Objectives Primary end point:- to define the MTD of IL-2, subcutaneously given once a day, 5 days per week, for 6 weeks, in combination with a fixed dose of sorafenib in patients with metastatic RCC, clear cell subtype. Secondary end points:- the…
ID
Source
Brief title
Condition
- Metastases
- Ureteric disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Only patients who start concurrent IL-2 treatment are evaluable for this study.
If treatment with sorafenib during the first 4 weeks has to be stopped,
interrupted or adjusted because of dose-limiting toxicity (DLT) (see for
definition of DLT below) or other reasons, patients will go off-study and will
be replaced. In these cases, patients are allowed to continue treatment with
sorafenib according to the treating physician*s opinion.
Adverse events that are encountered during the first cycle when IL-2 is
co-administered (6 weeks) will be used to guide dose escalation and to define
the MTD. Adverse events will be graded according to the NCI-CTC version 3.0.
Dose-limiting toxicity (DLT) will be defined as those adverse advents that are
considered possibly, probably, or definitely related to the study drugs.
DLT is defined as:
- grade 4 neutropenia or grade 4 thrombopenia
- grade 3 or greater non-hematologic adverse events except fever, rigor/chills,
renal dysfunction, hypertension, nausea/vomiting, diarrhea, and fatigue for
which the following criteria will apply:
o fever or rigor/chills of any grade will not be considered DLT
o creatinine >= 2 x ULN
o hypertension with systolic blood pressure >= 160 mmHg and/or diastolic blood
pressure >= 100 mmHg lasting longer than 14 days despite adequate treatment
o grade 3 or greater persistent (more than 7 days) nausea/vomiting despite
adequate treatment or prophylaxis
o grade 3 or greater (more than 7 days) diarrhea despite adequate treatment or
prophylaxis
o grade 4 fatigue
At each dose level, at least 3 patients will be treated. Patients in each dose
level will be treated for 4 weeks with sorafenib (400 mg bid) (run-in period).
After this, IL-2 will be administered at the designated dose for that dose
level. When each patient of the first three entered patients in a particular
dose level has had 6 weeks of treatment with the combination of sorafenib and
IL-2 without a DLT, the IL-2 dose will be escalated in the next cohort. In case
a single patient of the first three patients at a dose level encounters DLT,
then that dose level will be expanded to 6 patients. If no more DLTs occur in
the additional three patients (in total 1 DLT/6 patients), then the IL-2 dose
will be escalated in the next cohort. In case a total of two or more DLTs
develop in the first 6 patients of a cohort, then this dose level is declared
the toxic dose. The dose level below the toxic dose or the maximum dose level
explored will be expanded to a total of 10-12 patients to get more insight in
the exact toxicity profile and will be declared the maximum tolerated dose
(MTD) if the final DLT rate is < 33%.
Secondary outcome
Pharmacokinetics:
To assess whether concurrently administered IL-2 affects pharmacokinetics of
sorafenib, systemic blood levels of sorafenib will be determined at the end of
the run-in period at day 29 prior to the first administration of IL-2 alone
when sorafenib is given as single agent and at day 5 after starting IL-2 sc.
Per time point 20 ml will be sampled.
Cytokines:
To assess the effects of sorafenib as well as of the combination of sorafenib
and IL2 on VEGF and interleukin-6 (IL-6) levels in the peripheral circulation,
20 ml peripheral blood (serum) will be sampled at:
Base-line, day 29 run-in period prior to the first administration of IL-2, day
5 after start concomitant IL-2, day 43 after start concomitant IL-2.
Peripheral blood cells:
To assess the effects of sorafenib as well as of the combination of sorafenib
and IL2 on peripheral blood cells (NK-cells (CD56+, CD3-), Cytotoxic T-cells
(CD3+, CD8+), T-helper cells (CD3+, CD4+), Regulatory T-cells (CD3+, CD4+,
CD25bright/Foxp3)), 30 ml blood (EDTA/heparin) will be sampled at:
Base-line, day 29 run-in period prior to the first administration of IL-2, day
5 after start concomitant IL-2, day 42 after start concomitant IL-2.
Background summary
Renal cell carcinoma is a relatively rare tumor type accounting for
approximately 1500 new cases each year in The Netherlands, of which the clear
cell subtype is the most predominant one. The vast majority of patients
presents with localised disease, but dependent on stage at presentation many of
these patients experience metatastic disease later on. For these and for those
patients initially diagnosed with metastatic disease systemic treatment is
indicated.
Until recently, the only available treatment option for patients with
metastatic RCC was cytokine-based treatment with interferon-α (IFN-α) or
interleukin-2 (IL-2) containing regimens. It has been shown that only patients
with advanced RCC from the clear cell subtype benefit from cytokine-based
treatment, while patients with other tumor subtypes such as the chromophobic or
papillary subtype do not. Therefore, IFN-α or IL-2 based regimens have been
considered standard treatment for patients presenting with advanced clear cell
RCC with only few durable complete responses.
Recently, novel compounds have been developed inhibiting VEGF-R mediated
effects by targeting the tyrosine kinase domain of the VEGF-R, which is
essential for signal transduction of this receptor. One of these drugs is
sorafenib, which has recently been explored for its anti-tumor activity in
clear cell RCC. In a randomised, placebo-controlled trial in patients with
progressive disease after first line cytokine-based treatment, sorafenib
improved both progression-free and overall survival as compared to placebo at
the expense of an acceptable toxicity profile.
The combination of IL-2 and a VEGF-R tyrosine kinase inhibitor such as
sorafenib is a theoretically promising regimen in patients with advanced clear
cell RCC. Next to the fact that both sorafenib and IL-2 exhibit anti-tumor
activity against this tumor entity, synergistic activity may be expected when
these two drugs are concurrently applied.
Study objective
Objectives
Primary end point:
- to define the MTD of IL-2, subcutaneously given once a day, 5 days per week,
for 6 weeks, in combination with a fixed dose of sorafenib in patients with
metastatic RCC, clear cell subtype.
Secondary end points:
- the effect of IL-2 co-administration on plasma sorafenib pharmacokinetics.
- to evaluate disease response according to RECIST criteria and time to
progression.
- to establish the effect of treatment on immune cell populations and
cytokines.
Study design
This is a clinical phase I dose escalation study in metastatic clear cell renal
cancer patients with sorafenib and subcutaneous IL-2.
Intervention
All patients will be continuously treated with a fixed dose of sorafenib, 400
mg bid. If after 4 weeks of sorafenib treatment (run-in period), patients have
no signs of progressive disease and tolerate sorafenib well, IL-2 will be added
according to pre-defined dose cohorts with 3-6 patients per cohort.
Initial dose level:
During the first week 9 MU per day, in the subsequent 5 weeks the first two
days 4.5 MU per day followed by 9 MU per day for the remaining 3 days.
If the initial dose level is not the toxic dose, then the next and highest dose
level will be:
During the first week 18 MU per day, in the subsequent weeks the first two days
9 MU per day followed by 18 MU per day for the remaining 3 days.
If the initial dose level is the toxic dose, then the next and lowest dose
level will be:
During the first week 4.5 MU per day, in the subsequent weeks the first two
days 2.25 MU per day followed by 4.5 MU per day for the remaining 3 days.
Study burden and risks
For patients with advanced-stage renal cell cancer no curative treatment exists
except high-dose IL-2 that results in durable complete remissions in 7-8% of
cases. Also treatment with the new oral receptor tyrosine kinase inhibitors,
such as sorafenib and sunitinib, have not been shown to result in complete
remissions. Therefore, more research is required to improve the treatment of
these patients. The combination of sorafenib and IL-2 is potentially more
active than the drugs alone. Since this combination has not been tested before,
but both drugs are registered for treatment of advanced-stage RCC, a phase I
study is needed to define the toxicity and maxium tolerated dose of IL-2 in
combination with flat dose sorafenib.
The examinations required for participation in this trial are standard and the
extra blood sampling is not considered a heavy burden for these patients.
Plesmanlaan 121
1066 CX Amsterdam
NL
Plesmanlaan 121
1066 CX Amsterdam
NL
Listed location countries
Age
Inclusion criteria
- Patients with cytologically or histologically proven RCC, clear cell subtype, with documented progressive disease either after first line, interferon(IFN)-α- or interleukin-2-based therapy or for whom IFN-α-based treatment is not considered appropriate because of prognostic features according to Motzer.
- Evaluable and measurable disease (according to RECIST criteria)
- PF 0-1
- Adequate bone marrow, hepatic and renal function
- life expectancy of at least 3 months
- age of 18 or older
- willingness to use a medically approved method of contraception
- before patient randomization, written informed consent must be given and documented to ICH/EU GCP, and national/local regulatory requirements and the local rules followed in the institution
Exclusion criteria
- Uncontrolled or poorly controlled hypertension (systolic blood pressure >= 150 mmHg, diastolic blood pressure >= 90 mmHg). Initiation or adjustment of blood pressure medications is permitted prior to study treatment provided that 3 consecutive blood pressure readings are <= 150/90 mmHg, each separated by at least 24 hours
- Concurrent therapy with prohibited medication
- History of malabsorption syndrome or other disease that could significantly affect absorption of drugs
- Other malignancies (previous or current), except adequately treated basal or squamous cell carcinoma of the skin and carcinoma in situ of breast or cervix
- Prior treatment with VEGF or VEGF-R targeting agent (monoclonal antibody or tyrosine kinase inhibitor)
- Cytotoxic, hormonal, investigational treatment or immunotherapy within 4 weeks prior to day 1 of study treatment
- Major surgery within 4 weeks prior to study treatment
- Persistent grade 2 or greater toxicity related to prior treatment (except alopecia) (NCI-CTC version 3.0)
- History of any infection requiring hospitalisation or antibiotics within 2 weeks prior to study treatment
- Systemic steroids within 2 weeks prior to study treatment
- Myocardial infarction or cerebrovascular accident (CVA) within 6 months prior to study treatment
- Congestive heart failure requiring medication
- Known brain metastases
- Known human immunodeficiency virus (HIV) infection
- Known chronic or acute viral hepatitis
- Pregnant or breast-feeding women.
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 | EUCTR2006-004010-40-NL |
| CCMO | NL13627.031.06 |