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Trial registered on ANZCTR


Registration number
ACTRN12617000037303
Ethics application status
Approved
Date submitted
23/12/2016
Date registered
10/01/2017
Date last updated
4/03/2019
Date data sharing statement initially provided
23/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of EnGeneIC Dream Vectors (EDV's) packaged with the chemotherapy PNU-159682, given simultaneously as non-targeted EDVs carrying an immune enhancer called EDV-60mer, in participants with advanced cancer who have no curative treatment options. .
Scientific title
A Phase 1 Study of Anti-Human EGFR (Vectibix Sequence) Targeted EDVTMs Carrying the Cytotoxic Drug PNU-159682 (EGFR(V)-EDV-PNU) with Concurrent Non-Targeted EDVs Carrying an Immunomodulatory Adjuvant (EDV-60mer) in Subjects with Advanced Solid Tumours who have No Curative Treatment Options
Secondary ID [1] 290795 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Designer EDV / ENG8
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 301438 0
Advanced Solid Tumours 301439 0
Condition category
Condition code
Cancer 301159 301159 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is an open-label feasibility study of Epidermal Growth Factor Receptor (EGFR)(V)-EDVs containing PNU-159682 administered via intravenous (IV) infusion in combination with EDVs containing an immunomodulatory adjuvant (EDV-60mer), in subjects with advanced solid tumours who have no curative treatment options.

EGFR(V)-EDV-PNU and EDV-60mer will be mixed together and administered intravenously in cycles consisting of weekly infusions for 7 weeks (7 doses), followed by a treatment free week in which tumours are assessed radiologically (week 8).

Two dose levels will be explored according to standard 3+3 dose escalation guidelines. The first dose level of EGFR(V)-EDV-PNU will be 2.5 x 10^9. The starting dose of EDV-60mer will be 5 x 10^8,

EGFR(V)-EDV-PNU will be gradually escalated from dose 1 of the first treatment cycle to reach the required maximum dose level. Intra-cycle dose escalation is intended to build treatment toleration.

The second dose level will be 5 x 10^9 of EGFR(V)-EDV-PNU, the concurrent dose of EDV-60mer will be 2 x 10^9,

On determination of the recommended phase two dose (RP2D), additional participants will be enrolled at this dose level up to a total of 20 for the whole study. If both dose levels are deemed safe, then the highest dose level administered will be the RP2D (i.e. Dose Level 2 with 5 x 109 EGFR(V)-EDV-PNU and 2 x 109 EDV-60mer).

A participant may continue EGFR(V)-EDV-PNU with concurrent adjuvant EDV-60mer treatment as long as their disease is responding or remains stable, the participant does not experience any unacceptable toxicity or withdraws consent or at the discretion of the Investigator withdrawal is felt to be in the best interests of the participant.
Intervention code [1] 296707 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 300570 0
Assess the safety and tolerability of EGFR(V)-EDV-PNU (with adjuvant EDV-60mer) in subjects with advanced solid tumours.
Timepoint [1] 300570 0
Safety assessment will involve recording the incidence of Adverse Events (AEs) and clinically significant changes in vital signs and clinical laboratory tests. AE's and vital signs will be assessed pre-dose infusion and then at 1, 2 and 3 hours post each dose infusion and at 14 day withdrawal visit and 30-35 days post final dose.

A designated Safety Review Committee will assess if any reported adverse event including Serious Adverse Events (SAE's) and Suspected Unexpected Serious Adverse Reactions (SUSAR's) are attributable to the study treatment and fulfill the protocol defined criteria of a Dose Limiting Toxicity (DLT).

Participants will be assessed for DLTs within the first 28 days of treatment. and will include up to the first 6 subjects enrolled at each dose level. In the case of missed doses, the DLT evaluable period will be extended by 7 days for each missed dose so that a DLT evaluable subject is defined as having received 4 doses and been evaluated for 7 days following each dose.
Primary outcome [2] 300572 0
Assess anti-tumour response in subjects with advanced solid tumours who have exhausted all curative treatment options when administered EGFR(V)-EDV-PNU (with adjuvant EDV-60mer).
Timepoint [2] 300572 0
Evidence of anti-tumour activity will be assessed radiologically, and response graded according to iRECIST criteria. The overall response for each subject will be recorded at Week 8 of every cycle of treatment for the duration of treatment.. Results for best overall response (i-Complete Response, i-Partial Response, i-Stable Disease, i-Unconfirmed Progressive Disease, i-Progressive Disease) will be presented for individual subjects, and for the whole cohort or relevant subsets if applicable using frequency counts and percentages.
Primary outcome [3] 300648 0
Overall survival (OS) in subjects with advanced solid tumours who have exhausted all curative treatment options when administered EGFR(V)-EDV-PNU (with adjuvant EDV-60mer).
Timepoint [3] 300648 0
Survival will be presented as months following administration of Dose 1 for individual subjects, and overall or for relevant subsets if applicable (particularly the cohort treated at the RP2D). Survival will continue to be monitored for the duration of the long term follow-up (every 3 months from the safety follow-up visit, for a period of 12 months, and then for the extent of subject survival). Kaplan Meier curves will be utilised to determine percentage and median survival. There is no control arm for this study. Survival will be compared to historic survival data for individual tumour types.
Secondary outcome [1] 330339 0
Assess immune response in subjects administered EGFR(V)-EDV-PNU (with adjuvant EDV-60mer).
Timepoint [1] 330339 0
Blood samples will be collected from all subjects for culture of Peripheral Blood Mononuclear Cells (PBMCs) to assess immune response in vitro at screening and then at pre-Dose 7 (last dose) for each cycle.
Secondary outcome [2] 330503 0
Assess cytokine responses in subjects administered EGFR(V)-EDV-PNU (with adjuvant EDV-60mer).
Timepoint [2] 330503 0
At Cycle 1, collection of blood samples (pre-dose and 3 hours post-dose) will be taken for cytokine response analyses at each dose ,For all subsequent cycles the blood samples will be performed at dose 1 (pre and post dose) only.

Eligibility
Key inclusion criteria
1. Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
2. Life expectancy greater than 3 months
3. Histologically or cytologically confirmed advanced solid tumour that is metastatic or unresectable and for which standard curative or palliative measures are not available or are no longer effective.
4. Measurable disease per iRECIST criteria.
5. Able to undergo CT or MRI (+/- PET) evaluation as applicable to tumour type.
6. Available archived primary or metastatic neoplastic tumour tissue available for EGFR expression staining, if not already performed as standard of care.
6.. Adequate cardiac function with LVEF greater or equal to 50% at baseline.
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Significant pericardial effusions, pleural effusions or ascites.
2. Concurrent unstable diabetes mellitus or other contraindications for the use of dexamethasone.
3. Uncontrolled concurrent cardiac disease including, but not limited to symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia.
4. Known to be human immunodeficiency virus (HIV), hepatitis B surface antigen or hepatitis C positive; or with a history of chronic active hepatitis or cirrhosis.
5. History of uncontrolled arterial or venous thrombosis. Subjects with a history of arterial or venous thrombosis are eligible if the subject is controlled on low dose molecular weight heparins or low dose aspirin.
6. Uncontrolled brain metastases. Subjects with a history of brain metastases are eligible if the subject is stable and off corticosteroids for at least 2 weeks prior to treatment in the study. PAtients who have undergone glucocorticoid tapering but who have not tolerated complete withdrawal and still require a nominal maintenance dose, will be reviewed on a case by case basis.
7. Active or uncontrolled severe infection.
8. Previous or current primary malignancies at other sites within last 2 years, except:
- In situ carcinoma of the cervix
- Adequately treated basal cell or squamous cell carcinoma of the skin.
9. Received therapies or procedures within 28 days prior to Cycle 1, Dose 1 (or has not recovered from the toxic effects of such therapy) including:
- Therapy with an EGFR inhibitor e.g. cetuximab or erlotinib
- Anti-angiogenic therapy e.g. Bevacizumab (Avastin)
- Immunotherapeutic agents, vaccines, or monoclonal antibody therapy
- Alkylating agents
- Chemotherapy
- Radiotherapy with the exception of palliative radiotherapy
- Other investigational therapy.
- Any major surgery.
10. Prior exposure to PNU.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Due to the small number of subjects to be enrolled, and the range of tumour types for possible evaluation, findings will be presented in a descriptive manner with no formal statistical comparisons performed.

Data will be presented for individual subjects. Where feasible (e.g. for subjects with the same tumour type, or for variables relevant to general EDV administration), continuous data will be summarised by the following descriptive statistics: n (number of observations), mean, standard deviation, median, minimum, maximum. Categorical data will be summarised by frequencies and percentages.

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)
VIC
Recruitment hospital [1] 10229 0
Peninsula Oncology Centre - Frankston
Recruitment hospital [2] 10230 0
Peninsula Oncology Centre - Frankston
Recruitment postcode(s) [1] 21893 0
3199 - Frankston
Recruitment postcode(s) [2] 21894 0
3199 - Frankston

Funding & Sponsors
Funding source category [1] 295222 0
Commercial sector/Industry
Name [1] 295222 0
EnGeneIC Pty Limited
Address [1] 295222 0
Building 2/25 Sirius Rd.
Lane Cove West
NSW 2066
Country [1] 295222 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
EnGeneIC Pty Limited
Address
Building 2/25 Sirius Rd.
Lane Cove West
NSW 2066
Country
Australia
Secondary sponsor category [1] 294050 0
None
Name [1] 294050 0
Address [1] 294050 0
Country [1] 294050 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296566 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 296566 0
246 Clayton Road
Clayton
VIC 3168
Ethics committee country [1] 296566 0
Australia
Date submitted for ethics approval [1] 296566 0
01/12/2016
Approval date [1] 296566 0
30/03/2017
Ethics approval number [1] 296566 0
HREC/16/MonH/407
Ethics committee name [2] 299766 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [2] 299766 0
129 Glen Osmond Road
Eastwood
SA 5063
Ethics committee country [2] 299766 0
Australia
Date submitted for ethics approval [2] 299766 0
15/11/2017
Approval date [2] 299766 0
02/01/2018
Ethics approval number [2] 299766 0
2017-11-845
Ethics committee name [3] 299767 0
Bellberry Limited Human Research Ethics Committee
Ethics committee address [3] 299767 0
129 Glen Osmond Road
Eastwood
SA 5063
Ethics committee country [3] 299767 0
Australia
Date submitted for ethics approval [3] 299767 0
15/11/2017
Approval date [3] 299767 0
02/01/2018
Ethics approval number [3] 299767 0
2017-11-845

Summary
Brief summary
The primary purpose of this trial is to evaluate the safety and efficacy of a combination treatment of EnGeneIC Dream Vectors (EDV's) packaged with the chemotherapy PNU-159682, given with adjuvant EDV-60mer.

Who is it for?
You may be eligible to enroll in this trial if you are aged 18 to 75 years old and have an advanced solid tumour that is metastatic or unresectable which cannot be treated with standard care or for which standard care treatment is no longer effective.

Study details
All participants enrolled in this trial will receive combination treatment with the following:
1. The EnGeneIC Dream Vector(TM) (EDV(TM)). The EDVs are very small particles known as nanocells, which are made from Salmonella bacteria. The type of Salmonella is one that does not cause disease. The EDV is the delivery vehicle used to transport the study drug directly to the site of the cancer.
2. The Cancer Treatment. The study drug is called PNU-159682. PNU-159682 is a type of chemotherapy. The study drug is packaged inside the EDVs (EGFR(V)-EDV-PNU) and is delivered directly to the site of the tumour, rather than the body’s healthy cells and tissues. The EDVs will also be packaged with another substance that is designed to boost the immune system, called EDV-60mer.
3. Bispecific antibody. The EDV delivery system works in 2 ways, as well as carrying the study drug, the EDV surface is also coated with a bispecific antibody. A bispecific antibody is two antibodies linked together, such that one can attach to the EDV and the other to cancer cells. Once attached, the EDVs are taken up inside the cancer cells, and the study drug is delivered directly inside the cell itself, causing the cancer cell to die.

Treatment will be administered in 8-week cycles. The treatment is combined in a syringe and administered in to a vein (intravenous), over a period of 20 minutes using a special pump. One dose of the treatment is given each week for the first 7 weeks, followed by a treatment free week where a CT or MRI scanning is performed to evaluate the tumours response to treatment (Week 8). Treatment will continue for up to 12 months or until the patient or investigator deems it suitable to stop treatment, for example if serious side effects occur or if the patients disease continues to grow. Each participant will receive one of two possible dose levels, depending on when they are enrolled and on the drug effects in previous participants.

It is hoped that the findings from this trial will provide information on whether EGFR(V)-EDV-PNU and EDV-60mer treatment may be safe and effective for the treatment of otherwise incurable advanced solid tumours.
Trial website
paso.com.au
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 71298 0
A/Prof Vinod Ganju
Address 71298 0
Peninsula and Southeast Oncology Suite 7, Level 3 North Building, Frankston Private Hospital, 5 Susono Way, Frankston VIC 3199
Country 71298 0
Australia
Phone 71298 0
+61-3-9781-5244
Fax 71298 0
Email 71298 0
office@paso.com.au
Contact person for public queries
Name 71299 0
Mr Albert Goikhman
Address 71299 0
Peninsula and Southeast Oncology Suite 7, Level 3 North Building, Frankston Private Hospital, 5 Susono Way, Frankston VIC 3199
Country 71299 0
Australia
Phone 71299 0
+61-3-8572-2429
Fax 71299 0
Email 71299 0
office@paso.com.au
Contact person for scientific queries
Name 71300 0
Dr Jennifer MacDiarmid
Address 71300 0
EnGeneIC Pty Limited
Building 2/25 Sirius Rd.
Lane Cove West,
NSW 2066
Country 71300 0
Australia
Phone 71300 0
+61-2-9420-5833
Fax 71300 0
Email 71300 0
jmacdiarmid@engeneic.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results