The overall objective of this study is to evaluate the efficacy and safety of cabozantinib as 2nd line treatment in subjects with unresectable, locally advanced or metastatic renal cell carcinoma (RCC) with a clear-cell component, who progressed…
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Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Study Objective:
• To assess the efficacy of cabozantinib by the objective response rate (ORR)
per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 evaluated by
independent central review in cohort A.
Secondary outcome
Secondary Study Objectives:
• To assess other efficacy criteria of cabozantinib such as time to response
(TTR), duration of response (DOR), disease control rate (DCR), progression-free
survival (PFS) by independent and Investigator*s review;
• To assess objective response rate (ORR) by independent central review and
Investigator's review in cohort B;
• To assess objective response rate (ORR) by Investigator*s review in cohort A;
• To assess overall survival (OS);
• To assess the ORR and PFS by Investigator's review and OS in overall
population (cohorts A+B);
• To assess the change in disease-related symptoms as assessed by the
Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index (FKSI-DRS)
questionnaire;
• To assess the safety and tolerability of cabozantinib.
Background summary
Renal cell carcinoma (RCC) comprises a heterogeneous group of kidney cancers
and is one of the ten most common cancers worldwide, with more than 300,000 new
cases each year. The most common subtypes (>=5% incidence) include clear-cell
RCC (ccRCC), papillary RCC (pRCC) and chromophobe RCC (chRCC). The other
subtypes are either very rare (each with <=1% total incidence) or designated as
unclassified RCC (uRCC, approximately 4% total incidence) when it is not
possible to diagnose the tumour according to any other subtype. The ccRCC
subtype is associated with most kidney cancer deaths and is predominant in
metastatic disease (83-88%). It is estimated that around 25 50% of subjects
with localised disease eventually develop metastatic RCC and that up to 30% of
subjects considered disease-free after curative treatment for localised RCC
will relapse.
The purpose of this study is to find out how safe and effective cabozantinib is
for the treatment of unresectable, locally advanced metastatic RCC, after
cancer progression with CPI treatment combined or not, with anti-VEGF therapy.
The new drug used in this study is cabozantinib (known with the brand name
Cabometyx®), which will be referred to as the *study drug* in the remainder of
the document. The study drug belongs to a drug class that targets specific
proteins that blocks the cancer growth. This drug class has become the standard
of care for the treatment of patients with advanced RCC.
Study objective
The overall objective of this study is to evaluate the efficacy and safety of
cabozantinib as 2nd line treatment in subjects with unresectable, locally
advanced or metastatic renal cell carcinoma (RCC) with a clear-cell component,
who progressed after prior checkpoint inhibitors (CPI) therapy with ipilimumab
and nivolumab in combination or CPI combined with vascular endothelial growth
factor (VEGF)-targeted therapy.
Study design
This is a Phase II, multicentre, open-label study to evaluate the efficacy and
safety of cabozantinib 60 mg once daily (q.d.) in adults with unresectable,
locally advanced or metastatic RCC with a clear-cell component that progressed,
according to Investigator*s judgement, after prior CPI therapy (ipilimumab and
nivolumab) alone or CPI combined with VEGF-targeted therapy. Approximately 250
eligible subjects will receive cabozantinib (two independent cohorts with 125
subjects each).
Intervention
All subjects will be treated with oral cabozantinib 60 mg q.d. In case of
treatment-emergent toxicity, the Investigator may decide to reduce the dose to
40 mg or 20 mg according to the instructions specified in this protocol.
The date of the first dose of cabozantinib is defined as baseline (Day 1, Visit
2) and should occur within 15 days after the Screening visit. Doses will be
self-administered at home by taking cabozantinib q.d. at the same time each day
(preferably at bedtime). Cabozantinib should not be taken with food. The
subject should not eat anything for at least 2 hours before and 1 hour after
taking cabozantinib.
If a dose is missed, the missed dose should not be taken less than 12 hours
before the next one.
Study burden and risks
WHAT PARTICIPATION INVOLVES
If you participate, your participation will last a total of approximately 42
months.
You will come to the study center for 4 visits during the first month of the
study, after which you will have one visit per month until the end of your
treatment with the study medication. After the end of your treatment period,
you will receive a follow-up phone call every 12 weeks, up to the end of the
study. There may be additional unscheduled study visits based on your study
doctor*s decision of your medical needs. For a clear overview of the visits and
procedures done, please see appendix C in the ICF.
Screening
First, we determine whether you can participate. The following assessment and
procedures will take place during screening:
• The study doctor will review the entry criteria with you, to find out whether
or not you qualify to be in this study.
• You will be asked to sign this consent form if you agree to take part in this
study. You will read, review, and sign this ICF if you choose to take part in
this study.
• You will be asked about your demographic data (age, sex).
• You will be asked about your medical history and any medications you use/have
used.
• You will be asked about your RCC history and any surgery, radiotherapy,
chemotherapy, or medications related to the same.
• You will have a physical examination, your weight, height and vital signs
(blood pressure and heart rate) will be measured.
• You will have an Eastern Cooperative Oncology Group (ECOG) performance status
assessment to see how your cancer is progressing and to determine your level of
functioning in terms of your ability to take care of yourself, daily activities
and physical ability (walking, working, etc.).
• You will have an electrocardiogram (ECG). This is a painless, non-invasive
test that shows how your heart works (takes a picture of the electrical
activity of your heart).
• You will be asked to give blood and urine samples which will be tested to
assess your general well-being (including thyroid function and clotting of
blood) and to assess for any medical abnormalities.
• If you are a female and can get pregnant, you will have a blood test or a
urine pregnancy test to confirm that you are not pregnant. You will not have
this pregnancy test, if you had a previous hysterectomy (removal of your
uterus), bilateral oophorectomy (removal of both your ovaries), or your hormone
test (follicular stimulating hormone) indicates that you are post-menopausal.
• You will have a CT scan or a MRI scan within 28 days before you receive first
dose of study drug. These scans are performed to confirm and assess your
cancer. During the MRI scan, you may be asked to lie down on your back on a
table and you will need to stay still until the scan is over. Each MRI scan
will take less than 1 hour.
• You may have a brain CT or MRI scan and/or a bone scan, if your study doctor
suspects that you have developed brain and/or bone metastases, 28 days before
you receive first dose of the study drug. A bone scan is used to detect bone
tumors or cancer that has spread to the bone. For the bone scan, a radioactive
material is injected into the bloodstream. After a few hours, the radioactive
material collects in the bones and is detected by a scanner.
Sometimes we find something during the scans that requires further medical
investigation. We will always tell you. Further investigation is carried out by
the primary care physician or specialist. The cost of this will be borne by
your own insurance. You will be monitored for any side effects or symptoms
after signing of the ICF until the end of the study.
If you are found eligible and agree to be in this study, depending on the
duration of your first line treatment, you may not be included in the study, if
the maximum number of patients is reached. If applicable, your study doctor
will discuss this situation with you.
Treatment
We will treat you approximately 8 months with the study drug. The exact
duration will depend on the course of your disease. You will be given bottles
containing tablets of the study drug. This contains daily doses until your next
visit. You will start taking the study drug on the day of Visit 2 at home as
per the study doctor*s instructions. You will take 1 tablet daily with a full
glass of water 2 hours after your meal (e.g., your evening meal), at around the
same time every day. You cannot take the study drug with food; thus, you must
not have food 2 hours before and 1 hour after taking study drug. The tablet
must be taken whole, so you should not crush or chew the tablet. If you miss a
dose, you should not take additional tablets to make up for it, and you should
not take the missed dose if the next dose is to be taken in less than 12 hours.
During the study, your study doctor may reduce your dosage of study drug
according to your situation. In case of any uncertainties regarding dosage
please do not hesitate to contact your study doctor.
This study is *open label*, which means that both you and the study doctor will
know that you will receive cabozantinib.
Visits and tests
For the study, during the treatment period, you have to visit the hospital
every month except during the first month (then you need to visit the hospital
every2 weeks). A visit will take app 2.5 hours.
During these visits, most of the procedures from the screening will be
repeated. In addition, the following will take place:
• You will be asked about any medications you have taken since the last visit
or are currently taking.
• You will be asked if you have experienced new or worsening of any illness,
side effects or injury since your last visit.
• You will also be asked to complete a quality of life questionnaire before
being given the first dose of the study drug, which is a 9 item questionnaire
that includes questions related to your energy levels, general pain, weight
loss, bone pain, fatigue, shortness of breath, if you have been coughing, if
you are bothered by fevers, and if you have had blood in your urine. The
questionnaire will take approximately 10 minutes of your time.
• You will be given the bottle of study drug (30 tablets per bottle) and you
will be advised to take the study drug 60 mg (one tablet) once daily by
yourself at home. In case of any side effects, the study doctor may reduce the
study drug dose to 40 mg or 20 mg once daily.
• At some Visits, you will be asked to return any unused study drug and then be
given a fresh stock of study drug. You will be asked if you are taking the
study drug regularly and as instructed by the study doctor.
End of Study Treatment Visit
The End of Study Treatment visit will be carried out 30 days to 45 days after
you have received the last dose of the study drug and also for subjects who
have discontinued study treatment whatever the reason (e.g., disease
progression, unacceptable toxicity or withdrawal of consent).
Appendix C in the ICF states which procedures will take place at each of the
visits.
Post-Treatment Follow-up Period
If you discontinue study treatment you will enter the Post-Treatment Follow-Up
period. You will be contacted every 12 weeks after the End of Study Treatment
Visit and you will be asked about your other cancer treatments, and your health
status will be assessed. You may have a chest abdomen pelvic and/or a brain CT
or MRI scan and/or a bone scan based on your study doctor*s decision. You will
also be asked if you have experienced any side effects or symptoms after the
last dose of the study drug.
Early Study Withdrawal Visit
If you prematurely discontinue from the study during the Study Treatment
period, you will be invited to attend the Early Study Withdrawal Visit. All the
procedures applicable to End of Study Treatment Visit will be performed during
this visit.
Unscheduled visits
If an unexpected or unwanted event happens during the study, you may be asked
to come to the study center for more tests or procedures. Some of the tests or
procedures done during the study may have to be repeated at no extra cost, if
the results are not usable or are not normal. If additional visits are required
during your participation in this study, your study doctor may perform some
procedures and evaluations (see appendix C of the ICF for an overview).
POSSIBLE SIDE EFFECTS
The study drug and study procedures may involve unknown risks. Any medication
can have temporary and permanent side effects and can cause unforeseen adverse
reactions, although not everybody gets them. Results from completed clinical
studies suggest that cabozantinib is generally well tolerated.
If you have any side effects, your study doctor may tell you to take the study
drug at a lower dose. Your study doctor may also prescribe other medicines to
help control your side effects.
Tell your doctor straight away if you notice any of the following side effects
- you may need urgent medical treatment:
• Symptoms including pain in the abdomen, nausea (feeling sick), vomiting,
constipation, or fever. These may be signs of a gastrointestinal perforation, a
hole that develops in your stomach or intestine that could be life-threatening.
• Severe or uncontrollable bleeding with symptoms such as: vomiting blood,
black stools, bloody urine, headache, coughing up blood.
• Swelling, pain in your hands and feet, or shortness of breath.
• A wound that does not heal.
• Fits, headaches, confusion, or finding it difficult to concentrate. These may
be signs of a condition called reversible posterior leukoencephalopathy
syndrome (RPLS) and is also known as Posterior Reversible Encephalopathy
Syndrome (PRES). RPLS (or PRES) is rare (it affects less than 1 in 1000
people).
• Feeling drowsy, confused or loss of consciousness. This may be due to liver
problems.
Side Effects
These side effects are very common (Occurs in 1 in 10 people or more):
• Stomach upset, including diarrhoea, nausea, vomiting, constipation,
indigestion, abdominal pain
• Blisters, pain in the hands or soles of the feet, rash or redness of the skin
• Decreased appetite, weight loss, altered sense of taste
• Fatigue, weakness, headache, dizziness
• Hypertension (increase in blood pressure)
• Anaemia (low levels of red blood cells)
• Redness, swelling or pain in the mouth or throat, difficulty in speaking,
hoarseness, cough
• Shortness of breath
• Changes in blood tests used to monitor general health and function of your
organs (including the liver and kidney), low levels of electrolytes (like
magnesium or potassium)
• Reduced thyroid activity; symptoms can include: tiredness, weight gain,
constipation, feeling cold and dry skin
• Swelling in your legs and arms
Common and less common side effects and discomforts from tests performed during
the study, are described in Appendix D of the ICF.
Quai Georges Gorse 65
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FR
Quai Georges Gorse 65
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FR
Listed location countries
Age
Inclusion criteria
(1) Subjects must provide a signed informed consent prior to any study-related
procedures;
(2) Male or female subjects must be aged >=18 years on the day the informed
consent is signed;
(3) Subjects must have histologically confirmed unresectable, locally advanced
(defined as disease not eligible for curative surgery or radiation therapy) or
metastatic RCC with a clear-cell carcinoma component;
(4) Subjects must have radiographic disease progression, according to
Investigator*s judgement, following 1st line treatment with CPI (ipilimumab
plus nivolumab) (Cohort A) or CPI in combination with VEGF-targeted therapy
(Cohort B);
(5) Subjects present >=1 target lesion according to RECIST 1.1 per investigator;
(6) Subjects should have Eastern Cooperative Oncology Group (ECOG) status 0-1;
(7) Subjects with treated brain metastases are eligible if metastases have been
shown to be stable as per Investigator*s judgement;
(8) Subjects must have adequate organ and marrow function, based upon meeting
all of the following laboratory criteria within 15 days before baseline:
(a) Absolute neutrophil count (ANC) >= 1500/mm3 (>= 1.5 GI/L).
(b) Platelets >= 100,000/mm3 (>= 100 GI/L).
(c) Hemoglobin >= 9 g/dL (>= 90 g/L).
(d) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <
3.0 × upper limit of normal.
(e) Total bilirubin <= 1.5 × the upper limit of normal. For subjects with
Gilbert*s disease <= 3 mg/dL (<= 51.3 µmol/L).
(f) Fasting serum triglycerides <= 2.5 × upper limit of normal and total
cholesterol <= 300 mg/dL (<= 7.75 mmol/L). Lipid-lowering medication is allowed.
(g) Serum creatinine <= 2.0 × upper limit of normal or calculated creatinine
clearance >= 30 mL/min (>= 0.5 mL/sec) using the Cockcroft-Gault equation
(h) Urine protein-to-creatinine ratio (UPCR) <= 1 mg/mg (<= 113.2 mg/mmol)
creatinine or 24-hour urine protein < 1 g.
(9) Subject must have recovered to baseline or <= Grade 1 per Common Terminology
Criteria for Adverse Events (CTCAE) v5 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on
supportive therapy as determined by the investigator;
(10) Subjects must have completed a steroid taper, if he/she experienced an
immune-related adverse event associated with previous CPI treatment;
(11) Female subjects of childbearing potential (i.e. less than or equal to 2
years post-menopause and not surgically sterile) must provide a negative
pregnancy test within 7 days prior to the start of study treatment. If a urine
test cannot be confirmed as negative, a negative serum pregnancy test is
required;
(12) Female subjects of childbearing potential (i.e. less than or equal to 2
years post-menopause and not surgically sterile) and their partners must agree
to use highly effective methods of contraception that alone or in combination
result in a failure rate of less than 1% per year when used consistently and
correctly during the course of the study and for 4 months after the last dose
of study treatment;
(13) All male participants must agree to refrain from donating sperm and
unprotected sexual intercourse with female partners during the study and for
120 days after the last dose of study treatment;
(14) Subjects must be willing and able to comply with study requirements,
remain at the investigational site for the required duration of each study
visit and be willing to return to the investigational site for the follow up
evaluation, as specified in the protocol.
(15) Subjects must be covered by social security or be the beneficiary of such
a system (only applicable for French subjects).
Exclusion criteria
(1)Inability to swallow tablets;
(2)treated with any other investigational medicinal product (IMP) within the
last 30 days before baseline;
(3)previously treated with cabozantinib;
(4)Has a contraindication to Magnetic Resonance Imaging (MRI) or contrast
medium used for Contrast Tomography (CT)-scan;
(5)Presents untreated brain or leptomeningeal metastases, or current clinical
or radiographic progression of known brain metastases;
(6)diagnosis of a serious cardiovascular disorder:
(a)Congestive heart failure New York Heart Association class 3 or 4, unstable
angina pectoris, or serious cardiac arrhythmias;
(b)Uncontrolled hypertension, defined as sustained blood pressure (BP) (>140
mm Hg systolic or>90 mm Hg diastolic pressure) despite optimal
antihypertensive treatment;
(c)Stroke (including transient ischaemic attack (TIA)), myocardial infarction
(MI) or other ischaemic event, or thromboembolic event (e.g. deep venous
thrombosis, pulmonary embolism) within 6 months before screening;
(d)History of risk factors for torsades de pointes (eg, long QT syndrome);
(7)receiving a concomitant anticoagulation with oral anticoagulants (e.g.
warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors
Note:Low dose aspirin for cardioprotection (per local applicable guidelines)
and low dose LMWH are permitted.
(8)gastrointestinal (GI) disorder including those associated with a high risk
of perforation or fistula formation:
(a)Tumours invading the GI tract, active peptic ulcer disease, inflammatory
bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis, acute pancreatitis or acute obstruction of the pancreatic or
biliary duct, or gastric outlet obstruction;
(b)Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within 6 months before screening;
Note: Complete healing of an intra-abdominal abscess must have been confirmed
before screening.
(9)Presents a corrected QT (QTc) interval calculated by the Fridericia formula
(QTcF)>500 msec within 1 month prior to baseline;
Note: If a single ECG shows a QTcF with an absolute value>500 ms, two
additional ECGs at intervals of approximately 3 min must be performed within 30
min after the initial ECG, and the average of these three consecutive results
for QTcF will be used to determine eligibility
(10)clinically significant haematuria, hematemesis, or haemoptysis of >0.5
teaspoon (2.5 mL) of red blood, or other history of significant bleeding within
3 months before screening;
(11)cavitating pulmonary lesion(s) or known endobronchial disease manifestation;
(12)lesions invading major pulmonary blood vessels;
(13)diagnosed with other clinically significant disorders such as:
(a)Serious nonhealing wound/ulcer/bone fracture;
(b)Malabsorption syndrome;
(c)Free thyroxine (FT4) outside the laboratory normal reference range;
(d)Uncompensated/symptomatic hypothyroidism;
(e)Moderate to severe hepatic impairment
(f)Requirement for haemodialysis or peritoneal dialysis
(g)History of solid organ transplantation;
(14)predicted life expectancy of less than 3 months;
(15)prior surgery within 4 weeks prior to baseline. Note: If the subject has
undergone major surgery, complete wound healing must have occurred 1 month
prior to baseline.
(16)palliative radiation therapy for bone within 2 weeks or for radiation
fields including viscera within 4 weeks prior to baseline. Note:
Resolution/healing of side effects must be complete prior to baseline;
(17)history of another active malignancy within 3 years from screening except
for locally curable cancers that have been apparently cured, such as low-grade
thyroid carcinoma, prostate cancer not requiring treatment , basal or squamous
cell skin cancer, superficial bladder cancer, in situ melanoma, in situ
prostate, cervix or breast carcinoma or other treated malignancies with <5%
chance of relapse according to the Investigator;
(18)history of allergy to study treatment components or agents with a similar
chemical structure or any excipient used in the formulation as listed in the
SmPC document;
(19)rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption;
(20)serious medical or psychiatric condition that render the subject unable to
understand the nature, scope and possible consequences of the study, and/or
presents an uncooperative attitude;
(21) pregnant or breastfeeding. A β-human chorionic gonadotrophin (HCG) serum
pregnancy test will be performed up to 7 days prior to baseline for all female
subjects of childbearing potential (i.e. less than or equal to 2 years
post-menopause and not surgically sterile);
(22)likely to require treatment during the study with drugs that are not
permitted by the study protocol;
(23)abnormal baseline findings, any other medical condition(s) or laboratory
findings that, in the opinion of the Investigator, might jeopardise the
subject*s safety.
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 | EUCTR2018-002820-18-NL |
| ClinicalTrials.gov | NCT03945773 |
| CCMO | NL72371.028.19 |