ANZCTR - Registration

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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

12/07/2023

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]

Nil known

Universal Trial Number (UTN)

Trial acronym

Designer EDV / ENG8

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Cancer

Advanced Solid Tumours

Condition category

Condition code

Cancer

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]

Treatment: Drugs

Comparator / control treatment

No control group

Control group

Uncontrolled

Outcomes

Primary outcome [1]

Assess the safety and tolerability of EGFR(V)-EDV-PNU (with adjuvant EDV-60mer) in subjects with advanced solid tumours.

Timepoint [1]

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]

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]

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]

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]

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]

Assess immune response in subjects administered EGFR(V)-EDV-PNU (with adjuvant EDV-60mer).

Timepoint [1]

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]

Assess cytokine responses in subjects administered EGFR(V)-EDV-PNU (with adjuvant EDV-60mer).

Timepoint [2]

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

Sex

Both males and females

Can healthy volunteers participate?

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

Active, not recruiting

Date of first participant enrolment

Anticipated

19/05/2017

Actual

19/05/2017

Date of last participant enrolment

Anticipated

30/09/2019

Actual

22/01/2020

Date of last data collection

Anticipated

31/12/2023

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Peninsula Oncology Centre - Frankston

Recruitment hospital [2]

Peninsula Oncology Centre - Frankston

Recruitment postcode(s) [1]

3199 - Frankston

Recruitment postcode(s) [2]

3199 - Frankston

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

EnGeneIC Pty Limited

Address [1]

Building 2/25 Sirius Rd.
Lane Cove West
NSW 2066

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Monash Health Human Research Ethics Committee

Ethics committee address [1]

246 Clayton Road
Clayton 
VIC 3168

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

01/12/2016

Approval date [1]

30/03/2017

Ethics approval number [1]

HREC/16/MonH/407

Ethics committee name [2]

Bellberry Limited Human Research Ethics Committee

Ethics committee address [2]

129 Glen Osmond Road 
Eastwood
SA 5063

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

15/11/2017

Approval date [2]

02/01/2018

Ethics approval number [2]

2017-11-845

Ethics committee name [3]

Bellberry Limited Human Research Ethics Committee

Ethics committee address [3]

129 Glen Osmond Road 
Eastwood
SA 5063

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

15/11/2017

Approval date [3]

02/01/2018

Ethics approval number [3]

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

A/Prof Vinod Ganju

Address

Peninsula and Southeast Oncology Suite 7, Level 3 North Building, Frankston Private Hospital, 5 Susono Way, Frankston VIC 3199

Country

Australia

Phone

+61-3-9781-5244

Fax

office@paso.com.au

Contact person for public queries

Name

Albert Goikhman

Address

Peninsula and Southeast Oncology Suite 7, Level 3 North Building, Frankston Private Hospital, 5 Susono Way, Frankston VIC 3199

Country

Australia

Phone

+61-3-8572-2429

Fax

office@paso.com.au

Contact person for scientific queries

Name

Jennifer MacDiarmid

Address

EnGeneIC Pty Limited
Building 2/25 Sirius Rd.
Lane Cove West,
NSW 2066

Country

Australia

Phone

+61-2-9420-5833

Fax

jmacdiarmid@engeneic.com

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Cyto-Immuno-Therapy for Cancer: A Pathway Elicited by Tumor-Targeted, Cytotoxic Drug-Packaged Bacterially Derived Nanocells.	2020	https://dx.doi.org/10.1016/j.ccell.2020.02.001

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added manually

Documents added automatically