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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

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ClinicalTrials.gov Identifier: NCT03003676
Recruitment Status : Recruiting
First Posted : December 28, 2016
Last Update Posted : October 25, 2018
Sponsor:
Information provided by (Responsible Party):
Targovax ASA ( Targovax Oy )

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: prior PD1 monotherapy or prior PD1 plus ipilimumab given sequentially or concomitantly.

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
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
Estimated Primary Completion Date : June 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Experimental: ONCOS-102+cyclophosphamide+pembrolizumab
Patients will receive 3 doses of intratumoral (i.t.) injection of ONCOS-102 (days 1, 4, and 8) at 3x1011 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).
Biological: ONCOS-102
Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)

Drug: Cyclophosphamide
Pre-treatment

Drug: Pembrolizumab
PD1 blockade




Primary Outcome Measures :
  1. Safety of sequential treatment with ONCOS-102 followed by pembrolizumab by assessment of laboratory parameters (routine haematology and biochemistry), vital signs and recording of adverse events. [ 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 ]


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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.
  • 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.
  • 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.
  • 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.

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.
  • Receipt of Investigational agents within 28 days prior to first dose of protocol therapy.
  • 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.
  • Women who are pregnant or breast-feeding currently or are planning to do so during or up to 3 months after the end of protocol therapy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03003676


Contacts
Contact: Karianne Risberg Handeland, PhD +4790030831 karianne.risberg.handeland@targovax.com
Contact: Magnus Jäderberg, MD +447791443820 magnus.jaderberg@targovax.com

Locations
United States, Maryland
University of Maryland Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States
Contact: Thomas Hornyak, MD         
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States
Contact: Alexander Shoushtari, MD         
United States, Pennsylvania
Fox Chase Cancer Center Recruiting
Philadelphia, Pennsylvania, United States
Contact: Olzanski Anthony, MD         
Sponsors and Collaborators
Targovax Oy

Responsible Party: Targovax Oy
ClinicalTrials.gov Identifier: NCT03003676     History of Changes
Other Study ID Numbers: ONCOS C824
First Posted: December 28, 2016    Key Record Dates
Last Update Posted: October 25, 2018
Last Verified: October 2018

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