Objectives: 1. The primary objective is to evaluate the safety and immune modulation of TIL plus IFN* in epithelial ovarian cancer (EOC) patients and to determine the optimal dose of IFN* that can be given in combination with chemotherapy.2.…
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Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of this phase I clinical trial is to evaluate the safety
and toxicity of Adoptive T cell therapy in combination with IFN* according to
CTCAE version 4.0 criteria.
For platinum sensitive patients this will be studied in combination with
chemotherapy and three cohorts of a reduced dose of IFN*.
For these 3 cohorts a phase I design will be followed: If a dose-limiting
toxicity (DLT) occurs in one of the three patients
within one cohort, then three additional patients will be treated at that dose
level. If a DLT occurs in 2/3 or 2/6 patients, the previous dose level will be
expanded to at least 6 patients.
DLT is defined as follows:
Any DLT must be a toxicity that is considered related to study drug.
Hematologic
* Absolute neutrophil count (ANC) < 0.5 x 109/L for at least 7 days
* Febrile Neutropenia (ANC < 1.0 x 109/L, fever > 38.5oC)
* Platelets < 25 x 109/L
* Bleeding felt to be due to thrombocytopenia
Non-Hematologic:
* Diarrhoea > Grade 3 despite optimal loperamide use persisting * 2 weeks
* Nausea / vomiting > grade 3 despite optimal use of anti-emetics, persisting *
2 weeks.
* Other grade 3 / 4 effects thought to be treatment related
Secondary outcome
Secondary endpoints are the evaluation of a clinical response according to
RECIST 1.1 and immune response criteria (irRC), progression free survival (PFS)
and overall survival (OS). Clinical benefit is defined as Stable Disease (SD),
Partial Response (PR), or Complete response (CR). Additional endpoints are
blood CA125 levels and analysis of (induced) immune parameters in patient*s
blood and serum, in the T cells used for infusion and in the primary tumor.
Background summary
The 5 year survival of patients with epithelial ovarian cancer (EOC), despite
standard therapy with surgery and if indicated perioperative chemotherapy, is
35%. There is an urgent need for an improved therapy.
The successful use of adoptive T-cell therapy (ACT) in melanoma and the clear
correlation between T cell infiltration and disease progression in EOC suggests
that EOC may display a similar sensitivity to TIL treatment. In order to be
effective, transferred TIL should survive and persist in vivo, migrate to the
tumor and eradicate tumor cells. To obtain TIL persistence and increase TIL
survival after transfer we combine TIL infusions with low dose IFN-alpha
(IFN*). We previously showed that this combination resulted in clinical benefit
in 50% of the melanoma patients treated with ACT using PBMC-derived
tumor-specific T cells [Verdegaal et al Canc.Immunol. Immunoth. 2011].
Recently, clinical benefit was also obtained in patients treated with
tumor-derived TIL plus IFN* [unpublished data]. Once migrated to the tumor, the
anti-tumor activity of T cells is dramatically affected by the presence of
myeloid-derived suppressor cells (MDSC) in the tumor-microenvironment. From our
clinical trials in patients with recurrent cervical cancer we know that the
frequency of circulating myeloid cells (macrophages and MDSC) is increased in
these patients, but that the myeloid cell compartment is normalized to levels
observed in healthy subjects, after carboplatin+paclitaxel chemotherapy. We
also observed this normalisation circulating myeloid cells after chemotherapy
in patients with recurrent ovarian cancer treated with gemcitabine. Notably, we
showed that chemotherapy could be excellently combined with immunotherapy. The
myeloid cell population is also altered in patients with ovarian cancer. As the
patients in the current trial are also treated with carboplatin+paclitaxel or
gemcitabine, a chemotherapy-driven normalization of the myeloid cell population
and hence a better response to immunotherapy is expected. We therefore suggest
to study whether clinical benefit can be obtained in ovarian cancer patients
with a combination of TIL + low dose IFN* and chemotherapy.
Study objective
Objectives:
1. The primary objective is to evaluate the safety and immune modulation of TIL
plus IFN* in epithelial ovarian cancer (EOC) patients and to determine the
optimal dose of IFN* that can be given in combination with chemotherapy.
2. Secondary objectives:
a. Evaluation of the clinical response (according to RECIST 1.1 criteria) and
immune response criteria (irRC), progression free survival (PFS) and overall
survival (OS).
b. Immunological parameters will be evaluated and correlated to clinical
response parameters.
Study design
This phase I clinical trial is a controlled intervention study. The safety,
toxicity, clinical and immunological response will be evaluated.
Intervention
TIL for treatment will be cultured from tumor material obtained from primary
surgery, as well as from biopsies . The latter reflect the way tumor material
will be acquired from stage IIb-IIIb patients and for stage IIIc and IV tumor
material will be obtained at primary surgery.
Patients with platinum sensitive tumor recurrence (n=6-18):
Patients will be treated with TIL infusions + IFN* in combination with
chemotherapy. TIL therapy will be similar as described above.
Since we do not know whether the standard dose of IFN* that was used during ACT
treatment of melanoma patients is tolerated when patients receive concomitant
chemotherapy, we will study the combined TIL plus chemotherapy treatment in
three cohorts using a reduced dose of IFN* (3x10e6 U every other day, n=3), the
standard dose of IFN* (3x10e6 U daily, n=3) or pegylated- IFN* (PEG-Intron, 0,5
*g/kg (maximum dose 50 *g) once a week, n=3).
Patients with platinum resistant disease (n=6):
will be treated with TIL infusions + the standard dose of IFN* (3x10e6 U daily)
combined with standard chemotherapy, gemcitabine.
Study burden and risks
Risk:
The risk of participation are toxicity of the ACT plus IFN*. For most patients
tissue will be obtained at primary surgery and for some patients an extra
biopsy will be necessary. An extra biopsy is painfull but rarely gives a
bleeding or infection.
Benefit:
Patients with recurrent ovarian cancer, have a poor prognosis for which
further improvement of alternative treatment options is necessary. The chance
to obtain clinical benefit in these patients, that otherwise have a very bad
prognosis, justifies for the burden and possible toxicities.
Albinusdreef 2
Leiden 2333ZA
NL
Albinusdreef 2
Leiden 2333ZA
NL
Listed location countries
Age
Inclusion criteria
* Age * 18 years.
* Histologically proven epithelial ovarian cancer.
* Recurrent ovarian cancer
* Presence of measurable progressive disease according to RECIST version 1.1 or
elevated CA125, 2 times the upper normal limit (UNL) within 3 months and
confirmed.
* Expected survival of at least 3 months.
* WHO performance status 0-2.
* Within the last 2 weeks prior to study day 0, 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 * 50 min/ml
Serum bilirubin * 40 *mol/l
ASAT and ALAT * 5 x the normal upper limit
LDH * 2 x the normal upper limit
* Viral tests:
o Negative for HIV type 1/2, HTLV and TPHA
o No HBV (hepatitis B virus) antigen or antibodies against HBc in the serum
o No antibodies against HCV (hepatitis C virus) in the serum
* Able and willing to give valid written informed consent.
* Prior treatment, including immunotherapy e.g. with anti-PD(L)1, is allowed but
systemic therapy and radiotherapy must have been discontinued for at least two
weeks before study entry.
* Patients should have PD.
Exclusion criteria
Patients will be excluded from the study for any of the following reasons:
* Patients with brain metastases
* 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 or autoimmune disease requiring immune suppressive drugs. Vitiligo is not an exclusion criterion.
* 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.
* Lack of availability for follow-up assessments.
* Pregnancy or breastfeeding.
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 | EUCTR2016-002404-25-NL |
| CCMO | NL56136.000.16 |