Vemurafenib and TIL Therapy for Metastatic Melanoma

NCT02354690 | Completed Phase 1 Results DMC

• 1 other identifier: MM1414
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Melanoma

Outcome Measures

Primary Outcomes (1)

• 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.

  0-40 weeks

Secondary Outcomes (4)

• Treatment Related Immune Responses

  0-24 weeks

• Objective Response Rate

  Up to 12 months

• Overall Survival

  Up to 40 months

• Progression Free Survival

  Up to 40 months

Study Arms (1)

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.

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

Interventions

Vemurafenib DRUG

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).

Also known as: Zelboraf, BRAF inhibitor

A

Lymphodepleting chemotherapy DRUG

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).

Also known as: cyclophosphamide, fludarabine

A

TIL infusion DRUG

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).

Also known as: Adoptive cell transfer, T cell therapy

A

Interleukin-2 DRUG

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)

Also known as: IL-2

A

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Inge Marie Svane: lead

Study Sites (1)

Center for Cancer Immune Therapy, Dept. of Haematology/Oncology

Copenhagen, Herlev, 2730, Denmark

Location

Related Publications (1)

• 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.

  PMID: 32747469 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Vemurafenib; Cyclophosphamide; fludarabine; Adoptive Transfer; Immunotherapy, Adoptive; Interleukin-2

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Phosphoramides; Organophosphorus Compounds; Immunization, Passive; Immunization; Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Results Point of Contact

• Title: Inge Marie Svane
• Organization: National Center for Cancer Immune Therapy

inge.marie.svane@regionh.dk

0045386889339

Study Officials

• Inge Marie Svane, Prof., MD

  Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark

  STUDY DIRECTOR

• Troels Holz Borch, MD

  Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor, MD

Study Record Dates

• First Submitted: January 26, 2015
• First Posted: February 3, 2015
• Study Start: November 1, 2014
• Primary Completion: December 31, 2018
• Study Completion: December 31, 2018
• Last Updated: March 23, 2020
• Results First Posted: February 24, 2020

Record last verified: 2020-03

Locations

DK (1)