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Trial registered on ANZCTR


Registration number
ACTRN12614001248651
Ethics application status
Approved
Date submitted
10/11/2014
Date registered
28/11/2014
Date last updated
6/10/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
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
Scientific title
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
Secondary ID [1] 284415 0
Nil
Universal Trial Number (UTN)
U1111-1157-4960
Trial acronym
MesomiR 1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Malignant Pleural Mesothelioma 291615 0
Advanced Non Small Cell Lung Cancer 291616 0
Condition category
Condition code
Cancer 291989 291989 0 0
Lung - Mesothelioma
Cancer 291990 291990 0 0
Lung - Non small cell

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 289164 0
Treatment: Drugs
Comparator / control treatment
No control
Control group
Uncontrolled

Outcomes
Primary outcome [1] 292244 0
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.

Timepoint [1] 292244 0
DLTs specifically are assessed in the first 2 weeks of a patient's treatment.
patients are assessed 3 times/ 24 hours from pre-dose timepoint for blood changes and 5 times/ 24 hours from pre-dose timepoint for physical changes.
(From week 3 onwards, labs are checked twice in 24 hours and physical assessments performed 3 times in 24 hours.)

MTD is declared when a maximum of 1 patient out of 6 experiences a DLT at the dose level below the maximally administered dose.
Primary outcome [2] 292246 0
to evaluate the effect of multiple dosing of TargomiRs using physical and lab assessments as well as tumour response via PET/CT.
Timepoint [2] 292246 0
the laboratory and physical assessments are conducted multiple times in a 24 hour period starting with pre-dose assessments for each dose received until the patient comes off treatment. At the end of an 8 week cycle, PET/CT is also used for tumour measurement.
Primary outcome [3] 292247 0
to detect early signs of efficacy using QoL questionnaires and tumour response via PET/CT.
Timepoint [3] 292247 0
8 weeks, when formal assessment with RECIST applied and QoL questionnaires assessed.
Secondary outcome [1] 308535 0
QOL assessment (EORTC QLQ-C30 (Version 3))
Timepoint [1] 308535 0
Patients will complete a QoL questionnaire prior to each dose they receive. These questionnaires will be evaluated after each 8 week cycle (or when the patient finishes treatment prior to 8 weeks).
Secondary outcome [2] 308536 0
to monitor changes in ECOG PS during treatment
Timepoint [2] 308536 0
ECOG PS will be assessed prior to each dose the patient receives.
Any change occurring in ECOG over the course of treatment will be evaluated at the end of an 8 week cycle or when a patient comes off treatment prior to that.
Patients are required to have an ECOG of 0 or 1 to come on the trial. If their ECOG ever drops to a 2 or below, they will assessed for suitability to continue.
Secondary outcome [3] 308537 0
to monitor pulmonary function parameters during treatment using FEV1 and Vital Capacity measurements.
Timepoint [3] 308537 0
Pulmonary function is measured in screening and at follow up after the patient comes off treatment.

Eligibility
Key inclusion criteria
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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
A potential patient will undergo general screening according to the inclusion and exclusion criteria. When screening requires study specific procedures, a patient will go through the informed consent process and after signing consent will complete the specific screening elements by site staff.
When a site deems a patient eligible for registration on the study, ADRI (the sponsor) will be responsible for monitoring eligibility and then registering a patient. There is only 1 arm and 1 treatment on this trial. If a patient is registering onto Phase 1, they will be allocated into the next space available which may be the same dose escalation cohort as the previous patient, or the next cohort if the previous cohort is complete.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
There is no randomisation process on this trial. Participants will be registered. They will be numbered sequentially taking into account what number patient they are on the trial, what cohort they are part of and what position within the cohort they are.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Analysis will be done based on the 3+3 design.
Simple Phase 1 assessment

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 2537 0
Concord Repatriation Hospital - Concord
Recruitment hospital [2] 2538 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [3] 3130 0
Northern Cancer Institute - Frenchs Forest - Frenchs Forest
Recruitment postcode(s) [1] 8218 0
2139 - Concord Repatriation Hospital
Recruitment postcode(s) [2] 8881 0
2050 - Camperdown
Recruitment postcode(s) [3] 8882 0
2065 - St Leonards

Funding & Sponsors
Funding source category [1] 289337 0
Charities/Societies/Foundations
Name [1] 289337 0
Asbestos Disease Research Foundation
Address [1] 289337 0
Bernie Banton Centre
Gate 3
Hospital Rd
Concord NSW 2139
Australia
Country [1] 289337 0
Australia
Funding source category [2] 289404 0
Commercial sector/Industry
Name [2] 289404 0
EnGeneIC
Address [2] 289404 0
2/25 Sirius Road
Lane Cove West
NSW Australia 2066
Country [2] 289404 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Asbestos Disease Research Institute
Address
PO Box 3628
Rhodes NSW 2138
Australia
Country
Australia
Secondary sponsor category [1] 288023 0
None
Name [1] 288023 0
Address [1] 288023 0
Country [1] 288023 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291110 0
Sydney Local Health District Research Ethics Committee - Concord Repatriation General Hospital
Ethics committee address [1] 291110 0
Concord Repatriation General Hospital
Hospital Rd,
Concord, 2139
NSW
Australia
Ethics committee country [1] 291110 0
Australia
Date submitted for ethics approval [1] 291110 0
27/08/2013
Approval date [1] 291110 0
15/11/2013
Ethics approval number [1] 291110 0
HREC/13/CRGH/199

Summary
Brief 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.
Trial website
nil
Trial related presentations / publications
Annals of Oncology 24: 3128–3135, 2013
Restoring expression of miR-16: a novel approach to therapy for malignant pleural mesothelioma
G. Reid1*, M. E. Pel1,2, M. B. Kirschner1, Y. Y. Cheng1, N. Mugridge3, J. Weiss3, M. Williams1,
C. Wright1, J. J. B. Edelman4, M. P. Vallely4, B. C. McCaughan4, S. Klebe5, H. Brahmbhatt3,
J. A. MacDiarmid3 & N. van Zandwijk1
Public notes
The HREC approval listed is the first one. There have been subsequent approvals of amendments by the CRGH HREC since the original approval.

Contacts
Principal investigator
Name 47630 0
Prof Nico van Zandwijk
Address 47630 0
Asbestos Diseases Research Institute
PO Box 3628
Rhodes NSW 2138
Country 47630 0
Australia
Phone 47630 0
+ 61 2 9767 9800
Fax 47630 0
+ 61 2 9767 9860
Email 47630 0
nico.vanzandwijk@sydney.edu.au
Contact person for public queries
Name 47631 0
Ms Yennie Huynh
Address 47631 0
ADRI
PO Box 3628
Rhodes NSW 2138
Country 47631 0
Australia
Phone 47631 0
+61 2 9767 9866
Fax 47631 0
+ 61 2 9767 9860
Email 47631 0
yennie.huynh@sydney.edu.au
Contact person for scientific queries
Name 47632 0
Prof Nico van Zandwijk
Address 47632 0
ADRI
PO Box 3628
Rhodes NSW 2138
Country 47632 0
Australia
Phone 47632 0
+ 61 2 9767 9800
Fax 47632 0
+ 61 2 9767 9860
Email 47632 0
nico.vanzandwijk@sydney.edu.au

No information has been provided regarding IPD availability
Summary results
No Results