RecruitingPhase 1ACTRN12614001248651

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

MesomiR 1: A Phase I study of intravenously administered Epidermal Growth Factor Receptor (EGFR)-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 standard therapy

Sponsor

Asbestos Disease Research Institute

Enrollment

30 participants

Start Date

Sep 29, 2014

Study Type

Interventional

Conditions

Malignant Pleural Mesothelioma

Summary

This study will evaluate the safety and effect of a new treatment known as TargomiRs in patients with malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC). Who is it for? You may be eligible to join this study if you are aged 18 years or above, and have a confirmed diagnosis of MPM or NSCLC, with evidence of Epidermal growth factor receptor (EGFR) in tumour tissue. Study details: All participants in this study will receive treatment with a new targeted therapy known as TargomiRs. Treatment will be administered by injection into the vein (i.e. intravenously) at a frequency of once or twice weekly until it is clear that you are not benefitting from the treatment. Initially a low dose will be administered to participants. If this dose is tolerated, then it will be increased in the next group of patients and so on until the maximum tolerated dose is determined. All participants will be regularly monitored for safety and toxicity of the treatment for 24 hours after each treatment in the first 2 weeks and 3 hours after treatment from week 3 onwards. They will also be required to complete QoL questionnaires each treatment and have PET scans and lung function tests approximately once every 8 weeks in order to evaluate treatment effect and quality of life. It is hoped that the treatment offered will cause the diseased tissues to respond in a way that will block uncontrolled tumour growth resulting in tumour control and give patients a longer life.

Eligibility

Sex: Both males and femalesMin Age: 18 Yearss

Inclusion Criteria18

Histological or cytological documentation of MPM or NSCLC and evidence of EGFR expression in tumour tissue. (The availability of an archival tumour specimen is mandatory).
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. The investigator or a designated associate is requested to advise the subject how to achieve adequate birth control. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care.
Adequate bone marrow, liver and renal function as assessed by the following laboratory testing conducted within 7 days of starting to study treatment:
Total bilirubin < 1.5 x the upper limit of normal (ULN)
Alanine transaminase (ALT) and aspartate aminotransferase (AST) < 2.5 x ULN
Amylase < 1.5 x ULN
Serum creatinine < 1.5 x ULN
Glomerular filtration rate (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 Criteria22

Previous phase I drug treatment for the current diagnosis (MPM or NSCLC).
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
Known history of human immunodeficiency virus (HIV) infection.
Known history of 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.

Interested in this trial?

Get notified about updates and connect with the research team.

Interventions

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 a week with cardiac monitoring Dose level 5: 2.5 billion twice a week with dexamethasone challenge and cardiac monitoring All patients begin on modified, micro doses to allow the body the opportunity to adjust to the introduction of EDVs into the body. The full phase 1 dose for a patient is reached in treatment 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. Cardiac monitoring includes a Sestamibi scan and Echo before the patient begins on TargomiR treatment and if any cardiac changes are observed whilst the patient receives treatment, these scans are to be repeated and a Troponin blood level obtained. ECGs are obtained on the same schedule as all previous cohorts. Dexamethasone is one of the pre-medications given prior to TargomiRs. The dexamethasone challenge seeks to reduce the amount of dexamethasone given to patients during the course of their treatment period. The schedule is to reduce the dose from 4mg to nil over the course of 8 weeks so long as the patient does not experience undue allergic actions to the TargomiRs. 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.