Melanoma Stage IIIPhase 2NIVECNCT04330430
Neo-adjuvant T-VEC + Nivolumab Combination Therapy for Resectable Early Metastatic (stage IIIB/C/D-IV M1a) Melanoma with Injectable Disease
A Phase 2 study testing T-VEC in people with Melanoma Stage III and Melanoma Stage IV, run by The Netherlands Cancer Institute at 1 site in Netherlands.
Trial summary
Currently, standard treatment options available for Stage III melanoma include locoregional management (i.e. surgery) or systemic treatment (adjuvant to surgery or primarily in the case of unresectable disease). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma Stage III, Melanoma Stage IV
- What is being tested?
- T-VEC
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteNetherlands
- Study dates
- 8 Sep 2020to 29 Jan 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adults at least 18 years of age
- WHO performance score of 0 or 1
- Cytologically or histologically confirmed diagnosis of stage IIIB/C/D/IVM1a (AJCC 8th edition) melanoma, eligible for surgical resection.
- Subjects must have measurable disease according to RECIST 1.1 and must be a candidate for intralesional therapy with at least one injectable cutaneous, subcutane-ous or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
- Prior isolated limb perfusion (ILP) is allowed (≥ 12 weeks prior to enrolment)
- Screening laboratory values must meet the following criteria:
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- WBC ≥ 2.0x10^9/L, Neutrophils ≥1.5x10^9/L, Platelets ≥100 x10^9/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN
- LDH < 2 x ULN
- Women of childbearing potential (WOCBP) must use highly effective method(s) of contraception (see paragraph 5.2) during T-VEC and nivolumab treatment and for a period of 5 months after the last dose of nivolumab.
- Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to enrollment and within 24 hours prior to the start of Nivolumab
- Men receiving nivolumab and who are sexually active with WOCBP should use contraception during treatment and for a period of 7 months after the last dose of nivolumab
- Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year.
- Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception
- Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document.
- Inhaled or topical steroids, and adrenal replacement steroid < 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
- International normalization ratio (INR) or prothrombin time (PT) ≤1.5 x ULN, unless the subject is receiving anticoagulant therapy, in which case PT and partial thrombo-plastin time (PTT)/ activated PTT (aPTT) must be within therapeutic range of intended use of anticoagulants.
Who cannot join
- Liver, Bone, Lung, Brain or other Visceral Metastases.
- No measurable lesion according to RECIST 1.1
- Prior radiotherapy for melanoma
- Prior systemic cancer therapies, including, but not limited to anti-CTLA-4, anti-PD-1, anti-PD-L1
- No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years.
- Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection
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- Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- History or evidence of active autoimmune disease that requires high dose systemic treatment (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic cortico-steroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Evidence of clinically significant immunosuppression such as the following:
- Primary immunodeficiency state such as Severe Combined Immunodeficiency Dis-ease.
- Concurrent opportunistic infection.
- Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 7 days prior to enrollment
- Active herpetic skin lesions or prior complications of HSV-1 infection (e.g., herpetic keratitis or encephalitis).
- Requirement of intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic drug (e.g., acyclovir), other than intermittent topical use.
- Previous treatment with talimogene laherparepvec or any other oncolytic virus.
- Received live vaccine within 30 days prior to enrollment.
- Subject has known sensitivity to talimogene laherparepvec or nivolumab or any of its components to be administered during dosing.
- Female subject of childbearing potential who is unwilling to use highly effective meth-od(s) of effective contraception during study treatment and through 5 months after the last dose of study medication (per protocol through 3 months after the last dose of talimogene laherparepvec and through 5 months after the last dose of nivolumab).
- Sexually active subjects and their partners unwilling to use male or female latex condom to avoid potential viral transmission during sexual contact while on treatment and within 30 days after treatment with talimogene laherparepvec.
- Subjects who are unwilling to minimize exposure with his/her blood or other body flu-ids to individuals who are at higher risks for HSV-1 induced complications such as immunosuppressed individuals, individuals known to have HIV infection, pregnant women, or infants under the age of 3 months, during talimogene laherparepvec treatment and through 30 days after the last dose of talimogene laherparepvec.
- No Allergies and Adverse Drug Reaction
- History of allergy to study drug components
- History of severe hypersensitivity reaction to any monoclonal antibody
- No underlying medical conditions that, in the Investigator's opinion, will make the ad-ministration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events;
- No use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion
Trial locations and contacts
1 site in 1 country.
Netherlands1 site
Antoni van Leeuwenhoek ziekenhuis
Amsterdam, North Holland, 1066CX
About this study
Currently, standard treatment options available for Stage III melanoma include locoregional management (i.e. surgery) or systemic treatment (adjuvant to surgery or primarily in the case of unresectable disease).
Adjuvant treatment options have shown major improvements in overall survival (OS) and relapse free survival (RFS) in resected stage III or IV melanoma.
Read more
In daily practice, T-VEC monotherapy is used for unresectable Stage IIIB-IVM1a (injectable) disease, whereas Nivolumab is used for stage IV melanoma (among other systemic therapies).
The next major developments are in neo-adjuvant treatment options for resectable stage III disease, where 3 small studies reported high response rates with systemic immunotherapy.
This study evaluates the combination treatment of T-VEC + Nivolumab in the neo-adjuvant setting. The concept is that T-VEC can turn an immune desolate "cold" tumor into an immunogenic "hot" tumor. The hypothesis is that this will upregulate the expression of PD-L1 and make it more susceptible for treatment with an anti-PD-1 agent. The investigators believe neo-adjuvant Nivolumab + T-VEC will thus change the tumor microenvironment in patients with stage IIIB/C/D/IVM1a (AJCC 8) melanoma with resectable cutaneous or subcutaneous satellite or in-transit metastases (ITM) and/or tumor positive lymph nodes. With this trial the investigators aim to determine safety and feasibility of combination neo-adjuvant Nivolumab + T-VEC in patients with stage III melanoma with resectable ITM and/or tumor positive lymph nodes. The treatment schedule is based on 4 courses of intralesional T-VEC and 3 courses of intravenous Nivolumab. T-VEC first, in order to achieve the best synergistic effect with influx of CD8+ T cells prior to the first Nivolumab dose. T-VEC monotherapy with the dose 108 PFU/mL is given every 2 weeks (± 3) days after 3 weeks of the first T-VEC dose (with the first dose of T-VEC 106 PFU/mL to allow for seroconversion) , and Nivolumab can be given either every 2 weeks or every 4 weeks. Therefore we suggest the same dosing schedule for T-VEC and Nivolumab every 2 weeks for the purpose of this trial.
- Conditions
- Melanoma Stage III, Melanoma Stage IV
- Being tested
- T-VEC
- Keywords
- Melanoma, Neo-adjuvant, T-VEC, Nivolumab
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
T-VECDrug
Also called Nivolumab
The treatment schedule is based on 4 courses of intralesional T-VEC and 3 courses of intraveneous Nivolumab. T-VEC first, in order to achieve the best synergistic effect with influx of CD8+ T-cells prior to the first Nivolumab dose. T-VEC monotherapy with the dose 10^8 PFU/mL is given every 2 weeks after 3 weeks of the first T-VEC dose (with the first dose of T-VEC 10^6 PFU/mL to allow for seroconversion), and Nivolumab will be given every 2 weeks.
| Study group | Role | What they receive |
|---|---|---|
| T-VEC + Nivolumab | Experimental | Patients will receive pre-surgically 4 courses T-VEC (up to 4ml; first dose 10^6 PFU per mL, subsequent doses at 10^8 PFU per mL). Patients will also receive a flatdose of 240mg Nivolumab every 2 weeks after the first T-VEC injections (starting at 2nd T-VEC course at week 3, followed by the next doses at week 5 and 7). Receives: Drug: T-VEC |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pathologic response
Pathologic response according to central revision by pathology of NKI (complete response, near complete response (<10% vital tumor remaining)
Measured: 12 weeks
Secondary outcomes (8)
Rate of delay of surgery > 14 days
Measured: 9 weeks
Rate of failure to perform surgery defined as no surgery at all (due to progressive disease or adverse events)
Measured: 9 weeks
Relapse free survival (RFS)
Relapse free survival as defined from date of surgery until date of first relapse (regardless of site)
Measured: Up to 2 years after treatment
Safety of neo-adjuvant combination of T-VEC and nivolumab according to CTCAE v5.0
Measured: 12 weeks
Acquiring tumor tissue
The objective is to acquire tumor tissue for prognostic biomarker research, for example CD8
Measured: Up to 2 years after treatment
Acquiring tumor tissue
The objective is to acquire tumor tissue for prognostic biomarker research, for example IFN-γ
Measured: Up to 2 years after treatment
Acquiring tumor tissue
The objective is to acquire tumor tissue for prognostic biomarker research, for example PD-L1
Measured: Up to 2 years after treatment
Acquiring tumor tissue
The objective is to acquire tumor tissue for exploration of expansion of tumor-resident T cells in the tumor
Measured: Up to 2 years after treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Apr 2020
- Study start8 Sep 2020
- Primary completion9 Apr 2023
- Study completion29 Jan 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Melanoma Stage IIIStudies of the same condition, open and under way.
- More trials run by The Netherlands Cancer InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Netherlands Cancer Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Amgen
- Responsible party
- Sponsor
- Investigators
- John Haanen, Prof., Principal investigator, Medical oncologist/researcher
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04330430
- Sponsor's protocol ID
- N19TVN
- Acronym
- NIVEC
- Status last verified
- Mar 2025
- First submitted
- 13 Feb 2020
- Last updated
- 12 Mar 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Rohaan MW, Stahlie EHA, Franke V, Zijlker LP, Wilgenhof S, van der Noort V, van Akkooi ACJ, Haanen JBAG. Neoadjuvant nivolumab + T-VEC combination therapy for resectable early stage or metastatic (IIIB-IVM1a) melanoma with injectable disease: study protocol of the NIVEC trial. BMC Cancer. 2022 Aug 4;22(1):851. doi: 10.1186/s12885-022-09896-4.
PubMed 35927710
Study at a glance
From the registry record, last updated by the sponsor on 12 Mar 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Neo-adjuvant T-VEC + Nivolumab Combination Therapy for Resectable Early Metastatic (stage IIIB/C/D-IV M1a) Melanoma with Injectable Disease
- ClinicalTrials.gov ID
- NCT04330430
- Acronym / sponsor ID
- NIVEC / N19TVN
- Conditions
- Melanoma Stage III, Melanoma Stage IV
- Keywords
- Melanoma, Neo-adjuvant, T-VEC, Nivolumab
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- The Netherlands Cancer InstituteUniversity, hospital or other
- Collaborators
- Amgen
- Study start
- 8 Sep 2020 (actual)
- Primary completion
- 9 Apr 2023 (actual)
- Study completion
- 29 Jan 2025 (actual)
- First posted
- 1 Apr 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Currently, standard treatment options available for Stage III melanoma include locoregional management (i.e. surgery) or systemic treatment (adjuvant to surgery or primarily in the case of unresectable disease).
Adjuvant treatment options have shown major improvements in overall survival (OS) and relapse free survival (RFS) in resected stage III or IV melanoma.
In daily practice, T-VEC monotherapy is used for unresectable Stage IIIB-IVM1a (injectable) disease, whereas Nivolumab is used for stage IV melanoma (among other systemic therapies).
The next major developments are in neo-adjuvant treatment options for resectable stage III disease, where 3 small studies reported high response rates with systemic immunotherapy.
This study evaluates the combination treatment of T-VEC + Nivolumab in the neo-adjuvant setting. The concept is that T-VEC can turn an immune desolate "cold" tumor into an immunogenic "hot" tumor. The hypothesis is that this will upregulate the expression of PD-L1 and make it more susceptible for treatment with an anti-PD-1 agent. The investigators believe neo-adjuvant Nivolumab + T-VEC will thus change the tumor microenvironment in patients with stage IIIB/C/D/IVM1a (AJCC 8) melanoma with resectable cutaneous or subcutaneous satellite or in-transit metastases (ITM) and/or tumor positive lymph nodes. With this trial the investigators aim to determine safety and feasibility of combination neo-adjuvant Nivolumab + T-VEC in patients with stage III melanoma with resectable ITM and/or tumor positive lymph nodes. The treatment schedule is based on 4 courses of intralesional T-VEC and 3 courses of intravenous Nivolumab. T-VEC first, in order to achieve the best synergistic effect with influx of CD8+ T cells prior to the first Nivolumab dose. T-VEC monotherapy with the dose 108 PFU/mL is given every 2 weeks (± 3) days after 3 weeks of the first T-VEC dose (with the first dose of T-VEC 106 PFU/mL to allow for seroconversion) , and Nivolumab can be given either every 2 weeks or every 4 weeks. Therefore we suggest the same dosing schedule for T-VEC and Nivolumab every 2 weeks for the purpose of this trial.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| T-VEC + Nivolumab | Experimental | Drug: T-VECPatients will receive pre-surgically 4 courses T-VEC (up to 4ml; first dose 10^6 PFU per mL, subsequent doses at 10^8 PFU per mL). Patients will also receive a flatdose of 240mg Nivolumab every 2 weeks after the first T-VEC injections (starting at 2nd T-VEC course at week 3, followed by the next doses at week 5 and 7). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (16 listed)
- Adults at least 18 years of age
- WHO performance score of 0 or 1
- Cytologically or histologically confirmed diagnosis of stage IIIB/C/D/IVM1a (AJCC 8th edition) melanoma, eligible for surgical resection.
- Subjects must have measurable disease according to RECIST 1.1 and must be a candidate for intralesional therapy with at least one injectable cutaneous, subcutane-ous or nodal melanoma lesion (≥ 10 mm in longest diameter) or with multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm.
- Prior isolated limb perfusion (ILP) is allowed (≥ 12 weeks prior to enrolment)
Key exclusion criteria (24 listed)
- Liver, Bone, Lung, Brain or other Visceral Metastases.
- No measurable lesion according to RECIST 1.1
- Prior radiotherapy for melanoma
- Prior systemic cancer therapies, including, but not limited to anti-CTLA-4, anti-PD-1, anti-PD-L1
- No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| T-VECAlso: NivolumabThe treatment schedule is based on 4 courses of intralesional T-VEC and 3 courses of intraveneous Nivolumab. T-VEC first, in order to achieve the best synergistic effect with influx of CD8+ T-cells prior to the first Nivolumab dose. T-VEC monotherapy with the dose 10^8 PFU/mL is given every 2 weeks after 3 weeks of the first T-VEC dose (with the first dose of T-VEC 10^6 PFU/mL to allow for seroconversion), and Nivolumab will be given every 2 weeks. | Drug | T-VEC + Nivolumab |
Primary outcome
Pathologic response
Time frame: 12 weeks
Pathologic response according to central revision by pathology of NKI (complete response, near complete response (<10% vital tumor remaining)
8 secondary outcomes
Rate of delay of surgery > 14 days
Time frame: 9 weeks
Rate of failure to perform surgery defined as no surgery at all (due to progressive disease or adverse events)
Time frame: 9 weeks
Relapse free survival (RFS)
Time frame: Up to 2 years after treatment
Safety of neo-adjuvant combination of T-VEC and nivolumab according to CTCAE v5.0
Time frame: 12 weeks
Acquiring tumor tissue
Time frame: Up to 2 years after treatment
Acquiring tumor tissue
Time frame: Up to 2 years after treatment
Acquiring tumor tissue
Time frame: Up to 2 years after treatment
Acquiring tumor tissue
Time frame: Up to 2 years after treatment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Mar 2025.
- Derived from this study: PubMed 35927710Rohaan MW, Stahlie EHA, Franke V, Zijlker LP, Wilgenhof S, van der Noort V, van Akkooi ACJ, Haanen JBAG. Neoadjuvant nivolumab + T-VEC combination therapy for resectable early stage or metastatic (IIIB-IVM1a) melanoma with injectable disease: study protocol of the NIVEC trial. BMC Cancer. 2022 Aug 4;22(1):851. doi: 10.1186/s12885-022-09896-4.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John Haanen, Prof. principal investigator
Medical oncologist/researcher
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing T-VEC in people with Melanoma Stage III and Melanoma Stage IV, run by The Netherlands Cancer Institute at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 16 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Mar 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pathologic response (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04330430, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Mar 2025.