The primary objective of the study is to demonstrate that lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone (Arm C) in improving progressionfree survival (PFS) (by independent imaging…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Progression-free survival (PFS) by independent review is defined as the time
from the date of randomization to the date of the first documentation of
disease progression or death (whichever occurs first) as determined by IIR
using RECIST 1.1. PFS censoring rules will follow the FDA guidance of 2007;
specifics of this will be detailed in the Statistical Analysis Plan.
Secondary outcome
• Objective response rate (ORR) is defined as the proportion of subjects who
have best overall response of CR or PR as determined by IIR using RECIST 1.1.
• Overall survival (OS) is defined as the time from the date of randomization
to the date of death from any cause. Subjects who are lost to follow-up and
those who are alive at the date of data cut-off will be censored at the date
the subject was last known alive, or date of data cut-off, whichever occurs
first.
• Safety will be assessed summarizing the incidence of treatmentemergent
adverse events (TEAEs) and SAEs together with all other safety parameters.
• Proportion of subjects who discontinued treatment due to toxicity is defined
as the proportion of subjects who discontinue study treatment due to
treatment-emergent adverse events (TEAEs).
• Time to treatment failure due to toxicity is defined as the time from the
date of first dose to the date that a subject discontinues study treatment due
to TEAEs.
• Health-Related Quality of Life (HRQoL) will be assessed using the Functional
Assessment of Cancer Therapy Kidney Syndrome Index- Disease-Related Symptom
(FKSI-DRS), the European Organization for the Research and Treatment of Cancer
(EORTC) QLQ-C30 and the European Quality of Life (EuroQOL) EQ-5D-3L instruments.
• PFS on next-line of therapy (PFS2) is defined as the time from randomization
to disease progression on next-line of treatment, or death from any cause,
(whichever occurs first).
Background summary
Renal cell carcinoma (RCC), which originates within the renal cortex from the
proximal
renal tubular epithelium, is the most common kidney cancer, constituting 80 to
85 percent of primary renal neoplasms. An estimated 365,943 new cases of kidney
(renal) cancer are expected to be diagnosed in 2015, and an estimated 155,520
deaths
from kidney cancer are expected to occur in 2015.
The current treatment approach for patients with metastatic RCC consists of
sequential
administration of single-agent therapies that target either the vascular
endothelial growth factor (VEGF)/VEGF receptor (VEGFR) or mammalian target of
rapamycin (mTOR)
pathways First-line therapy consists of treatment with anti-VEGF agents,
typically sunitinib or pazopanib, however, all patients ultimately progress
after therapy and will need further treatment.
Study objective
The primary objective of the study is to demonstrate that lenvatinib in
combination with everolimus (Arm A) or pembrolizumab (Arm B) is superior
compared to sunitinib alone (Arm C) in improving progressionfree survival (PFS)
(by independent imaging review [IIR] using Response Evaluation Criteria In
Solid Tumors [RECIST 1.1]) as first-line
treatment in subjects with advanced renal cell carcinoma (RCC).
Study design
This is a multicenter, randomized, open-label, Phase 3 study to compare the
efficacy and safety of lenvatinib in combination with everolimus or
pembrolizumab versus sunitinib as first-line treatment in subjects with
advanced RCC.
Intervention
Test Arm (Arm A): Lenvatinib is provided as 4-mg and 10-mg capsules. Everolimus
is provided as 5-mg tablets. Lenvatinib 18 mg (one 10-mg plus two 4-mg
capsules) plus everolimus 5 mg will be taken orally once daily in each 21-day
cycle.
Test Arm (Arm B): Lenvatinib is provided as 4-mg and 10-mg capsules. Lenvatinib
20 mg (two 10-mg capsules) once daily will be taken orally in each 21-day cycle.
Pembrolizumab is provided as a sterile, preservative-free, clear to slightly
opalescent, colorless to slightly yellow solution that requires dilution for
intravenous infusion. Each vial contains 100 mg of pembrolizumab in 4 mL of
solution. Each 1 mL of solution contains 25 mg of pembrolizumab Pembrolizumab
will be administered at a dose of 200 mg IV over 30 minutes on Day 1 of each
21-day cycle.
Comparator Arm (Arm C): Sunitinib malate will be provided as 12.5-mg and 25-mg
capsules.
Sunitinib 50 mg once daily will be administered orally for 4 weeks on treatment
followed by 2 weeks off (Schedule 4/2) in each 21-day cycle.
Study burden and risks
Based on the available data to date for the two investigational treatment arms
(ie, Arms A and B), the benefit/risk profile for subjects who participate in
Study 307 is positive. With the measures contained within the protocol, the
safety will continue to be assessed moving forward.
Mosquito Way -
Hatfield AL10 9SN
GB
Mosquito Way -
Hatfield AL10 9SN
GB
Listed location countries
Age
Inclusion criteria
1. Histological or cytological confirmation of RCC with a clear-cell component
(original tissue diagnosis of RCC is acceptable).
2. Documented evidence of advanced RCC.
3. At least 1 measurable target lesion according to RECIST 1.1 meeting the
following criteria:
• Lymph node (LN) lesion that measures at least 1 dimension as >=1.5 cm in the
short axis
• Non-nodal lesion that measures >=1.0 cm in the longest diameter
•The lesion is suitable for repeat measurement using computerized
tomography/magnetic resonance imaging (CT/MRI). Lesions that have had external
beam radiotherapy (EBRT) or locoregional therapy must show radiographic
evidence of disease progression based on RECIST 1.1 to be deemed a target
lesion.
4. Male or female subjects age >=18 years (or any age greater than 18 years of
age if that age is considered to be an adult per the local jurisdiction) at the
time of informed consent
5. Karnofsky Performance Status (KPS) of >=70.
6. Adequately controlled blood pressure (BP) with or without antihypertensive
medications, defined as BP <=150/90 mmHg at Screening and no change in
antihypertensive medications within 1 week before the Cycle 1/Day 1.
7. Adequate renal function as creatinine <=1.5× upper limit of normal (ULN); or
for subjects with creatinine >1.5×ULN, the calculated creatinine clearance >=30
mL/min (per the Cockcroft-Gault formula) is acceptable.
8. Adequate bone marrow function defined by:
• Absolute neutrophil count (ANC) >=1500/mm3
• Platelets >=100,000/mm3
• Hemoglobin >=9 g/dL.
9. Adequate blood coagulation function defined by International Normalized
ratio (INR) <=1.5 unless participant is receiving anticoagulant therapy, as long
as INR is within therapeutic range of intended use of anticoagulants
10. Adequate liver function defined by:
• Total bilirubin <=1.5 x ULN except for unconjugated hyperbilirubinemia of
Gilbert's syndrome.
• Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate
aminotransferase (AST) <=3×ULN (in the case of liver metastases <=5×ULN), unless
there are bone metastases. Subjects with ALP values >3xULN and known to have
bone metastases can be included.
11. Provide written informed consent.
12. Willing and able to comply with all aspects of the protocol.
Exclusion criteria
1. Subjects who have received any systemic anticancer therapy for RCC,
including anti-VEGF therapy, or any systemic investigational anticancer agent.
Prior adjuvant treatment with an investigational anticancer agent is not
allowed unless the investigator can provide evidence of subject's randomization
to placebo arm.
2. Subjects with CNS metastases are not eligible, unless they have completed
local therapy (eg, whole brain radiation therapy [WBRT], surgery or
radiosurgery) and have discontinued the use of corticosteroids for this
indication for at least 4 weeks before starting treatment in this study. Any
signs (eg, radiologic) or symptoms of brain
metastases must be stable for at least 4 weeks before starting study treatment.
3. Active malignancy (except for RCC, definitively treated basal or squamous
cell carcinoma of the skin, and carcinoma in-situ of the cervix or bladder)
within the past 24 months. Subjects with history of localized & low risk
prostate cancer are allowed in the study if they were treated with curative
intent and there is no PSA recurrence within the past 5 years.
4. Prior radiation therapy within 21 days prior to start of study treatment
with the exception of palliative radiotherapy to bone lesions, which is allowed
if completed 2 weeks prior to study treatment start.
5. Subjects who are using other investigational agents or who had received
investigational drugs <=4 weeks prior to study treatment start.
6. Received a live vaccine within 30 days of planned start of study treatment
(Cycle 1/Day 1). Examples of live vaccines include, measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies,
Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza
vaccines for injection are generally killed virus vaccines and are allowed;
however intranasal influenza vaccines (eg, FluMist®) are live attenuated
vaccines and are not allowed within 30 days of C1D1.
7. Subjects with proteinuria >1+ on urine dipstick testing will undergo 24-h
urine collection for quantitative assessment of proteinuria.
Subjects with urine protein >=1 g/24 h will be ineligible
8. Fasting total cholesterol >300 mg/dL (or >7.75 mmol/L) and/or fasting
triglycerides level >2.5 x ULN. NOTE: these subjects can be included after
initiation or adjustment of lipid-lowering medication.
9. Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN.
Note: these subjects can be included after initiation or adjustment of
glucose-lowering medication.
10. Prolongation of QTc interval to >480 ms.
11. Subjects who have not recovered adequately from any toxicity and/or
complications from major surgery prior to starting therapy.
12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other
condition that might affect the absorption of lenvatinib, everolimus, and/or
sunitinib.
13. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage.
The degree of tumor invasion/infiltration of major blood vessels (eg, carotid
artery) should be considered because of the potential risk of severe hemorrhage
associated with tumor
shrinkage/necrosis following lenvatinib therapy.
14. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to
the first dose of study drug.
15. Significant cardiovascular impairment within 12 months of the first dose of
study drug: history of congestive heart failure greater than New York Heart
Association (NYHA) Class II, unstable angina, myocardial infarction or stroke,
cerebrovascular accident (CVA), or cardiac arrhythmia associated with
hemodynamic instability.
The following is also excluded:
Left ventricular ejection fraction (LVEF) below the institutional normal range
as determined by MUGA or echocardiogram.
16. Active infection (any infection requiring systemic treatment).
17. Subjects known to be positive for Human Immunodeficiency Virus (HIV).
18. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA
[qualitative] is detected).
19. Known history of, or any evidence of, interstitial lung disease or active
non-infectious pneumonitis.
20. Any medical or other condition that in the opinion of the investigator(s)
would preclude the subject's participation in a clinical study.
20.Has a history of (non-infectious) pneumonitis that required steroids, or
current pneumonitis.
22. Subjects with a diagnosis of immunodeficiency or who are receiving chronic
systemic steroid therapy or any other form of immunosuppressive therapy within
7 days prior to the first dose of study treatment.
23. Active autoimmune disease (with the exception of psoriasis) that has
required systemic treatment in the past 2 years.
24. Females who are breastfeeding or pregnant at Screening or Baseline.
25. Females of childbearing potential who do not agree to use a highly
effective method of contraception for the entire study period and for 120 days
after study discontinuation.
27. Males who have not had a successful vasectomy and do not agree to use
condom + spermicide OR have a female partner who does not meet the criteria
above.
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 | EUCTR2016-000916-14-NL |
| ClinicalTrials.gov | NCT02811861 |
| CCMO | NL64847.029.18 |