Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer

Brief summary public domain (ClinicalTrials.gov)

This Phase I/II trial evaluates LOAd703 in patients with cancer (pancreatic, biliary, colorectal or ovarian) together with their standard of care chemotherapy or using gemcitabine immune-conditioning. LOAd703 is administered by intratumoral image-guided injections. Maximum 50 patients can be enrolled. LOAd703 is an immunostimulatory gene therapy using an selection replication competent adenovirus as a gene vehicle. The virus is derived from serotype 5 adenovirus with the fiber from serotype 35. It expresses the transgenes trimerized membrane-bound isoleucine zipper (TMZ) TMZ-CD40L and 41BBL under control of a cytomegalovirus (CMV) promoter.

Detailed description public domain (ClinicalTrials.gov)

The trial is a Phase I/II trial evaluating the effect of LOAd703 in patients with pancreatic cancer, biliary cancer, ovarian cancer and colorectal cancer. LOAd703 is an oncolytic adenovirus serotype 5/35 encoding immunostimulatory transgenes: TMZ-CD40L and 41BBL. In Phase I, three doses (total viral load - 1x10e11, 5x10e11, 1x10e12 viral particles (VP)) of LOAd703 will be tested as add-on to standard of care or immune-conditioning gemcitabine chemotherapy. 8 treatments of LOAd703 will be delivered by image-guided intratumoral injection at the same time of chemotherapy. In Phase II stage of the study, patients will be treated at maximum tolerated dose/maximum tolerated study dose as defined in the Phase I stage. In both phases: tumor biopsies, blood samples and radiological imaging will be performed to evaluate safety, effect and mechanisms of action. Further, patients will be subjected to oral and rectal swabs, and urine sampling to determine virus shedding. The patients will be monitored for time to progression, progression free survival and overall survival.

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Safety: Toxicity Symptoms Graded According to CTCAE v4.03. [Up to 50 weeks]. Number, Number of Events. All adverse events (AE): Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 61; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 139; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 411. All serious adverse events (SAEs): Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 7; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 31; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 63. Serious adverse reactions (SARs) related to LOAd703: Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 3; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 4; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 21. AE leading to withdrawal from the study: Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 0; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 1; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 2. AE leading to LOAd703 discontinuation: Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 0; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 2; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 6. AE leading to death: Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 0; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 0; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 1. AE related to LOAd703: Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 29; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 33; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 169. AE related to LOAd703 grade 1: Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 15; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 29; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 111. AE related to LOAd703 grade 2: Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 14; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 3; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 52. AE related to LOAd703 grade 3: Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 0; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 0; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 6. AE related to LOAd703 grade 4: Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 0; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 1; Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication (n=26): 0. AE related to LOAd703 grade 5: Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication (n=3): 0; Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication (n=12): 0; Group 3 LOAd70

Posted results (ClinicalTrials.gov registry) · primary outcome public domain (ClinicalTrials.gov)

Immune Reactions to LOAd703 Virus as Assessed by Anti-adenovirus Ig ELISA [Up to 50 weeks]. Mean, fold change (Standard Deviation). LOAd703 Dose 5x10e10 VP (n=3): 41.63 (8.39); LOAd703 Dose 1x10e11 VP (n=12): 15.81 (10.33); LOAd703 Dose 5x10e11 VP (n=24): 31.77 (24.31).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Response on Tumor Size by Dose and Cancer Diagnosis [Up to 50 weeks]. Count Of Participants, Participants. Complete response (CR): LOAd703 Dose 5x10e10 VP (n=3): 0; LOAd703 Dose 1x10e11 VP (n=10): 0; LOAd703 Dose 5x10e11 VP (n=22): 0; Colorectal Cancer (n=5): 0; Biliary Cancer (n=3): 0; Pancreatic Cancer (n=24): 0; Ovarian Cancer (n=3): 0. Partial response (PR): LOAd703 Dose 5x10e10 VP (n=3): 0; LOAd703 Dose 1x10e11 VP (n=10): 3; LOAd703 Dose 5x10e11 VP (n=22): 3; Colorectal Cancer (n=5): 0; Biliary Cancer (n=3): 0; Pancreatic Cancer (n=24): 6; Ovarian Cancer (n=3): 0. Stable disease (SD): LOAd703 Dose 5x10e10 VP (n=3): 1; LOAd703 Dose 1x10e11 VP (n=10): 4; LOAd703 Dose 5x10e11 VP (n=22): 11; Colorectal Cancer (n=5): 2; Biliary Cancer (n=3): 1; Pancreatic Cancer (n=24): 11; Ovarian Cancer (n=3): 2. Progressive disease (PD): LOAd703 Dose 5x10e10 VP (n=3): 2; LOAd703 Dose 1x10e11 VP (n=10): 3; LOAd703 Dose 5x10e11 VP (n=22): 8; Colorectal Cancer (n=5): 3; Biliary Cancer (n=3): 2; Pancreatic Cancer (n=24): 7; Ovarian Cancer (n=3): 1. Overall response rate (ORR): LOAd703 Dose 5x10e10 VP (n=3): 0; LOAd703 Dose 1x10e11 VP (n=10): 3; LOAd703 Dose 5x10e11 VP (n=22): 3; Colorectal Cancer (n=5): 0; Biliary Cancer (n=3): 0; Pancreatic Cancer (n=24): 6; Ovarian Cancer (n=3): 0. Clinical benefit rate (CBR): LOAd703 Dose 5x10e10 VP (n=3): 1; LOAd703 Dose 1x10e11 VP (n=10): 7; LOAd703 Dose 5x10e11 VP (n=22): 14; Colorectal Cancer (n=5): 2; Biliary Cancer (n=3): 1; Pancreatic Cancer (n=24): 17; Ovarian Cancer (n=3): 2.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Overall Survival [From registration date to date of death, assessed up to 40 months]. Median, Months (95% Confidence Interval). LOAd703 Dose 5x10e10 VP (n=3): 4.40 (3.02 to 12.85); LOAd703 Dose 1x10e11 VP (n=10): 8.44 (2.66 to 40.54); LOAd703 Dose 5x10e11 VP (n=22): 7.38 (5.39 to 10.71); Colorectal Cancer (n=5): 5.36 (3.02 to 8.44); Biliary Cancer (n=3): 6.64 (5.26 to 7.46); Pancreatic Cancer (n=24): 7.29 (5.39 to 12.85); Ovarian Cancer (n=3): 40.54 (9.69 to 40.54).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Time to Progression [From registration date to date of progression, assessed up to 40 months]. Median, Months (95% Confidence Interval). LOAd703 Dose 5x10e10 VP (n=3): 2.40 (1.74 to 3.68); LOAd703 Dose 1x10e11 VP (n=10): 3.79 (1.81 to 5.49); LOAd703 Dose 5x10e11 VP (n=22): 3.88 (1.87 to 5.72); Colorectal Cancer (n=5): 2.40 (1.74 to 3.84); Biliary Cancer (n=3): 1.81 (1.58 to 4.76); Pancreatic Cancer (n=24): 3.75 (2.27 to 5.72); Ovarian Cancer (n=3): 3.88 (1.87 to 20.07).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Progression Free Survival [From registration date to date of progression, or date of death, which ever came first, assessed up to 40 months]. Median, Months (95% Confidence Interval). LOAd703 Dose 5x10e10 VP (n=3): 2.40 (1.74 to 3.68); LOAd703 Dose 1x10e11 VP (n=10): 3.79 (1.81 to 5.49); LOAd703 Dose 5x10e11 VP (n=22): 4.32 (1.87 to 5.72); Colorectal Cancer (n=5): 2.40 (1.74 to 5.36); Biliary Cancer (n=3): 1.81 (1.58 to 4.76); Pancreatic Cancer (n=24): 4.62 (2.27 to 5.72); Ovarian Cancer (n=3): 3.88 (1.87 to 20.07).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Systemic Immune Activation [Up to 50 weeks]. Number, Percentage of Participants. LOAd703 Dose 5x10e10 VP (n=3): 100; LOAd703 Dose 1x10e11 VP (n=11): 100; LOAd703 Dose 5x10e11 VP (n=25): 100.

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Immune Cell Activation [Up to 50 weeks]. Mean, fold change (Standard Deviation). LOAd703 Dose 5x10e10 VP (n=3): 1.01 (0.39); LOAd703 Dose 1x10e11 VP (n=11): 1.19 (0.32); LOAd703 Dose 5x10e11 VP (n=25): 1.17 (0.48).

Posted results (ClinicalTrials.gov registry) · secondary outcome public domain (ClinicalTrials.gov)

Presence of LOAd703 Virus in Blood [Up to 50 weeks]. Number, Percentage of positive samples. LOAd703 Dose 5x10e10 VP (n=3): 22.22; LOAd703 Dose 1x10e11 VP (n=12): 16.13; LOAd703 Dose 5x10e11 VP (n=26): 35.48.