• To estimate the difference in the efficacy and safety of RAD001 10 mg p.o. daily dose in combination with bevacizumab 10 mg/kg administered intravenously every two weeks for first-line treatment of patients with metastatic carcinoma of the kidney…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary:
To assess the treatment effect on progression-free survival (PFS) of patients
who receive RAD001 plus bevacizumab versus patients who receive IFN plus
bevacizumab, in order to estimate the chance of success of a possible
subsequent phase III study.
Secondary outcome
Secondary:
• To estimate the overall survival (OS) treatment effect in patients who
receive RAD001 plus bevacizumab versus patients who receive IFN plus
bevacizumab.
• To estimate the objective response rate and response duration differences in
patients who receive RAD001 plus bevacizumab versus patients who receive IFN
plus bevacizumab.
• To describe the safety profile of RAD001 plus bevacizumab versus IFN plus
bevacizumab.
• To estimate patient reported outcomes on quality of life (QoL) from patients
treated with RAD001 plus bevacizumab versus patients treated with IFN plus
bevacizumab.
• To measure the exposure of RAD001 in patients randomized to the treatment
combination of RAD001 plus bevacizumab.
Exploratory:
• To determine the effects of RAD001 on plasma angiogenic molecules e.g., VEGF,
basic FGF, PLGF, sVEGFR1, and sVEGFR2 and other markers of hypoxia e.g., LD
isoenzyme 5 and carbonic anhydrase IX (CA9).
• To characterize pre-treatment tumor samples by immunohistochemical and
genetic analyses for activation of the mTOR and angiogenic/hypoxia pathways.
• Relationships between response and RAD001 Cmin will be explored. RAD001 Cmin
represents the minimum exposure of the drug in blood during daily
administration. Exploration of the relationship between RAD001 Cmin and
response helps to determine the minimum effective concentration of RAD001 in
the target patient population.
Background summary
RAD001 (everolimus) is a derivative of rapamycin which acts as a signal
transduction inhibitor. Its target is mTOR (mammalian target of rapamycin), a
key protein kinase regulating cell growth, proliferation and survival. The mTOR
pathway activity is modulated by the PI3K/AKT pathway, a pathway known to be
dysregulated in numerous human cancers.
RAD001 is being investigated as an anticancer agent based on its potential to
act:
• directly on the tumor cells by inhibiting tumor cell growth and proliferation
• indirectly by inhibiting angiogenesis leading to reduced tumor vascularity
(via potent inhibition of tumor cell HIF-1 activity and vascular endothelial
growth factor (VEGF) production and VEGF-induced proliferation of endothelial
cells). The role of angiogenesis in the maintenance of solid tumor growth is
well established, and the mTOR pathway has been implicated in the regulation of
tumor production of proangiogenic factors as
well as modulation of VEGFR signaling in endothelial cells. RAD001 is approved
since 2003 in more than 60 countries (trade name: Certican®) for the prevention
of organ rejection in patients with renal and cardiac transplantation.
Bevacizumab (Avastin®) is a recombinant humanized monoclonal IgG1 antibody that
binds and prevents the interaction of VEGF to
its receptors VEGF receptors-1 and -2 (also known as Flt-1 and KDR or Flk-
2.2). Bevacizumab has been approved since 2003 for the treatment of metastatic
colorectal cancer in combination with chemotherapy; approvals for the treatment
of metastatic breast and non-small cell lung cancer have more recently been
added in many countries.
Based on the results from a randomized, double blind phase III trial of
first-line bevacizumab plus interferon alfa-2a (IFN) versus IFN in patients
with metastatic renal cell cancer, bevacizumab received approval in December
2007 in the EU for this indication. Bevacizumab is not yet approved in the US
for the treatment of metastatic renal cell cancer. 641 patients were treated in
this study in 18 countries. The objective response rate was 30.6% for
bevacizumab plus IFN compared to 12.4% IFN and a progression-free survival of
10.2 months for bevacizumab plus IFN compared to 5.4 months for IFN (Escudier,
et al 2007). Patients receiving bevacizumab plus IFN experienced the following
Grade 3/4 adverse events: fatigue 12%, asthenia 10%,proteinuria 7%, neutropenia
4%, and bleeding, hypertension influenza-likesyndrome, anorexia, and anemia
(all 3% each).
Phase 1 and 2 studies investigating the combination of RAD001 and bevacizumab
are ongoing. To date, full dose of bevacizumab 10 mg/kg, i.v. every 2 weeks and
full dose of RAD001 10 mg, p.o. daily given together has shown to be tolerable.
An ongoing Phase II trial of RAD001 and bevacizumab in patients with advanced
clear cell cancer of the kidney has enrolled 44 patients to date; 30 of which
were treatment naive. Patient accrual is still ongoing for the cohort of
patients with prior treatment. Preliminary data from 28 of 30 patients with no
prior treatment showed: 6 partial responses, 15 stable disease, 2 progressive
disease, 5 unevaluable, and 2 not yet available (Hainsworth, Sarah Cannon
Cancer Center, direct communication on September 6, 2007; study title: Phase II
study of bevacizumab and everolimus (RAD001) in the treatment of advanced renal
cell carcinoma (RCC)).
A Phase 1 dose-escalation study of bevacizumab, RAD001, and erlotinib in
patients with advanced-stage solid tumor demonstrated that the combination of
RAD001 and bevacizumab was well tolerated, allowing full doses of both
agents to be administered. The study included four dose levels:
Bevacizumab RAD001 Erlotinib
Dose Level 1 10 mg/kg every 2 wks 5 mg/day *
Dose Level 2 10 mg/kg every 2 wks 10 mg/day *
Dose Level 3 10 mg/kg every 2 wks 10 mg/day 75 mg/day
Dose Level 4 5 mg/kg every 2 wks 5 mg/day 75 mg/day
A total of 20 patients received bevacizumab and RAD001. Fifteen patients were
treated in Dose Level 2 (bevacizumab 10 mg/kg every 2 weeks and RAD001 10 mg
daily), and no dose-limiting toxicities were seen at this dose level (Bendell,
2007). The most common adverse events were mild or moderate mucositis, fatigue,
rash, and musculo-skeletal pain. In the group of patients who received RAD001
and bevacizumab (20), there were six Grade 3 events, one of each of the
following: proteinuria, deep vein thrombosis, cardiac ischemia, liver enzyme
elevation, partial bowel obstruction, and rash. There were three Grade 4
events, one of each of the following: proteinuria, left ventricular thrombus,
and left ventricular systolic dysfunction (Bendell, 2007).
Study objective
• To estimate the difference in the efficacy and safety of RAD001 10 mg p.o.
daily dose in combination with bevacizumab 10 mg/kg administered intravenously
every two weeks for first-line treatment of patients with metastatic carcinoma
of the kidney compared to treatment with IFN dose escalating from 3 MIU
(million international unit) during week one of
treatment, 6 MIU during week two of treatment, and 9 MIU during week 3 and
subsequently (if tolerated), given subcutaneously three times weekly in
combination with bevacizumab 10 mg/kg administered intravenously every two
weeks.
Rationale:
• RAD001 has a potential to act directly on the tumor cells as well as
indirectly by inhibiting angiogenesis.
• RAD001 has shown anti-tumor activity in patients with renal cell carcinoma
in phase I and II clinical trials.
• Bevacizumab interferes with angiogenesis by blocking the interaction of
VEGF with its receptors.
• mTOR inhibition by RAD001 affects a different biochemical pathway than
VEGF inhibition by bevacizumab.
• RAD001 and bevacizumab exhibit non-overlapping toxicity profiles.
Study design
This is a randomized, open-label, multi-center phase II study. The estimated
progression-free survival (PFS) treatment effect from this study will be used
to calculate a predictive power. This predictive power will be used to estimate
the
chance that a possible subsequent phase III study would demonstrate a
significant improvement in PFS.
The final analysis of this phase II study will be performed when a total of 230
PFS events (per independent central radiological review) are observed in the
Full Analysis Set (FAS) population. Assuming a study duration of 24 months, a
total of 360 patients must be randomized, which includes 10% of patients lost
to follow up during the study. See Statistical Methods section for additional
details. As part of safety monitoring, an early safety analysis is planned when
safety
listings on the first 100 randomized patients who have been treated for at
least 1 cycle are available. This study will be supported by a independent
central radiology panel for efficacy and safety (assessing non-infectious
pneumonitis), central laboratory for analysis of blood samples, and IVRS for
randomization.
Stratification: For randomization and primary efficacy analyses, patients will
be stratified according to the Memorial Sloan Kettering Cancer Center (MSKCC)
risk criteria for treatment-naïve patients (favorable vs. intermediate vs. poor
risk groups, based on Karnofsky performance, time from initial diagnosis to
treatment < 1 year, LDH, hemoglobin, and corrected serum
calcium laboratory values reported by the central laboratory).
Randomization ratio: 1:1
Screening phase: Screening evaluations will be performed within 21 days prior
to the first dose of the study treatment (Day -20 to Day 0).
Baseline phase: Baseline evaluations will be performed within 1 week prior to
the first dose of study treatment (Day -6 to Day 0). Baseline tumor assessment
will be acceptable within 35 days prior to treatment start (Day -34 to Day 0).
Treatment phase/duration of treatment: Patients will receive their first dose
of study drugs (IFN or RAD001 and bevacizumab) on Day 1, Cycle 1. All patients
will be treated with either RAD001 10 mg, p.o. daily plus bevacizumab
10 mg/kg, i.v. every two weeks or IFN dose escalating from 3 MIU during week
one, 6 MIU during week two, and 9 MIU during week 3 of treatment and
subsequently (if tolerated), s.c. three times per week plus bevacizumab 10
mg/kg, i.v. every two weeks until tumor progression (by RECIST criteria, as
assessed by the investigator), unacceptable toxicity, death, or discontinuation
from the study for any other reason. The combination of IFN and bevacizumab
should be continued as long as the patient does not have disease progression
and tolerates the combination. When bevacizumab and IFN are given on the same
day, IFN will be administered after the bevacizumab. On the days of PK
blood sampling, the dose of RAD001 will be taken at the center after the PK
blood sampling.
Tumor assessments will be performed every 12 weeks (± 1 week) from
randomization until the start of another anticancer therapy. A partial or
complete response warrants confirmation no sooner than 4 weeks and no later
than 6 weeks after its initial observation.
6 Month Follow-up period: Any patient who is discontinued from study treatment
for any reason will continue to have tumor assessments every 12 weeks (± 1
week) until the patient starts another anticancer therapy. The investigator or
his/her designee will continue collecting information on the initiation of
additional anticancer therapies until the date of data cutoff for the final
analysis. All new anticancer therapy therapies after the last dose of study
treatment will be recorded on the appropriate CRF.
Patients who have ongoing hypertension at the end-of-treatment visit or who
experience a new hypertensive event during the 6 month follow-up period will
have their blood pressure and use of anti-hypertensive medications monitored.
Monitoring will take place at the 3 month follow-up and 6 month follow-up
visits or until blood pressure returns to within
normal range (systolic blood pressure <= 140 mmHg and diastolic blood pressure <=
90 mmHg).
• Patients who have ongoing proteinuria events at the end-of-treatment visit or
who experience a new proteinuria event during the 6 month follow-up period will
be monitored for 24-hour urine collection at the 3 Month Followup and 6 Month
Follow-up visits or until total 24-hour urine protein improves to <= 1g.
• An adverse event of wound healing complication, gastrointestinal
perforations, and arterial thromboembolic event, irrespective of causal
relationship, should be reported during the 6 month follow-up period. Patients
who have ongoing wound healing complications at the end-oftreatment visit or
who experience a new wound healing event during the 6
month follow-up period will have their wound healing complications monitored
every 4 weeks until the events have resolved.
28 Day Follow-up Visit: All patients will have a follow-up visit scheduled 28
days after the end-of-treatment visit to follow for AEs and SAEs that may have
occurred after discontinuation from the study. 3 Month & 6 Month Follow-up
Visits: All patients will have a 3 month followup and a 6 month follow-up
visits scheduled after the end-of-treatment visit to
monitor for hypertension, proteinuria, wound healing complication,
gastrointestinal perforations, surgical procedure, major injury, and arterial
thromboembolic event, irrespective of causal relationship. Any major injury or
surgical procedure must be reported during the follow-up period.
Central radiological review: The primary analysis of PFS will be based on an
independent central radiology review. All CT scans, MRIs, bone scans, and
MRI-Quickscans (at baseline only) obtained at baseline, during the treatment
period, and after the study treatment discontinuation until patient starts
another anticancer therapy will be sent to the independent central radiologist.
Survival data collection: After the 6 month follow-up period or patient*s last
visit, all patients will be followed every 2 months for survival up to 2 years
after the last patient is randomized to the study.
Intervention
Study treatment will start on Day 1, Cycle 1 until progression of disease (per
the investigator), unacceptable toxicity, death or discontinuation from the
study for any other reason. A treatment cycle consists of 4 continuous weeks
(or 28
continuous days) of study treatment.
Arm 1:
RAD001 :10 mg/day, p.o., daily (two 5 mg tablets)
Bevacizumab: 10 mg/kg, i.v., every 2 weeks
Arm 2:
IFN: Week 1: 3 MIU, Week 2: 6 MIU, Week 3: 9 MIU, Subsequently: 9 MIU (if
tolerated) s.c., 3 times weekly (administered after bevacizumab if given on
same day)
Bevacizumab: 10 mg/kg, i.v., every 2 weeks
Study burden and risks
This research study may involve unpredictable risks to the participants.
The most common possible side effects of the study drug RAD001 are skin changes
(rash) including redness, itching or irritation, mouth lining changes
(stomatitis) manifested as redness, irritation, swelling in the mouth or mouth
ulcers, fatigue, nausea, decrease of appetite (anorexia), headache, vomiting,
diarrhea, constipation, abdominal distension and occasionally infections. There
could be a lowering of the number of red blood cells, white blood cells and
platelets as well as lowering in levels of some electrolytes (potassium,
sodium, calcium, magnesium or phosphate) in the blood. The levels of glucose,
lipids (triglycerides and cholesterol) or liver enzymes (transaminases)in the
blood could increase (increased levels of cholesterol are an important factor
of risk of heart disease), and therefore the blood glucose, lipid and liver
enzymes levels will be regularly monitored in this study.
RAD001 may be associated with changes within lungs such as inflammation
(pneumonitis). Some patients have no symptoms associated with lung changes,
while others may develop a cough and/or shortness of breath.
RAD may predispose bleeding specially when number of platelets in the blood is
low. Very rarely, RAD001 may cause toxicity to your kidneys and the levels of
blood creatinine in your blood could increase. Therefore, blood creatinine
levels will be regularly monitored in this study.
Please also see section E9 of this form.
Albinusdreef 2
2333 ZA Leiden
NL
Albinusdreef 2
2333 ZA Leiden
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Age
Inclusion criteria
1. Age >= 18 years old
2. Patients with metastatic renal cell carcinoma and with histological or cytological confirmation of clear cell RCC (pathology report based on the tissue from the original diagnosis of renal cell cancer is acceptable). Any percentage of clear cell histology is acceptable.
3. Patients with at least one measurable lesion at baseline as per the RECIST criteria. If skin lesions are reported as target lesions, they must be documented (at baseline and at every physical exam) using color photography and a measuring device (such as a caliper) in clear focus to allow the size of the lesion(s) to be determined from the photograph.
4. Patients with progressive metastatic renal cell carcinoma (by RECIST
criteria) requiring treatment.
5. Patients who had a prior partial or complete nephrectomy. Partial nephrectomy is allowed only if the resection margins were clearly negative.
6. Patients with a Karnofsky Performance Status >=70%.
7. Adequate bone marrow function as shown by: ANC >= 1.5 x 109/L,
Platelets >= 100 x 109/L, Hb >9 g/dL.
8. Adequate liver function: serum bilirubin: <= 1.5 x ULN, ALT and AST <=
2.5x ULN. Patients with known liver metastases: AST and ALT <= 5x
ULN.
9. Adequate renal function: serum creatinine <= 2.0 x ULN.
10. INR and PTT <= 1.5 (Anticoagulation is allowed if target INR <= 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for >2 weeks at time of randomization.)
11. Adequate lipid profile: total cholesterol < 300 mg/dL and triglyceride < 200 mg/dL.
12. Women of childbearing potential must have had a negative serum pregnancy test 72 hours prior to the administration of the study treatment start.
13. Patients who give a written informed consent obtained according to
local guidelines.
Exclusion criteria
1. Patients within 4 weeks post-major surgery (e.g., intra-thoracic, intraabdominal
or intra-pelvic), open biopsy, or significant traumatic injury to avoid wound healing complications. Minor procedures and percutaneous biopsies or placement of vascular access device require 7 days prior to study entry.
2. Patients who had radiation therapy within 4 weeks prior to start of study treatment (palliative radiotherapy to bone lesions allowed within 2 weeks prior to study treatment start).
3. Patients in anticipation of the need for major surgical procedure during the course of the study.
4. Patients with a serious non-healing wound, ulcer, or bone fracture.
5. Patients with a history of seizure(s) not controlled with standard
medical therapy.
6. Patients who have received prior systemic treatment for their metastatic RCC. Adjuvant immunotherapy (vaccines acceptable, but no cytokines) completed 3 months prior to study treatment start is acceptable.
7. Patients who received prior therapy with VEGF pathway inhibitor (even in the adjuvant setting), such as sunitinib, sorafenib, and bevacizumab.
8. Patients who have previously received systemic mTOR inhibitors (sirolimus, temsirolimus, everolimus).
9. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients.
10. Patients with evidence of current central nervous system (CNS) metastases or spinal cord compression.
11. Patients with a history of abdominal fistula, gastrointestinal perforation,
or intra-abdominal abscess within 6 months prior to study enrollment.
12. Patients with proteinuria at screening as demonstrated by either:
- Urine protein: creatinine (UPC) ratio >= 1.0 at screening.
- Urine dipstick for proteinuria >= 2+ (patients discovered to have >=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate <= 1g of protein in 24 hours to be eligible).
13. Patients with inadequately controlled hypertension (defined as a blood pressure of > 150 mmHg systolic and/or > 100 mmHg diastolic on medication), or any prior history of hypertensive crisis or hypertensive encephalopathy.
14. Patients receiving ongoing or with recent (within 10 days prior to study
treatment start) need for full therapeutic dose of oral or parenteral anticoagulants or chronic daily treatment with aspirin (> 325 mg/day) or clopidogrel (>75 mg/day).
15. Patients receiving chronic systemic treatment with corticosteroids (dose of >= 10 mg/day methylprednisone equivalent) or another immunosuppressive agent. Inhaled and topical steroids are acceptable.
16. Patients with a known history of HIV seropositivity.
17. Patients with hypersensitivity to IFN or any component of the product.
18. Patients with an active, bleeding diathesis or coagulopathy or recurrent
thromboembolism (>1 episode of DVT/PE during the past year).
19. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
- unstable angina pectoris, symptomatic congestive heart failure (NYHA II, III, IV), myocardial infarction <= 6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia, cerebrovascular accidents <= 6 months before study treatment start,
- severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air,
- poorly controlled diabetes as defined by fasting serum glucose >2.0 x ULN,
- any active (acute or chronic) or uncontrolled infection/disorders that impair the ability to evaluate the patient or for the patient to complete the study,
- nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by this study treatment, such as severe hypertension that is not controlled with medical management and thyroid abnormalities whose thyroid function cannot be maintained in the normal range by medication,
- liver disease such as cirrhosis, decompensated liver disease, chronic active hepatitis or chronic persistent hepatitis.
20. Patients who have a history of another primary malignancy and off treatment for <= 3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix.
21. Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Oral contraceptives are not acceptable.
22. Patients who are using other investigational agents or who had received investigational drugs <= 4 weeks prior to study treatment start.
23. Patients unwilling to or unable to comply with the protocol.
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 | 2008-000077-38 |
| ClinicalTrials.gov | NCT00719264 |
| CCMO | NL25381.058.08 |