A Study of BBI608 in Combination With Pemetrexed and Cisplatin in Adult Patients With Malignant Pleural Mesothelioma

Study Overview
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Brief Summary
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This is an open-label, multicenter, phase 1/2 study of BBI608 in combination with pemetrexed and cisplatin chemotherapy as a 1st line treatment for Malignant Pleural Mesothelioma (MPM).

Official Title
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A Phase I/II Clinical Study of BBI608 in Combination With Pemetrexed and Cisplatin in Adult Patients With Malignant Pleural Mesothelioma

Conditions
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Malignant Pleural Mesothelioma, Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: BBI608
* Drug: Pemetrexed
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Phase 1 Inclusion Criteria: Histologically confirmed diagnosis of Malignant Pleural Mesothelioma (MPM) or Non-Small Cell Lung Cancer (NSCLC). Measurable disease as defined by the modified Response Evaluation Criteria in Solid Tumors (mRECIST) for MPM or the RECIST 1.1 for NSCLC. ≥ 20 years of age. Provision of written informed consent. For male or female patient of child producing potential: Must agree to use contraception or take measures to avoid pregnancy during the study and for 30 days after the last protocol treatment dose. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Hemoglobin (Hb) ≥ 9.0 g/dL. Neutrophils ≥ 1500/μL. Platelets ≥ 100,000/μL. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5-fold the upper limit of normal range (ULN) [≤ 5-fold ULN with any liver metastasis]. Total bilirubin ≤ 1.5-fold ULN. Creatinine clearance (estimated value) ≥ 60 mL/min. Life expectancy ≥ 3 months. Females of childbearing potential have a negative urine pregnancy test. Phase 2 Inclusion Criteria: Histologically confirmed diagnosis of MPM. Treatment naïve and not indicated for resection. Measurable disease as defined by the modified RECIST. ≥ 20 years of age. Provision of written informed consent. For male or female patient of child producing potential: Must agree to use contraception or take measures to avoid pregnancy during the study and for 30 days after the last protocol treatment dose. ECOG Performance Status of 0 or 1. Hb ≥ 9.0 g/dL. Neutrophils ≥ 1500/μL. Platelets ≥ 100,000/μL. AST and ALT ≤ 2.5-fold ULN [≤ 5-fold ULN for patients with any liver metastasis]. Total bilirubin ≤ 1.5-fold ULN. Creatinine clearance (estimated value) > 60 mL/min. Life expectancy ≥ 3 months. Females of childbearing potential have a negative urine pregnancy test. Both Phase 1 and 2 Exclusion Criteria: Prior anti-cancer chemotherapy and radiotherapy. Prior hormonal therapy, immunotherapy, thermotherapy, operation. Any brain metastasis requiring treatment or symptomatic. Active multiple primary cancers. Crohn's disease, ulcerative colitis, small intestine resection. Abnormal ECGs. Prior myocardial infarction. Current use of antiarrhythmic medication. Uncontrolled concurrent diseases. Known severe hypersensitivity to pemetrexed, cisplatin or other drugs containing platinum. Women who are pregnant or breastfeeding. Received other investigational drugs. Unable or unwilling to swallow BBI608 capsules daily. Prior treatment with BBI608. Ineligible for participation in the study in the opinion of the Investigators.

Ages Eligible for Study
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Minimum Age: 20 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BBI608 puls pemetrexed and cisplatin<br> | Drug: BBI608<br>* 480 mg orally twice daily (960 mg total daily dose)<br>Drug: Pemetrexed<br>* 500 mg/m2 I.V. infusion on Day 1 of each treatment cycle (except for cycle 1, in which Pemetrexed will be given on Day 3).<br>Drug: Cisplatin<br>* 75 mg/m2 I.V. infusion on Day 1 of each treatment cycle (except for Cycle 1, in which Cisplatin will be given on Day 3).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 Part: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Drug Reactions (ADRs) | An AE is any untoward medical occurrence in a study subject administered an investigational drug and which does not necessarily have a causal relationship with this treatment. A SAE was an AE that met one or more of the following criteria: Results in death Is life-threatening Requires hospitalization or prolongation of existing hospitalization Results in persistent or significant disability or incapacity Is a congenital anomaly or birth defect Is an important medical event that may jeopardize the subject or may require a medical or surgical intervention to prevent one of the outcomes listed above. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization. An ADR was defined as adverse events assessed to be related to the investigational drug | Between initial dosing of the investigational drug and final evaluation in the follow-up observation period, about 17 months | 
| Phase 1 Part: Number of Participants With Dose-limiting Toxicities (DLTs) | DLT was defined as an adverse event meeting any of the following that occurred during the DLT evaluation period in any participants given BBI608 with the causal relationship to BBI608 assessed as Definite, Probable, or Possible. The severity of adverse events was graded according to the CTCAE v4.0-JCOG. Grade 4 neutropenia persisting for ≥ 7 days Grade ≥ 3 febrile neutropenia persisting for ≥ 5 days Grade 3 thrombocytopenia requiring platelet transfusions, grade 4 thrombocytopenia Grade ≥ 3 non-hematotoxicity except the following: Inappetence, nausea, vomiting and electrolyte abnormality which, within 3 days of onset, improved to grade ≤ 2 or resolved after appropriate treatment Diarrhoea and fatigue which, within 5 days of onset, improved to grade ≤ 2 or resolved after appropriate treatment Other clinically significant signs in the opinion of the investigator | From Day 1 of Cycle 1 to Day 24 pre-dose examination (23 days) | 
| Phase 1 Part: Maximum Observed Concentration (Cmax) and Minimum Observed Concentration (Cmin) of BBI608 When Administered With Pem and CDDP |  | Cycle 1 Day 1 (Cmax only) and Day 23 | 
| Phase 1 Part: Area Under the Concentration-time Curve | AUC0-12: Area under the concentration-time curve from time zero to 12 hours, AUC0-24: Area under the concentration-time curve from time zero to 24 hours, AUC0-inf: Area under the concentration-time curve from time zero to infinity | Cycle 1 Day 1 and Day 23 | 
| Phase 2 Part: Progression-free Survival (PFS) | PFS was defined as the time from BBI608 administration to documented PD (as assessed according to the mRECIST or RECIST 1.1) or death, whichever is earlier. The result of imaging assessment by the imaging assessment committee was used for phase 2 part. | From BBI608 administration to documented PD or death, whichever is earlier, about 17 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response | The best overall response is the best response recorded from the start of the study treatment until the end of treatment. The RECIST 1.1 was used for the evaluation of tumor response and overall response in patients with NSCLC, and also the evaluation of any non-pleural lesions in patients with MPM. The mRECIST was used for the evaluation of tumor response and overall response in patients with MPM. The result of imaging assessment by study site was used for phase 1 part, and the result of imaging assessment by the imaging assessment committee was used for phase 2 part. | Every 6 weeks from the first dose of BBI608 until Week 30, and every 9 weeks from Week 31. | 
| Response Rate (RR) and Disease Control Rate (DCR) | Response rate (RR): Proportion of subjects whose best overall response is CR or PR. Disease control rate (DCR): Proportion of subjects whose best overall response is CR, PR or SD. The result of imaging assessment by study site was used for phase 1 part, and the result of imaging assessment by the imaging assessment committee was used for phase 2 part. | From BBI608 administration to death from any cause, about 17 months | 
| Overall Survival(OS) | OS was defined as the time from BBI608 administration to death from any cause. Participants alive at final observation or lost to follow-up were censored at their last contact (i.e., visit or telephone) date. | From BBI608 administration to death from any cause, up to 31 months | 
| Respiratory Function Tests (Vital Capacity [VC] and Forced Vital Capacity [FVC]) |  | Every 6 weeks from the first dose of BBI608 until Week 30, and then every 9 weeks from Week 31 [Actually up to Week 111] | 
| Respiratory Function Tests (Forced Expiratory Volume in the First Second [FEV1]) |  | Every 6 weeks from the first dose of BBI608 until Week 30, and then every 9 weeks from Week 31 [Actually up to Week 111] |