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Antineoplastic Agents, Immunological

Patients will receive gemcitabine intravenously at a dose of 1000mg/m2 + nab-paclitaxel 125 mg/m2 as per hospital standards. One cycle will be one dose of gemcitabine +nab-paclitaxel given on days 1, 8, and 15 of a 28 day cycle. LOAd703 will be given every other week for 6 doses starting on day 15 of the first cycle of chemotherapy. There is an option for an additional 6 doses if patients benefit from treatment.

The following LOAd703 doses will be evaluated:

Dose level 1: 5 X 10\^10 viral particles per treatment Dose level 2: 1 X 10\^11 viral particles per treatment Dose level 3: 5 X 10\^11 viral particles per treatment

Patients will receive gemcitabine intravenously at a dose of 1000mg/m2 + nab-paclitaxel 125 mg/m2 as per hospital standards. One cycle will be one dose of gemcitabine +nab-paclitaxel given on days 1, 8, and 15 of a 28 day cycle. LOAd703 will be given every other week for 6 doses starting on day 15 of the first cycle of chemotherapy. There is an option for an additional 6 doses if patients benefit from treatment. A fixed dose of atezolizumab 1680 mg will be given every 4 weeks on day 1 of each chemotherapy cycle.

Patients will be assigned to the following LOAd703 doses:

Dose level 1: 1 X 10\^11 viral particles per treatment Dose level 2: 5 X 10\^11 viral particles per treatment

oncolytic virus encoding TMZ-CD40L and 4-1BBL

delolimogene mupadenorepvec

gemcitabine

nab-paclitaxel

atezolizumab

Benjamin Musher, MD

Monica Francois

Angelica Loskog, PhD

The purpose of this study is to see if LOAd703 (an oncolytic adenovirus) can be safely given to patients with pancreatic cancer. The study will also evaluate whether or not intratumoral injection of LOAd703 will support current standard of care treatment to reduce the size of the tumor and improve survival of the patients.

Adenoviruses are known as the "common cold" virus and most individuals have had multiple infections during their lifetime. Oncolytic adenoviruses are adenoviruses that are modified so they cannot multiply and spread (known as replicating) properly in normal (e.g. healthy) cells, but instead, they infect and replicate very well in cancer cells. This strong replication leads to the death of the cancer cell. Oncolytic viruses have been evaluated in multiple clinical trials for cancer treatment during the past decade and been proven safe. It is common to have a fever the first day or two after virus injection since the immune system will react to the virus infection. The immune system can also kill cancer cells but to do so it needs to be properly stimulated. Oncolytic viruses alone do not seem to be strong enough to activate clinically relevant anti-cancer responses. However, it is thought that if additional immune system stimulators are added to the oncolytic viruses they may be able to result in clinical relevant antic-cancer responses.

LOAd703 is an oncolytic adenovirus that has been modified to include additional immune system stimulators. Specifically, genes that stimulate the immune system have been added to the oncolytic adenovirus. Once the oncolytic adenovirus infects the cancer cells, the genes will be expressed, resulting in activation of the immune response so it can attack and kill cancer cells.

In this study, LOAd703 will be given by intratumoral injections. It will be given in addition to standard of care treatment with gemcitabine and nab-paclitaxel +/- the anti-PD-L1 antibody atezolizumab. Because this is an experimental therapy, there will be extra visits for disease monitoring and samples accordingly to the detailed information below. The LOAd703 is an investigational agent not approved by the FDA.

The research will be conducted at Baylor College of Medicine (BCM) and Baylor St. Luke's Medical Center (BSLMC).

All patients will receive standard of care treatment for their pancreatic cancer. Standard of care treatment will be gemcitabine in combination with nab-paclitaxel given on days 1, 8, and 15 of a 28 day cycle.

Arm 1: LOAd703 treatment will be initiated at day 15 of the first cycle and given every other week for 6 doses. Depending on the location of the tumor the injection of LOAd703 can be given in different ways. The most common route of injection is ultrasound-guided percutaneous injection, but endoscopic ultrasound-guidance will be used for some patients as appropriate. All patients will receive anti-anxiety drugs or sedation as needed for comfort during the procedure. This study evaluates different doses of LOAd703. All patients will receive six injections of LOAd703. If patients in either phase of the study are judged by the investigator to be deriving clinical benefit from LOAd703 once all scheduled injections have been administered, they will be eligible to receive up to 6 additional biweekly doses of LOAd703.

Arm 2: the same procedures as arm 1 in regard to LOAd703. In addition, the arm 2 patients will receive atezolizumab at a fixed dose, every chemotherapy cycle day 1. The treatments can continue until the final follow-up visit.

Follow-up visits: Besides visits to receive treatments, patients will continue to visit BCM/BSLMC or their local doctor for evaluation of health status and side effects. At some visits blood samples will be obtained. Some of the blood samples being obtained are considered standard of care to ensure patient safety for standard of care treatment and the LOAd703 injection. However, some blood and biopsy samples (in applicable patients) will be collected to be analyzed for the presence of LOAd703, atezolizumab tumor markers and immunology markers. The extra blood will be 5-15 ml (3 teaspoonfuls) of blood collected at the screening visit and at eight different time points both during treatment and after treatments are completed. Imaging of the tumor to determine tumor size will be done every two to three months, which is routine for the monitoring of patients with pancreatic cancer. Patients will actively participate in the study for about 9 months when the final follow-up visit will be scheduled (or 12 months if additional doses of LOAD703 are given). After their active participation is completed patients will continue to receive routine care and will be contacted by the study team every 3 months to provide follow up on the status of their disease.

LOAd703 Oncolytic Virus Therapy for Pancreatic Cancer

Phase I/IIa Trial Evaluating Safety of LOAd703, an Armed Oncolytic Adenovirus for Pancreatic Cancer

Maximum tolerated dose of multiple (6x) image-guided intratumoral injections of LOAd703 at three dose levels in combination with standard of care therapy

To determine the percentage of subjects achieving a partial response or better (according to RECIST 1.1) to repeat doses of LOAd703 (at the highest dose as determined in Phase I) combined with standard of care treatment with and without atezolizumab in pancreatic cancer.

To determine the survival days post study initiation

Lokon Pharma AB

Skin and Connective Tissue Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Delolimogene mupadenorepvec plus atezolizumab

LOAd703 is an oncolytic adenovirus encoding TMZ-CD40L and 4-1BBL

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.

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

Tolerability is evaluated by the NCI CTCAE v5.0 based on interim medical history, physical examination and hematological and clinical chemistry laboratory studies

Tumor size evaluations accordingly to RECIST 1.1

Number of antibodies targeting adenovirus (LOAd703) in serum

Presence of immune cells (MFI) in blood and their fold change over time compared to baseline as determined by flow cytometry

Number of detected virus particles are evaluated in blood, urine, oral and rectal swabs

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
LOAd703 Oncolytic Virus Therapy for Pancreatic Cancer	NCT02705196	Pancreatic Canc...	delolimogene mu... gemcitabine nab-paclitaxel atezolizumab	18 Years -	Lokon Pharma AB
LOAd703 Oncolytic Virus Therapy for Pancreatic Cancer	NCT02705196	Pancreatic Canc...	delolimogene mu... gemcitabine nab-paclitaxel atezolizumab	18 Years -	Lokon Pharma AB
A Phase I/II Trial Investigating LOAd703 in Combination With Atezolizumab in Malignant Melanoma	NCT04123470	Malignant Melan...	delolimogene mu... atezolizumab	18 Years -	Lokon Pharma AB

Spots Global Cancer Trial Database for delolimogene mupadenorepvec