Clinical trial NCT03225989: Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer
Official title: Phase I/II Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Pancreatic Adenocarcinoma
Ovarian Cancer
Biliary Carcinoma
Colorectal Cancer
Lead sponsor: Lokon Pharma AB
Sponsor class: INDUSTRY
Collaborators: name: Uppsala University
First posted: 2017-07-21
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Participants treated with LOAd703 at three dose levels (5x10e10 VP, 1x10e11 VP, 5x10e11 VP) and SOC tailored to the indication
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Safety: Toxicity Symptoms Graded According to CTCAE v4.03.
timeFrame: Up to 50 weeks
measure: Immune Reactions to LOAd703 Virus as Assessed by Anti-adenovirus Ig ELISA
timeFrame: Up to 50 weeks
Secondary outcomes:
measure: Response on Tumor Size by Dose and Cancer Diagnosis
timeFrame: Up to 50 weeks
measure: Overall Survival
timeFrame: From registration date to date of death, assessed up to 40 months
measure: Time to Progression
timeFrame: From registration date to date of progression, assessed up to 40 months
measure: Progression Free Survival
timeFrame: From registration date to date of progression, or date of death, which ever came first, assessed up to 40 months
measure: Systemic Immune Activation
timeFrame: Up to 50 weeks
measure: Immune Cell Activation
timeFrame: Up to 50 weeks
measure: Presence of LOAd703 Virus in Blood
timeFrame: Up to 50 weeks
Other outcomes:
Locations:
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Huddinge
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
Study officials:
affiliation: Lokon Pharma AB
name: Angelica Loskog, PhD
role: STUDY_CHAIR
References: