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.
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.
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
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
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.
1. Malignant melanoma that is uveal.
2. Subjects considered by the investigator to have rapid clinical progression due to
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
7. Treatment with biologic therapy within 21 days of the first dose of
8. Treatment with cytotoxic anticancer therapy within 14 days of the first dose of
9. Treatment with wide-field radiation within 14 days of the first dose of
10. Prior treatment with an adenovirus-based gene therapy.
11. Use of any investigational agents within 21 days of the first dose of
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
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
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
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
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.