Trial Outcomes & Findings for Trial of Radiation and Gene Therapy Before Nivolumab for Metastatic Non-Small Cell Lung Carcinoma and Uveal Melanoma (NCT NCT02831933)
NCT ID: NCT02831933
Last Updated: 2023-09-21
Results Overview
Determine the ORR of ADV/HSV-tk plus Valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before nivolumab. Administration of ADV/HSV-tk + Valacyclovir in combination with SBRT before nivolumab represents a novel window of opportunity to enhance nivolumab efficacy by boosting endogenous immune-mediated antitumor activity and neoantigen expression. The concepts of the irRC are combined with RECIST 1.1 to come up with the modified irRC, which uses unidimensional measurements. For modified irRC, only target and measurable lesions are taken into account. The same assessment method and technique should be used to characterize each identified and reported target lesion(s) at baseline, during the trial, and at EOT. All measurements should be recorded in metric notation.
Recruitment status
TERMINATED
Study phase
PHASE2
Target enrollment
11 participants
Primary outcome timeframe
30 days after the last dose of nivolumab, up to 6 months
Results posted on
2023-09-21
Participant Flow
Recruitment was terminated early due to termination of funding by sponsor
Participant milestones
| Measure |
Experimental
ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on day 0 of the study.
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from day 1 to day 15 of the study.
SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from day 2 to day 16 of the study.
Nivolumab (480 mg) will be administered intravenously over 30 minutes every 4 weeks starting on day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 12 months in patients without disease progression.
ADV/HSV-tk: Replication-defective recombinant adenovirus vector
Valacyclovir: Prodrug of the antiviral drug acyclovir
SBRT: Low-dose SBRT
nivolumab: Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody
|
|---|---|
|
Overall Study
STARTED
|
11
|
|
Overall Study
COMPLETED
|
0
|
|
Overall Study
NOT COMPLETED
|
11
|
Reasons for withdrawal
| Measure |
Experimental
ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on day 0 of the study.
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from day 1 to day 15 of the study.
SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from day 2 to day 16 of the study.
Nivolumab (480 mg) will be administered intravenously over 30 minutes every 4 weeks starting on day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 12 months in patients without disease progression.
ADV/HSV-tk: Replication-defective recombinant adenovirus vector
Valacyclovir: Prodrug of the antiviral drug acyclovir
SBRT: Low-dose SBRT
nivolumab: Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody
|
|---|---|
|
Overall Study
Physician Decision
|
11
|
Baseline Characteristics
Trial of Radiation and Gene Therapy Before Nivolumab for Metastatic Non-Small Cell Lung Carcinoma and Uveal Melanoma
Baseline characteristics by cohort
| Measure |
Experimental
n=11 Participants
ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on day 0 of the study.
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from day 1 to day 15 of the study.
SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from day 2 to day 16 of the study.
Nivolumab (480 mg) will be administered intravenously over 30 minutes every 4 weeks starting on day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 12 months in patients without disease progression.
ADV/HSV-tk: Replication-defective recombinant adenovirus vector
Valacyclovir: Prodrug of the antiviral drug acyclovir
SBRT: Low-dose SBRT
nivolumab: Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody
|
|---|---|
|
Age, Continuous
|
68.77 years
n=5 Participants
|
|
Sex: Female, Male
Female
|
2 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
9 Participants
n=5 Participants
|
|
Race (NIH/OMB)
American Indian or Alaska Native
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Asian
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Black or African American
|
1 Participants
n=5 Participants
|
|
Race (NIH/OMB)
White
|
9 Participants
n=5 Participants
|
|
Race (NIH/OMB)
More than one race
|
0 Participants
n=5 Participants
|
|
Race (NIH/OMB)
Unknown or Not Reported
|
0 Participants
n=5 Participants
|
|
Primary Diagnosis
Non-Small Cell Lung Carcinoma
|
4 Participants
n=5 Participants
|
|
Primary Diagnosis
Uveal Melanoma
|
7 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 30 days after the last dose of nivolumab, up to 6 monthsDetermine the ORR of ADV/HSV-tk plus Valacyclovir therapy in combination with SBRT used as a window of opportunity treatment before nivolumab. Administration of ADV/HSV-tk + Valacyclovir in combination with SBRT before nivolumab represents a novel window of opportunity to enhance nivolumab efficacy by boosting endogenous immune-mediated antitumor activity and neoantigen expression. The concepts of the irRC are combined with RECIST 1.1 to come up with the modified irRC, which uses unidimensional measurements. For modified irRC, only target and measurable lesions are taken into account. The same assessment method and technique should be used to characterize each identified and reported target lesion(s) at baseline, during the trial, and at EOT. All measurements should be recorded in metric notation.
Outcome measures
| Measure |
Experimental
n=11 Participants
ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on day 0 of the study.
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from day 1 to day 15 of the study.
SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from day 2 to day 16 of the study.
Nivolumab (480 mg) will be administered intravenously over 30 minutes every 4 weeks starting on day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 12 months in patients without disease progression.
ADV/HSV-tk: Replication-defective recombinant adenovirus vector
Valacyclovir: Prodrug of the antiviral drug acyclovir
SBRT: Low-dose SBRT
nivolumab: Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody
|
|---|---|
|
Overall Response Rate (ORR)
Complete response (CR)
|
0 Participants
|
|
Overall Response Rate (ORR)
Partial response (PR)
|
0 Participants
|
|
Overall Response Rate (ORR)
Stable disease (SD)
|
0 Participants
|
|
Overall Response Rate (ORR)
Progressive disease (PD)
|
11 Participants
|
SECONDARY outcome
Timeframe: 30 days after the last dose of nivolumab, up to 6 monthsDetermine the OS rate. Months from start of treatment till date of death.
Outcome measures
| Measure |
Experimental
n=11 Participants
ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on day 0 of the study.
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from day 1 to day 15 of the study.
SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from day 2 to day 16 of the study.
Nivolumab (480 mg) will be administered intravenously over 30 minutes every 4 weeks starting on day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 12 months in patients without disease progression.
ADV/HSV-tk: Replication-defective recombinant adenovirus vector
Valacyclovir: Prodrug of the antiviral drug acyclovir
SBRT: Low-dose SBRT
nivolumab: Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody
|
|---|---|
|
Overall Survival (OS) Rate
|
15 Months
Interval 1.0 to 45.0
|
SECONDARY outcome
Timeframe: 30 days after the last dose of nivolumab, up to 6 monthsDetermine the Progression Free Survival (PFS) rate. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, using the smallest sum on study (includes the baseline sum) as the reference. In addition to the relative 20% increase, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression) Overall irPD: ≥ 20% increase in the sum of the longest diameters of target and new measurable lesions increases (compared to nadir), confirmed by a repeat, consecutive observation at least 6 weeks (normally it should be done at 8 weeks) from the date first documented. Documentation of immune-related PD (based on modified irRC) does not mandate discontinuation of the study treatment even after irPD is confirmed with CT scan 6 weeks after the initial observation of irPD.
Outcome measures
| Measure |
Experimental
n=11 Participants
ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on day 0 of the study.
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from day 1 to day 15 of the study.
SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from day 2 to day 16 of the study.
Nivolumab (480 mg) will be administered intravenously over 30 minutes every 4 weeks starting on day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 12 months in patients without disease progression.
ADV/HSV-tk: Replication-defective recombinant adenovirus vector
Valacyclovir: Prodrug of the antiviral drug acyclovir
SBRT: Low-dose SBRT
nivolumab: Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody
|
|---|---|
|
Progression Free Survival (PFS) Rate
|
0 Participants
|
SECONDARY outcome
Timeframe: 30 days after the last dose of nivolumab, up to 6 monthsEstimate the CBR as assessed by RECIST 1.1 and modified immune-related criteria
Outcome measures
| Measure |
Experimental
n=11 Participants
ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on day 0 of the study.
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from day 1 to day 15 of the study.
SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from day 2 to day 16 of the study.
Nivolumab (480 mg) will be administered intravenously over 30 minutes every 4 weeks starting on day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 12 months in patients without disease progression.
ADV/HSV-tk: Replication-defective recombinant adenovirus vector
Valacyclovir: Prodrug of the antiviral drug acyclovir
SBRT: Low-dose SBRT
nivolumab: Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody
|
|---|---|
|
Clinical Benefit Rate (CBR)
Partial response (PR)
|
0 Participants
|
|
Clinical Benefit Rate (CBR)
Stable disease (SD)
|
0 Participants
|
|
Clinical Benefit Rate (CBR)
Progressive disease (PD)
|
11 Participants
|
|
Clinical Benefit Rate (CBR)
Complete response (CR)
|
0 Participants
|
Adverse Events
Experimental
Serious events: 4 serious events
Other events: 11 other events
Deaths: 1 deaths
Serious adverse events
| Measure |
Experimental
n=11 participants at risk
ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on day 0 of the study.
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from day 1 to day 15 of the study.
SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from day 2 to day 16 of the study.
Nivolumab (480 mg) will be administered intravenously over 30 minutes every 4 weeks starting on day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 12 months in patients without disease progression.
ADV/HSV-tk: Replication-defective recombinant adenovirus vector
Valacyclovir: Prodrug of the antiviral drug acyclovir
SBRT: Low-dose SBRT
nivolumab: Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody
|
|---|---|
|
Respiratory, thoracic and mediastinal disorders
Pneumonia
|
18.2%
2/11 • Number of events 2 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Blood and lymphatic system disorders
Hypoglycemia
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Blood and lymphatic system disorders
non-traumatic intracranial hematoma
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Metabolism and nutrition disorders
Metabolic encephalopathy and dehydration
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
General disorders
Progression of disease that resulted in Death
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Cardiac disorders
Atrial fibrillation
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory Failure
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Respiratory, thoracic and mediastinal disorders
Pleural Effusion
|
9.1%
1/11 • Number of events 3 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
Other adverse events
| Measure |
Experimental
n=11 participants at risk
ADV/HSV-tk (5 x 1011 viral particles) in a 2-mL total volume will be injected intratumorally on day 0 of the study.
Valacyclovir will be orally administered at a dose of 2 g three times daily for 14 days. Valacyclovir treatment will be administered 24 hours after the gene vector injection from day 1 to day 15 of the study.
SBRT of 30 gray (Gy; 6 Gy X 5 fractions) will be administered over 2 weeks from day 2 to day 16 of the study.
Nivolumab (480 mg) will be administered intravenously over 30 minutes every 4 weeks starting on day 17 of the study and continuing until disease progression, unacceptable toxicity, or up to 12 months in patients without disease progression.
ADV/HSV-tk: Replication-defective recombinant adenovirus vector
Valacyclovir: Prodrug of the antiviral drug acyclovir
SBRT: Low-dose SBRT
nivolumab: Fully human immunoglobulin (Ig) G4 anti-PD-1 monoclonal antibody
|
|---|---|
|
Metabolism and nutrition disorders
Weight loss
|
27.3%
3/11 • Number of events 3 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
36.4%
4/11 • Number of events 4 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
General disorders
Dyspnea
|
18.2%
2/11 • Number of events 2 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Metabolism and nutrition disorders
Hypoglycemia
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Respiratory, thoracic and mediastinal disorders
Pneumonia
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Gastrointestinal disorders
Abdominal Pain
|
18.2%
2/11 • Number of events 2 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
General disorders
Chills
|
9.1%
1/11 • Number of events 3 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Gastrointestinal disorders
Constipation
|
18.2%
2/11 • Number of events 2 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Gastrointestinal disorders
Nausea
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
General disorders
Dehydration
|
27.3%
3/11 • Number of events 3 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Cardiac disorders
Bradycardia
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Psychiatric disorders
Confusion
|
27.3%
3/11 • Number of events 3 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Blood and lymphatic system disorders
Hyponatremia
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Gastrointestinal disorders
Gastroesophageal reflux disease
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Metabolism and nutrition disorders
Anorexia
|
27.3%
3/11 • Number of events 3 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Cardiac disorders
Atrial fibrillation
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Psychiatric disorders
Anxiety
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Musculoskeletal and connective tissue disorders
Arthritic pain
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Musculoskeletal and connective tissue disorders
Back pain
|
27.3%
3/11 • Number of events 3 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Respiratory, thoracic and mediastinal disorders
Bronchitis
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Eye disorders
Cataract surgery
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Cardiac disorders
Chest palpitations
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Psychiatric disorders
Depression
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Nervous system disorders
Dizziness
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Gastrointestinal disorders
Dysphagia
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
General disorders
Fatigue
|
54.5%
6/11 • Number of events 6 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
General disorders
Hypokalemia
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Musculoskeletal and connective tissue disorders
Inguinal pain
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
General disorders
Intractable itchiness
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Metabolism and nutrition disorders
Loss of appetite
|
27.3%
3/11 • Number of events 3 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Cardiac disorders
Migratory chest pain
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Respiratory, thoracic and mediastinal disorders
Hemoptysis
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Skin and subcutaneous tissue disorders
Psoriasiform dermatitis
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
General disorders
Night sweats
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Nervous system disorders
Sleep disturbance
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory failure
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
Skin and subcutaneous tissue disorders
Rash
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
|
General disorders
Nasal discharge
|
9.1%
1/11 • Number of events 1 • From informed consent signing up to and including 30 days after the last treatment dose of Nivolumab.
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place