MesomiR 1: A Phase I Study of TargomiRs as 2nd or 3rd Line Treatment for Patients With Recurrent MPM and NSCLC

Study Overview
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Brief Summary
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The first testing of TargomiRs in the human setting: dose-finding studies in patients with recurrent malignant pleural mesothelioma and non-small cell lung cancer

Detailed Description
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TargomiRs are targeted minicells containing a microRNA mimic. They consist of three components: 1. A miR-16-based microRNA mimic. The miR-16 family has been implicated as a tumour suppressor in a range of cancer types. The mimic is a double-stranded, 23 base pair, synthetic RNA molecule. 2. Drug delivery vehicle - EDVs. EDVs are nonliving bacterial minicells (nanoparticles). They function as leak resistant micro-reservoir carriers that allow efficient packaging of a range of different drugs, proteins or nucleic acids. 3. Targeting moiety. The EDVs are targeted to EGFR-expressing cancer cells with an anti-EGFR bispecific antibody. TargomiRs are IV injected. Phase 1 Planned dose levels Dose level 1: 5 billion once a week Dose level 2: 5 billion twice a week Dose level 3: 5 billion once a week with cardiac monitoring Dose level 4: 2.5 billion twice and week with cardiac monitoring Dose level 5: as above with an additional dexamethasone challenge All patients begin on a micro dose of 1 billion once a week and escalate to the full phase 1 dose for their dose level on week 3. Duration of treatment for each dose level is on a patient by patient basis. Officially the cycle is 8 weeks long however a patient can continue on treatment if they are deriving clinical benefit from the treatment. If at any time point before or after the 8 week mark, a patient progresses, experiences ongoing or unreasonable toxicities or withdraws from the study, they will cease treatment. Escalation of dose in cohorts of 3-6 patients per dose level. If at least 2 patients are observed to experience Dose Limiting Toxicity (DLT), the prior dose level is defined as the MTD. Adherence to the protocol tends not to be problematic in patient groups where the trial treatment is their only treatment option. They are often very keen to participate and motivated to be part of the research.

Official Title
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MesomiR 1: A Phase I Study of Intravenously Administered Epidermal Growth Factor Receptor -Targeted, EnGeneIC Delivery Vehicle (EDV)-Packaged, miR-16 Mimic (TargomiRs) for Patients With Malignant Pleural Mesothelioma (MPM) and Advanced Non-Small Cell Lung Cancer (NSCLC) Failing on Std Therapy

Conditions
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Malignant Pleural Mesothelioma, Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: TargomiRs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological documentation of MPM or NSCLC and evidence of EGFR expression in tumour tissue. Progression during or following the administration of standard 1st, 2nd or 3rd line therapy regimens. Patient must have at least one measurable lesion according to the RECIST criteria version 1.1 for NSCLC and modified RECIST criteria for MPM Male or female patients at least 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Life expectancy of at least 3 months. Women of childbearing potential and men must agree to use adequate contraception from the time of signing of the informed consent form until at least 3 months after the last study drug administration. Total bilirubin < 1.5 x the upper limit of normal (ULN) ALT and AST < 2.5 x ULN Amylase < 1.5 x ULN Serum creatinine < 1.5 x ULN GFR > 60 ml/min/m2 INR/PTT < 1.5 x ULN (patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring with at least weekly evaluations will be performed until INR/APTT is stable (prior to administering the first dose)). Platelet count > 100.000 and < 800.000, Hemoglobin (Hb) > 9 g/dl, Absolute Neutrophil count (ANC) > 1500/mm3. Alkaline phosphatase limit < 2.5 x ULN. Exclusion Criteria: Previous phase I drug treatment for the current diagnosis. Previous or concurrent cancer that is distinct in primary site or histology from MPM or NSCLC within 10 years from the date of screening EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumours (Ta, Tis and T1). Presence of Salmonella antibodies. Herbal supplements (such as St John's Wort), nutritional supplements and also (multi)-vitamins taken within the last 30 days prior to dosing on Day 1 (and continued use, if appropriate), must be reviewed and approved by the local investigator. Major surgical procedures in the last four weeks. Pregnancy or breast-feeding. Congestive heart failure > New York Heart Association (NYHA) class 2. Unstable angina (angina at rest) or new-onset angina (< 3 months). Myocardial infarction less than 6 months before eligibility screening. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted). Uncontrolled hypertension (Systolic blood pressure > 150 mmHg or diastolic pressure > 90 mm Hg despite optimal medical management). Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including Transient Ischemic Attacks), deep vein thrombosis or pulmonary embolism within 6 months before the screening radiographic studies. Ongoing infection > grade 2 NCI-CTCAE version 4.0 HIV infection. Chronic hepatitis B or C. Patients with a seizure disorder requiring medication. Symptomatic brain metastasis(es). The patient must not be undergoing acute steroid therapy or steroid tapering (Chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies). Patients with a history of bleeding diathesis: Any hemorrhage or bleeding event of CTCAE Grade 3 within 4 weeks of the proposed start of study medication. Renal failure requiring hemo-or peritoneal dialysis. Substance abuse, medical, psychological or social conditions that in the opinion of the investigator may interfere with the patient's participation in the study or evaluation of the study results. Known hypersensitivity to bacterial proteins. Any medical condition that is unstable or could jeopardize the safety of the patient and his/her compliance in the study. Unresolved toxicity higher than NCI-CTCAE (version 4.0) Grade 2 attributed to any prior therapy/procedure excluding alopecia.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single arm, open label TargomiRs<br>TargomiRs are IV injected. Phase 1 Planned dose levels Dose level 1: 5 billion once a week Dose level 2: 5 billion twice a week Dose level 3: 5 billion once a week with cardiac monitoring Dose level 4: 2.5 billion twice a week with cardiac monitoring Dose level 5: as for dose level #3 with a dexamethasone challenge All patients begin on a micro dose of one billion and increase their dose over 2 weeks and reach their phase 1 dose level on week 3. Schedule of assessments includes laboratory and physical assessments in the 24 hours after each treatment as well as periodic assessments such as PET and CT scans for tumour assessment. 100% of the data will be source data verified. Analysis will be simple phase 1 analysis based on a 3+3 model. | Drug: TargomiRs<br>* TargomiRs are targeted minicells containing a microRNA mimic. They consist of three components: 1. A miR-16-based microRNA mimic. The miR-16 family has been implicated as a tumour suppressor in a range of cancer types. The mimic is a double-stranded, 23 base pair, synthetic RNA molecule. 2. Drug delivery vehicle - EDVs. EDVs are nonliving bacterial minicells (nanoparticles). They function as leak resistant micro-reservoir carriers that allow efficient packaging of a range of different drugs, proteins or nucleic acids. 3. Targeting moiety. The EDVs are targeted to EGFR-expressing cancer cells with an anti-EGFR bispecific antibody. TargomiRs are IV injected.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| There is a composite primary outcome to establish maximum tolerated dose and dose limiting toxicities The MTD will be determined by the assessment of dose limiting toxicities. | There is a composite primary outcome to establish maximum tolerated dose and dose limiting toxicities. The MTD will be determined by the assessment of dose limiting toxicities. Toxicities, in the first 2 weeks of treatment for any given patient, are assessed with physical assessments 5 times in the 24 hours starting with a pre-dose assessment, and with laboratory assessments which are assessed 3 times in the 24 hours starting with pre-dose assessment. All adverse events are graded according to the CTCAE v4.0. | DLTs assessed from treatment 1 for 2 weeks. MTD is measured from first treatment to toxicity (up to 18 months). | 
| to evaluate the effect of multiple dosing of TargomiRs | to evaluate the effect of multiple dosing of TargomiRs using physical and lab assessments as well as tumour response via PET/CT. | the lab and physical assessments are conducted from first treatment, multiple times in a 24 hour period after treatment for up to 18 months | 
| to detect early signs of efficacy | to detect early signs of efficacy using QoL questionnaires and tumour response via PET/CT. | 8 weeks, when formal assessment with RECIST is applied and QoL questionnaires assessed. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QOL assessment | QOL assessment using EORTC QLQ-C30 (Version 3) | Baseline & weekly or twice weekly (depending on patient's cohort) up to 8 weeks | 
| ECOG PS change | to monitor changes in ECOG PS during treatment | ECOG PS will be assessed from baseline til 8 weeks | 
| Pulmonary function change | to monitor pulmonary function parameters during treatment using FEV1 and Vital Capacity measurements. | Pulmonary function is measured in screening and at 8 weeks |