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

• ClinicalTrials.gov Identifier: NCT04123470
• Recruitment Status: Recruiting
• First Posted: October 11, 2019
• Last Update Posted: April 6, 2022
• Sponsor: Lokon Pharma AB
• Collaborator: Precision Oncology LLC
• Information provided by (Responsible Party): Lokon Pharma AB

Study Description

Brief Summary:

This study aims to evaluate safety and effect of combining an oncolytic adenovirus (delolimogene mupadenorepvec; LOAd703) with atezolizumab in patients with melanoma. LOAd703 will be administered intratumorally for up to 12 injections while atezolizumab will be administered intravenously for the duration of the active study visits (up to 57 weeks). The patients are then monitored for survival for maximum study participation of 48 months. The treatments will be given every 3 weeks. The patients will then be monitored for toxicity, PK, ADA, immune responses, virus shedding, tumor response by RECIST 1.1 and survival.

Condition or disease	Intervention/treatment	Phase
Malignant Melanoma	Genetic: delolimogene mupadenorepvec; Biological: atezolizumab	Phase 1; Phase 2

Detailed Description:

This is a single arm, open-label, multicenter trial. This study aims to evaluate safety and effect of combining an oncolytic adenovirus (delolimogene mupadenorepvec; LOAd703) with atezolizumab in patients with melanoma. Patients will receive up to 12 LOAd703 intratumoral treatments in combination with intravenous infusions of atezolizumab. LOAd703 will be tested at two dose levels to determine the maximum tolerated dose (MTD) of LOAd703 evaluated in the study using a BOIN design. The LOAd703 dose can be divided for intratumoral injection into as many as 3 tumor lesions. Atezolizumab will be tested at a fixed dose. At least 25 response evaluable patients will be enrolled at the MTD for evaluation of their response using binominal testing. The maximum number of evaluable patients in the study is 35. The patients will then be monitored for toxicity, PK, ADA, immune responses, virus shedding, tumor response by RECIST 1.1 and survival.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial Investigating LOAd703 in Combination With Atezolizumab in Malignant Melanoma
• Actual Study Start Date: January 28, 2020
• Estimated Primary Completion Date: June 30, 2023
• Estimated Study Completion Date: June 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment; Delolimogene mupadenorepvec plus atezolizumab	Genetic: delolimogene mupadenorepvec; LOAd703 is an oncolytic adenovirus encoding TMZ-CD40L and 4-1BBL; Other Name: LOAd703; Biological: atezolizumab; Atezolizumab is an anti-PD-L1 antibody

Outcome Measures

Primary Outcome Measures :

1. Number of patients with toxicities [ Time Frame: Up to 57 weeks post treatment initiation ]
   Tolerability is evaluated by the NCI CTCAE v5.0 based on interim medical history, physical examination and hematological and clinical chemistry laboratory studies

Secondary Outcome Measures :

1. Overall response rate [ Time Frame: Up to 57 weeks post treatment initiation ]
   Tumor size evaluations accordingly to RECIST 1.1
2. Overall survival [ Time Frame: From treatment initiation post 12 months after last patients last visit ]
   Survival status of patients
3. Antibodies against LOAd703 [ Time Frame: Up to 57 weeks post treatment initiation ]
   Number of antibodies targeting adenovirus (LOAd703) in serum
4. Immune cell phenotype [ Time Frame: Up to 57 weeks post treatment initiation ]
   Presence of immune cells (MFI) in blood and their fold change over time compared to baseline as determined by flow cytometry
5. Virus shedding [ Time Frame: Up to 57 weeks post treatment initiation ]
   Number of detected virus particles are evaluated in blood, urine, oral and rectal swabs

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Pathological confirmation of melanoma.
2. A life expectancy of at least 3 months as per the investigator
3. Valid for Swedish patients: Patients has locally advanced melanoma or metastatic melanoma, but not eligible for complete resection of melanoma Valid for US patients: Patients has locally advanced melanoma or metastatic 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. Valid for Swedish patients: Patients whose advanced melanoma has a B-Raf mutation must have received appropriate therapy with tyrosine kinase inhibitor(s) and/or MEK inhibitor Valid for US patients: Patients whose advanced melanoma has a B-Raf mutation may 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 mg/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.

Exclusion Criteria:

1. Malignant melanoma that is uveal.
2. Subjects considered by the investigator to have rapid clinical progression due to melanoma
3. Subjects 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 the first dose of LOAd703/atezolizumab.
6. Therapeutic treatment with systemic antibiotics within 14 days of the first dose of LOAd703/atezolizumab.
7. Treatment with biologic therapy within 21 days of the 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 to grade 0-1 and requirement for treatment 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 eligible (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 18.
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:

    1. Rash must cover <10% of body surface area.
    2. Disease is well-controlled at baseline and requires only low-potency topical corticosteroids.
    3. 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. Unstable angina, uncontrolled cardiac arrhythmia, recent (within 3 months) history of myocardial infarction or stroke, or New York Class III/IV congestive heart failure.
25. Major surgical procedure other than for the malignant melanoma diagnosis, within 4 weeks prior to initiation of the study treatment, or anticipation of the need for a major surgical procedure during the study.
26. Prior allogeneic stem cell or solid organ transplantation.
27. History of severe allergic anaphylactic reactions to chimeric human or humanized antibodies, or fusion proteins.
28. Known hypersensitivity to CHO cell products or any component of the atezolizumab formulation.
29. Uncontrolled intercurrent illness including, but not limited to, psychiatric illness/social situations that in the opinion of the Investigator would compromise compliance to study requirements or put the patient at unacceptable risk.
30. Other malignancy within the past 2 years (not including basal cell or squamous cell carcinoma of the skin, prostate cancer without the need of other treatment than hormones or in situ cervix, breast or melanoma).
31. Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior to initiation of study treatment, during treatment, and for 5 months after the final dose of atezolizumab and/or LOAd703.

Contacts and Locations

Locations

United States, California

Cedars-Sinai Medical Center, The Angeles Clinic and Research Institute; Recruiting

Los Angeles, California, United States, 90025

Contact: Omar Hamid, MD 310-582-7900 ohamid@theangelesclinic.org

United States, Texas

Baylor St Luke's Medical Center; Recruiting

Houston, Texas, United States, 77030

Contact: Daniel Wang, MD 713-798-3750 daniel.wang2@bcm.edu

Sweden

Uppsala University Hospital; Recruiting

Uppsala, Sweden, 75185

Contact: Annika Liden, nurse 018-6110000 annika.liden@akademiska.se

Contact: Gustav Ullenhag, MD PhD 018-6110000

Sponsors and Collaborators

Lokon Pharma AB

Precision Oncology LLC

Investigators

• Study Chair: Angelica Loskog, PhD; Lokon Pharma AB

More Information

• Responsible Party: Lokon Pharma AB
• ClinicalTrials.gov Identifier: NCT04123470
• Other Study ID Numbers: LOKON003; 2019-003300-12 ( EudraCT Number )
• First Posted: October 11, 2019
• Last Update Posted: April 6, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Atezolizumab; Antineoplastic Agents