Clinical trial NCT03003676: A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After Programmed Cell Death Protein 1 (PD1) Blockade
Official title: A Pilot Study of Sequential ONCOS-102, an Engineered Oncolytic Adenovirus Expressing GMCSF, and Pembrolizumab in Patients With Advanced or Unresectable Melanoma Progressing After PD1 Blockade
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced or Unresectable Melanoma Progressing After PD1 Blockade
Lead sponsor: Targovax ASA
Sponsor class: INDUSTRY
First posted: 2016-12-28
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a multi center, phase I pilot study of sequential ONCOS-102 and pembrolizumab in patients with advanced or unresectable melanoma progressing after PD1 blockade. The primary objective of the study is to determine the safety of sequential treatment with ONCOS-102 followed by pembrolizumab. The protocol aims to enroll patients into two cohorts: Part I: up to 12 patients will receive sequential treatment with ONCOS-102 followed by pembrolizumab. Part II: up to 12 patients will receive an initial treatment phase with ONCOS-102 followed by a treatment phase with ONCOS-102 in combination with pembrolizumab.


Eligibility criteria: Inclusion Criteria:

* Adults 18 years of age or older.
* For US sites: Histopathologically confirmed melanoma with an injectable cutaneous or lymph node metastasis that has progressed in the opinion of the treating investigator despite administering a Food and Drug Administration (FDA) approved anti-PD1 agent, with or without ipilimumab.
* For European sites: Histopathologically confirmed melanoma with an injectable cutaneous or lymph node metastasis that has progressed in the opinion of the treating investigator despite administering a regulatory approved anti-PD1 agent, with or without ipilimumab.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
* Measurable disease according to RECIST 1.1.
* Acceptable coagulation status: international normalised ratio (INR) of blood clotting, prothrombin time and activated partial thromboplastin time within ≤1.5 x upper limit of normal (ULN).
* Completion of local therapy, such as radiation, surgical resection, injectable immunebased therapy, or topical pro-inflammatory agent, 21 days prior to first dose of protocol therapy.
* Adverse events from previous cancer therapies (excluding alopecia) must have recovered to grade 1 (CTCAE, most recent version). Stable grade 2 AEs such as endocrine conditions are allowed, and other chronic stable AEs may be considered on a case by case basis by the Principal Investigator.
* Clinical stability of brain metastases for at least 4 weeks prior to first day of study therapy.
* Acceptable liver and renal functions defined as:

  * Total bilirubin ≤1.5 x ULN (does not include patients with Gilbert's Disease)
  * Aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT) ≤3.0 x ULN
  * Serum creatinine ≤1.5 x ULN
* Acceptable haematological function defined as (Patients can be transfused to meet the haemoglobin entry criteria):

  * Haemoglobin ≥9 g/dL
  * Neutrophils ≥1.5 x 10\^9/L
  * Platelet count ≥75 x 10\^9/L
* Able to provide valid written informed consent.
* All women of childbearing potential must have a negative urine or serum pregnancy test at screening.
* For US sites: All patients must agree to use barrier contraception (i.e. condom) during study treatment and for 2 months after the last virus treatment and 4 months after the last dose of chemotherapy and pembrolizumab.
* For European sites: All patients must agree to use highly effective contraception for at least 6 months (according to the latest country specific SmPC) after administration of CPO, up to 4 months after last dose of pembrolizumab, and up to 2 months after last dose of ONCOS-102, whichever comes last.
* For European sites: All women of child-bearing potential must agree to perform pregnancy testing throughout the study starting at baseline, every 3 weeks from day 22 until last dose of study medication (ONCOS-102 and pembrolizumab) and then every month for at least 6 months.

Exclusion Criteria:

* A concomitant medical condition requiring receipt of a therapeutic anticoagulant that in the opinion of the treating physician cannot safely allow for therapeutic injection of ONCOS-102 and tumor biopsies. Local clinical practice can be followed with regard to holding a therapeutic anticoagulant during invasive procedures such as biopsies.
* A concomitant medical condition that in the opinion of the treating physician would pose unreasonable additional risk to therapeutic injection of ONCOS-102.
* For US sites: Receipt of Investigational agents within 28 days prior to first dose of protocol therapy.
* For European sites: Current participation or participation in a study of an investigational agent within 28 days prior to first dose of protocol therapy. Note: participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
* Any symptomatic autoimmune disease (such as lupus, scleroderma, Crohn's disease, ulcerative colitis) that requires administration of \>10mg of prednisone equivalent. Lower dose steroids for conditions such as hypophysitis are allowed.
* Any prior severe adverse event attributed to prior anti-PD1 therapy that, in the Principal investigator's opinion, would contraindicate pembrolizumab administration such as:

  * Grade 2 or higher pneumonitis
  * Grade 4 AST or ALT elevation
  * Grade 3 or higher colitis attributable to PD1 blockade; note that colitis attributable to ipilimumab is not excluded
  * Note: in the absence of clinical symptoms of pancreatitis, elevations of amylase or lipase are not contraindications to therapy on this trial
* Known active infection with Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), or HIV. Cleared HBV/HCV infection is not an exclusion, nor is HIV infection with cluster of differentiations 4 (CD4) counts \>500 and an undetectable viral load.
* Active bacterial, viral, or fungal infections, requiring systemic therapy apart from anti-viral maintenance therapy for HIV.
* History of organ transplant.
* Patients requiring chronic systemic immunosuppressants, including steroids (prednisone daily equivalent of \>10 mg).
* Brain metastases that are clinically unstable (e.g. showing unequivocal growth on imaging, requiring radiation therapy, or steroids \>10mg of prednisone equivalent) within 4 weeks of first dose of study drug.
* Known severe congenital or acquired cellular or humoral immunodeficiency such as common variable immunodeficiency.
* For US sites: Women who are pregnant or breast-feeding currently or are planning to conceive during or up to 4 months after end of protocol therapy.
* For European sites: Women who are currently pregnant or breast-feeding or are planning to conceive during or up to 6 months after end of protocol therapy.

Primary outcomes:
measure: Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE).
timeFrame: 6 months
Secondary outcomes:
measure: Objective Response Rates by RECIST 1.1 and irRECIST.
timeFrame: 6 months
measure: Changes in Immune Cell Subsets in Tumor Tissue Before and After ONCOS-102 and Pembrolizumab.
timeFrame: 6 months
measure: Changes in Immune Cell Subsets in Peripheral Blood Before and After ONCOS-102 and Pembrolizumab.
timeFrame: 6 months
measure: Correlation of Tumour Infiltrating Lymphocytes (TILs) and Overall Response Rate (ORR).
timeFrame: 6 months
measure: Progression Free Survival (PFS) Assessed by RECIST 1.1 and irRECIST.
timeFrame: 6 months
measure: Clinical Benefit Rate, Defined as Any Confirmed Objective Response by RECIST 1.1 or Stable Disease.
timeFrame: 6 months
measure: Clinical Benefit Rate, Defined as Any Objective Response by irRECIST Criteria or Immune-related Stable Disease.
timeFrame: 6 months
measure: Change in Size in Individual Lesions.
timeFrame: 6 months
Other outcomes:
measure: Somatic Mutational Rate and Neoepitope Burden in Tumors and Explore Relationship to Response.
timeFrame: 6 months
measure: Changes in T Cell Receptor Clonality in Infiltrating and Circulating T Cells.
timeFrame: 6 months
measure: Gene Expression Changes in the Tumor Microenvironment and Peripheral Blood.
timeFrame: 6 months
Locations:
city: Baltimore
country: United States
facility: University of Maryland Comprehensive Cancer Center
state: Maryland
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Oslo
country: Norway
facility: Oslo University Hospital - The Norwegian Radium Hospital
Study officials:
References:
citation: Kuryk L, Moller AW, Jaderberg M. Combination of immunogenic oncolytic adenovirus ONCOS-102 with anti-PD-1 pembrolizumab exhibits synergistic antitumor effect in humanized A2058 melanoma huNOG mouse model. Oncoimmunology. 2018 Oct 29;8(2):e1532763. doi: 10.1080/2162402X.2018.1532763. eCollection 2019.