Clinical Trials Register

Summary
EudraCT Number:	2019-003300-12
Sponsor's Protocol Code Number:	LOKON003
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:	2019-10-04
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Sweden - MPA

A.2

EudraCT number

2019-003300-12

A.3

Full title of the trial

A Phase I/II Trial Investigating LOAd703 in Combination with Atezolizumab in Malignant Melanoma

A.3.1

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

Clinical evaluation of virus therapy for malignant melanoma

A.4.1

Sponsor's protocol code number

LOKON003

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	Lokon Pharma AB
B.5.2	Functional name of contact point	Anna Pauter
B.5.3	Address:
B.5.3.1	Street Address	Bredgränd 14
B.5.3.2	Town/ city	Uppsala
B.5.3.3	Post code	75230
B.5.3.4	Country	Sweden
B.5.6	E-mail	anna.pauter@lokonpharma.com

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.IMP: 2
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	Yes
D.2.1.1.1	Trade name	Tecentriq
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Tecentriq
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous drip use (Noncurrent)
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)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
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	No
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

Malignant melanoma

E.1.1.1

Medical condition in easily understood language

Malignant melanoma

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	HLT
E.1.2	Classification code	10027156
E.1.2	Term	Skin melanomas (excl ocular)
E.1.2	System Organ Class	100000004858

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to determine the tolerability of LOAd703 administered by intratumoral injections in combination with intravenous atezolizumab.

E.2.2

Secondary objectives of the trial

The secondary objectives are to determine the antitumor activity as well as the pharmacokinetics and biological mechanisms-of-action of LOAd703 in combination with atezolizumab.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Pathological confirmation of melanoma.
2. A life expectancy of at least 3 months as per investigator.
3. Patients has locally advanced melanoma or metastatic melanoma, but not eligible for complete resection of melanoma.
4. The patient has measurable disease (e.g., measurable tumor lesions must be present that can accurately be measured in at least one dimension with a minimum size of 10 mm by CT scan and MRI, 10 mm caliper measurement by clinical exam (when superficial), and/or 20 mm by chest X-ray).
5. Patient has at least one injectable tumor lesion that has not been irradiated or has been irradiated but disease progression documented at the site subsequent to radiation therapy.
6. The patient has received appropriate treatment with an anti-PD-1 or anti-PD-L1 antibody with or without an anti-CTLA4.
7. Patients whose advanced melanoma has a B-Raf mutation must have received appropriate therapy with tyrosine kinase inhibitor(s) and/or MEK inhibitor as assessed by the investigator.
8. Age ≥ 18 years.
9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
10. Serum albumin ≥ 2.5 g/dL.
11. Absolute neutrophil count (ANC) ≥ 1.0 x 10e9/L.
12. Platelet count ≥ 100 x 10e9/L.
13. Prothrombin (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 times ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤ 1.5 times the ULN.
14. Bilirubin < 1.5 times the institutional upper limit of normal (ULN).
15. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 (≤5 if liver metastases are present) times the institutional ULN.
16. The patient must have signed informed consent.

E.4

Principal exclusion criteria

1.Malignant melanoma that is uveal. 2.Subjects considered by the investigator to have a rapid progression of melanoma. 3. Patients must not have greater than 3 cerebral melanoma metastases, and/or clinically active cerebral melanoma metastases, and/or a requirement for corticosteroid therapy, and/or carcinomatous meningitis regardless of clinical stability. 4.Any concurrent treatment that would interfere with the effect mechanisms of atezolizumab and LOAd703, including, but not limited to, continuous high-dose corticosteroids (>10 mg per day), lymphodepleting antibodies, or cytotoxic agents. 5.Treatment with inhibitors of immune function, such as lymphotoxic monoclonal antibodies (e.g., alemtuzumab), or rapamycin/rapamycin analogs, or cytotoxic agents within 21 days of first dose of LOAd703/atezolizumab. 6.Therapeutic treatment with systemic antibiotics within 14 days of first dose of LOAd703/atezolizumab. 7.Treatment with biologic therapy within 21 days of first dose of LOAd703/atezolizumab. 8. Treatment with cytotoxic anticancer therapy within 14 days of the first dose of LOAd703/atezolizumab. 9. Treatment with wide-field radiation within 14 days of the first dose of LOAd703/atezolizumab. 10. Prior treatment with an adenovirus-based gene therapy. 11. Use of any investigational agents within 21 days of the first dose of LOAd703/atezolizumab). 12. The use of systemic immunostimulatory agents (including, but not limited to, interferons and IL2) are prohibited within 21 days or 5 half-lives (whichever is longer) of the first dose of LOAd703/atezolizumab. 13. Failed resolution/improvement of AEs including those related to anti-PD-1/anti-PD-L1 antibody back to grade 0-1 and requirementfo treamtent with >10 mg/day prednisone (or equivalent) for at least two weeks prior to registration. 14. History of CTCAE grade 4 immune-related AEs from monotherapy using an anti-PD-1/anti-PD-L1 antibody 15. History of CTCAE grade 4 AE that require steroid treatment (<10 mg/day prednisone or equivalent) for >12 weeks.
16. Patients requiring warfarin are not egible (low molecular weight heparin
is permitted).
17.Women who are pregnant (as confirmed by pregnancy test during screening in applicable patients), breastfeeding, or planning to become pregnant during the study period, or women of childbearing potential who are not using acceptable highly effective contraceptive methods. A woman is considered of childbearing potential if she is not surgically sterile or is less than 1 year since her last menstrual period. The following are acceptable as highly effective contraceptive methods: 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 or abstinence of heterosexual intercourse during the entire study period (depending on the preferred and usual life style of the subject). 18.Men who do not consent to the use of condoms during intercourse during study participation or has a partner of childbearing potential, who will not use any of the highly effective contraceptive methods exemplified in exclusion criteria no 17. 19.Known active hepatitis B or C infection, or HIV infection.
20.Patients with active, severe autoimmune disease or immune deficiency or previous Guillain-Barré syndrome. Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
a.Rash must cover <10% of body surface area. b.Disease is well-controlled at baseline and requires only low-potency topical corticosteroids. c.Occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months. 21.History of leptomeningeal disease. 22.Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). 23.History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan or tested reduced functional respiration capacity. However, history of radiation pneumonitis in the radiation field (fibrosis) is permitted.24-31(...)32.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)

1.The primary endpoint is safety, determined by the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE v5.0).

E.5.1.1

Timepoint(s) of evaluation of this end point

Vital signs before LOAd703 injection and then every 30 minutes for 2 hours, and at 3, 4, 5, 6, 8, 10, 14 hours post dose and then every 4 hours until discharge. If no immediate toxicities occurred after the first 2 treatments the patient will be observed for a minimum of 8 hours post injection at the 3rd and 4th injection, and for a minimum of 6 hours post injection. Prior to each LOAd703 and/or atezolizumab treatment (within -2 days), the Investigator must do a complete AE evaluation (including laboratory values and meeting the patient) and assess the toxicity screening to assure that the patient is able to receive further treatments

E.5.2

Secondary end point(s)

1.Overall response rate evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST), v1.1.
2.Shedding determined as levels of LOAd703 in shedding samples at different time points post-treatment.
3.LOAd703 leakage to blood determined as levels of LOAd703 in blood at different time points post-treatment.
4.Anti-adenovirus immunity determined as anti-viral antibodies and T cells after combination therapy compared to baseline.
5.Pharmacokinetics of atezolizumab determined as the level of atezolizumab in blood at different time points post-treatment.
6.Immunity to atezolizumab determined as the level of anti-drug antibodies (ADA) targeting atezolizumab at different time points post-treatment compared to baseline.
7.Immune profile as determined by changes in immune cell populations and their activation markers in tumor tissue and blood after combination therapy compared to baseline.
8.Protein profile as determined by changes in protein profile in blood after combination therapy compared to baseline.

E.5.2.1

Timepoint(s) of evaluation of this end point

1.ORR every two months post-treatment initiation
2.LOAd703 in shedding samples pre-dose w 0, 1, 9, 18, 27, 33, 36, 45 and final FU.
24 hrs post- treatment w 0, 9, 18 and 27, and 7 d post-treatment w 1,19 and 34.
3.LOAd703 in blood pre-dose w 0, 1, 9, 18, 19, 27, 33, 34, 36, 45 and final FU. 24 hrs post- treatment w 0, 9, 18 27 and 33, and7 d post-treatment w 1,19 and 34.
4.Anti-adenovirus immunity w 0, 3, 6, 9, 21 and final FU
5.PK atezolizumab w 0, 3, 6, 9, 21 and final FU
6.ADA targeting atezolizumab w 0, 3, 6, 9, 21 and final FU
7.Changes in immune cell populations and their activation markers in tumor w 0, 9, 18, 27, 36, 45 and final FU
8.Changes in protein profile in blood w 0, 9, 18, 27, 36, 45 and final FU (immunology sampling); tumor biopsies w 0, 9 and 27

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 response against tumour 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

Yes

E.8.4

The trial involves multiple sites in the 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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United States

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

The last visit of the last subject (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