Paclitaxel | Napabucasin 400mg BID Plus Paclitaxel | Napabucasin 480mg BID Plus Paclitaxel | Napabucasin 500mg BID Plus Paclitaxel | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 56.0 years STANDARD_DEVIATION 19.8 | 61.3 years STANDARD_DEVIATION 10.14 | 64.8 years STANDARD_DEVIATION 8.06 | 62.7 years STANDARD_DEVIATION 10.42 | 60.5 years STANDARD_DEVIATION 10.72 | 62.0 years STANDARD_DEVIATION 10.38 |
| Race/Ethnicity, Customized Asian | 0 Participants | 14 Participants | 0 Participants | 18 Participants | 2 Participants | 34 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 10 Participants | 0 Participants | 21 Participants | 6 Participants | 37 Participants |
| Race/Ethnicity, Customized Caucasian | 2 Participants | 149 Participants | 4 Participants | 259 Participants | 49 Participants | 463 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 9 Participants | 0 Participants | 11 Participants | 0 Participants | 20 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 3 Participants | 0 Participants | 8 Participants | 0 Participants | 11 Participants |
| Sex: Female, Male Female | 2 Participants | 115 Participants | 1 Participants | 174 Participants | 24 Participants | 316 Participants |
| Sex: Female, Male Male | 0 Participants | 70 Participants | 3 Participants | 143 Participants | 33 Participants | 249 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 2 | 150 / 185 | 4 / 4 | 292 / 317 | 54 / 57 |
| other Total, other adverse events | 2 / 2 | 183 / 185 | 4 / 4 | 317 / 317 | 57 / 57 |
| serious Total, serious adverse events | 1 / 2 | 15 / 185 | 2 / 4 | 28 / 317 | 7 / 57 |
Outcome results
Primary
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.
Time frame: 28 days
Population: The Phase 1b portion of the study consisted of the first 24 patients enrolled in the study. These 24 patients, who received at least one dose of study drug, comprised the DLT Analysis Set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Napabucasin 200mg BID Plus Paclitaxel | Determination of the Recommended Phase 2 Dose by Assessing Dose-limiting Toxicities (DLTs) | 500 mg |
Primary
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
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Napabucasin 200mg BID Plus Paclitaxel | Number of Participants With Adverse Events and Serious Adverse Events | 2 Participants |
| Napabucasin 240mg BID Plus Paclitaxel | Number of Participants With Adverse Events and Serious Adverse Events | 183 Participants |
| Napabucasin 400mg BID Plus Paclitaxel | Number of Participants With Adverse Events and Serious Adverse Events | 4 Participants |
| Napabucasin 480mg BID Plus Paclitaxel | Number of Participants With Adverse Events and Serious Adverse Events | 317 Participants |
| Napabucasin 500mg BID Plus Paclitaxel | Number of Participants With Adverse Events and Serious Adverse Events | 57 Participants |
Secondary
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
Time frame: Blood samples drawn on days 16 and 17 of the first study cycle
Population: Sponsor's decision to terminate further development of the napabucasin program. Data were not collected.
Secondary
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.
Time frame: From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 60 months.
Population: Patients who received at least 1 cycle of study treatment and had at least 1 disease assessment following the initiation of therapy. Patients missing imaging assessment following the initiation of treatment are not included in the assessment for DCR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Napabucasin 200mg BID Plus Paclitaxel | Disease Control Rate | 100 percentage of participants |
| Napabucasin 240mg BID Plus Paclitaxel | Disease Control Rate | 53.1 percentage of participants |
| Napabucasin 400mg BID Plus Paclitaxel | Disease Control Rate | 0 percentage of participants |
| Napabucasin 480mg BID Plus Paclitaxel | Disease Control Rate | 56.1 percentage of participants |
| Napabucasin 500mg BID Plus Paclitaxel | Disease Control Rate | 51.7 percentage of participants |
Secondary
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
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Napabucasin 200mg BID Plus Paclitaxel | Overall Survival of Patients With Advanced Malignancies | NA months |
| Napabucasin 240mg BID Plus Paclitaxel | Overall Survival of Patients With Advanced Malignancies | 7.79 months |
| Napabucasin 400mg BID Plus Paclitaxel | Overall Survival of Patients With Advanced Malignancies | NA months |
| Napabucasin 480mg BID Plus Paclitaxel | Overall Survival of Patients With Advanced Malignancies | 6.51 months |
| Napabucasin 500mg BID Plus Paclitaxel | Overall Survival of Patients With Advanced Malignancies | 7.10 months |
Secondary
Pharmacodynamics
To determine the response (increase or decrease) of biomarkers from biopsied tumors following the administration of napabucasin
Time frame: Day 17 of cycle 1
Population: No on-treatment biopsies were performed therefore no pharmacodynamic testing on tumor tissue was conducted.
Secondary
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.
Time frame: 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
Population: Data were not collected.
Secondary
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
Time frame: 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
Population: Patients had a baseline scan and at least 1 on study scan or died from any cause.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Napabucasin 200mg BID Plus Paclitaxel | Progression Free Survival of Patients With Advanced Malignancies | NA months |
| Napabucasin 240mg BID Plus Paclitaxel | Progression Free Survival of Patients With Advanced Malignancies | 2.23 months |
| Napabucasin 400mg BID Plus Paclitaxel | Progression Free Survival of Patients With Advanced Malignancies | NA months |
| Napabucasin 480mg BID Plus Paclitaxel | Progression Free Survival of Patients With Advanced Malignancies | 2.07 months |
| Napabucasin 500mg BID Plus Paclitaxel | Progression Free Survival of Patients With Advanced Malignancies | 2.3 months |
Secondary
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.
Time frame: From the date of first treatment, every 8 weeks, until the date of first documented objective disease progression, up to 60 months
Population: Patients had a baseline scan and at least 1 disease assessment following the initiation of therapy.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Napabucasin 200mg BID Plus Paclitaxel | The Objective Response Rate of Napabucasin Administered in Combination With Paclitaxel in Patients With Advanced Malignancies | 0 Participants |
| Napabucasin 240mg BID Plus Paclitaxel | The Objective Response Rate of Napabucasin Administered in Combination With Paclitaxel in Patients With Advanced Malignancies | 23 Participants |
| Napabucasin 400mg BID Plus Paclitaxel | The Objective Response Rate of Napabucasin Administered in Combination With Paclitaxel in Patients With Advanced Malignancies | 0 Participants |
| Napabucasin 480mg BID Plus Paclitaxel | The Objective Response Rate of Napabucasin Administered in Combination With Paclitaxel in Patients With Advanced Malignancies | 9 Participants |
| Napabucasin 500mg BID Plus Paclitaxel | The Objective Response Rate of Napabucasin Administered in Combination With Paclitaxel in Patients With Advanced Malignancies | 6 Participants |