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

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

Sponsors

Lead sponsor: Lokon Pharma AB

Collaborator: Precision Oncology LLC

Source Lokon Pharma AB
Brief Summary

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.

Detailed Description

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.

Overall Status Recruiting
Start Date January 28, 2020
Completion Date December 31, 2023
Primary Completion Date December 31, 2022
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Number of patients with toxicities Up to 57 weeks post treatment initiation
Secondary Outcome
Measure Time Frame
Overall response rate Up to 57 weeks post treatment initiation
Overall survival From treatment initiation post 12 months after last patients last visit
Antibodies against LOAd703 Up to 57 weeks post treatment initiation
Immune cell phenotype Up to 57 weeks post treatment initiation
Virus shedding Up to 57 weeks post treatment initiation
Enrollment 35
Condition
Intervention

Intervention type: Genetic

Intervention name: delolimogene mupadenorepvec

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

Arm group label: Treatment

Other name: LOAd703

Intervention type: Biological

Intervention name: atezolizumab

Description: Atezolizumab is an anti-PD-L1 antibody

Arm group label: Treatment

Eligibility

Criteria:

Inclusion Criteria:

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 therapy.

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 > or 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 the ULN.

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.

Exclusion Criteria:

1. Malignant melanoma that is uveal or mucosal.

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 treatment setting.

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 metastases.

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 (e.g. first dose of LOAd703/atezolizumab).

7. Therapeutic treatment with systemic antibiotics within 14 days of registration (i.e. first dose of LOAd703/atezolizumab).

8. Treatment with biologic therapy within 21 days of registration (i.e. first dose of LOAd703/atezolizumab).

9. Treatment with cytotoxic anticancer therapy within 21 days of registration (i.e. first dose of LOAd703/atezolizumab).

10. Treatment with wide-field radiation within 21 days of registration (i.e. first dose of LOAd703/atezolizumab).

11. Prior treatment with an adenovirus-based gene therapy.

12. Use of any investigational agents within 21 days of registration (i.e. first dose of LOAd703/atezolizumab).

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 highly effective 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 as highly effective 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 or abstinence of heterosexual intercourse during the entire study period (depending on the preferred and usual life style of the subject).

19. Men who do not consent to the use of condoms during intercourse during study participation or has a partner of childbearing potential, who will not use any of the highly effective contraceptive methods exemplified in exclusion criteria no 18.

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 corticosteroids.

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 or tested reduced functional respiration capacity. 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 formulation.

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.

Gender: All

Minimum age: 18 Years

Maximum age: N/A

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
Angelica Loskog, PhD Study Chair Lokon Pharma AB
Location
facility status contact
Cedars-Sinai Medical Center, The Angeles Clinic and Research Institute | Los Angeles, California, 90025, United States Recruiting Omar Hamid, MD 310-582-7900 [email protected]
Baylor St Luke's Medical Center | Houston, Texas, 77030, United States Recruiting Daniel Wang, MD 713-798-3750 [email protected]
Uppsala University Hospital | Uppsala, 75185, Sweden Recruiting Annika Liden, nurse 018-6110000 [email protected]
Location Countries

Sweden

United States

Verification Date

April 2020

Responsible Party

Responsible party type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Arm group label: Treatment

Arm group type: Experimental

Description: Delolimogene mupadenorepvec plus atezolizumab

Patient Data No
Study Design Info

Allocation: N/A

Intervention model: Single Group Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov