Clinical Trials Register

Summary
EudraCT Number:	2017-002565-22
Sponsor's Protocol Code Number:	LOKON002
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-07-05
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2017-002565-22

A.3

Full title of the trial

Phase I/II Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Clinical evaluation of virus therapy for cancer

A.4.1

Sponsor's protocol code number

LOKON002

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03225989

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Lokon Pharma AB
B.1.3.4	Country	Sweden
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Lokon Pharma AB
B.4.2	Country	Sweden
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Uppsala Clinical Research Center
B.5.2	Functional name of contact point	Karin Dannaeus
B.5.3	Address:
B.5.3.1	Street Address	Dag Hammarskjöldsväg 38
B.5.3.2	Town/ city	Uppsala
B.5.3.3	Post code	751 85
B.5.3.4	Country	Sweden
B.5.6	E-mail	karin.dannaeus@ucr.uu.se

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	LOAd703
D.3.2	Product code	LOAd703
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intratumoral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	Yes
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	Yes
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Colorectal, ovarian, pancreatic, gallbladder and bile duct cancer

E.1.1.1

Medical condition in easily understood language

Cancer

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10007050
E.1.2	Term	Cancer
E.1.2	System Organ Class	100000004864

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to determine the tolerability of increasing doses of LOAd703 intratumoral injections during standard of care or added conditioning chemotherapy.

E.2.2

Secondary objectives of the trial

The secondary objective is to determine the effects of LOAd703 intratumoral injections at MTD, or maximum tested dose, during standard of care or added conditioning chemotherapy.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Have histologic or cytologic evidence of colorectal carcinoma (CRC), pancreatic carcinoma (PC), biliary cancer, or epithelial ovarian carcinoma (EOC which may encompass epithelial ovarian, fallopian tube or primary peritoneal carcinoma).
2.Have advanced disease, defined as cancer that is either metastatic or locally advanced, unresectable, and for which radiotherapy or other locoregional therapies are not considered treatment of choice but systemic chemotherapy or no therapy is planned.
3.Have one of the following treatment situations apply:
a)Colorectal carcinoma (CRC), Phase I and Phase IIa only:
i.A patient with refractory or recurrent metastatic CRC who has either received all conventional therapy; or is entering a “resting” phase between reasonable conventional treatments.
ii.A patient who is amenable to treatment with LOAd703 plus gemcitabine as a single agent conditioning regimen.
b)Pancreatic cancer
i.A patient with either locally advanced, unresectable or metastatic disease who is eligible to receive first or second line of conventional treatment consisting of gemcitabine and/or nab-paclitaxel.
ii.A patient who is amenable to treatment with LOAd703 as an “add-on” to standard-of-care gemcitabine-based or nab-paclitaxel-based regimens or gemcitabine or nab-paclitaxel as single agents.
c)Biliary cancer, Phase I and Phase IIa only
I.A patient with either locally advanced unresectable or metastatic biliary cancer who is either treatment-naïve or has received any number of lines of treatment.
II.Patient who is amenable to treatment with LOAd703 as an “add-on” to standard-of-care treatment consisting of gemcitabine combined with other agents (e.g. gemcitabine/low-dose cisplatin, gemcitabine/oxaliplatin, etc) in the first line setting or gemcitabine in a combination regimen or as a single agent in latter lines of treatment.
d)Ovarian Cancer
I.A patient with either epithelial ovarian, fallopian tube or primary peritoneal carcinoma.
II.The patient has either:
i) 〈removed in amendment no.5 2021-12-06〉
ii)Platinum-sensitive relapse (platinum free interval ≥ 6 months) and have previously received at least one line of chemotherapy and not eligible for PARP-inhibitor maintenance after chemotherapy.
iii)Platinum-resistant relapse (platinum free interval < 6 months), who have not received more than two lines of appropriate standard of care and not eligible for bevacizumab. Maintenance treatment does not count as a line of therapy.
iv)The patient has received appropriate therapy with PARP inhibitors if eligible.
II.Amenable to treatment with LOAd703 as an “add-on” to standard-of-care (excluding bevacizumab).
4.Have a disease burden that is considered low (i.e. low tumor burden), which is defined on a patient-by-patient basis as per Principal Investigator’s discretion. A rough guideline for defining low tumor burden is that the sum of the product of the bidimensional measurements for all lesions is ≤ 70 cm2.
5.Have a measurable disease by standard imaging techniques per RECIST criteria. Measurable lesions must be outside of any prior radiation field(s), unless disease progression has been documented at that disease site subsequent to radiation.
6.At least one non-irradiated (or irradiated but disease progression documented at the site subsequent to radiation) lesion must be suitable for image-guided intratumoral injection and needle biopsy.
7.Be medically suited to sedation if required during intratumoral injections.
8.Be at least 18 years-old.
9.Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2.
10.Have no remaining acute toxic effects from previous anticancer therapy > grade 1 except for any grade of alopecia.
11.Have adequate baseline organ/hematological function, as demonstrated by the following:
a)Absolute neutrophil count (ANC) ≥1.0 x 109/l
b)Hemoglobin ≥9 g/dl
c)Platelet count ≥ 100 x 109/l
d)Bilirubin < 1.5 times the institutional upper limit of normal (ULN)
e)Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 (3 if liver metastases are present) times the institutional ULN
f)Serum creatinine <1.5 times the institutional ULN or calculated creatinine clearance ≥35 mL/min
g)Prothrombin (INR)≤1.5 or prothrombin time (PT) ≤1.5 ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤ 1.5 times the ULN.
12.The patient must understand and be willing to provide written informed consent.

E.4

Principal exclusion criteria

1.Any concurrent treatment that would compromise the study including but not limited to continuous high dose corticosteroids (>0.5mg/kg), lymphodepleting antibodies or cytotoxic agents.
2.Treatment with high dose immune inhibitors including lymphotoxic monoclonal antibodies such as alemtuzumab (Campath), or sirolimus (Rapamune) and its analogs, biological therapy, cytotoxic agents or any investigational agents within 21 days of registration.
3.Ovarian carcinoma patients should not be eligible to PARP inhibitor treatment.
4.Patients on warfarin are not eligible.
5.Women who are pregnant, lactating, or planning to become pregnant during the study period, or women of childbearing potential who are not using acceptable contraceptive methods. A woman is considered of childbearing potential if she is not surgically sterile or is less than 1 year since last menstrual period. Acceptable contraceptive methods are: combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progesterone-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion and vasectomized partner.
6. Men who do not consent to the use of condom during intercourse during study participation.
7.Known active hepatitis B or C infection, or HIV infection.
8.Patients with active, severe autoimmune disease.
9.Uncontrolled intercurrent illness including but not limited to psychiatric illness/social situations that in the opinion of the Investigator would compromise compliance of study requirements or put the patient at unacceptable risk.
10.Other malignancies within the past 2 years (not including basal and squamous cell carcinoma of the skin, localized prostate cancer or in situ cervix carcinoma).
11. Patients must agree to not to vaccinate with living vaccines during participation in the trial.
12.Prior treatment with an adenovirus-based gene therapy
13.Adenovirus-based vaccines (e.g Vaxzevria, known as COVID-19 vaccine Astra Zeneca, J&J Covid-19 vaccine) are prohibited 3 months prior to initiation of study treatment, during treatment and 6 months after the final dose of LOAd703.

E.5 End points

E.5.1

Primary end point(s)

Phase I
1.Tolerability is determined by physical examination, hematological and clinical chemistry analysis using CTCAE v 4.03.
2.LOAd703 virus copies (shedding) in biopsies, blood, oral and rectal swabs and urine using quantitative real time PCR.
3.Anti-adenoviral antibodies in blood using ELISA.

Phase II
1.Tolerability is determined by physical examination, hematological and clinical chemistry analysis using CTCAE v 4.03.
2.LOAd703 virus copies (shedding) in biopsies, blood, oral and rectal swabs, and urine using quantitative real time PCR.
3.Anti-adenoviral antibodies in blood using ELISA.

E.5.1.1

Timepoint(s) of evaluation of this end point

1) Tolerability is evaluated until four months post final dose. DLT assessment is done after 3rd dose.
2) LOAd703 viral copies are evaluated at week 1, 7, 13, 17, 25, 33 and 40.

E.5.2

Secondary end point(s)

Phase I
1.Immunological protein profile in blood and by ELISA and/or multiplex-based methods.
2.Immunological cell profile in blood by flow cytometry and ELISPOT.
3.Local and distant anti-tumoral effects assessed by appropriate imaging dependent on tumor localization and by monitoring tumor marker/s when available. Responses are judged accordingly to RECIST 1.1.
4.Effects are evaluated as time to tumor progression (TTP), progression free survival (PFS) and overall survival (OS).

Phase II
1.Local and distant anti-tumoral effects on tumor assessed by appropriate imaging dependent on tumor localization and by monitoring tumor marker/s when available. Objective responses are measured using RECIST 1.1.
2.Effect evaluated as TTP, PFS and OS.
3.Immunological protein profile in blood and tumor lysates by ELISA and/or a multiplex-based method.
4.Immunological cell profile in blood by flow cytometry and ELISPOT.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Immunological protein profile is evaluated at week 1, 7, 13, 17, 25, 33 and 40.
2. Immune cell profile is evaluated at week 1, 7, 13, 17, 25, 33 and 40.
3. Tumor effect is evaluated every other month until six months post final dose (week 40).
4. TTP, PFS and OS are noted at the time of the event.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immune responses against tumor and virus LOAd703

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Phase I/II trial, not first in man, but other cancer types than tested before

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception