Pancreatic Adenocarcinoma, Ovarian Cancer, Biliary Carcinoma, Colorectal Cancer
Conditions
Brief summary
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
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.
Interventions
DRUGLOAd703
Oncolytic adenovirus serotype 5/35 encoding TMZ-CD40L and 4-1BBL
Sponsors
Uppsala University
Lokon Pharma AB
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants treated with LOAd703 at three dose levels (5x10e10 VP, 1x10e11 VP, 5x10e11 VP) and SOC tailored to the indication
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have histologic or cytologic evidence of colorectal carcinoma (CRC), pancreatic carcinoma (PC), biliary cancer, or epithelial ovarian carcinoma (EOC which may encompass epithelial ovarian, fallopian tube or primary peritoneal carcinoma). 2. Have advanced disease, defined as cancer that is either metastatic or locally advanced, unresectable, and for which radiotherapy or other locoregional therapies are not considered treatment of choice but systemic chemotherapy or no therapy is planned. 3. Have one of the following treatment situations apply: 1. Colorectal carcinoma (CRC) I. A patient with refractory or recurrent metastatic CRC who has either received all conventional therapy; or is entering a resting phase between reasonable conventional treatments. II. A patient who is amenable to treatment with LOAd703 plus gemcitabine as a single agent conditioning regimen. 2. Pancreatic cancer I. A patient with either locally advanced, unresectable or metastatic disease who is eligible to receive any line of conventional treatment consisting of gemcitabine and/or nab-paclitaxel. II. A patient who is amenable to treatment with LOAd703 as an add-on to standard-of-care gemcitabine-based or nab-paclitaxel- based regimens or gemcitabine or nab-paclitaxel as single agents. c. Biliary cancer I. A patient with either locally advanced unresectable or metastatic biliary cancer who is either treatment-naïve or has received any number of lines of treatment. II. Patient who is amenable to treatment with LOAd703 as an add-on to standard-of-care treatment consisting of gemcitabine combined with other agents (e.g. gemcitabine/low-dose cisplatin, gemcitabine/oxaliplatin, etc) in the first line setting or gemcitabine in a combination regimen or as a single agent in latter lines of treatment. d. Ovarian Cancer I. A patient with either epithelial ovarian, fallopian tube or primary peritoneal carcinoma. II. The patient has either: i) Residual disease following first-line standard-of-care combination chemotherapy. ii) Platinum-sensitive disease (platinum free interval ≥ 6 months) in early relapse following first-line standard-of care combination chemotherapy. iii) Platinum-resistant disease and received at least 3 lines of standard treatment. These treatments should have included bevacizumab and/or PARP inhibitors if they are reasonable candidates for such. III. Amenable to treatment with LOAd703 as an add-on to standard-of-care paclitaxel-based regimens (excluding bevacizumab), paclitaxel as a single agent, or gemcitabine as a single agent. 4. Have a disease burden that is considered low (i.e. low tumor burden), which is defined on a patient-by-patient basis as per principal investigator's discretion. A rough guideline for defining low tumor burden is that the sum of the product of the bidimensional measurements for all lesions is \< 70 cm2. 5. Have a measurable disease by standard imaging techniques per RECIST criteria. Measurable lesions must be outside of any prior radiation field(s), unless disease progression has been documented at that disease site subsequent to radiation. 6. At least one non-irradiated (or irradiated but disease progression documented at the site subsequent to radiation) lesion must be suitable for image-guided intratumoral injection and needle biopsy. 7. Be medically suited to sedation if required during intratumoral injections. 8. Be at least 18 years-old. 9. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2. 10. Have no remaining acute toxic effects from previous anticancer therapy \> grade 1 except for any grade of alopecia. 11. Have adequate baseline organ/hematological function, as demonstrated by the following: 1. Absolute neutrophil count (ANC) ≥1.0 x 109/l 2. Hemoglobin ≥9 g/dl 3. Platelet count ≥ 100 x 109/l 4. Bilirubin \< 1.5 times the institutional upper limit of normal (ULN) 5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<2.5 (3, if liver metastases are present) times the institutional ULN. 6. Serum creatinine \<2 times the institutional ULN or calculated creatinine clearance \>35 mL/min 7. Prothrombin (INR)\<1.5 or prothrombin time (PT) \<1.5 ULN; and either partial thromboplastin time or activated partial thromboplastin time (PTT or aPTT) ≤ 1.5 times the ULN. 12. The patient must understand and be willing to provide written informed consent.
Exclusion criteria
1. Any concurrent treatment that would compromise the study including but not limited to continuous high dose corticosteroids (\>0.5mg/kg), lymphodepleting antibodies or cytotoxic agents. 2. Treatment with high dose immune inhibitors including lymphotoxic monoclonal antibodies such as alemtuzumab (CampathR), or sirolimus (RapamuneR) and its analogs, biological therapy, cytotoxic agents or any investigational agents within 21 days of registration. 3. Ovarian carcinoma patients should not be eligible to PARP inhibitor treatment. 4. Patients on warfarin (or other anti-coagulants) are not eligible. 5. Women who are pregnant, lactating, 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 last menstrual period. Acceptable contraceptive methods are: 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. 6. Men who do not consent to the use of condom during intercourse during study participation. 7. Known active hepatitis B or C infection, or HIV infection. 8. Patients with active, severe, autoimmune disease. 9. Uncontrolled intercurrent illness including but not limited to psychiatric illness/social situations that in the opinion of the Investigator would compromise compliance of study requirements or put the patient at unacceptable risk. 10. Other malignancies within the past 2 years (not including basal and squamous cell carcinoma of the skin, localized prostate cancer or in situ cervix carcinoma). 11. Patients must agree to not to vaccinate with living vaccines during participation in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | Up to 50 weeks | The toxicity symptoms were graded according to CTCAE v4.03. |
| Immune Reactions to LOAd703 Virus as Assessed by Anti-adenovirus Ig ELISA | Up to 50 weeks | Fold change between baseline and evaluation visit for anti-adenovirus antibodies (LOAd703). The baseline is the last available measurement taken before the first LOAd703 treatment. Evaluation is a measurement taken from subjects receiving at least 3 LOAd703 treatments. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | From registration date to date of progression, assessed up to 40 months | Time to progression from registration by dose and cancer diagnosis |
| Progression Free Survival | From registration date to date of progression, or date of death, which ever came first, assessed up to 40 months | Months of progression free survival (PFS) from registration by dose and cancer diagnosis |
| Response on Tumor Size by Dose and Cancer Diagnosis | Up to 50 weeks | Local and distant anti-tumoral size changes assessed by appropriate imaging accordingly to RECIST 1.1. Complete Response (CR), complete macroscopic disappearance of all tumors; Partial Response (PR), a reduction of at least 30% in the sum of all tumor diameters from baseline; one/more lesions fulfilling the criteria for PR and other/others for progressive disease (PD); Stable disease (SD), Neither PR nor PD; Progressive disease (PD), at least 20% increase in the sum of all tumor diameters from the smallest tumor size and/or the appearance of new tumor lesion/s; Overall response rate (ORR) = CR + PR; Clinical benefit rate (CBR) = CR + PR + SD. |
| Immune Cell Activation | Up to 50 weeks | Fold change between baseline and evaluation visit for CD8+ CD3+ T cells activation evaluated by flow cytometry. The baseline is the last available measurement taken before the first LOAd703 treatment. Evaluation is a measurement taken from subjects receiving at least 3 LOAd703 treatments. |
| Presence of LOAd703 Virus in Blood | Up to 50 weeks | Percentage of PK samples analyzed that were positive for viral DNA/ml in serum. |
| Systemic Immune Activation | Up to 50 weeks | Percentage of participants with upregulated immune marker in blood at evaluation as compared to baseline. The baseline is the last available measurement taken before the first LOAd703 treatment. Evaluation is a measurement taken from subjects receiving at least 3 LOAd703 treatments. |
| Overall Survival | From registration date to date of death, assessed up to 40 months | Months of overall survival (OS) from registration by dose and cancer diagnosis |
Countries
Sweden
Participant flow
Pre-assignment details
Overall, a total of 47 subjects signed the informed consent, 5 out of 47 subjects were screening failures and 42 subjects were assigned to the study treatment (Group 1, 2 or 3). One subject was assigned to Group 3, but was not exposed to the study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication LOAd703 (5x10e10 VP) oncolytic adenovirus administered add-on to standard of care chemotherapy or gemcitabine immune-conditioning if standard of care is no longer an option (e.g. after last line)
LOAd703: Oncolytic adenovirus serotype 5/35 encoding TMZ-CD40L and 4-1BBL | 3 |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication LOAd703 (1x10e11 VP) oncolytic adenovirus administered add-on to standard of care chemotherapy or gemcitabine immune-conditioning if standard of care is no longer an option (e.g. after last line)
LOAd703: Oncolytic adenovirus serotype 5/35 encoding TMZ-CD40L and 4-1BBL | 12 |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication LOAd703 (5x10e11 VP) oncolytic adenovirus administered add-on to standard of care chemotherapy or gemcitabine immune-conditioning if standard of care is no longer an option (e.g. after last line)
LOAd703: Oncolytic adenovirus serotype 5/35 encoding TMZ-CD40L and 4-1BBL | 27 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Group 1: LOAd703 Dose Level 5x10e10VP | Progressive Disease | 2 | 0 | 0 |
| Group 2: LOAd703 Dose Level 1x10e11 VP | Adverse Event | 0 | 1 | 0 |
| Group 2: LOAd703 Dose Level 1x10e11 VP | Death | 0 | 1 | 0 |
| Group 2: LOAd703 Dose Level 1x10e11 VP | Other Reason | 0 | 1 | 0 |
| Group 2: LOAd703 Dose Level 1x10e11 VP | Progressive Disease | 0 | 7 | 0 |
| Group 3: LOAd703 Dose Level 5x10e11VP | Adverse Event | 0 | 0 | 2 |
| Group 3: LOAd703 Dose Level 5x10e11VP | Death | 0 | 0 | 4 |
| Group 3: LOAd703 Dose Level 5x10e11VP | Not Exposed to LOAd703 | 0 | 0 | 1 |
| Group 3: LOAd703 Dose Level 5x10e11VP | Other Reason | 0 | 0 | 1 |
| Group 3: LOAd703 Dose Level 5x10e11VP | Physician Decision | 0 | 0 | 1 |
| Group 3: LOAd703 Dose Level 5x10e11VP | Progressive Disease | 0 | 0 | 16 |
| Group 3: LOAd703 Dose Level 5x10e11VP | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication |
|---|---|---|---|---|
| Age, Continuous | 62.5 years STANDARD_DEVIATION 9.7 | 63.1 years STANDARD_DEVIATION 8.1 | 62.9 years STANDARD_DEVIATION 12.4 | 55.7 years STANDARD_DEVIATION 12.7 |
| Cancer Diagnosis Biliary cancer | 3 participants | 3 participants | 0 participants | 0 participants |
| Cancer Diagnosis Colorectal carcinoma | 5 participants | 1 participants | 2 participants | 2 participants |
| Cancer Diagnosis Ovarian cancer | 5 participants | 4 participants | 1 participants | 0 participants |
| Cancer Diagnosis Pancreatic cancer | 29 participants | 19 participants | 9 participants | 1 participants |
| Current oncological disease Locally advanced | 8 participants | 4 participants | 4 participants | 0 participants |
| Current oncological disease Metastatic | 34 participants | 23 participants | 8 participants | 3 participants |
| ECOG score ECOG score 0 | 26 participants | 21 participants | 4 participants | 1 participants |
| ECOG score ECOG score 1 | 15 participants | 6 participants | 7 participants | 2 participants |
| ECOG score ECOG score 2 | 1 participants | 0 participants | 1 participants | 0 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 42 Participants | 27 Participants | 12 Participants | 3 Participants |
| Region of Enrollment Sweden | 42 participants | 27 participants | 12 participants | 3 participants |
| Sex: Female, Male Female | 23 Participants | 17 Participants | 6 Participants | 0 Participants |
| Sex: Female, Male Male | 19 Participants | 10 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 10 / 12 | 23 / 26 |
| other Total, other adverse events | 3 / 3 | 11 / 12 | 26 / 26 |
| serious Total, serious adverse events | 3 / 3 | 12 / 12 | 20 / 26 |
Outcome results
Primary
Immune Reactions to LOAd703 Virus as Assessed by Anti-adenovirus Ig ELISA
Fold change between baseline and evaluation visit for anti-adenovirus antibodies (LOAd703). The baseline is the last available measurement taken before the first LOAd703 treatment. Evaluation is a measurement taken from subjects receiving at least 3 LOAd703 treatments.
Time frame: Up to 50 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Immune Reactions to LOAd703 Virus as Assessed by Anti-adenovirus Ig ELISA | 41.63 fold change | Standard Deviation 8.39 |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Immune Reactions to LOAd703 Virus as Assessed by Anti-adenovirus Ig ELISA | 15.81 fold change | Standard Deviation 10.33 |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Immune Reactions to LOAd703 Virus as Assessed by Anti-adenovirus Ig ELISA | 31.77 fold change | Standard Deviation 24.31 |
Primary
Safety: Toxicity Symptoms Graded According to CTCAE v4.03.
The toxicity symptoms were graded according to CTCAE v4.03.
Time frame: Up to 50 weeks
Population: Overall, a total of 42 subjects were assigned to the study treatment, 1 out of 42 did not receive the study treatment and it was not included in the safety evaluation. The subject who did not receive the study treatment was assigned to group 3.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | All serious adverse events (SAEs) | 7 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE leading to LOAd703 discontinuation | 0 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 5 | 0 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | All adverse events (AE) | 61 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE leading to death | 0 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 4 | 0 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE unrelated to LOAd703 | 32 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 | 29 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 1 | 15 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 3 | 0 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | Serious adverse reactions (SARs) related to LOAd703 | 3 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 2 | 14 Number of Events |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE leading to withdrawal from the study | 0 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 2 | 3 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 3 | 0 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 4 | 1 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 5 | 0 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE leading to withdrawal from the study | 1 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE unrelated to LOAd703 | 106 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 | 33 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE leading to LOAd703 discontinuation | 2 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | All serious adverse events (SAEs) | 31 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE leading to death | 0 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | All adverse events (AE) | 139 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 1 | 29 Number of Events |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | Serious adverse reactions (SARs) related to LOAd703 | 4 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE unrelated to LOAd703 | 242 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 | 169 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | All adverse events (AE) | 411 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | All serious adverse events (SAEs) | 63 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | Serious adverse reactions (SARs) related to LOAd703 | 21 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE leading to withdrawal from the study | 2 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE leading to LOAd703 discontinuation | 6 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE leading to death | 1 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 1 | 111 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 2 | 52 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 3 | 6 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 4 | 0 Number of Events |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Safety: Toxicity Symptoms Graded According to CTCAE v4.03. | AE related to LOAd703 grade 5 | 0 Number of Events |
Secondary
Immune Cell Activation
Fold change between baseline and evaluation visit for CD8+ CD3+ T cells activation evaluated by flow cytometry. The baseline is the last available measurement taken before the first LOAd703 treatment. Evaluation is a measurement taken from subjects receiving at least 3 LOAd703 treatments.
Time frame: Up to 50 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Immune Cell Activation | 1.01 fold change | Standard Deviation 0.39 |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Immune Cell Activation | 1.19 fold change | Standard Deviation 0.32 |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Immune Cell Activation | 1.17 fold change | Standard Deviation 0.48 |
Secondary
Overall Survival
Months of overall survival (OS) from registration by dose and cancer diagnosis
Time frame: From registration date to date of death, assessed up to 40 months
Population: OS was evaluated in participants who have received at least 3 doses of LOAd703 and performed computed tomography (CT) evaluation at baseline and at week 9 (Visit 5). Group 1 (5x10e10 VP): all the 3 participants met the criteria to be included in this analysis; Group 2 (1x10e11 VP): from a total of 12 participants, 10 met the criteria to be included in this analysis; Group 3 (5x10e11 VP): from a total of 27 participants, 22 met the criteria to be included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Overall Survival | 4.40 Months |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Overall Survival | 8.44 Months |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Overall Survival | 7.38 Months |
| Colorectal Cancer | Overall Survival | 5.36 Months |
| Biliary Cancer | Overall Survival | 6.64 Months |
| Pancreatic Cancer | Overall Survival | 7.29 Months |
| Ovarian Cancer | Overall Survival | 40.54 Months |
Secondary
Presence of LOAd703 Virus in Blood
Percentage of PK samples analyzed that were positive for viral DNA/ml in serum.
Time frame: Up to 50 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Presence of LOAd703 Virus in Blood | 22.22 Percentage of positive samples |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Presence of LOAd703 Virus in Blood | 16.13 Percentage of positive samples |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Presence of LOAd703 Virus in Blood | 35.48 Percentage of positive samples |
Secondary
Progression Free Survival
Months of progression free survival (PFS) from registration by dose and cancer diagnosis
Time frame: From registration date to date of progression, or date of death, which ever came first, assessed up to 40 months
Population: PFS was evaluated in participants who have received at least 3 doses of LOAd703 and performed computed tomography (CT) evaluation at baseline and at week 9 (Visit 5). Group 1 (5x10e10 VP): all the 3 participants met the criteria to be included in this analysis; Group 2 (1x10e11 VP): from a total of 12 participants, 10 met the criteria to be included in this analysis; Group 3 (5x10e11 VP): from a total of 27 participants, 22 met the criteria to be included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Progression Free Survival | 2.40 Months |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Progression Free Survival | 3.79 Months |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Progression Free Survival | 4.32 Months |
| Colorectal Cancer | Progression Free Survival | 2.40 Months |
| Biliary Cancer | Progression Free Survival | 1.81 Months |
| Pancreatic Cancer | Progression Free Survival | 4.62 Months |
| Ovarian Cancer | Progression Free Survival | 3.88 Months |
Secondary
Response on Tumor Size by Dose and Cancer Diagnosis
Local and distant anti-tumoral size changes assessed by appropriate imaging accordingly to RECIST 1.1. Complete Response (CR), complete macroscopic disappearance of all tumors; Partial Response (PR), a reduction of at least 30% in the sum of all tumor diameters from baseline; one/more lesions fulfilling the criteria for PR and other/others for progressive disease (PD); Stable disease (SD), Neither PR nor PD; Progressive disease (PD), at least 20% increase in the sum of all tumor diameters from the smallest tumor size and/or the appearance of new tumor lesion/s; Overall response rate (ORR) = CR + PR; Clinical benefit rate (CBR) = CR + PR + SD.
Time frame: Up to 50 weeks
Population: Response on tumor size was evaluated in participants who have received at least 3 doses of LOAd703 and performed computed tomography (CT) evaluation at baseline and at week 9 (Visit 5). Group 1 (5x10e10 VP): all the 3 participants met the criteria to be included in this analysis; Group 2 (1x10e11 VP): from a total of 12 participants, 10 met the criteria to be included in this analysis; Group 3 (5x10e11 VP): from a total of 27 participants, 22 met the criteria to be included in this analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Clinical benefit rate (CBR) | 1 Participants |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Overall response rate (ORR) | 0 Participants |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Partial response (PR) | 0 Participants |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Complete response (CR) | 0 Participants |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Stable disease (SD) | 1 Participants |
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Progressive disease (PD) | 2 Participants |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Partial response (PR) | 3 Participants |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Progressive disease (PD) | 3 Participants |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Complete response (CR) | 0 Participants |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Clinical benefit rate (CBR) | 7 Participants |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Overall response rate (ORR) | 3 Participants |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Stable disease (SD) | 4 Participants |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Stable disease (SD) | 11 Participants |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Overall response rate (ORR) | 3 Participants |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Progressive disease (PD) | 8 Participants |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Complete response (CR) | 0 Participants |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Partial response (PR) | 3 Participants |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Response on Tumor Size by Dose and Cancer Diagnosis | Clinical benefit rate (CBR) | 14 Participants |
| Colorectal Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Complete response (CR) | 0 Participants |
| Colorectal Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Partial response (PR) | 0 Participants |
| Colorectal Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Stable disease (SD) | 2 Participants |
| Colorectal Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Progressive disease (PD) | 3 Participants |
| Colorectal Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Overall response rate (ORR) | 0 Participants |
| Colorectal Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Clinical benefit rate (CBR) | 2 Participants |
| Biliary Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Stable disease (SD) | 1 Participants |
| Biliary Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Clinical benefit rate (CBR) | 1 Participants |
| Biliary Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Progressive disease (PD) | 2 Participants |
| Biliary Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Partial response (PR) | 0 Participants |
| Biliary Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Overall response rate (ORR) | 0 Participants |
| Biliary Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Complete response (CR) | 0 Participants |
| Pancreatic Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Clinical benefit rate (CBR) | 17 Participants |
| Pancreatic Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Stable disease (SD) | 11 Participants |
| Pancreatic Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Overall response rate (ORR) | 6 Participants |
| Pancreatic Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Progressive disease (PD) | 7 Participants |
| Pancreatic Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Complete response (CR) | 0 Participants |
| Pancreatic Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Partial response (PR) | 6 Participants |
| Ovarian Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Partial response (PR) | 0 Participants |
| Ovarian Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Complete response (CR) | 0 Participants |
| Ovarian Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Stable disease (SD) | 2 Participants |
| Ovarian Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Overall response rate (ORR) | 0 Participants |
| Ovarian Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Clinical benefit rate (CBR) | 2 Participants |
| Ovarian Cancer | Response on Tumor Size by Dose and Cancer Diagnosis | Progressive disease (PD) | 1 Participants |
Secondary
Systemic Immune Activation
Percentage of participants with upregulated immune marker in blood at evaluation as compared to baseline. The baseline is the last available measurement taken before the first LOAd703 treatment. Evaluation is a measurement taken from subjects receiving at least 3 LOAd703 treatments.
Time frame: Up to 50 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Systemic Immune Activation | 100 Percentage of Participants |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Systemic Immune Activation | 100 Percentage of Participants |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Systemic Immune Activation | 100 Percentage of Participants |
Secondary
Time to Progression
Time to progression from registration by dose and cancer diagnosis
Time frame: From registration date to date of progression, assessed up to 40 months
Population: Time to progression was evaluated in participants who have received at least 3 doses of LOAd703 and performed computed tomography (CT) evaluation at baseline and at week 9 (Visit 5). Group 1 (5x10e10 VP): all the 3 participants met the criteria to be included in this analysis; Group 2 (1x10e11 VP): from a total of 12 participants, 10 met the criteria to be included in this analysis; Group 3 (5x10e11 VP): from a total of 27 participants, 22 met the criteria to be included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 LOAd703 5x10e10 VP + SOC Tailored to the Indication | Time to Progression | 2.40 Months |
| Group 2 LOAd703 1x10e11 VP + SOC Tailored to the Indication | Time to Progression | 3.79 Months |
| Group 3 LOAd703 5x10e11 VP + SOC Tailored to the Indication | Time to Progression | 3.88 Months |
| Colorectal Cancer | Time to Progression | 2.40 Months |
| Biliary Cancer | Time to Progression | 1.81 Months |
| Pancreatic Cancer | Time to Progression | 3.75 Months |
| Ovarian Cancer | Time to Progression | 3.88 Months |