Back to resultsTIL and Anti-PD1 in Metastatic Melanoma (ACTME)
Primary Purpose
Toxicity, Drug, Adverse Drug Event, Effects of Immunotherapy
Status
Recruiting
Phase
Phase 1
Locations
Netherlands
Study Type
Interventional
Intervention
Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha
Sponsored by
About this trial
This is an interventional treatment trial for Toxicity, Drug focused on measuring Metastatic melanoma, anti-PD1, TIL, interferon-alpha, adoptive cell therapy, nivolumab
Eligibility Criteria
Inclusion Criteria:
- Age ≥ 18 years
- Histologically or cytologically proven metastatic skin melanoma
Melanoma must be at one of the following AJCC 2009 stages:
- Unresectable (or residual) regional metastatic melanoma, i.e. in terms of AJCC 2009 classification unresectable stage III melanoma, or
- Stage IV melanoma, i.e. distant metastatic disease (any T, any N, M1a, M1b or M1c), and normal LDH
- Patients have failed on standard treatment options
- Patients with brain metastases have to be neurologically stable for at least 2 months and should not use dexamethasone
- Presence of measurable progressive disease according to RECIST version 1.1
- Expected survival of at least 3 months
- WHO performance status ≤1
Within the last 2 weeks prior to study day 1, vital laboratory parameters should be within normal range, except for the following laboratory parameters, which should be within the ranges specified:
Lab Parameter Range Hemoglobin ≥ 6,0 mmol/l Granulocytes ≥ 1,500/µl Lymphocytes ≥ 700/µl Platelets ≥ 100,000/µl Creatinine clearance ≥ 60 min/ml Serum bilirubin ≤ 40 µmol/l ASAT and ALAT ≤ 5 x the normal upper limit LDH ≤ 2 x the normal upper limit
Viral tests must be performed at least 30 days before surgery:
- Negative for HIV type 1/2, HTLV and TPHA
- No HBV (hepatitis B virus) antigen or antibodies against HBc in the serum
- No antibodies against HCV (hepatitis C virus) in the serum
- Able and willing to give valid written informed consent.
- Progressive disease on prior treatment with f.e. BRAF-inhibitors, MEK-inhibitors or immunotherapy, including anti-PD1 treatment. Systemic therapy must have been discontinued for at least four weeks before start of study treatment.
Exclusion Criteria:
- Patients with brain metastases who are neurologically unstable and/or use dexamethasone
- Clinically significant heart disease (NYHA Class III or IV)
- Other serious acute or chronic illnesses, e.g. active infections requiring antibiotics, bleeding disorders, or other conditions requiring concurrent medications not allowed during this study
- Active immunodeficiency disease, autoimmune disease requiring immune suppressive drugs or autoimmune adverse events following treatment with checkpoint inhibitors. Vitiligo is not an exclusion criterion
- Subjects with a condition requiring systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any immunosuppressive therapy within 14 days prior to planned date for first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids, and adrenal replacement therapy are allowed.
- Other malignancy within 2 years prior to entry into the study, except for treated non-melanoma skin cancer and in situ cervical carcinoma
- Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study
- Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the associated with the participation, study drug administration, or would impair the ability of the patient to receive protocol therapy
- Lack of availability for follow-up assessments
- Pregnancy or breastfeeding
- Known allergy to penicillin or streptomycin (used during the culturing of T cells)
Sites / Locations
- Leiden University Medical CenterRecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Treatment with nivolumab plus TIL
Treatment with Nivolumab plus TIL and IFN-alpha
Arm Description
In the first cohort the subcutaneous IFN-alpha injections will be omitted and the combination of nivolumab and TIL is given. Nivolumab is given 3mg/kg i.v. once every two weeks and starts 4 weeks before the first TIL infusion TILs are given at a dose ranging between 2.5-7.5x10^8 T cells i.v. once every three weeks, three times per cycle.
In the second cohort of the first phase and the second phase of the trial patients will be treated with subcutaneous IFN-alpha injections in combination with TIL and nivolumab. IFN-alpha is given at a fixed dose of 3 million IU s.c. every day, for 11 weeks, starting one week before the first TIL infusion Nivolumab is given 3mg/kg i.v. once every two weeks and starts 4 weeks before the first TIL infusion TILs are given at a dose ranging between 2.5-7.5x10^8 T cells i.v. once every three weeks, three times per cycle.
Outcomes
Primary Outcome Measures
Incidence of treatment-related serious adverse events as assessed by CTCAE 4.0 criteria
To evaluate the safety and toxicity of ACT with nivolumab, followed by evaluating the safety and toxicity of IFN-alpha, and nivolumab plus ACT according to the common terminology criteria of adverse events (CTCAE) 4.0 criteria. Treatment related adverse events grade 3 or less and SAE related to treatment that do not result in treatment termination are considered acceptable for continuation of the study.
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL
Grade 3: Severe or medically significant but not immediately life-threatening hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL
Grade 4: Life-threatening consequences; urgent intervention indicated
Grade 5: Death related to AE
Secondary Outcome Measures
Evaluation of disease control rate according to RECIST 1.1 criteria
Disease control is defined by complete response, partial response or stable according to RECIST 1.1 versus no clinical benefit defined as progressive disease.
Complete response: Disappearance of all target and nontarget lesions, nodes must regress to <10mm short axis, no new lesions, confirmation required Partial response: ≥30% decrease in tumor burden compared with baseline, confirmation required Progressive disease: ≥20% + 5 mm absolute increase in tumor burden compared with nadir, appearance of new lesions or progression of nontarget lesions Stable disease: neither partial response nor progressive disease
Evaluation of disease control rate according to immune RECIST response criteria
Disease control is defined by complete response, partial response or stable according to the iRECIST versus no clinical benefit defined as progressive disease.
Complete response: Disappearance of all lesions Partial response: ≥30% decrease in tumor burden compared with baseline. Progressive disease: ≥20% + 5 mm absolute increase in tumor burden compared with nadir Stable disease: neither progressive disease nor partial response
To study the potential working mechanisms of the different treatment compounds. Therefore, blood will be drawn to analyse changes in circulating immune cells and their function during treatment.
The investigators will analyse the patients their tumor material, blood, serum and the TILs used for infusion
To establish a possible prognostic biomarker profile in patients tumor material, blood, serum and TILs used for infusion
The investigators will analyse the patients their tumor material, blood, serum and the TILs used for infusion to look at changes in the number and phenotype of circulating immune cells, the cytokines that are produced by these cells and serum/plasma markers of persistence.
To characterize the infusion product
The expression of co-inhibitory molecules on T cells and regulatory T cells will be measured by flow cytometry. Furthermore, the investigators will assess the fraction of tumor-specific TIL, their cytolytic capacity as well as to analyse their persistence in the circulation. The supernatants of T cell are used for cytokine analysis assays.
To analyse potential correlations between the clinical response and hypothesis related immune parameters
To analyse the overall survival following treatment
The overall survival of all patients entering the study will be monitored
Full Information
NCT ID
NCT03638375
First Posted
July 5, 2018
Last Updated
August 16, 2022
Sponsor
Leiden University
Collaborators
Bristol-Myers Squibb
1. Study Identification
Unique Protocol Identification Number
NCT03638375
Brief Title
TIL and Anti-PD1 in Metastatic Melanoma
Acronym
ACTME
Official Title
Adoptive TIL Therapy With Low-dose IFN-alpha Plus Anti-PD1 in Metastatic Melanoma
Study Type
Interventional
2. Study Status
Record Verification Date
August 2022
Overall Recruitment Status
Recruiting
Study Start Date
July 31, 2018 (Actual)
Primary Completion Date
November 1, 2022 (Anticipated)
Study Completion Date
November 1, 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Leiden University
Collaborators
Bristol-Myers Squibb
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The ACTME study is an investigator initiated, single center phase I/II clinical trial for patients with progressive unresectable stage III or stage IV melanoma. The trial consists of both a phase I part to determine safety and feasibility and a phase II part to evaluate first clinical activity of IFN-alpha, nivolumab and TIL. The treatment with IFN-alpha will be added after the combination of TIL and nivolumab has proven to be safe.
Detailed Description
The ACTME is an investigator initiated, single center phase I/II clinical trial for patients with progressive unresectable stage III or stage IV melanoma.
Patients are conditioned by low-dose IFN-alpha and treated with ACT and PD-1 antibodies. With this approach the investigators hope to solve 4 of the most important aspects curtailing the efficacy of current immunotherapies in metastatic melanoma:
the lack of sufficient numbers of activated tumor-reactive T cells in patients by providing ACT; and
the inhibition of T-cell effector function through PD-1 signalling by administration of nivolumab; as well as
the toxicity of high-dose IL-2, and
long term hospitalization of patients due to the conditioning-regimen used in most ACT protocols by replacing it with low-dose IFN-alpha treatment.
The trial consists of both a phase I part to determine safety and feasibility and a phase II part to evaluate first clinical activity of IFN-alpha, nivolumab and TIL.
The treatment with IFN-alpha will be added after the combination of TIL and nivolumab has proven to be safe in the first cohort of the phase I part of the trial.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Toxicity, Drug, Adverse Drug Event, Effects of Immunotherapy
Keywords
Metastatic melanoma, anti-PD1, TIL, interferon-alpha, adoptive cell therapy, nivolumab
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Model Description
The ACTME trial consists of both a phase I part to determine safety and feasibility and a phase II part to evaluate first clinical activity of IFN-alpha, nivolumab and TIL. The treatment with IFN-alpha will be added after the combination of TIL and nivolumab has proven to be safe.
Phase 1, Cohort 1: Adding TIL therapy to anti-PD1 immunotherapy. Phase 1, Cohort 2: Adding IFN-alpha to the treatment with TIL and anti-PD1 immunotherapy.
Phase 2: Patients will be treated with TIL, IFN-alpha and anti-PD1 according to the same schedule as used in phase 1 cohort 2.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
34 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Treatment with nivolumab plus TIL
Arm Type
Experimental
Arm Description
In the first cohort the subcutaneous IFN-alpha injections will be omitted and the combination of nivolumab and TIL is given.
Nivolumab is given 3mg/kg i.v. once every two weeks and starts 4 weeks before the first TIL infusion
TILs are given at a dose ranging between 2.5-7.5x10^8 T cells i.v. once every three weeks, three times per cycle.
Arm Title
Treatment with Nivolumab plus TIL and IFN-alpha
Arm Type
Experimental
Arm Description
In the second cohort of the first phase and the second phase of the trial patients will be treated with subcutaneous IFN-alpha injections in combination with TIL and nivolumab.
IFN-alpha is given at a fixed dose of 3 million IU s.c. every day, for 11 weeks, starting one week before the first TIL infusion
Nivolumab is given 3mg/kg i.v. once every two weeks and starts 4 weeks before the first TIL infusion
TILs are given at a dose ranging between 2.5-7.5x10^8 T cells i.v. once every three weeks, three times per cycle.
Intervention Type
Drug
Intervention Name(s)
Nivolumab & Tumor Infiltrating Lymphocytes with/without Interferon-Alpha
Intervention Description
During 15 weeks patients will be treated with nivolumab (3mg/kg i.v.) once every two weeks. Four weeks after starting nivolumab, patients will receive their first TIL infusion (2.5-7.5x10^8 T cells i.v.) once every three weeks for three infusions.
In the second group treatment with IFN-alpha (3 million IU s.c.) daily will be added one week before the first TIL infusion and will be continued for 11 weeks.
Primary Outcome Measure Information:
Title
Incidence of treatment-related serious adverse events as assessed by CTCAE 4.0 criteria
Description
To evaluate the safety and toxicity of ACT with nivolumab, followed by evaluating the safety and toxicity of IFN-alpha, and nivolumab plus ACT according to the common terminology criteria of adverse events (CTCAE) 4.0 criteria. Treatment related adverse events grade 3 or less and SAE related to treatment that do not result in treatment termination are considered acceptable for continuation of the study.
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL
Grade 3: Severe or medically significant but not immediately life-threatening hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL
Grade 4: Life-threatening consequences; urgent intervention indicated
Grade 5: Death related to AE
Time Frame
14 weeks after start of treatment
Secondary Outcome Measure Information:
Title
Evaluation of disease control rate according to RECIST 1.1 criteria
Description
Disease control is defined by complete response, partial response or stable according to RECIST 1.1 versus no clinical benefit defined as progressive disease.
Complete response: Disappearance of all target and nontarget lesions, nodes must regress to <10mm short axis, no new lesions, confirmation required Partial response: ≥30% decrease in tumor burden compared with baseline, confirmation required Progressive disease: ≥20% + 5 mm absolute increase in tumor burden compared with nadir, appearance of new lesions or progression of nontarget lesions Stable disease: neither partial response nor progressive disease
Time Frame
14 weeks after first nivolumab infusion
Title
Evaluation of disease control rate according to immune RECIST response criteria
Description
Disease control is defined by complete response, partial response or stable according to the iRECIST versus no clinical benefit defined as progressive disease.
Complete response: Disappearance of all lesions Partial response: ≥30% decrease in tumor burden compared with baseline. Progressive disease: ≥20% + 5 mm absolute increase in tumor burden compared with nadir Stable disease: neither progressive disease nor partial response
Time Frame
14 weeks after first nivolumab infusion
Title
To study the potential working mechanisms of the different treatment compounds. Therefore, blood will be drawn to analyse changes in circulating immune cells and their function during treatment.
Description
The investigators will analyse the patients their tumor material, blood, serum and the TILs used for infusion
Time Frame
Within 5 years after first inclusion
Title
To establish a possible prognostic biomarker profile in patients tumor material, blood, serum and TILs used for infusion
Description
The investigators will analyse the patients their tumor material, blood, serum and the TILs used for infusion to look at changes in the number and phenotype of circulating immune cells, the cytokines that are produced by these cells and serum/plasma markers of persistence.
Time Frame
Within 5 years after first inclusion
Title
To characterize the infusion product
Description
The expression of co-inhibitory molecules on T cells and regulatory T cells will be measured by flow cytometry. Furthermore, the investigators will assess the fraction of tumor-specific TIL, their cytolytic capacity as well as to analyse their persistence in the circulation. The supernatants of T cell are used for cytokine analysis assays.
Time Frame
Within 5 years after first inclusion
Title
To analyse potential correlations between the clinical response and hypothesis related immune parameters
Time Frame
Within 5 years after first inclusion
Title
To analyse the overall survival following treatment
Description
The overall survival of all patients entering the study will be monitored
Time Frame
Within 5 years after first inclusion
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Age ≥ 18 years
Histologically or cytologically proven metastatic skin melanoma
Melanoma must be at one of the following AJCC 2009 stages:
Unresectable (or residual) regional metastatic melanoma, i.e. in terms of AJCC 2009 classification unresectable stage III melanoma, or
Stage IV melanoma, i.e. distant metastatic disease (any T, any N, M1a, M1b or M1c), and normal LDH
Patients have failed on standard treatment options
Patients with brain metastases have to be neurologically stable for at least 2 months and should not use dexamethasone
Presence of measurable progressive disease according to RECIST version 1.1
Expected survival of at least 3 months
WHO performance status ≤1
Within the last 2 weeks prior to study day 1, vital laboratory parameters should be within normal range, except for the following laboratory parameters, which should be within the ranges specified:
Lab Parameter Range Hemoglobin ≥ 6,0 mmol/l Granulocytes ≥ 1,500/µl Lymphocytes ≥ 700/µl Platelets ≥ 100,000/µl Creatinine clearance ≥ 60 min/ml Serum bilirubin ≤ 40 µmol/l ASAT and ALAT ≤ 5 x the normal upper limit LDH ≤ 2 x the normal upper limit
Viral tests must be performed at least 30 days before surgery:
Negative for HIV type 1/2, HTLV and TPHA
No HBV (hepatitis B virus) antigen or antibodies against HBc in the serum
No antibodies against HCV (hepatitis C virus) in the serum
Able and willing to give valid written informed consent.
Progressive disease on prior treatment with f.e. BRAF-inhibitors, MEK-inhibitors or immunotherapy, including anti-PD1 treatment. Systemic therapy must have been discontinued for at least four weeks before start of study treatment.
Exclusion Criteria:
Patients with brain metastases who are neurologically unstable and/or use dexamethasone
Clinically significant heart disease (NYHA Class III or IV)
Other serious acute or chronic illnesses, e.g. active infections requiring antibiotics, bleeding disorders, or other conditions requiring concurrent medications not allowed during this study
Active immunodeficiency disease, autoimmune disease requiring immune suppressive drugs or autoimmune adverse events following treatment with checkpoint inhibitors. Vitiligo is not an exclusion criterion
Subjects with a condition requiring systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any immunosuppressive therapy within 14 days prior to planned date for first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids, and adrenal replacement therapy are allowed.
Other malignancy within 2 years prior to entry into the study, except for treated non-melanoma skin cancer and in situ cervical carcinoma
Mental impairment that may compromise the ability to give informed consent and comply with the requirements of the study
Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the associated with the participation, study drug administration, or would impair the ability of the patient to receive protocol therapy
Lack of availability for follow-up assessments
Pregnancy or breastfeeding
Known allergy to penicillin or streptomycin (used during the culturing of T cells)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ellen Kapiteijn, Dr.
Phone
071 526 9111
Email
H.W.kapiteijn@lumc.nl
First Name & Middle Initial & Last Name or Official Title & Degree
Monique K. van der Kooij, Drs.
Phone
071 526 9111
Email
m.k.van_der_kooij@lumc.nl
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ellen Kapiteijn, Dr.
Organizational Affiliation
LUMC
Official's Role
Principal Investigator
Facility Information:
Facility Name
Leiden University Medical Center
City
Leiden
ZIP/Postal Code
2333 ZA
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ellen Kapiteijn, Dr.
Phone
+3371 526 9111
Email
h.w.kapiteijn@lumc.nl
First Name & Middle Initial & Last Name & Degree
Ellen Kapiteijn, Dr.
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33234662
Citation
van der Kooij MK, Verdegaal EME, Visser M, de Bruin L, van der Minne CE, Meij PM, Roozen ICFM, Jonker MA, van den Bosch S, Liefers GJ, Speetjens FM, van der Burg SH, Kapiteijn E. Phase I/II study protocol to assess safety and efficacy of adoptive cell therapy with anti-PD-1 plus low-dose pegylated-interferon-alpha in patients with metastatic melanoma refractory to standard of care treatments: the ACTME trial. BMJ Open. 2020 Nov 24;10(11):e044036. doi: 10.1136/bmjopen-2020-044036.
Results Reference
derived
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TIL and Anti-PD1 in Metastatic Melanoma
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