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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 : Completed
First Posted : December 28, 2016
Results First Posted : August 9, 2021
Last Update Posted : November 8, 2021
Sponsor:
Information provided by (Responsible Party):
Targovax ASA ( Targovax Oy )

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Advanced or Unresectable Melanoma Progressing After PD1 Blockade
Interventions Biological: ONCOS-102
Drug: Cyclophosphamide
Drug: Pembrolizumab
Enrollment 21
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab - Part 1 Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab - Part 2
Hide Arm/Group Description

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 receive pembrolizumab i.v., 2mg/kg or 200 mg flat dose on day 22 (Week 3) and every three weeks thereafter until Day 169/Week 24.

ONCOS-102: Engineered oncolytic adenovirus expressing Granulocyte-macrophage colony stimulating factor (GM-CSF)

Cyclophosphamide: Pre-treatment

Pembrolizumab: PD1 blockade

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

Period Title: Overall Study
Started 9 12
Completed 3 4
Not Completed 6 8
Reason Not Completed
Lack of Efficacy             5             7
Withdrawal by Subject             0             1
Hepatitis B infection             1             0
Arm/Group Title Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2 Total
Hide Arm/Group Description

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

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

Total of all reporting groups
Overall Number of Baseline Participants 9 12 21
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 12 participants 21 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
2
  22.2%
6
  50.0%
8
  38.1%
>=65 years
7
  77.8%
6
  50.0%
13
  61.9%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 9 participants 12 participants 21 participants
69.1  (13.68) 67.3  (13.50) 68.1  (13.26)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 12 participants 21 participants
Female
4
  44.4%
6
  50.0%
10
  47.6%
Male
5
  55.6%
6
  50.0%
11
  52.4%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 9 participants 12 participants 21 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
1
   8.3%
1
   4.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
  11.1%
0
   0.0%
1
   4.8%
White
8
  88.9%
11
  91.7%
19
  90.5%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 9 participants 12 participants 21 participants
United States 8 10 18
Norway 1 2 3
1.Primary Outcome
Title Incidence of Treatment-emergent Adverse Events Including Treatment-emergent Serious Adverse Events Assessed by Common Terminology Criteria for Adverse Events (CTCAE).
Hide Description [Not Specified]
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2
Hide Arm/Group Description:

Part I1 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

Part 2: 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

Overall Number of Participants Analyzed 9 12
Measure Type: Number
Unit of Measure: participants
Number of patients with Treatment Emergent Adverse Event (TEAE) 9 12
Number of patients with Treatment Emergent Adverse Serious Event (TESAE) 4 2
Number of patients with Grade 3 or 4 Treatment Emergent Adverse Event (TEAE) 5 4
Number of patients with Treatment Emergent Adverse Event related to any of the study treatments 8 11
Number of patients with fatal events 0 0
Number of patients discontinuing for Adverse Events 0 1
2.Secondary Outcome
Title Objective Response Rates by RECIST 1.1 and irRECIST.
Hide Description [Not Specified]
Time Frame 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Part 1 Part 2
Hide Arm/Group Description:

Part 1: 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

Part 2: 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

Overall Number of Participants Analyzed 8 12
Measure Type: Count of Participants
Unit of Measure: Participants
Number of patient with Complete Response or Partial Response
3
  37.5%
4
  33.3%
Number of patients with Stable Disease or Progressive Disease
5
  62.5%
8
  66.7%
3.Secondary Outcome
Title Changes in Immune Cell Subsets in Tumor Tissue Before and After ONCOS-102 and Pembrolizumab.
Hide Description [Not Specified]
Time Frame 6 months
Outcome Measure Data Not Reported
4.Secondary Outcome
Title Changes in Immune Cell Subsets in Peripheral Blood Before and After ONCOS-102 and Pembrolizumab.
Hide Description [Not Specified]
Time Frame 6 months
Outcome Measure Data Not Reported
5.Secondary Outcome
Title Correlation of Tumour Infiltrating Lymphocytes (TILs) and Overall Response Rate (ORR).
Hide Description [Not Specified]
Time Frame 6 months
Outcome Measure Data Not Reported
6.Secondary Outcome
Title Progression Free Survival (PFS) Assessed by RECIST 1.1 and irRECIST.
Hide Description [Not Specified]
Time Frame 6 months
Outcome Measure Data Not Reported
7.Secondary Outcome
Title Clinical Benefit Rate, Defined as Any Confirmed Objective Response by RECIST 1.1 or Stable Disease.
Hide Description [Not Specified]
Time Frame 6 months
Outcome Measure Data Not Reported
8.Secondary Outcome
Title Clinical Benefit Rate, Defined as Any Objective Response by irRECIST Criteria or Immune-related Stable Disease.
Hide Description [Not Specified]
Time Frame 6 months
Outcome Measure Data Not Reported
9.Secondary Outcome
Title Change in Size in Individual Lesions.
Hide Description [Not Specified]
Time Frame 6 months
Outcome Measure Data Not Reported
10.Other Pre-specified Outcome
Title Somatic Mutational Rate and Neoepitope Burden in Tumors and Explore Relationship to Response.
Hide Description [Not Specified]
Time Frame 6 months
Outcome Measure Data Not Reported
11.Other Pre-specified Outcome
Title Changes in T Cell Receptor Clonality in Infiltrating and Circulating T Cells.
Hide Description [Not Specified]
Time Frame 6 months
Outcome Measure Data Not Reported
12.Other Pre-specified Outcome
Title Gene Expression Changes in the Tumor Microenvironment and Peripheral Blood.
Hide Description [Not Specified]
Time Frame 6 months
Outcome Measure Data Not Reported
Time Frame 27 weeks
Adverse Event Reporting Description Adverse events were reported according to NCI CTCAE vs 5.0
 
Arm/Group Title Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2
Hide Arm/Group Description

Part 1: 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

Part 2: 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

All-Cause Mortality
Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2
Affected / at Risk (%) Affected / at Risk (%)
Total   0/9 (0.00%)      0/12 (0.00%)    
Hide Serious Adverse Events
Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/9 (44.44%)      2/12 (16.67%)    
Blood and lymphatic system disorders     
Haemolytic anaemia * 1  1/9 (11.11%)  1 0/12 (0.00%)  0
Gastrointestinal disorders     
Abdominal pain * 1  0/9 (0.00%)  0 1/12 (8.33%)  1
Diarrhoea * 2  1/9 (11.11%)  1 0/12 (0.00%)  0
Enterocolitis * 2  0/9 (0.00%)  0 1/12 (8.33%)  1
General disorders     
Non-cardiac chest pain * 2  0/9 (0.00%)  0 1/12 (8.33%)  1
Pyrexia * 2  0/9 (0.00%)  0 2/12 (16.67%)  4
Infections and infestations     
Large intestine infection * 1  1/9 (11.11%)  1 0/12 (0.00%)  0
Pneumonia * 2  1/9 (11.11%)  1 0/12 (0.00%)  0
Staphylococcal infection * 1  1/9 (11.11%)  1 0/12 (0.00%)  0
Investigations     
Blood bilirubin increased * 2  1/9 (11.11%)  1 0/12 (0.00%)  0
Metabolism and nutrition disorders     
Diabetic ketoacidosis * 2  1/9 (11.11%)  1 0/12 (0.00%)  0
Hyponatraemia * 2  1/9 (11.11%)  1 0/12 (0.00%)  0
Type 1 diabetes mellitus * 2  1/9 (11.11%)  1 0/12 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Muscular weakness * 2  1/9 (11.11%)  1 0/12 (0.00%)  0
Nervous system disorders     
Syncope * 2  0/9 (0.00%)  0 1/12 (8.33%)  2
Respiratory, thoracic and mediastinal disorders     
Cough * 2  0/9 (0.00%)  0 1/12 (8.33%)  1
Dyspnoea * 2  0/9 (0.00%)  0 1/12 (8.33%)  1
Pneumothorax * 2  1/9 (11.11%)  1 0/12 (0.00%)  0
1
Term from vocabulary, MedDRA
2
Term from vocabulary, MedDRA, CTCAE v5.0
*
Indicates events were collected by non-systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 1 Experimental: ONCOS-102+Cyclophosphamide+Pembrolizumab Part 2
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   9/9 (100.00%)      12/12 (100.00%)    
Blood and lymphatic system disorders     
Anaemia * 1  2/9 (22.22%)  2 3/12 (25.00%)  4
Gastrointestinal disorders     
Abdominal distension * 2  1/9 (11.11%)  1 1/12 (8.33%)  1
Abdominal pain * 2  1/9 (11.11%)  1 2/12 (16.67%)  2
Constipation * 2  1/9 (11.11%)  2 3/12 (25.00%)  3
Diarrhoea * 2  4/9 (44.44%)  8 1/12 (8.33%)  1
Nausea * 2  3/9 (33.33%)  3 4/12 (33.33%)  9
Vomiting * 2  2/9 (22.22%)  2 3/12 (25.00%)  3
General disorders     
Chills * 2  5/9 (55.56%)  8 4/12 (33.33%)  15
Fatigue * 1  3/9 (33.33%)  3 3/12 (25.00%)  3
Injection site pain * 2  1/9 (11.11%)  2 3/12 (25.00%)  4
Injection site reaction * 2  0/9 (0.00%)  0 3/12 (25.00%)  3
Malaise * 2  2/9 (22.22%)  2 0/12 (0.00%)  0
Oedema peripheral * 2  2/9 (22.22%)  3 1/12 (8.33%)  2
Pain * 2  0/9 (0.00%)  0 2/12 (16.67%)  2
Pyrexia * 2  3/9 (33.33%)  7 7/12 (58.33%)  23
Infections and infestations     
Urinary tract infection * 2  2/9 (22.22%)  3 1/12 (8.33%)  1
Investigations     
Alanine aminotransferase increased * 2  4/9 (44.44%)  5 3/12 (25.00%)  5
Aspartate aminotransferase increased * 2  2/9 (22.22%)  8 3/12 (25.00%)  6
Blood alkaline phosphatase increased * 2  0/9 (0.00%)  0 3/12 (25.00%)  4
Weight decreased * 2  1/9 (11.11%)  1 1/12 (8.33%)  1
White blood cell count decreased * 1  1/9 (11.11%)  1 1/12 (8.33%)  4
Blood bilirubin increased * 1  2/9 (22.22%)  2 0/12 (0.00%)  0
Metabolism and nutrition disorders     
Hypoalbuminaemia * 2  2/9 (22.22%)  3 2/12 (16.67%)  3
Hyponatraemia * 2  1/9 (11.11%)  2 2/12 (16.67%)  2
Musculoskeletal and connective tissue disorders     
Back pain * 2  2/9 (22.22%)  2 1/12 (8.33%)  1
Myalgia * 2  3/9 (33.33%)  6 0/12 (0.00%)  0
Muscular weakness * 2  2/9 (22.22%)  2 0/12 (0.00%)  0
Nervous system disorders     
Dizziness * 2  0/9 (0.00%)  0 2/12 (16.67%)  2
Headache * 2  3/9 (33.33%)  6 0/12 (0.00%)  0
Renal and urinary disorders     
Pollakisuria * 2  1/9 (11.11%)  1 1/12 (8.33%)  1
Respiratory, thoracic and mediastinal disorders     
Cough * 2  1/9 (11.11%)  1 2/12 (16.67%)  2
Dyspnoea * 2  1/9 (11.11%)  2 3/12 (25.00%)  3
Hiccups * 2  1/9 (11.11%)  1 1/12 (8.33%)  1
Nasal congestion * 2  3/9 (33.33%)  3 0/12 (0.00%)  0
Oropharyngeal pain * 2  1/9 (11.11%)  1 1/12 (8.33%)  1
Skin and subcutaneous tissue disorders     
Dermatitis bullous * 2  0/9 (0.00%)  0 2/12 (16.67%)  2
Dry skin * 2  0/9 (0.00%)  0 2/12 (16.67%)  2
Pruritus * 2  3/9 (33.33%)  4 4/12 (33.33%)  4
Rash * 2  2/9 (22.22%)  3 1/12 (8.33%)  1
Rash maculo-papular * 2  2/9 (22.22%)  2 3/12 (25.00%)  4
Vascular disorders     
Embolism * 2  1/9 (11.11%)  1 1/12 (8.33%)  1
Hypertension * 2  5/9 (55.56%)  7 4/12 (33.33%)  5
Hypotension * 1  0/9 (0.00%)  0 2/12 (16.67%)  2
1
Term from vocabulary, MedDRA
2
Term from vocabulary, MedDRA, CTCAE v5.0
*
Indicates events were collected by non-systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Dr. Lone H. Ottesen, Chief Development Officer
Organization: Targovax
Phone: +44 7920567911
EMail: lone.ottesen@targovax.com
Layout table for additonal information
Responsible Party: Targovax ASA ( Targovax Oy )
ClinicalTrials.gov Identifier: NCT03003676    
Other Study ID Numbers: ONCOS C824
First Submitted: December 19, 2016
First Posted: December 28, 2016
Results First Submitted: July 16, 2021
Results First Posted: August 9, 2021
Last Update Posted: November 8, 2021