The primary endpoint is the evaluation of the safety and toxicity of TIL with nivolumab and, thereafter, the safety and toxicity of the combination of PEG-IFNa, nivolumab plus TIL. Safety and toxicity will be evaluated according to CTCAE 4.0…
ID
Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Evaluating the safety and toxicity of first TIL and nivolumab and later of the
combination of TIL, PEG-IFNa and nivolumab based on the CTCAE 4.0 criteria.
Secondary outcome
Secondary objectives include the evaluation of the disease control rate
according to RECIST 1.1 criteria and immune response criteria (irRC),
progression-free survival (PFS), overall survival (OS), and quality of life.
- Potential working mechanisms of the different treatment compounds will be
studied in PBMCs of the patients
- We will investigate a prognostic biomarker profile while investigating
amongst others the blood counts and values, markers on the infused TIL*s,
changes in the PBMCs and responses on previous treatments
- To find potential differences between the patients that have a clinical
response and/or had a clinical response in the past on immunotherapy with
immunomonitoring of the infusion T cell product
- To determine whether there is a potential correlations between the clinical
response and hypothesis related immune parameters in the patient*s tumor
material, blood, serum and the TILs used for infusion
- To study differences in immunological characteristics between CD8-rich and
CD8-poor metastases within a patient detected using CD8-immunoPET/CT, including
differences between TIL derived from both locations.
- To describe the clinical response to ACT in relation to [89Zr]Zr-crefmirlimab
berdoxam uptake on a lesion level.
- To study if [89Zr]Zr-crefmirlimab berdoxam uptake in non-affected tissues is
related to immune-related adverse events caused by ACT.
Background summary
The number of people diagnosed with melanoma has increased significantly in
recent years. Many patients already have advanced stages of melanoma at the
moment of diagnosis, which limits the survival. Despite the fact that a number
of drugs have been approved for the treatment of advanced melanoma, there is
still a need for new treatments for this disease. Patients with an irresectable
stage III or metastatic stage IV melanoma have a very poor prognosis with a
median survival of 6-9 months. The patients participating in this trial have
already had progressive disease on the standard lines of treatment.
In 2011, we published the results of our clinical study in patients with
metastatic skin melanoma treated with adoptive T-cell transfusion in
combination with low-dose IFNa. This treatment was safe and five out of ten
patients treated showed a clinical improvement. The T-cells used for these
infusions were PBMC-derived. Afterwards we started to grow T-cells from the
tumor, namely tumor infiltrating lymphocytes (TIL). In recent years, we have
treated 24 patients with TIL and IFNa. In contrast to the previous 10 patients,
18/24 patients had already been pre-treated with, amongst others,
immunotherapy.
Seven out of the 24 (5 of the 18 pre-treated) patients had clinical improvement
after T-cell transfusion with IFN-alpha, namely stable disease.
Compared to the Rosenberg protocol used in many other centers/countries (T-cell
transfusion in combination with high dose IL-2, chemotherapy and possibly
radiation) our protocol is much less toxic. To improve clinical effectiveness,
we want to add nivolumab to our schedule.
The majority of the T-cells administered is PD-1 positive. We believe that the
clinical benefit of ACT can be increased by combining this with anti-PD1
(nivolumab), as this will increase both the tumor reactivity of the normally
occurring tumor infiltrating lymphocytes and that of the adoptively infused T
cells.
With this new protocol we aim to solve 4 of the most important aspects
curtailing the efficacy of these immunotherapies:
1) the lack of sufficient numbers of activated tumor-reactive T cells in
patients by providing ACT
2) the inhibition of T-cell effector function through PD-1 signalling by
administration of nivolumab
3) the toxicity of high-dose IL-2
4) long term hospitalization of patients due to the conditioning-regimen used
in most ACT protocols by replacing it with low-dose PEG-IFNa treatment.
Notably, PD-1 antibodies in combination with PEG-IFNa at higher and comparable
doses has been tested and shown to have an acceptable safety profile. The
combination of TIL and IFNa have also been shown to be safe. This suggests that
the combination of these three compounds should be feasible.
Finally, in an expansion cohort of 12 patients, we will analyse if ACT derived
from CD8-rich metastases show higher (in vitro) antitumor activity than from
CD8-poor metastases as determined with CD8-immunoPET/CT imaging.
Study objective
The primary endpoint is the evaluation of the safety and toxicity of TIL with
nivolumab and, thereafter, the safety and toxicity of the combination of
PEG-IFNa, nivolumab plus TIL. Safety and toxicity will be evaluated according
to CTCAE 4.0 criteria.
Secondary endpoints include the evaluation of the disease control rate assessed
by physical examination and imaging studies (CT and/or MRI) and will be
evaluated according to RECIST 1.1 and immune related response criteria (irRC).
Furthermore, overall survival (OS) and progression-free survival (PFS) will be
evaluated and immune related parameters will be analysed. The CD8-immunoPET/CT
will be used to study the heterogeneity in CD8 T cell infiltration in the
different metastases within a patient.
Study design
Is a prospective, single centre, investigator initiated, phase I/II clinical
trial.
Intervention
Phase 1, Cohort 1 (n=9): Adding TIL therapy to anti-PD1 immunotherapy. The TIL
will be added 4 weeks after the first nivolumab infusion (on the same day as
the third nivolumab infusions). TIL will be given three times, three-weekly.
Phase 1, Cohort 2 (n=9): Adding PEG-IFNa to the treatment with TIL and
nivolumab immunotherapy. PEG-IFNa will be added 3 weeks after the first
nivolumab administration. Thereafter, PEG-IFNa will be continued for 11 weeks
in total. If no trSAE occur during the first treatment cycle, within a month
after ending the first cycle a second cycle can be given.
Phase 2 (n=25, including the 9 patients that were already treated in phase 1
cohort 2): Patient will be treated with TIL, PEG-IFNa and nivolumab. In this
phase of the trial we will use the international standard dosing of nivolumab:
480mg every four weeks. Whether the second treatment cycle will be given
depends on the effectiveness of the treatment. If the tumor has progressed of a
complete response occurs, the second treatment cycle will not be given.
Finally, in an expansion cohort of 12 patients, we will analyse if ACT derived
from CD8-rich metastases show higher (in vitro) antitumor activity than from
CD8-poor metastases as determined with CD8-immunoPET/CT imaging.
Study burden and risks
The risk of participating in the trial is the toxicity of TIL and nivolumab,
with or without the combination low dose PEG-IFNa. So far there are two
publications showing that the combination of PEG-IFNa in the same or higher
dose as we use is well tolerated in combination with nivolumab. Furthermore,
our own research groups and recently another group has shown that the
combination of IFN-alpha with TIL is also well tolerated. Therefore, we will
first start with the combination TIL and anti-PD1 in 9 patients to investigate
the safety of this combination.
In all patients participating in this trial tissue will be obtained by means of
a (small) surgical procedure. If possible, tissue will be taken again after the
cycle(s) have been completed. The surgical procedure can be painful and in rare
cases there may be bleeding and/or infection. There are no known side-effects
from the immuno-PET scan.
The appointments for TIL and anti-PD1 treatment are combined as much as
possible. As the second TIL administration falls between two nivolumab
infusions, patients will therefore have to come to the hospital extra for this.
Two hospital visits will be omitted in the phase II part of the trial, by using
the international standard nivolumab dose of 480mg every four weeks.
In addition, extra blood will be taken at fixed time-points. Each cycle
includes 7 blood samples, 350ml blood will be taken in total.
The patients who undergo immuno-PET scan wil have an extra appointment for this
scan.
Albinusdreef 2 2
2333ZA Leiden 2333 ZA
NL
Albinusdreef 2 2
2333ZA Leiden 2333 ZA
NL
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years.
2. Histologically or cytologically proven metastatic skin melanoma.
3. 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.
4. Patients with brain metastases have to be neurologically stable for at least
2 months and should not use dexamethasone.
5. Presence of measurable progressive disease according to RECIST version 1.1.
6. Expected survival of at least 3 months.
7. WHO performance status <=1.
8. 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
9. Viral tests:
-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
10. Able and willing to give valid written informed consent.
11. Progressive disease on prior treatment with f.e. BRAF-inhibitors,
MEK-inhibitors or immunotherapy, including anti-PD1 treatment. Systemic therapy
with BRAF-/MEK-inhibitors must have been discontinued for at least two weeks
before start of study treatment. Treatment with immunotherapy must have been
discontinued for at least four weeks before start of study treatment.
Exclusion criteria
1. Patients with brain metastases who are neurologically unstable and/or use
dexamethasone.
2. Clinically significant heart disease (NYHA Class III or IV).
3. 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.
4. Active immunodeficiency disease, or autoimmune disease requiring immune
suppressive drugs or autoimmune adverse events following treatment with
checkpoint inhibitors. Vitiligo is not an exclusion criterion
5. Other malignancy within 2 years prior to entry into the study, except for
treated non-melanoma skin cancer and in situ cervical carcinoma.
6. Mental impairment that may compromise the ability to give informed consent
and comply with the requirements of the study.
7. Lack of availability for follow-up assessments.
8. Pregnancy or breastfeeding.
9. 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.
10. 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
11. Known allergy to penicillin or streptomycin (used during the culturing of
T cells)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-004426-41-NL |
| CCMO | NL64805.000.18 |