To determine the safety and tolerability of L19-IL2 combined with SABR.
ID
Source
Brief title
Condition
- Other condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Health condition
Solide tumoren
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety and Tolerability of the combination treatment (CTCAE4.03).
Secondary outcome
Progression-free survival, overall survival, local control rate, quality of
life (EORTC QLQ-C30 version 3.0 and QLQ-LC13 questionnaires).
Background summary
The formation of metastasis is responsible for as much as 90% of
cancer-associated mortality. Numerous patients with locoregional disease of a
solid tumor initially treated with curative intent develop (oligo)metastases
during the course of disease. In both instances, these stage IV patients are
generally considered to be incurable and mostly treated palliatively.
Oligometastases, defined as 1-5 sites of active disease on whole body imaging,
was coined to refer to isolated sites of metastasis resembling limited tumor
metastatic capacity. The implication of this concept is that local cancer
treatments are curative in a proportion of patients with metastases (1) and
that incorporating local therapy is a conceptually attractive approach (1, 2).
In several, but not all, academic centers the standard treatment of patients
with oligometastases in good general health is standard systemic therapy
followed by surgery or by Stereotactic Ablative Body Radiotherapy (SABR) with
radical dose on the macroscopic visible tumors.
The widespread introduction of SABR and of minimally invasive surgery has
fuelled research in treating patients with oligometastases (3-11). Indeed,
local control of metastases can be obtained in virtually all parts of the body
with a low proportion of patients experiencing severe side effects. In the few
prospective studies published to date, approximately 20% of patients remained
free of recurrence several years after treatment when all sites of disease were
targeted by radiation.
Along with standard anti-cancer therapeutic modalities like chemotherapy and
radiotherapy (RT), immunotherapy has recently gained a lot of attention.
Angiogenesis is one of the hallmarks of cancer, and therefore, considerable
efforts have been made to exploit this unique target for selective drug
delivery. One of the appealing targets for both approaches is the splice
variant of fibronectin containing extra domain B (EDB), which is abundantly
expressed in vascular endothelial cells of a variety of primary tumors as well
as metastases , but virtually absent in normal tissues (12-14). Recently, a
human recombinant scFv fragment directed against EDB, designated L19, was
developed (15) and subsequently combined with the pro-inflammatory
interleukin-2 (IL2), resulting in the immunocytokine L19-IL2. L19-IL2 delivers
high doses of IL2 to the (metastatic) tumor site(s) exploiting the selective
expression of EDB on newly formed blood vessels. Interleukin-2 (IL2) plays an
essential role in the activation phases of both specific and natural immune
responses. Even though it has no direct cytotoxic effects on cancer cells, it
can induce tumor regression by stimulating a potent cell-mediated response
(16). In summary, L19-IL2 is an immunocytokine which will stimulate immune
response specifically in tumors with angiogenesis and tissue remodeling.
Radiotherapy is a particularly interesting partner for immunotherapy, since it
can be harnessed to specifically modify the immunogenicity of the primary
tumors and their microenvironment, in the attempt to generate an in situ
immunization of the host against a patient*s own cancer. Our overall hypothesis
is that three independent therapeutic approaches will synergize to improve
dramatically survival in patients with oligometastases of solid tumors.
The three hypotheses pursued are that combining L19-IL2 with SABR will lead to:
* Direct cytotoxic effect of SABR to all detected metastatic lesions;
* Immunogenic cell death induced by radiation creating an abscopal systemic
effect of SABR thus eliminating micrometastases;
* Modification of tumor immunogenicity with L19-IL2 treatment (systemic).
Study objective
To determine the safety and tolerability of L19-IL2 combined with SABR.
Study design
This study includes patients who were diagnosed with metastasized cancer as
well as patients who have developed metastases in the course of the disease
(possibly after surgery of radiation).
(1) Information about the standard treatment will be given by the treating
physician.
(2) The study treatment consists of the administration of L19-IL2, which starts
one week after completion of the radiotherapy. L19-IL2 will be administered via
an intervenous infusion on day 1, 3 and 5 of every cycly of 3 weeks (with a
maximum of 6 courses in total). The dose of L19-IL2 will be increased in 3
steps from low dosage to high dosage.
L19-IL2 is administered on day 1, 3 and 5 of every cycle via an intravenous
infusion during three hours. A cycle will take 3 weeks and in total, a patient
can receive 6 cycles. The total treatment time therefore is 18 weeks maximum.
For the L19-IL2 infusion, we advise to take 1000mg of paracetamol to prevent
any possible flew-like complaints.
The first group of patients will be administered 15 Mio international units
(IU) via infusion. If no dose limiting toxicities occur, the dosis will be
increased to 22,5 Mio IU with a new group of patients. The dosage for an
individual patient will remain identical during the maximum of 6 cycles.
Intervention
Intravenous treatment with L19-IL2 on day 1, 3 and 5 of every cycle of three
weeks. To a maximum of six cycles.
Prior to start of radiation extra examinations:
* Bloodtest
* 18FDG-PET-CT scan (standard)
Prior to start of the intravenous treatment extra examinations:
* Bloodtest
* After 3 cycles of L19-IL2 and three months after the end of the last
intravenous treatment every time an 18FDG-PET-CT scan. The data of these scans
will probably in the future help selecting patients who benefit from the
proposed study treatment.
* If additional consent was given: tissue sampling of the tumour or metastases.
This shall prefarably take place before, during and after treatment. This
examination will be focussed on the underlying reaction of the tumourtissue to
the treatment in the laboratory. Depending on the localisation of the
tumour/metastases, the treating physician will offer this examination and
discuss with the patient how to approach this in a way the burden for the
patient will be minimal.
* If addition consent was given: blood sampling at 5 moments during the study
which will be stored at Biobank UM for immunological assessment.
Study burden and risks
Known/potential risks include: fever with chills, fatigue, nausea, vomiting,
asthenia, (peripheral) edema, skin rash, hyperhydrosis, chest pain, pruritus,
elevated serum creatinine levels and pain at tumor site. Signs of mild
capillary leak syndrome and hypotension were found in the dose-limiting dosage
level that is subsequently not studied here.
The (potential) benefit found in stage IV melanoma/renal cell carcinoma
patients is a prolonged progression-free survival and possibly overall
survival. However, these questions will be the subject of the possible
subsequent phase II/III clinical studies combining L19-IL2 with SABR.
Furthermore there are the (small) risks of bloodwithdrawal and the intravenous
administration. Also, patients will receive a higher level of radiation as a
consequence of the extra scans.
Dr. Tanslaan 12
Maastricht 6229 ET
NL
Dr. Tanslaan 12
Maastricht 6229 ET
NL
Listed location countries
Age
Inclusion criteria
-Histological or cytological confirmed oligometastatic originating from non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), renal cell carcinima (RCC) and melanoma occurring synchronous (at time of diagnosis) or metachronous (> 6 months after radical treatment for primary tumor; i.e., surgically). A biopsy could be omitted in selected cases if a biopsy is medically contraindicated or unfeasible (e.g. fear of entmetastasis, lesion not accessible). In this case the diagnosis of metastatic disease should be certified using an alternative approach (e.g. imaging,...);
-More diffuse metastasized NSCLC patients, with up to 10 metastasis that received standar of care primary chemotherapy with a platinum doublet for a maximum of 6 cycles are also allowed in case these patients showed at least disease control under this treatment (complete remission, partial respnse or stable disease according to RECIST1.1);
-All oligometastatic tumor sites (including brain) are eligible;
-* 5 metastases, or 4 if the primary tumor is to be treated concomitantly;
-* 3 metastatic lesions confined to one organ;
-* 2 organ systems affected with metastases;
-WHO performance status 0-2;
-Adequate bone marrow: Normal white blood cell count and formula, normal platelet count, no anemia requiring blood transfusion or erythropoietin;
-Adequate hepatic function: total bilirubin * 1.5 x upper limit of normal (ULN) for the institution; ALT, AST, and alkaline phosphatase * 2.5 x ULN for the institution);
-Adequate renal function: MDRD calculated creatinine clearance at least 60 ml/min;
-The patient is capable of complying with study procedures;
-Signed and dated written informed consent;
-Life expectancy of at least 12 weeks;
-For women of childbearing potential, a negative pregnancy test prior to the first dose of study treatment;
-Men and women with reproductive potential must be willing to practice acceptable methods of birth control during the study and for up to 12 weeks after the last dose of study medication.
Exclusion criteria
-Other oligometastatic (hormone-sensitive) solid tumors;
-Previous radiotherapy to an area that would be re-treated by SABR;
-Previous systemic treatment to treat recurrent disease;
-Other active malignancy or malignancy within the last 2 years (with exception of localized skin basal/squamous cell carcinoma, bladder in situ carcinoma);
-History of allergy to intravenously administered proteins/peptides/antibodies;
-HIV infection, active infection, or active hepatitis;
-Chronic use of corticosteroids used in the management of cancer or non-cancer-related illness;
-Acute or sub-acute coronary syndromes within the last year, acute inflammatory heart disease, heart insufficiency or irreversible cardiac arrhythmias;
- Impaired cardiac function defined as left ventricular ejection fraction (LVEF) <50% (or below the studý site's lower limit of normal) as measured by MUGA of echo. (LVEF measurements dating back up to 8 weeks will be acceptable in the absence of incurrent use of potentially cardiotoxic treatment or cardiac medical history);
- Uncontrolled hypertensive disease;
-History or evidence of active autoimmune disease;
-Severe diabetic retinopathy;
-Major trauma including surgery within 4 weeks prior to the first L19-IL2 infusion. Focal biopsies in the tumor are allowed;
-Any underlying medical or psychiatric condition which in the opinion of the investigator will make administration of study drug hazardous or hinder the interpretation of study results (e.g., AE);
-Unstable or serious concurrent uncontrolled medical conditions;
-Pregnancy or breast-feeding.
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 | EUCTR2014-001955-22-NL |
| ClinicalTrials.gov | NCT02086721 |
| CCMO | NL49389.068.14 |