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Dovitinib In 1st-Line Renal Cell Carcinoma, an Investigation Into Tumour GENe Status and Correlation With Efficacy - 1st Exploratory Study

Phase 2
18 Years
Open (Enrolling)
Clear Cell Renal Cell Carcinoma

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Trial Information

Dovitinib In 1st-Line Renal Cell Carcinoma, an Investigation Into Tumour GENe Status and Correlation With Efficacy - 1st Exploratory Study

The purpose of this prospective, single centre, non-randomised, open-label, phase II study
will evaluate the activity of dovitinib in the treatment naïve population of patients with
advanced RCC.

Background: Prior to the middle of last decade, the only systemic therapy for patients with
advanced RCC was immunotherapy (interleukin-2 and interferon-alpha) with limited
effectiveness and a multitude of side-effects. Since 2006, there have been 6 targeted
therapies that have been FDA-registered for the treatment of advanced RCC; the anti-VEGFR
tyrosine kinase inhibitors (sunitinib, sorafenib and pazopanib), the anti-VEGF antibody
bevacizumab (with interferon-alpha) and the mTOR inhibitors (everolimus and temsirolimus).
These treatments have significantly advanced outcomes for patients with this disease but
unfortunately they do not represent cures. The median overall survival for patients treated
with a standard first-line therapy (sunitinib) is just over 2 years and the median PFS for
subjects receiving this agent is only 11 months. This means that the typical time it takes
for subjects to develop resistance to standard first-line tyrosine kinase inhibitor (TKI)
treatment, as evidenced by significant tumour growth on imaging, is under 1 year.

Despite the recent rapid advancements in the treatment options for subjects with advanced
RCC, there is still an unmet need for more effective therapeutic options for patients with
this disease so as to improve survival and make steps towards the ultimate treatment aim for
patients with metastatic disease - cure. Available data suggests that dovitinib is a very
active agent in metastatic RCC. If it has efficacy in the heavily pre-treated RCC
population, one would expect it to be considerably more active when it is moved forward into
the first-line setting.

Dovitinib is a broad-targeted receptor Tyrosine Kinase Inhibitor (TKI) primarily active
against three receptors that mediate tumour growth and survival: vascular endothelial
growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and
fibroblast growth factor receptor (FGFR). A distinguishing feature of dovitinib (compared
to other anti-VEGFR TKI's) is its FGFR inhibition. Up-regulation of the fibroblast growth
factor receptor 1 (FGFR1) pathway has been demonstrated in metastatic RCC and is a
postulated mechanism of resistance to anti-VEGFR therapies. This is thought to be one of
the reasons why dovitinib has activity in subjects treated with prior anti-VEGFR therapies.
If we move the FGFR inhibition forward into the first-line setting (by using dovitinib) we
hope to be able prevent or delay the development of resistance acquired through FGFR
up-regulation. We hope this may allow subjects to remain on first-line therapy for much
longer and in doing so improve survival and outcomes for this group of patients.

Dovitinib has been studied in heavily pre-treated subjects with metastatic RCC, and in these
phase I/II studies it looks very active. If it has efficacy in the heavily pre-treated RCC
population, it is possible it would be more active when it is moved forward in to the
first-line setting.

While we have good prognostic markers to risk-stratify subjects with RCC, there is a lack of
predictive markers to guide us as to which patients are best served with each of the
different agents available for use. It is therefore imperative that drug development studies
in this disease have companion biomarker analysis to identify potentially useful predictive
biomarkers for future research. This study also aims to explore (using FISH) the
amplification/deletion status of range of genes-of-interest, selected for their relevance to
the biology of RCC and the mechanism-of-action of dovitinib. Amplification/deletion of these
genes will be further validated using DNA sequencing. The status of these genes-of-interest
will be correlated with outcomes of these subjects treated with dovitinib.

The hypothesis of this study is that dovitinib will demonstrate anti-tumour activity when
administered to subjects with advanced RCC in the first-line setting and that this activity
will correlate with FGFR gene amplification status.

The primary objective is to evaluate the activity of dovitinib in the treatment naïve
population of patients with advanced RCC.

Secondary Objectives:

- To determine the gene amplification status for FGFR-1,-2,-3 in this patient population

- To measure the strength of the correlation between measures of clinical efficacy and
FGFR gene amplification status

- To further evaluate safety

Exploratory Objectives:

- To assess for amplifications/deletions for genes related to RCC biology in this group
of subjects treated with dovitinib.

- To correlate gene amplification status with DNA gene sequence.

- To evaluate differences in tumour gene status between primary and metastatic samples
from same subject and again on post-treatment biopsy to elucidate mechanisms of
resistance to dovitinib.

- To evaluate effects of dovitinib on bone metastases and pain.

Investigational treatment: Thirty patients from the greater Auckland region will be treated
with dovitinib (500 mg p.o. o.d., 5 days on/2 days off) until disease progression,
unacceptable toxicity, patient withdrawal or death.

The primary analysis will be performed when 20 progression and/or death events have
occurred. No interim efficacy analysis is planned for this study. However, an independent
Data Monitoring Committee (DMC) will review data collection (including analysing the adverse
event information) and will meet at specified time points during the study.

Visit schedule: Patients will attend clinic visits every 3 weeks while on treatment. Tumour
response assessments will occur every 9 weeks until week 54, then every 12 weeks thereafter
until disease progression (estimated median time to disease progression = 16 months). Once
all patients have completed study treatment, patients will continue to be followed up
3-monthly until approximately 2 months after 20 death events have occurred.

For each patient there will be three separate phases in the study: pre-treatment (screening
& baseline), treatment and follow-up.

Pre-treatment phase (Screening/Baseline): The patient must provide a signed informed
consent form (ICF) prior to any study related procedure. A screening period of 28 days is
allowed to assess eligibility. Radiologic evaluation (CT of the head, chest, abdomen and
pelvis) and baseline tumour measurement using RECIST v1.1 will be performed. Other screening
and baseline assessments include ECG & echocardiogram to assess cardiac function,
performance status assessment (ECOG & WHO), physical examination (including the buccal
cavity), height, weight & vital signs. Laboratory investigations include haematology,
chemistry, amylase, lipase, serum lipid profile, coagulation, urinalysis, thyroid function,
cardiac enzymes and pregnancy test (if applicable). Disease specific information, general
medical information including medical history, concomitant medications, prognostic group
according to Heng criteria and demographic data will also be collected.

Treatment phase: This study does not have a fixed treatment duration, as patients will
continue therapy until disease progression, intolerable toxicity or withdrawal. Following
study inclusion and initiation of study treatment, the patient should visit the site on day
1, 8 and 15 during cycle 1, then day 1 of every subsequent cycle. Patients will have their
first dose of study treatment on Day 1, Cycle 1. A study cycle is defined as a period of 21

Tumour response will be evaluated every 3 cycles after registration until week 54, then
every 4 cycles until documented disease progression. ECOG performance status will be
assessed on day 1 of every cycle. Safety assessments are routinely performed including
collection of adverse events (AEs), Serious Adverse Events (SAEs), concomitant medications,
vital signs, physical examination, weight, haematological and biochemistry assessments,
urinalysis, thyroid function and cardiac enzymes. ECG, amylase, lipase, serum lipids and
coagulation will be measured if clinically indicated. An echocardiogram will be performed
at weeks 12 and 24, and as clinically indicated. Plasma for storage will be collected on
Day 1 of Cycles 1 and 3. Participants with bone metastases will have plasma collected for
C-telopeptide testing on day 1 of weeks 1, 2 and 13, and will complete a Quality of Life
questionnaire (FACT-BP) at 4 time points: on day 1 of weeks1, 2, 4 and 13.

The End of Treatment (EOT) visit will take place approximately 7 days after the last dose of
dovitinib. At this visit the following assessments will be performed and the following data
collected: physical examination, ECOG performance status, weight, vital signs, adverse
events, concomitant medications, antineoplastic therapies, haematology, biochemistry,
amylase and lipase measurements.

Safety follow-up: All patients who discontinue study treatment will have a safety follow-up
visit within 30 days of the last dose of dovitinib. Safety assessments will include
collection of AEs, SAEs, vital signs, concomitant medications and any new antineoplastic
therapies. Patients who progress will be invited to provide an (optional) additional biopsy
sample of their tumour, at least 10 days after the last dose of dovitinib, but before any
new anticancer therapies are initiated.

Efficacy follow-up: Patients who discontinue the study treatment for reasons other than
progression will continue to have radiologic assessments, using the same schedule as for
patients who remain on treatment, until documented disease progression.

Survival follow-up: Patients who have discontinued study treatment will be followed-up for
survival every 3 months by clinical visits or telephone call until death occurs, the patient
is lost to follow-up, or withdraws consent for follow-up for survival. Further treatment
will be at the discretion of the investigator.

Statistical Methods: All data will be presented descriptively as means, medians or
proportions. Progression free and overall survival from the first dose of dovitinib until
disease progression or death will be determined using the method of Kaplan-Meier. The
correlation between PFS, OS and baseline biomarker status as well as FGFR gene amplification
status will be measured using Spearman's rho. Generalized estimating equations (GEE) for
repeated measures will also be used to test the significance of changes in biomarker
amplification status relative to baseline. Ordinal logistic regression analysis using a
repeated measures structure will be applied to compare bone pain control over the treatment
period relative to baseline.

Sample Size Calculation and Expected Duration: The response rate (RR) reported for
sunitinib, when studied in a phase III trial versus interferon in the first-line setting was
approximately 31%, with a 95%CI ranging from 26 to 36% (Motzer, NEJM 356: 115, 2007). The
target sample size in this phase II study is 30, which was based on the assumption that the
RR for dovitinib would fall within the range of sunitinib. With such a sample size, the
prevalence of dovitinib RR using RECIST 1.1 will be measured with a precision that extends
to 15 percentage points, with a 95% probability.

Inclusion Criteria:

- Advanced renal cell (clear cell) carcinoma confirmed histologically, including either
distant metastases or locally advanced disease that is not resectable or potentially
resectable following response. Sarcomatoid change is allowed if clear cell
predominant. Histological variants, papillary, chromophobe and collecting duct
carcinoma are not allowed.

- Availability of FFPE tissue for gene status analysis. If unavailable, an
image-guided biopsy of a metastatic disease site is required.

- Evaluable disease by RECIST 1.1 criteria

- ECOG (WHO) performance status 0 or 1

- Age ≥ 18 years

- Absolute neutrophil count ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L; haemoglobin > 9
g/dL; serum total bilirubin ≤ 1.5 x ULN; ALT and AST ≤ 3.0 x ULN; serum creatinine ≤
1.5 x ULN or creatinine clearance >35 ml/min by Cockcroft and Gault.

Exclusion Criteria:

- Uncontrolled brain metastases. For know brain metastases, definitive treatment with
either surgery, stereotactic radiotherapy or whole brain radiotherapy is required.
Patients must be neurologically stable for > 4 weeks after CNS treatment ends, and
either be off corticosteroids or receiving a low daily dose.

- Another primary malignancy within 3 years prior to starting study treatment, except
for adequately treated basal cell carcinoma, squamous cell carcinoma or other
non-melanomatous skin cancer, or in-situ carcinoma of the uterine cervix. If another
primary tumour was noted within this period, a metastatic disease site biopsy is
required to confirm renal origin.

- Prior systemic anticancer treatment for renal carcinoma. Prior bisphosphonates are

- Radiotherapy ≤ 4 weeks prior to starting the study drug or non-recovery from related
toxicities. Palliative radiotherapy for bone lesions ≤ 2 weeks prior to starting
study drug is allowed.

- Major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic) ≤ 4 weeks prior
to starting study treatment or non-recovery from surgical side effects.

- History of pulmonary embolism or untreated deep venous thrombosis within the past 6
months. If a history of PE or DVT within the past 6 months is present, patients must
be clinically stable on appropriate doses of anticoagulation as per thrombosis
specialist advice.

- Impaired cardiac function or clinically significant cardiac diseases, including
history of serious uncontrolled ventricular arrhythmias; clinically significant
resting bradycardia; LVEF assessed by 2-D echocardiogram < 50% or lower limit of
normal (whichever is higher) or multiple gated acquisition scan < 45% or lower limit
of normal (whichever is higher). Within 6 months prior to starting study drug:
myocardial infarction, severe/unstable angina, coronary artery bypass graft,
congestive heart failure, cerebrovascular accident, transient ischemic attack;
uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 90 mm Hg, with or
without anti-hypertensive medication. Initiation or adjustment of antihypertensive
medication is allowed before study entry.

- Impaired gastrointestinal function or GI disease that may significantly alter
dovitinib absorption, e.g. ulcerative diseases, uncontrolled nausea, vomiting,
diarrhoea, malabsorption syndrome, or small bowel resection.

- Cirrhosis, chronic active hepatitis or chronic persistent hepatitis

- Known diagnosis of human immunodeficiency virus infection (testing is not mandatory)

- Current full dose anticoagulation treatment with therapeutic doses of warfarin,
dabigatran or anti-platelet therapy. Treatment with ≤ 100mg acetylsalicyclic acid
daily is allowed as are therapeutic or prophylactic doses of low molecular weight
heparin, provided there is no recent evidence of bleeding.

- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.
infection, diabetes) that could cause unacceptable safety risks or compromise
protocol compliance.

- Pregnant or breast-feeding women

- Women of child-bearing potential or fertile males not using effective contraception.

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival (PFS) as assessed by RECIST 1.1.

Outcome Description:

Description: Subjects will undergo baseline radiology assessment with a CT scan of the chest, abdomen, pelvis and head within 4 weeks of registration. Thereafter subjects will then undergo CT scans of the chest, abdomen and pelvis (where possible using the same technique) every 9 weeks until week 54. From week 54 onward, subjects will undergo CT scans of the chest, abdomen and pelvis every 12 weeks until disease progression. Tumour responses will be evaluated using RECIST 1.1. Confirmation of responses (PR/CR) with repeat CT is not required as the primary end-point is PFS. CT will be the only imaging modality required for subjects on study. The RECIST 1.1 assessments will be done in Auckland by one of the members of the Tumour Response EvAluation Team (TREAT) who have expertise in RECIST reporting.

Outcome Time Frame:

From baseline until documented disease progression, estimated to be up to 65 weeks

Safety Issue:


Principal Investigator

Reuben Broom, MBChB, FRACP

Investigator Role:

Study Chair

Investigator Affiliation:

Auckland Hospital


New Zealand: Medsafe

Study ID:




Start Date:

March 2012

Completion Date:

April 2015

Related Keywords:

  • Clear Cell Renal Cell Carcinoma
  • Renal cell
  • Kidney
  • Cancer
  • Metastatic carcinoma
  • Carcinoma
  • Carcinoma, Renal Cell