Vemurafenib and TIL Therapy for Metastatic Melanoma

• Sponsor: Inge Marie Svane (Other)
• Overall Status: Completed
• CT.gov ID: NCT02354690
• Collaborator: (none)
• Enrollment: 13
• Location: 1
• Arm: 1
• Actual Duration (Months): 50
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma	Drug: Vemurafenib; Drug: Lymphodepleting chemotherapy; Drug: TIL infusion; Drug: Interleukin-2	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated Metastatic Melanoma
• Actual Study Start Date: Nov 1, 2014
• Actual Primary Completion Date: Dec 31, 2018
• Actual Study Completion Date: Dec 31, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: A 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; 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).; Other Names: Zelboraf BRAF inhibitor ; Drug: Lymphodepleting chemotherapy; 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).; Other Names: cyclophosphamide fludarabine ; Drug: TIL infusion; 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).; Other Names: Adoptive cell transfer T cell therapy ; Drug: Interleukin-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); Other Names: IL-2

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Center for Cancer Immune Therapy, Dept. of Haematology/Oncology	Copenhagen	Herlev	Denmark	2730

Sponsors and Collaborators

• Inge Marie Svane

Investigators

• Study Director: Inge Marie Svane, Prof., MD, Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark
• Principal Investigator: Troels Holz Borch, MD, Department of Oncology, Copenhagen University Hospital, Herlev, Herlev Ringvej 75, DK-2730 Herlev, Denmark

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 24, 2019

More Information

Publications

None provided.

• Responsible Party: Inge Marie Svane, Professor, MD, Herlev Hospital
• ClinicalTrials.gov Identifier: NCT02354690
• Other Study ID Numbers: MM1414
• First Posted: Feb 3, 2015
• Last Update Posted: Mar 23, 2020
• Last Verified: Mar 1, 2020

• Additional relevant MeSH terms: Melanoma; Cyclophosphamide; Fludarabine; Interleukin-2; Vemurafenib

Study Results

Participant Flow

Pre-assignment Detail	One patient was enrolled in the trial and started vemurafenib, but had rapid progression of a brain metastasis and it was deemed unsafe to continue with protocol treatment. Thus, the patient was excluded before receiving T cell infusion and did not complete treatment.

Arm/Group Title	T Cell Therapy With Vemurafenib Pretreatment
Arm/Group Description	7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2. Vemurafenib: 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 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 infusion: A tumor is surgically removed 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-2 is administered 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)
Period Title: Overall Study
STARTED	13
COMPLETED	12
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	T Cell Therapy With Vemurafenib Pretreatment
Arm/Group Description	7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2. Vemurafenib: 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 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 infusion: A tumor is surgically removed 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-2 is administered 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)
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 83.3%
>=65 years	2 16.7%
Sex: Female, Male (Count of Participants)
Female	5 41.7%
Male	7 58.3%
Race and Ethnicity Not Collected (Count of Participants)
Stage at inclusion (Count of Participants)
M1a	1 8.3%
M1b	1 8.3%
M1c	10 83.3%

Outcome Measures

1. Primary Outcome

Title	Number of Reported Adverse Events
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.
Time Frame	0-40 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Therapy With Vemurafenib Pretreatment
Arm/Group Description	7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2. Vemurafenib: 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 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 infusion: A tumor is surgically removed 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-2 is administered 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)
Measure Participants	12
Total	124
Grade 1-2	89
Grade 3-4	35

2. Secondary Outcome

Title	Treatment Related Immune Responses
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.
Time Frame	0-24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Therapy With Vemurafenib Pretreatment
Arm/Group Description	7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2. Vemurafenib: 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 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 infusion: A tumor is surgically removed 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-2 is administered 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)
Measure Participants	12
Count of Participants [Participants]	10 83.3%

3. Secondary Outcome

Title	Objective Response Rate
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
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Therapy With Vemurafenib Pretreatment
Arm/Group Description	7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2. Vemurafenib: 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 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 infusion: A tumor is surgically removed 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-2 is administered 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)
Measure Participants	12
Count of Participants [Participants]	9 75%

4. Secondary Outcome

Title	Overall Survival
Description	Overall survival (OS), defined as the time from the start of treatment to death, will be described with the Kaplan-Meier curve.
Time Frame	Up to 40 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Therapy With Vemurafenib Pretreatment
Arm/Group Description	7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2. Vemurafenib: 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 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 infusion: A tumor is surgically removed 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-2 is administered 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)
Measure Participants	12
Median (Full Range) [Months]	28.8

5. Secondary Outcome

Title	Progression Free Survival
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.
Time Frame	Up to 40 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	T Cell Therapy With Vemurafenib Pretreatment
Arm/Group Description	7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2. Vemurafenib: 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 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 infusion: A tumor is surgically removed 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-2 is administered 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)
Measure Participants	12
Median (Full Range) [Months]	4.8

Adverse Events

Time Frame	Adverse events were collected from start of treatment until 24 weeks after T cell infusion.
Adverse Event Reporting Description	Adverse events were collected continually and as a minimum systematically at baseline, each treatment visit and at follow-up visits until 24 weeks after T cell infusion.
Arm/Group Title	T Cell Therapy With Vemurafenib Pretreatment
Arm/Group Description	7 days before tumor harvest, patients will begin taking vemurafenib until admission for lymphodepleting chemotherapy followed by TIL infusion and interleukin-2. Vemurafenib: 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 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 infusion: A tumor is surgically removed 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-2 is administered 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)
All Cause Mortality
	T Cell Therapy With Vemurafenib Pretreatment
	Affected / at Risk (%)	# Events
Total	7/12 (58.3%)
Serious Adverse Events
	T Cell Therapy With Vemurafenib Pretreatment
	Affected / at Risk (%)	# Events
Total	4/12 (33.3%)
Endocrine disorders
Pancreatitis	1/12 (8.3%)	1
Gastrointestinal disorders
Colitis	1/12 (8.3%)	1
General disorders
Pyrexia	2/12 (16.7%)	2
Other (Not Including Serious) Adverse Events
	T Cell Therapy With Vemurafenib Pretreatment
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	12/12 (100%)	12
Neutropenia	12/12 (100%)	13
Lymphopenia	12/12 (100%)	13
Thrombocytopenia	12/12 (100%)	13
Cardiac disorders
Atrial fibrillation	1/12 (8.3%)	1
Electrocardiogram QT prolonged	3/12 (25%)	3
Ear and labyrinth disorders
Hypoacusis	3/12 (25%)	3
Eye disorders
Uveitis	1/12 (8.3%)	1
Gastrointestinal disorders
Nausea	9/12 (75%)	9
Vomiting	2/12 (16.7%)	2
Constipation	1/12 (8.3%)	1
Oral mucositis	5/12 (41.7%)	5
General disorders
Pyrexia	1/12 (8.3%)	1
Fatique	12/12 (100%)	14
Hepatobiliary disorders
Hepatic enzyme increased	1/12 (8.3%)	1
Immune system disorders
Rhinitis atrophic	1/12 (8.3%)	1
Infections and infestations
Infection	5/12 (41.7%)	5
Musculoskeletal and connective tissue disorders
Myalgia	11/12 (91.7%)	11
Nervous system disorders
Neuropathy peripheral	1/12 (8.3%)	1
Psychiatric disorders
Delirium	2/12 (16.7%)	2
Hallucination	2/12 (16.7%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	10/12 (83.3%)	10
Skin and subcutaneous tissue disorders
Rash maculo-papular	12/12 (100%)	14
Petechiae	1/12 (8.3%)	1
Alopecia	12/12 (100%)	13
Vitiligo	1/12 (8.3%)	1
Dry skin	4/12 (33.3%)	4
Papilloma	1/12 (8.3%)	1
Actinic keratosis	1/12 (8.3%)	1
Hyperkeratosis	2/12 (16.7%)	2
Photosensitivity	5/12 (41.7%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.