Vemurafenib and TIL Therapy for Metastatic Melanoma

Phase 1

Completed

Conditions: Metastatic Melanoma

Interventions: Drug: Vemurafenib
Drug: Lymphodepleting chemotherapy
Drug: TIL infusion
Drug: Interleukin-2

Registration Number: NCT02354690

Lead Sponsor: Inge Marie Svane

Brief 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. 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 13

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
A	Interleukin-2	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.
A	Lymphodepleting chemotherapy	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.
A	TIL infusion	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.
A	Vemurafenib	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.

Primary Outcome Measures

Name	Time	Method
Number of Reported Adverse Events	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.

Secondary Outcome Measures

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