Trial Outcomes & Findings for Vemurafenib and TIL Therapy for Metastatic Melanoma (NCT NCT02354690)

Last Updated: 2020-03-23

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

13 participants

Primary outcome timeframe

0-40 weeks

Results posted on

2020-03-23

Participant Flow

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.

Participant milestones

Participant milestones
Measure	T Cell Therapy With Vemurafenib Pretreatment 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 Study STARTED	13
Overall Study COMPLETED	12
Overall Study NOT COMPLETED	1

Reasons for withdrawal

Reasons for withdrawal
Measure	T Cell Therapy With Vemurafenib Pretreatment 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 Study Physician Decision	1

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	T Cell Therapy With Vemurafenib Pretreatment n=12 Participants 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)
Age, Categorical <=18 years	0 Participants n=12 Participants
Age, Categorical Between 18 and 65 years	10 Participants n=12 Participants
Age, Categorical >=65 years	2 Participants n=12 Participants
Sex: Female, Male Female	5 Participants n=12 Participants
Sex: Female, Male Male	7 Participants n=12 Participants
Stage at inclusion M1a	1 Participants n=12 Participants
Stage at inclusion M1b	1 Participants n=12 Participants
Stage at inclusion M1c	10 Participants n=12 Participants

PRIMARY outcome

Timeframe: 0-40 weeks

Outcome measures

Outcome measures
Measure	T Cell Therapy With Vemurafenib Pretreatment n=12 Participants 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)
Number of Reported Adverse Events Total	124 Treatment related adverse events
Number of Reported Adverse Events Grade 1-2	89 Treatment related adverse events
Number of Reported Adverse Events Grade 3-4	35 Treatment related adverse events

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	T Cell Therapy With Vemurafenib Pretreatment n=12 Participants 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)
Treatment Related Immune Responses	10 Participants

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	T Cell Therapy With Vemurafenib Pretreatment n=12 Participants 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)
Objective Response Rate	9 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	T Cell Therapy With Vemurafenib Pretreatment n=12 Participants 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 Survival	28.8 Months Interval 5.2 to 39.9

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	T Cell Therapy With Vemurafenib Pretreatment n=12 Participants 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)
Progression Free Survival	4.8 Months Interval 2.5 to 36.1

Adverse Events

T Cell Therapy With Vemurafenib Pretreatment

Serious events: 4 serious events

Other events: 12 other events

Deaths: 7 deaths

Serious adverse events

Serious adverse events
Measure	T Cell Therapy With Vemurafenib Pretreatment n=12 participants at risk 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)
General disorders Pyrexia	16.7% 2/12 • Number of events 2 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Endocrine disorders Pancreatitis	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Gastrointestinal disorders Colitis	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.

Other adverse events

Other adverse events
Measure	T Cell Therapy With Vemurafenib Pretreatment n=12 participants at risk 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)
Blood and lymphatic system disorders Febrile neutropenia	100.0% 12/12 • Number of events 12 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Infections and infestations Infection	41.7% 5/12 • Number of events 5 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
General disorders Pyrexia	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
General disorders Fatique	100.0% 12/12 • Number of events 14 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Respiratory, thoracic and mediastinal disorders Dyspnea	83.3% 10/12 • Number of events 10 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Gastrointestinal disorders Nausea	75.0% 9/12 • Number of events 9 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Gastrointestinal disorders Vomiting	16.7% 2/12 • Number of events 2 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Gastrointestinal disorders Constipation	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Gastrointestinal disorders Oral mucositis	41.7% 5/12 • Number of events 5 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Skin and subcutaneous tissue disorders Rash maculo-papular	100.0% 12/12 • Number of events 14 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Musculoskeletal and connective tissue disorders Myalgia	91.7% 11/12 • Number of events 11 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Cardiac disorders Atrial fibrillation	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Skin and subcutaneous tissue disorders Petechiae	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Psychiatric disorders Delirium	16.7% 2/12 • Number of events 2 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Psychiatric disorders Hallucination	16.7% 2/12 • Number of events 2 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Ear and labyrinth disorders Hypoacusis	25.0% 3/12 • Number of events 3 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Skin and subcutaneous tissue disorders Alopecia	100.0% 12/12 • Number of events 13 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Skin and subcutaneous tissue disorders Vitiligo	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Nervous system disorders Neuropathy peripheral	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Skin and subcutaneous tissue disorders Dry skin	33.3% 4/12 • Number of events 4 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Immune system disorders Rhinitis atrophic	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Cardiac disorders Electrocardiogram QT prolonged	25.0% 3/12 • Number of events 3 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Skin and subcutaneous tissue disorders Papilloma	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Skin and subcutaneous tissue disorders Actinic keratosis	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Skin and subcutaneous tissue disorders Hyperkeratosis	16.7% 2/12 • Number of events 2 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Skin and subcutaneous tissue disorders Photosensitivity	41.7% 5/12 • Number of events 5 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Hepatobiliary disorders Hepatic enzyme increased	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Eye disorders Uveitis	8.3% 1/12 • Number of events 1 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Blood and lymphatic system disorders Neutropenia	100.0% 12/12 • Number of events 13 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Blood and lymphatic system disorders Lymphopenia	100.0% 12/12 • Number of events 13 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.
Blood and lymphatic system disorders Thrombocytopenia	100.0% 12/12 • Number of events 13 • Adverse events were collected from start of treatment until 24 weeks after T cell infusion. 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.

Additional Information

Inge Marie Svane

National Center for Cancer Immune Therapy

Phone: 0045386889339

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place