Purpose: This is a pilot study that aims to develop a lung cancer screening program for workers in British Columbia, Canada exposed to asbestos who are at risk of developing lung cancer/pleural mesothelioma. This is high risk population is at of respiratory system diseases as a result of their occupational exposures. Additionally, knowledge garnered from this study will allow us to develop other studies that will further our understanding of asbestos related lung cancer and mesothelioma.
Pleural Mesothelioma
Phase II Study of Six Hours Low Dose Gemcitabine Plus Cisplatin in the Treatment for Advanced Pleural Mesothelioma
Purpose
Malignant pleural mesothelioma (MPM) is a rare disease, but with a very high mortality. MPM is frequently found in advanced stages. The standard treatment in advanced pleural mesothelioma is cisplatin-based chemotherapy combined with pemetrexed/raltitrexed (phase III studies showed its benefit in response and overall survival compared with cisplatin alone). There are other active drugs such as liposomal doxorubicin and gemcitabine. Unfortunately, cost is an important factor to consider in our population and standard treatments are very expensive. Gemcitabine 250 mg infused over 6 hrs in combination with cisplatin, compared to the standard administration of gemcitabine 1250 mg infusion of 30 minutes in NSCLC, combined with cisplatin showed 75 mg shown in a study to be equally effective in treating cancer non-small cell lung. A phase II study using this strategy for advanced MPM has shown promising results. Gemcitabine administered in low dose in a six hour infusion may reduce cost of treatment without altering the effectiveness.
Placebo Controlled Study of VS-6063 in Subjects With Malignant Pleural Mesothelioma (COMMAND)
Purpose: This study is a Phase 2, randomized, double-blind, placebo-controlled, multicenter study of defactinib (VS-6063) in subjects with malignant pleural mesothelioma (MPM) who have not progressed (confirmed partial response or stable disease) following ≥ 4 cycles of treatment with pemetrexed/cisplatin or pemetrexed/carboplatin. Prior to entry and randomization to the study, each subject must have tumor Merlin status(high or low) established by immunohistochemistry performed at a central laboratory. Subjects will be randomized in a 1:1 ratio to receive oral VS-6063 400 mg twice per day, or matched placebo. Randomization will be stratified by tumor Merlin status (high versus low). Progression will be assessed both locally and by central review using the Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1. Subjects will continue to receive treatment until disease progression or other discontinuation criteria are met. Following documentation of nonfatal disease progression, all subjects will be followed for overall survival by telephone contact every 2 months until end of life or the close of the study.
Adjuvant Tumor Lysate Vaccine and Iscomatrix With or Without Metronomic Oral Cyclophosphamide and Celecoxib in Patients With Malignancies Involving Lungs, Esophagus, Pleura, or Mediastinum
Purpose: During recent years, cancer-testis (CT) antigens (CTA), particularly those encoded by genes on the X chromosome (CT-X genes), have emerged as attractive targets for cancer immunotherapy. Whereas malignancies of diverse histologies express a variety of CTAs, immune responses to these proteins appear uncommon in cancer patients, possibly due to low-level, heterogeneous antigen expression, as well as immunosuppressive regulatory T cells present within tumor sites and systemic circulation of these individuals. Conceivably, vaccination of cancer patients with tumor cells expressing high levels of CTAs in combination with regimens that deplete or inhibit T regulatory cells will induce broad immunity to these antigens. In order to examine this issue, patients with primary lung and esophageal cancers, pleural mesotheliomas, thoracic sarcomas, thymic neoplasms and mediastinal germ cell tumors, as well as sarcomas, melanomas, germ cell tumors, or epithelial malignancies metastatic to lungs, pleura or mediastinum with no evidence of disease (NED) or minimal residual disease (MRD) following standard multidisciplinary therapy will be vaccinated with H1299 tumor cell lysates with Iscomatrix adjuvant. Vaccines will be administered with or without metronomic oral cyclophosphamide (50 mg PO BID x 7d q 14d), and celecoxib (400 mg PO BID). Serologic responses to a variety of recombinant CTAs as well as immunologic responses to autologous tumor or epigenetically modified autologous EBVtransformed lymphocytes will be assessed before and after a six month vaccination period.
Multicentre Study Comparing Indwelling Pleural Catheter With Talc Pleurodesis for Malignant Pleural Effusion Management
Purpose: Malignant pleural effusion (MPE) accounts for 50% of all pleural effusions and affects about 300,000 patients annually (UK and USA). Lung and breast cancers account for majority of malignant pleural effusions; 1 in 3 breast cancer, 1 in 4 lung cancer as well as > 90% of patients with mesothelioma develop pleural effusions. Breathlessness from MPE is disabling and impairs quality of life. Median survival ranges between 4-6 months. Although thoracentesis provides effective symptom relief, most effusions recur and pleurodesis is the standard of care. Pleurodesis can be performed via chest tube or applied during pleuroscopy, and talc is the most effective agent. For successful pleurodesis to occur the underlying lung must expand after fluid drainage and trapped lung due to metastatic disease occurs up to 30%. Symptomatic patients require hospitalization for these procedures which are likely to fail if trapped lungs are encountered, and pose significant burden to health services. Tunneled indwelling pleural catheter (IPC) is emerging as a viable alternative which provides access to the pleural space for fluid drainage when breathlessness arise. IPC can be performed at ambulatory setting without hospital admission. Case series have demonstrated long-term safety of IPC even in patients undergoing chemotherapy with acceptable complication rates. By keeping the pleural cavity free of fluid, IPC has led to spontaneous pleurodesis in 50% of patients, which allows its removal. Presently IPC is indicated for trapped lung or when talc pleurodesis has failed. A randomised comparative trial with talc pleurodesis is necessary to determine role of IPC as first-line therapy of MPE, if IPC leads to reduction in hospitalizations, adverse events and healthcare costs, and if it improves quality of life. The multicenter trial randomizes symptomatic patients 1:1 to IPC or talc pleurodesis, and endpoints include hospitalization days till death or end of study, adverse events, quality of life, and healthcare costs.
- Arm: Experimental: Indwelling Pleural Catheter
- Day-case IPC insertion. Attendance d10 for drainage, stitch removal and education in catheter care.
- Device: Indwelling Pleural Catheter
- Arm: Active Comparator: Talc Pleurodesis
- Hospital admission for chest drain insertion and suction if needed, plus talc pleurodesis by slurry or poudrage if >75% of visceral and parietal pleura in direct contact on chest x-ray.
- Procedure: Talc Pleurodesis
MARS 2: A Feasibility Study Comparing (Extended) Pleurectomy Decortication Versus no Pleurectomy Decortication in Patients With Malignant Pleural Mesothelioma (MARS2)
Purpose: Mesothelioma is a cancer of the thin membrane that lines the chest and abdomen. Around 2300 people in the UK are diagnosed with mesothelioma each year and the average survival is approximately 17 months. Exposure to asbestos is the most common cause although the cancer does not usually become apparent until 30-40 years after exposure. Anti-cancer drugs (chemotherapy) are usually given to help treat mesothelioma and sometimes lung-sparing surgery (pleurectomy decortication) surgery is undertaken. However, it is not known if this surgery, in addition to chemotherapy, can increase survival and improve the quality of life for patients. The aim of the MARS2 study is to determine if it is feasible to enrol patients with mesothelioma into a study randomising them to chemotherapy only or chemotherapy and lung-sparing surgery. Patients will be followed up regularly at their usual clinic visits for to 5 years. Patients will be asked to complete a Quality of Life Questionnaire at these visits. Tissue samples will be taken at the time of diagnosis and at surgery (if they are randomised to surgery) for mesothelioma research central storage and blood samples will be taken at the clinic visits up to 12 months for mesothelioma research central storage. If we can show the feasibility of recruitment we will apply to continue the study to include more patients in order to determine if lung-sparing surgery improves survival and quality of life for mesothelioma patients.
Ph 1 Study in Subjects With Tumors Requiring Arginine to Assess ADI-PEG 20 With Pemetrexed and Cisplatin (TRAP)
Purpose: A study of ADI-PEG 20 (pegylated arginine deiminase), an arginine degrading enzyme in patients with malignant pleural mesothelioma (MPM) and non-squamous non small cell lung cancer (NSCLC).
Window of Opportunity Study of VS-6063 (Defactinib) in Participants With Surgical Resectable Malignant Pleural Mesothelioma
Purpose: This is an open label neoadjuvant (treatment with VS-6063 prior to mesothelioma surgery) study in subjects with malignant pleural mesothelioma who are eligible for surgery. Subjects will receive VS-6063 (defactinib) for 12 days. Pre- and post-treatment biopsies and blood samples will be collected. The purpose of this study is to assess biomarker responses from tumor tissue. The safety, pharmacokinetics, and tumor response rate to VS-6063 (defactinib) will be also be assessed.
- Arms: Experimental: VS-6063 (defactinib)
- Administered orally (BID) for 12 days (+/- 2 days)
- Assigned Interventions
- Drug: VS-6063
- Other Name: defactinib
Intrapleural AdV-tk Therapy in Patients With Malignant Pleural Effusion (MpeTK01)
Purpose: This is a phase I study of intrapleural AdV-tk therapy in patients with malignant pleural effusion (MPE). The primary objective is to test the safety of intrapleural AdV-tk therapy. Secondary objectives are to evaluate clinical efficacy and biologic activity.
- Arms: Experimental: Study Arm
- AdV-tk administered intrapleural through pleural catheter followed by oral valacyclovir
- Assigned Interventions
- Biological: AdV-tk + valacyclovir
- Three dose levels of AdV-tk will be evaluated. Valacyclovir will be administered orally at a fixed dose for 14 days after each AdV-tk administration.
A Dose Escalation Study to Assess Safety of GSK2256098 (FAK Inhibitor) in Combination With Trametinib (MEK Inhibitor) in Subjects With Advanced Solid Tumors
Purpose: The purpose of this study is to assess the safety of combination treatment of GSK2256098 and trametinib in mesothelioma subjects and subjects with other selected tumor types. Also, the study will identify a maximum tolerated combination dose of GSK2256098 and trametinib. This study is a Phase I, open-label, dose-escalation study to determine maximal tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) and regimens for oral MEK inhibitor trametinib (once daily [OD]dosing) and the oral FAK inhibitor GSK2256098 (twice daily [BID] dosing). The synergy of the combination was observed over a wide range of concentrations and results in several-fold reduction in compound concentration to achieve equivalent biological responses compared to either single agent. The dose and schedule of dosing may be modified based on emerging safety, pharmacokinetic (PK), and pharmacodynamic (PD) data. The study will be conducted in two parts; Part 1 Dose Escalation to determine the MTD and RP2D and Part 2 Expansion Cohort to further evaluate the safety and tolerability of trametinib and GSK2256098 at the RP2D and determine clinical activity. Additionally, in Part 1 Dose Escalation, additional subjects with malignant pleural mesothelioma (MPM) will be recruited at doses that are considered tolerable in order to assess PD in MPM subjects at each dose (the Pharmacodynamic Cohort). The Expansion Cohort will be limited to subjects with MPM who have progressed or are intolerant to first-line therapy.
- Arm: Experimental: Part 1
- Part 1 will determine the MTD and RP2D based on the safety and tolerability of GSK2256098 administered with trametinib. Subject will be administered starting dose of 1.0 mg OD trametinib combined with 500 mg BID GSK2256098. Dose escalation will continue until the MTD is established.
- Assigned Interventions
- Drug: GSK2256098
GSK2256098 250 mg will be supplied as white to off-white, round, biconvex tablets with no markings. GSK2256098 will be administered 30 minutes after a light meal with approximately 240 milliliter of water.
- Drug: Trametinib
Trametinib 0.5 mg will be supplied as capsules with no identifying markings. Trametinib will be administered orally under fasting conditions two hours after a meal.
- Arm: Experimental: Part 2
- Based on determination of combination dose regimen in Part 1, dose expansion cohorts for Part 2 will be opened.
- Assigned Interventions
- Drug: GSK2256098
GSK2256098 250 mg will be supplied as white to off-white, round, biconvex tablets with no markings. GSK2256098 will be administered 30 minutes after a light meal with approximately 240 milliliter of water.
- Drug: Trametinib
Trametinib 0.5 mg will be supplied as capsules with no identifying markings. Trametinib will be administered orally under fasting conditions two hours after a meal.
