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

• ClinicalTrials.gov Identifier: NCT03003676
• Recruitment Status: Completed
• First Posted: December 28, 2016
• Results First Posted: August 9, 2021
• Last Update Posted: November 8, 2021
• Sponsor: Targovax Oy
• Information provided by (Responsible Party): Targovax ASA ( Targovax Oy )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Advanced or Unresectable Melanoma Progressing After PD1 Blockade	Biological: ONCOS-102; Drug: Cyclophosphamide; Drug: Pembrolizumab	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: December 2016
• Actual Primary Completion Date: July 2020
• Actual Study Completion Date: October 2020

Arms and Interventions

Arm

Intervention/treatment

Experimental: Experimental: ONCOS-102+cyclophosphamide+pembrolizumab; Part I: Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. They will then receive pembrolizumab i.v., 2mg/kg or 200mg flat dose, on day 22 (Week 3) and every 3 weeks thereafter until the end of treatment visit on day 169 (Week 24). Part II: Patients will receive 4 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, 8 and 15) at 3x10^11 viral particles (VP), preceded by intravenous (i.v.) cyclophosphamide priming 1-3 days prior to day 1. ONCOS-102 will be given in combination with Pembrolizumab starting on Day 22/Week 3 and every three weeks thereafter until Day 169/Week 24 or until unacceptable toxicity or clinically relevant disease progression, whichever occurs first. Pembrolizumab will be given according to institutional practice (2mg/kg or 200mg flat dose).

Biological: ONCOS-102; Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF); Drug: Cyclophosphamide; Pre-treatment; Drug: Pembrolizumab; PD1 blockade

Outcome Measures

Primary Outcome Measures :

1. Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). [ Time Frame: 6 months ]

Secondary Outcome Measures :

1. Objective Response Rates by RECIST 1.1 and irRECIST. [ Time Frame: 6 months ]
2. Changes in Immune Cell Subsets in Tumor Tissue Before and After ONCOS-102 and Pembrolizumab. [ Time Frame: 6 months ]
3. Changes in Immune Cell Subsets in Peripheral Blood Before and After ONCOS-102 and Pembrolizumab. [ Time Frame: 6 months ]
4. Correlation of Tumour Infiltrating Lymphocytes (TILs) and Overall Response Rate (ORR). [ Time Frame: 6 months ]
5. Progression Free Survival (PFS) Assessed by RECIST 1.1 and irRECIST. [ Time Frame: 6 months ]
6. Clinical Benefit Rate, Defined as Any Confirmed Objective Response by RECIST 1.1 or Stable Disease. [ Time Frame: 6 months ]
7. Clinical Benefit Rate, Defined as Any Objective Response by irRECIST Criteria or Immune-related Stable Disease. [ Time Frame: 6 months ]
8. Change in Size in Individual Lesions. [ Time Frame: 6 months ]

Other Outcome Measures:

1. Somatic Mutational Rate and Neoepitope Burden in Tumors and Explore Relationship to Response. [ Time Frame: 6 months ]
2. Changes in T Cell Receptor Clonality in Infiltrating and Circulating T Cells. [ Time Frame: 6 months ]
3. Gene Expression Changes in the Tumor Microenvironment and Peripheral Blood. [ Time Frame: 6 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Maryland

University of Maryland Comprehensive Cancer Center

Baltimore, Maryland, United States

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States

United States, Pennsylvania

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Norway

Oslo University Hospital - The Norwegian Radium Hospital

Oslo, Norway

Sponsors and Collaborators

Targovax Oy

  Study Documents (Full-Text)

Documents provided by Targovax ASA ( Targovax Oy ):

Study Protocol  [PDF] November 12, 2018

Statistical Analysis Plan  [PDF] August 25, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Targovax Oy
• ClinicalTrials.gov Identifier: NCT03003676
• Other Study ID Numbers: ONCOS C824
• First Posted: December 28, 2016
• Results First Posted: August 9, 2021
• Last Update Posted: November 8, 2021
• Last Verified: July 2021

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Cyclophosphamide; Pembrolizumab; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors