Clinical Trials /

Vemurafenib and TIL Therapy for Metastatic Melanoma

NCT02354690

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

URL:

https://clinicaltrials.gov/show/NCT02354690

Trial Eligibility

Document

Title

  • Brief Title: Vemurafenib and TIL Therapy for Metastatic Melanoma
  • Official Title: T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated Metastatic Melanoma

Clinical Trial IDs

  • ORG STUDY ID: MM1414
  • NCT ID: NCT02354690

Conditions

  • Metastatic Melanoma

Interventions

DrugSynonymsArms
VemurafenibZelboraf, BRAF inhibitorA
Lymphodepleting chemotherapycyclophosphamide, fludarabineA
TIL infusionAdoptive cell transfer, T cell therapyA
Interleukin-2IL-2A

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
AExperimental7 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.
  • Vemurafenib
  • Lymphodepleting chemotherapy
  • TIL infusion
  • Interleukin-2

Eligibility Criteria

        Inclusion Criteria:

          -  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.

          -  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.

        Exclusion Criteria:

          -  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.

          -  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
Maximum Eligible Age:70 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Reported Adverse Events
Time Frame:0-40 weeks
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Treatment Related Immune Responses
Time Frame:0-24 weeks
Safety Issue:
Description: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.
Measure:Objective Response Rate
Time Frame:Up to 12 months
Safety Issue:
Description: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
Measure:Overall Survival
Time Frame:Up to 40 months
Safety Issue:
Description:Overall survival (OS), defined as the time from the start of treatment to death, will be described with the Kaplan-Meier curve.
Measure:Progression Free Survival
Time Frame:Up to 40 months
Safety Issue:
Description: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.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:Inge Marie Svane

Last Updated

March 23, 2020