Metastatic MelanomaPhase 1/2NCT02354690
Vemurafenib and TIL Therapy for Metastatic Melanoma
A Phase 1/2 study testing Vemurafenib, Lymphodepleting chemotherapy and TIL infusion in people with Metastatic Melanoma, run by Inge Marie Svane at 1 site in Denmark.
Trial summary
Background: Adoptive T cell therapy with tumor infiltrating lymphocytes (TILs) has been reported to induce durable clinical responses in patients with metastatic melanoma. From patients own tumor material T cells are extracted, expanded and activated in vitro in a 4-6 weeks culture period. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Metastatic Melanoma
- What is being tested?
- Vemurafenib, Lymphodepleting chemotherapy and TIL infusion
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 13 participants
- Where
- 1 siteDenmark
- Study dates
- Nov 2014to 31 Dec 2018
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed unresectable stage III or stage IV metastatic melanoma.
- Metastasis available for surgical resection (about 2 cm3) and residual measureable disease after resection.
- Pathologically verified BRAF mutation.
- ECOG performance status 0-1.
- Life expectancy ≥ 3 months.
- No significant toxicity (CTC ≤ 1) from prior treatments.
Show all 9Show fewer
- Adequate renal, hepatic and hematologic function.
- Women of childbearing potential (WOCBP) and men in a sexual relationship with a WOCBP must be using an effective method of contraception during treatment and for at least 6 months after completion of treatment.
- Able to comprehend the information given and willing to sign informed consent.
Who cannot join
- Other malignancies, unless followed for ≥ 5 years with no sign of disease, except squamous cell carcinoma or adequately treated carcinoma in situ colli uteri.
- Cerebral metastasis. Patients with previously treated CNS metastasis can participate if surgically removed or treated with stereotactic radiotherapy if stable > 28 days after treatment measured by MRI. Patients with asymptomatic and untreated CNS metastasis can participate based on investigators evaluation.
- Patients with ocular melanoma.
- Previous treatment with a BRAF inhibitor.
- Severe allergies, history of anaphylaxis or known allergies to drugs administered.
- Serious medical or psychiatric comorbidity.
Show all 15Show fewer
- QTc ≥ 450 ms.
- Clearance < 70 ml/min.
- Acute or chronic infection with e.g. HIV, hepatitis, tuberculosis
- Active autoimmune disease.
- Pregnant og nursing women.
- Need for immunosuppressive treatment, e.g. corticosteroids or methotrexate.
- Concomitant treatment with other experimental drugs.
- Patients with uncontrolled hypercalcemia
- More than four weeks must have elapsed since any prior systemic therapy at the time of treatment
Trial locations and contacts
1 site in 1 country.
Denmark1 site
Center for Cancer Immune Therapy, Dept. of Haematology/Oncology
Copenhagen, Herlev, 2730
About this study
Official title: T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated Metastatic Melanoma
Background:
Adoptive T cell therapy with tumor infiltrating lymphocytes (TILs) has been reported to induce durable clinical responses in patients with metastatic melanoma. From patients own tumor material T cells are extracted, expanded and activated in vitro in a 4-6 weeks culture period. Before TIL infusion patients are preconditioned with a lymphodepleting chemotherapeutic regimen. After TIL infusion, patients are treated with IL-2 to support T cell activation and expansion in vivo.
Read more
The BRAF inhibitor is an approved treatment of metastatic melanoma and functions by selectively inhibiting the BRAF mutated enzyme, consequently halting the proliferation of tumor cells. Furthermore, in vitro tests have shown that vemurafenib has immunomodulatory effects that are hypothesized to synergize with TIL therapy, which has been confirmed in animal studies.
Objectives:
- To evaluate safety and feasibility when combining vemurafenib and ACT with TILs.
- To evaluate treatment related immune responses
- To evaluate clinical efficacy
Design:
- Patients will be screened with a physical exam, medical history, blood samples and ECG.
- Patients will start vemurafenib 960 mg BID and will continue during TIL preparation.
- 7 days after start of vemurafenib, patients will undergo surgery to harvest tumor material for TIL production.
- Patient stops vemurafenib and is admitted day -8 in order to undergo lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7.
- On day 0 patients receive TIL infusion and shortly after starts IL-2 infusion continually following the decrescendo regimen.
- The patients will followed until progression or up to 5 years.
- Conditions
- Metastatic Melanoma
- Being tested
- Vemurafenib, Lymphodepleting chemotherapy, TIL infusion, Interleukin-2
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VemurafenibDrug
Also called Zelboraf, BRAF inhibitor
Vemurafenib is used to treat patients with BRAF mutated metastatic melanoma. Patients will start treatment in a dose of 960 BID 7 days before tumor harvest and ends at the day of admission (day -8).
Lymphodepleting chemotherapyDrug
Also called cyclophosphamide, fludarabine
First patients undergo lymphodepleting chemotherapy regimen consisting of cyclophosphamide 60 mg/kg for 2 days and fludarabine 25 mg/m2 for 5 days (constitutes day -7 to -1 of admission).
TIL infusionDrug
Also called Adoptive cell transfer, T cell therapy
7 days after start of vemurafenib treatment, patients undergo surgery to removal of a tumor in order to isolate, activate and expand tumor infiltrating lymphocytes (TIL) to high numbers. In vitro preparation usually takes 4-6 weeks using the young TIL method.
On day 0 patients receive an infusion of TIL (1x10e9-2x10e11 cells).
Interleukin-2Drug
Also called IL-2
After infusion of TILs, patients will receive interleukin-2 infusions according to the decrescendo regimen (18 MIU/m2 for 6 hours, 18 MIU/m2 for 12 hours, 18 MIU/m2 for 24 hours followed by 4,5 MIU/m2 for another 3 x 24 hours)
| Study group | Role | What they receive |
|---|---|---|
| A | Experimental | 7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy regimen of cyclophosphamide and fludarabine, followed by TIL infusion and interleukin-2. Receives: Drug: Vemurafenib; Drug: Lymphodepleting chemotherapy; Drug: TIL infusion; Drug: Interleukin-2 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Reported Adverse Events
Determine the safety of the administration of vemurafenib in combination with TIL therapy including lymphodepleting chemotherapy and interleukin-2 treatment by collecting adverse events according to CTCAE v. 4.0. From start of treatment until 24 weeks after T cell infusion.
Measured: 0-40 weeks
Secondary outcomes (4)
Treatment Related Immune Responses
Number of patients whose infusion product contained anti-tumor reactive T cells by in vitro testing.
Anti-tumor reactive T cells is defined by positive staining for two of the three markers (interferon gamma, tumor necrosis factor alpha and CD107a) in an intracellular cytokine staining using flow cytometry.
Measured: 0-24 weeks
Objective Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): Complete Response (CR), Disappearance of all target and non-target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR
Measured: Up to 12 months
Overall Survival
Overall survival (OS), defined as the time from the start of treatment to death, will be described with the Kaplan-Meier curve.
Measured: Up to 40 months
Progression Free Survival
Progression-free survival (PFS), defined as the time from start of treatment to disease progression, relapse or death due to any cause, whichever is earlier, will be described with the Kaplan-Meier curve.
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Measured: Up to 40 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Feb 2015 (estimated)
- Study startNov 2014
- Primary completion31 Dec 2018
- Study completion31 Dec 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Metastatic MelanomaStudies of the same condition, open and under way.
- 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- Inge Marie Svane
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Inge Marie Svane, Herlev Hospital
- Investigators
- Inge Marie Svane, Prof., MD, Study director, Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, DenmarkTroels Holz Borch, MD, Principal investigator, Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02354690
- Sponsor's protocol ID
- MM1414
- Status last verified
- Mar 2020
- First submitted
- 26 Jan 2015
- Last updated
- 23 Mar 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Borch TH, Andersen R, Ellebaek E, Met O, Donia M, Svane IM. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. J Immunother Cancer. 2020 Jul;8(2):e000668. doi: 10.1136/jitc-2020-000668.
PubMed 32747469
Study at a glance
From the registry record, last updated by the sponsor on 23 Mar 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated Metastatic Melanoma
- ClinicalTrials.gov ID
- NCT02354690
- Acronym / sponsor ID
- MM1414
- Conditions
- Metastatic Melanoma
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- Inge Marie SvaneUniversity, hospital or other
- Study start
- Nov 2014 (actual)
- Primary completion
- 31 Dec 2018 (actual)
- Study completion
- 31 Dec 2018 (actual)
- First posted
- 3 Feb 2015 (estimated)
- Results
- Posted 24 Feb 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background:
Adoptive T cell therapy with tumor infiltrating lymphocytes (TILs) has been reported to induce durable clinical responses in patients with metastatic melanoma. From patients own tumor material T cells are extracted, expanded and activated in vitro in a 4-6 weeks culture period. Before TIL infusion patients are preconditioned with a lymphodepleting chemotherapeutic regimen. After TIL infusion, patients are treated with IL-2 to support T cell activation and expansion in vivo.
The BRAF inhibitor is an approved treatment of metastatic melanoma and functions by selectively inhibiting the BRAF mutated enzyme, consequently halting the proliferation of tumor cells. Furthermore, in vitro tests have shown that vemurafenib has immunomodulatory effects that are hypothesized to synergize with TIL therapy, which has been confirmed in animal studies.
Objectives:
- To evaluate safety and feasibility when combining vemurafenib and ACT with TILs.
- To evaluate treatment related immune responses
- To evaluate clinical efficacy
Design:
- Patients will be screened with a physical exam, medical history, blood samples and ECG.
- Patients will start vemurafenib 960 mg BID and will continue during TIL preparation.
- 7 days after start of vemurafenib, patients will undergo surgery to harvest tumor material for TIL production.
- Patient stops vemurafenib and is admitted day -8 in order to undergo lymphodepleting chemotherapy with cyclophosphamide and fludara starting day -7.
- On day 0 patients receive TIL infusion and shortly after starts IL-2 infusion continually following the decrescendo regimen.
- The patients will followed until progression or up to 5 years.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| A | Experimental | Drug: Vemurafenib, Drug: Lymphodepleting chemotherapy, Drug: TIL infusion, Drug: Interleukin-27 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy regimen of cyclophosphamide and fludarabine, followed by TIL infusion and interleukin-2. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Histologically confirmed unresectable stage III or stage IV metastatic melanoma.
- Metastasis available for surgical resection (about 2 cm3) and residual measureable disease after resection.
- Pathologically verified BRAF mutation.
- ECOG performance status 0-1.
- Life expectancy ≥ 3 months.
Key exclusion criteria (15 listed)
- Other malignancies, unless followed for ≥ 5 years with no sign of disease, except squamous cell carcinoma or adequately treated carcinoma in situ colli uteri.
- Cerebral metastasis. Patients with previously treated CNS metastasis can participate if surgically removed or treated with stereotactic radiotherapy if stable > 28 days after treatment measured by MRI. Patients with asymptomatic and untreated CNS metastasis can participate based on investigators evaluation.
- Patients with ocular melanoma.
- Previous treatment with a BRAF inhibitor.
- Severe allergies, history of anaphylaxis or known allergies to drugs administered.
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 |
|---|---|---|
| VemurafenibAlso: Zelboraf, BRAF inhibitorVemurafenib is used to treat patients with BRAF mutated metastatic melanoma. Patients will start treatment in a dose of 960 BID 7 days before tumor harvest and ends at the day of admission (day -8). | Drug | A |
| Lymphodepleting chemotherapyAlso: cyclophosphamide, fludarabineFirst patients undergo lymphodepleting chemotherapy regimen consisting of cyclophosphamide 60 mg/kg for 2 days and fludarabine 25 mg/m2 for 5 days (constitutes day -7 to -1 of admission). | Drug | A |
| TIL infusionAlso: Adoptive cell transfer, T cell therapy7 days after start of vemurafenib treatment, patients undergo surgery to removal of a tumor in order to isolate, activate and expand tumor infiltrating lymphocytes (TIL) to high numbers. In vitro preparation usually takes 4-6 weeks using the young TIL method. On day 0 patients receive an infusion of TIL (1x10e9-2x10e11 cells). | Drug | A |
| Interleukin-2Also: IL-2After infusion of TILs, patients will receive interleukin-2 infusions according to the decrescendo regimen (18 MIU/m2 for 6 hours, 18 MIU/m2 for 12 hours, 18 MIU/m2 for 24 hours followed by 4,5 MIU/m2 for another 3 x 24 hours) | Drug | A |
Primary outcome
Number of Reported Adverse Events
Time frame: 0-40 weeks
Determine the safety of the administration of vemurafenib in combination with TIL therapy including lymphodepleting chemotherapy and interleukin-2 treatment by collecting adverse events according to CTCAE v. 4.0. From start of treatment until 24 weeks after T cell infusion.
4 secondary outcomes
Treatment Related Immune Responses
Time frame: 0-24 weeks
Objective Response Rate
Time frame: Up to 12 months
Overall Survival
Time frame: Up to 40 months
Progression Free Survival
Time frame: Up to 40 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Mar 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32747469Borch TH, Andersen R, Ellebaek E, Met O, Donia M, Svane IM. Future role for adoptive T-cell therapy in checkpoint inhibitor-resistant metastatic melanoma. J Immunother Cancer. 2020 Jul;8(2):e000668. doi: 10.1136/jitc-2020-000668.
Related trials for Metastatic Melanoma
RecruitingPhase 1/2
Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab (Keytruda®) in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)
Solid Tumor, Non-Small Cell Lung Cancer
RecruitingPhase 1
IL-17 Blockade to Decrease irAEs (REPLAY)
Metastatic Melanoma
RecruitingPhase 3
A Study With Combinations of Anti-LAG-3 and Anti-PD-1 Antibodies in Adult Participants With Advanced or Metastatic Melanoma (Harmony Head-to-Head)
Melanoma
RecruitingPhase 1
Pharmacokinetics, Safety, and Immunogenicity Comparison of Bmab1700 and Opdivo® as Adjuvant Monotherapy in Participants With Melanoma
Melanoma
Active, not recruitingPhase 1/2
A Study of ST-1898 for Unresectable or Metastatic Melanoma
Unresectable or Metastatic Melanoma
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.
Inge Marie Svane, Prof., MD study director
Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark
Troels Holz Borch, MD principal investigator
Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Vemurafenib, Lymphodepleting chemotherapy and TIL infusion in people with Metastatic Melanoma, run by Inge Marie Svane at 1 site in Denmark.
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 9 inclusion and 15 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 23 Mar 2020. 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 Denmark. 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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
Yes. Results are posted in the registry (first posted 24 Feb 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Number of Reported Adverse Events (time frame: 0-40 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 NCT02354690, 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 23 Mar 2020; AzTrials last refreshed its copy on 7 Nov 2026.