Advanced or Unresectable Melanoma Progressing After PD1 Blockade
Conditions
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.
Interventions
BIOLOGICALONCOS-102
Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)
DRUGCyclophosphamide
Pre-treatment
DRUGPembrolizumab
PD1 blockade
Sponsors
Targovax Oy
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | 6 months |
Secondary
| Measure | Time frame |
|---|---|
| Changes in Immune Cell Subsets in Tumor Tissue Before and After ONCOS-102 and Pembrolizumab. | 6 months |
| Changes in Immune Cell Subsets in Peripheral Blood Before and After ONCOS-102 and Pembrolizumab. | 6 months |
| Correlation of Tumour Infiltrating Lymphocytes (TILs) and Overall Response Rate (ORR). | 6 months |
| Progression Free Survival (PFS) Assessed by RECIST 1.1 and irRECIST. | 6 months |
| Clinical Benefit Rate, Defined as Any Confirmed Objective Response by RECIST 1.1 or Stable Disease. | 6 months |
| Objective Response Rates by RECIST 1.1 and irRECIST. | 6 months |
| Change in Size in Individual Lesions. | 6 months |
| Clinical Benefit Rate, Defined as Any Objective Response by irRECIST Criteria or Immune-related Stable Disease. | 6 months |
Other
| Measure | Time frame |
|---|---|
| Changes in T Cell Receptor Clonality in Infiltrating and Circulating T Cells. | 6 months |
| Gene Expression Changes in the Tumor Microenvironment and Peripheral Blood. | 6 months |
| Somatic Mutational Rate and Neoepitope Burden in Tumors and Explore Relationship to Response. | 6 months |
Countries
Norway, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 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).
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)
Cyclophosphamide: Pre-treatment
Pembrolizumab: PD1 blockade | 9 |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 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).
ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)
Cyclophosphamide: Pre-treatment
Pembrolizumab: PD1 blockade | 12 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Hepatitis B infection | 1 | 0 |
| Overall Study | Lack of Efficacy | 5 | 7 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 | Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 6 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 6 Participants | 8 Participants |
| Age, Continuous | 69.1 years STANDARD_DEVIATION 13.68 | 67.3 years STANDARD_DEVIATION 13.5 | 68.1 years STANDARD_DEVIATION 13.26 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 11 Participants | 19 Participants |
| Region of Enrollment Norway | 1 participants | 2 participants | 3 participants |
| Region of Enrollment United States | 8 participants | 10 participants | 18 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 12 |
| other Total, other adverse events | 9 / 9 | 12 / 12 |
| serious Total, serious adverse events | 4 / 9 | 2 / 12 |
Outcome results
Primary
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients with Treatment Emergent Adverse Event (TEAE) | 9 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients with Treatment Emergent Adverse Serious Event (TESAE) | 4 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients with Grade 3 or 4 Treatment Emergent Adverse Event (TEAE) | 5 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients with Treatment Emergent Adverse Event related to any of the study treatments | 8 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients with fatal events | 0 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients discontinuing for Adverse Events | 0 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients with fatal events | 0 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients with Treatment Emergent Adverse Event (TEAE) | 12 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients with Treatment Emergent Adverse Event related to any of the study treatments | 11 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients with Treatment Emergent Adverse Serious Event (TESAE) | 2 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients discontinuing for Adverse Events | 1 participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 | Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE). | Number of patients with Grade 3 or 4 Treatment Emergent Adverse Event (TEAE) | 4 participants |
Secondary
Change in Size in Individual Lesions.
Time frame: 6 months
Secondary
Changes in Immune Cell Subsets in Peripheral Blood Before and After ONCOS-102 and Pembrolizumab.
Time frame: 6 months
Secondary
Changes in Immune Cell Subsets in Tumor Tissue Before and After ONCOS-102 and Pembrolizumab.
Time frame: 6 months
Secondary
Clinical Benefit Rate, Defined as Any Confirmed Objective Response by RECIST 1.1 or Stable Disease.
Time frame: 6 months
Secondary
Clinical Benefit Rate, Defined as Any Objective Response by irRECIST Criteria or Immune-related Stable Disease.
Time frame: 6 months
Secondary
Correlation of Tumour Infiltrating Lymphocytes (TILs) and Overall Response Rate (ORR).
Time frame: 6 months
Secondary
Objective Response Rates by RECIST 1.1 and irRECIST.
Time frame: 6 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 | Objective Response Rates by RECIST 1.1 and irRECIST. | Number of patient with Complete Response or Partial Response | 3 Participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 | Objective Response Rates by RECIST 1.1 and irRECIST. | Number of patients with Stable Disease or Progressive Disease | 5 Participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 | Objective Response Rates by RECIST 1.1 and irRECIST. | Number of patient with Complete Response or Partial Response | 4 Participants |
| Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 | Objective Response Rates by RECIST 1.1 and irRECIST. | Number of patients with Stable Disease or Progressive Disease | 8 Participants |
Secondary
Progression Free Survival (PFS) Assessed by RECIST 1.1 and irRECIST.
Time frame: 6 months
Other Pre-specified
Changes in T Cell Receptor Clonality in Infiltrating and Circulating T Cells.
Time frame: 6 months
Other Pre-specified
Gene Expression Changes in the Tumor Microenvironment and Peripheral Blood.
Time frame: 6 months
Other Pre-specified
Somatic Mutational Rate and Neoepitope Burden in Tumors and Explore Relationship to Response.
Time frame: 6 months