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 study visits (up to 57 weeks). 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. Patients not eligible for complete resection of advanced melanoma.
3. 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).
4. 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
5. The patient has received appropriate treatment with an anti-PD-1 or anti-PD-L1
antibody with or without an anti-CTLA4.
6. Patients whose advanced melanoma has a B-Raf mutation must have received appropriate
therapy with tyrosine kinase inhibitor(s) and/or MEK inhibitor.
7. Age > 18 years.
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
9. Serum albumin ≥ 3.0 mg/dL.
10. Absolute neutrophil count (ANC) > 1.0 x 10e9/L.
11. Platelet count ≥ 100 x 10e9/L.
12. 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
13. Bilirubin < 1.5 times the institutional upper limit of normal (ULN).
14. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 (3 if liver
metastases are present) times the institutional ULN.
15. Lactate dehydrogenase ≤ 2 times the institutional ULN.
16. The patient must have signed informed consent.
1. Malignant melanoma that is uveal, mucosal, or acral.
2. Patients who developed progressive disease within the first 8 weeks of their first
treatment with a monoclonal antibody to PD-1 or PD-L1 with or without ipilimumab.
3. Patients who have had more than 3 prior lines of therapy in the metastatic/advanced
4. Patients with bone metastases, ≥3 visceral metastases (except lung or nodal metastases
associated with visceral organs), any visceral metastasis >3 cm, or active cerebral
5. 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.
6. 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 registration.
7. Therapeutic treatment with systemic antibiotics within 14 days of registration.
8. Treatment with biologic therapy within 21 days of registration.
9. Treatment with cytotoxic anticancer therapy within 21 days of registration.
10. Treatment with wide-field radiation within 21 days of registration
11. Prior treatment with an adenovirus-based gene therapy.
12. Use of any investigational agents within 21 days of registration.
13. The use of systemic immunostimulatory agents (including, but not limited to,
interferons and IL2) are prohibited within 4 weeks or 5 half-lives of the drug
(whichever is longer) prior to initiation of study treatment and during study
treatment because these agents could potentially increase the risk for autoimmune
conditions when given in combination with atezolizumab.
14. Failed resolution/improvement of AEs including those related to anti-PD-1/anti-PD-L1
back to grade 0-1 and requirement for treatment with >10 mg/day prednisone (or
equivalent) for at least two weeks prior to registration.
15. History of CTCAE grade 4 immune-related AEs from anti-PD-1/anti-PD-L1 antibody.
16. History of CTCAE grade 4 AE that require steroid treatment (>10 mg/day prednisone or
equivalent) for >12 weeks.
17. Patients on warfarin are not eligible.
18. 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 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
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.
19. Men who do not consent to the use of condoms during intercourse during study
20. Known active hepatitis B or C infection, or HIV infection.
21. 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.
22. History of leptomeningeal disease.
23. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently).
24. 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. However, history of
radiation pneumonitis in the radiation field (fibrosis) is permitted.
25. Unstable angina, uncontrolled cardiac arrhythmia, recent (within 3 months) history of
myocardial infarction or stroke, or New York Class III/IV congestive heart failure.
26. 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.
27. Prior allogeneic stem cell or solid organ transplantation.
28. History of severe allergic anaphylactic reactions to chimeric human or humanized
antibodies, or fusion proteins.
29. Known hypersensitivity to CHO cell products or any component of the atezolizumab
30. 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.
31. 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).
32. 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.