The primary objective of this trial are:- To determine the incidence of high-grade (CTCAE v4.0 Grade 3 orhigher), treatment related, select adverse events in patients withhistologically confirmed stage III (unresectable) or stage IV melanomaand…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective of this trial are:
- To determine the incidence of high-grade (CTCAE v4.0 Grade 3 or
higher), treatment related, select adverse events in patients with
histologically confirmed stage III (unresectable) or stage IV melanoma
and progression after prior treatment containing an anti-CTLA-4
monoclonal antibody.
Secondary outcome
The secondary objectives:
- To determine the incidence and to characterize the outcome of all highgrade
(CTCAE v4.0 Grade 3 or higher), select adverse events in patients
with histologically confirmed stage III (unresectable) or stage IV
melanoma and progression after prior treatment containing an anti-
CTLA-4 antibody, treated with nivolumab monotherapy.
- To estimate OS in all treated patients
- To estimate Investigator-assessed objective response rate (ORR)
Exploratory objectives: Refer to study protocol
Background summary
Bristol-Myers Squibb*s ongoing development program of nivolumab investigates
the efficacy and safety of anti-PD-1 or nivolumab, a fully human IgG4 (kappa)
isotype monoclonal antibody that binds PD-1 on activated immune cells and
disrupts engagement of the receptor with its ligands PD-L1 and PD-L2 in
advanced (unresectable and metastatic) melanoma patients.
There is currently an unmet medical need in patients with stage III
(unresectable) or stage IV
metastatic melanoma who have progressed or recurred after prior treatment
containing an anti-CTLA-4
monoclonal antibody.
The current is study is to determine the rate and frequency of high-grade
(CTCAE v4.0 Grade 3 or higher), treatment-related, select
adverse events in subjects with histologically confirmed stage III
(unresectable) or stage IV melanoma and progression post prior treatment
containing an anti-CTLA-4 monoclonal antibody, treated with nivolumabat a dose
of 3 mg/kg every two weeks for a maximum of 24 months.
Study objective
The primary objective of this trial are:
- To determine the incidence of high-grade (CTCAE v4.0 Grade 3 or
higher), treatment related, select adverse events in patients with
histologically confirmed stage III (unresectable) or stage IV melanoma
and progression after prior treatment containing an anti-CTLA-4
monoclonal antibody.
The secondary objectives:
- To determine the incidence and to characterize the outcome of all highgrade
(CTCAE v4.0 Grade 3 or higher), select adverse events in patients
with histologically confirmed stage III (unresectable) or stage IV
melanoma and progression after prior treatment containing an anti-
CTLA-4 antibody, treated with nivolumab monotherapy.
- To estimate OS in all treated patients
- To estimate Investigator-assessed objective response rate (ORR)
Exploratory objectives: Refer to study protocol
Study design
The study will include subjects with histologically-confirmed stage III
(unresecteable) or stage IV
advanced melanoma who have documented progression after treatment containing an
anti-CTLA-4 monoclonal
antibody. Patients will be treated with 3 mg/kg of nivolumab IV every 2 weeks
for a maximum of 24 months.
Since there is, to date, only limited information about safety of nivolumab in
subjects presenting with Performance
Status 2, a separate prospective cohort of a maximum of 300 subjects with
Performance Status 2 (Cohort 2) at initial
consultation will be enrolled to assess the safety and tolerability in this
specific population. Clinical risk/benefit ratio
will be monitored by the Scientific Steering Committee and evaluated after
treatment of n = 50 for at least 2 months
with consecutive decision about further enrollment.
Currently there is only little reliable data describing the percentage of
subjects with melanoma progressing after prior
therapy containing treatment with an anti-CTLA-4 antibody, presenting with
Performance Status 2 and eligible for
nivolumab treatment. It is estimated that a minimum of 20% to 30% of the
potential study population will initially
present with PS2. This estimation of Cohort 2 results in a maximum of 300
subjects.
Intervention
3 mg/kg of nivolumab every 2 weeks
Treat until progression* or unacceptable toxicities. Safety is followed
continuously. Subjects followed for ongoing drug-related AEs until resolution,
symptoms return to baseline, AE deemed irreversible, lost to follow/death,
disease progression,* or withdrawal of consent.
*Subjects may be treated beyond progression under protocol-defined
circumstances.
Study burden and risks
Information can be found in section 7 and 8 of the informed consent form: 7)
Which Risks / Possible Adverse Drug Reactions can the subject expect?
Treatments for cancer often have side effects, including some that are
life-threatening. There is the possibility of death occurring as a result of
this treatment and its side effects. There may be additional unknown and
potentially serious or life-threatening risks that could occur with the study
drug. If the subject experiences severe side effects associated with the study
drug, the doctor may prescribe medications to treat the side effect(s), future
treatments may be delayed, or treatment may be stopped permanently. Any
significant new findings that develop during the course of the research and may
relate to the subject*s willingness to continue participation will be provided
to the subject. Nivolumab Nivolumab may cause one or more of the side effects
listed below. This information is based on data from cancer subjects in other
clinical trials with nivolumab. In addition, there may be side effects that are
not yet known that may occur. The subject should tell the doctor or nurse right
away about any possible side effects the subject experiences. The most common
side effects of nivolumab are: • Fatigue • Rash • Itching • Diarrhea Some side
effects that have been observed in patients taking Nivolumab are less common or
even rare (but potentially serious). The subject can read more about these in
addendum VIII of the informed consent form. Lung Inflammation (pneumonitis): It
is possible that nivolumab may cause inflammation of the tissues of the lung.
This adverse effect has been reported in patients treated with nivolumab. While
many patients with x-ray or CT abnormalities have not developed any symptoms,
some patients have developed mild to severe symptoms and in rare cases, death
has occurred as a result of their lung inflammation. Signs and symptoms of lung
inflammation may include difficulty breathing, pain or discomfort while
breathing, chest pain, cough, shortness of breath, increased rate of breathing,
fever, low blood oxygen levels, or fatigue. The study doctor and nurse will
watch the subject closely for changes in the ability to breathe and for other
signs or symptoms that might show the subject is developing this type of lung
inflammation and will perform regular tests including physical exams,
measurement of oxygen levels through non-invasive testing (i.e., pulse
oximeter), blood tests, chest x-rays and/or CT scans. The subject should inform
the study doctor or nurse at once if the subject experiences any of the
following: • Any new or increased shortness of breath; • Any new or increased
chest pain; • Any new or increased pain/difficulty while breathing; • Any new
or increased cough or any significant change in type of cough; for example any
new or increased mucous or blood in your cough; • Any change in the amount of
oxygen the subject requires; • Any fever, fatigue, or other symptoms that occur
at the same time as any changes to breathing or other lung symptoms. If the
subject starts to develop symptoms, the study doctor will ask the subject to
return to the clinic for additional tests, which could include a physical exam,
measurement of oxygen levels, blood tests, chest x-rays, and/or CT scans. The
subject will be monitored very closely for changes in your overall lung
symptoms, monitoring may require hospitalization. The subject may require
specific treatment in order to control pneumonitis. The subject may also be
seen by a special doctor called a pulmonologist. Prolonged treatment with
medicines that suppress inflammation, sometimes needed to manage the side
effects of nivolumab treatment, may lower the body*s ability to fight off
certain infections (i.e., opportunistic infections). These infections may
require treatment with antibiotic or antifungal medications and may be fatal.
Other side effects: Side effects associated with blood draws or use of an IV
catheter may include infection, bruising, redness, discomfort, or bleeding at
the needle puncture site. Sometimes patients have allergic reactions to the
dyes used in CT scans. This is rare. It can involve itching or rash. In severe
cases, the subject may have difficulty breathing and dangerous lowering of the
blood pressure. If subject knows that he/she has an allergy to the dye, or to
iodine or shellfish, the subject should informthe study doctor and radiologist.
These scans are also associated with exposure to varying amounts of radiation.
There may be risks or side effects which are unknown at this time. The
subject*s condition may not get better or may become worse while he/sheis in
this study. Certain drugs may increase the severity of these side effects if
taken during the study. The subject should ask his/her study doctor for a full
list of prohibited medications. Risks to Reproduction, Unborn Babies and
Nursing Infants The subject cannot participate in this study in case she is
pregnant or breastfeeding. Participation in the study may have effects for the
unborn child. Although the use of nivolumab in pregnant women has not been
formally studied in clinical studies, there are indications from an animal
study which suggest a potential risk to human pregnancy if there is continued
treatment with nivolumab during pregnancy. These abnormal findings [e.g., late
stage pregnancy loss in monkeys] occurred at doses that are 9 times greater
than the human nivolumab dose of 3 mg/kg every 2 weeks used in this clinical
trial. More about reproductive risks and pregnancy prevention can be found in
the informed consent form in Addendum VIII. 8) What are the possible benefits
and disadvantages of participation in the study Nivolumab may or may not lead
to improvement of the subjects Melanoma. By taking part in this study, the
result may add to the understanding of the subject*s condition. It may also be
helpful for future patients. Disadvantages of participation are that the
subject has to make additional visits to the clinic, follow the instructions
for participation in the trial (section 3) and may experience side-effects
(section 7).
Chaussée de la Hulpe 185
Brussels 1170
BE
Chaussée de la Hulpe 185
Brussels 1170
BE
Listed location countries
Age
Inclusion criteria
1. Signed Written Informed Consent
a) Patients must have signed and dated an IRB/IEC approved written
informed consent
form in accordance with regulatory and institutional guidelines. This
must be obtained before the performance of any protocol-related
procedures that are not part of normal patient care.
b) Patients must be willing and able to comply with scheduled visits,
treatment schedule, laboratory tests, and other requirements of the
study.
2. Target Population
a) Patients with progression after prior treatment containing an anti-
CTLA-4 monoclonal antibody (Cohorts 1 and 2):
i) Patients with histologically confirmed malignant melanoma
ii) Eastern Cooperative Oncology Group (ECOG) PS:
(1) PS 0 to 1 (Cohort 1)
(2) PS 2 (Cohort 2; a minimum of 50 patients and a maximum of 185;
clinical risk benefit ratio of Cohort 2 will be monitored by the Scientific
Steering Committee)
iii) Previously treated unresectable stage III or stage IV melanoma as
per the American Joint Committee on Cancer 2010 Guidelines36
regardless of BRAF mutation status
iv) Patients must have experienced disease progression or recurrence
after prior treatment containing an anti-CTLA-4 monoclonal antibody
v) Prior treatment with chemotherapy, interferon (adjuvant setting), IL-
2, BRAF/MEK inhibitors for patients with known BRAF mutations, MEK
inhibitors for NRAS mutations, and cKIT inhibitor patients with known
cKIT mutations are allowed
vi) Patients with CNS metastases:
(1) Patients are eligible if CNS metastases are treated and patients are
neurologically returned to baseline (except for residual signs or
symptoms related to the CNS treatment) for at least 2 weeks prior to
enrollment. In addition, patients must be either off corticosteroids or on
a stable or decreasing dose 10 mg daily prednisone (or equivalent)
OR
(2) Patients are eligible if they have previously untreated CNS
metastases and are
neurologically asymptomatic. In addition, patients must be either off
corticosteroids or on a stable or decreasing dose of 10 mg daily
prednisone (or equivalent)
OR
(3) Patients with additional leptomeningeal metastases are eligible if
they are treated and neurologically returned to baseline (except for
residual signs or symptoms related to the CNS treatment) for at least 2
weeks prior to enrollment and have a life expectancy of at least 3
months. In addition, patients must be either off corticosteroids or on a
stable or decrease dose 10 mg daily prednisone (or equivalent)
vii)Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or
growth factor
given to control the cancer) must have been completed at least 4 weeks
before study drug administration, and all adverse events have either
returned to baseline or have been stabilized
viii) Prior palliative radiotherapy must have been completed at least 2
weeks prior to study drug administration
ix) Prior targeted therapy must have been completed at least 2 weeks
prior to study
drug administration
x) Prior anti-CTLA-4 therapy must have been completed at least 4 weeks
before study drug administration
xi) Prior radiotherapy or radiosurgery must have be completed at least 2
weeks prior
to the first dose of study drug
xii)Primary uveal (minimum of 30 patients) and mucosal melanoma are
allowed
xiii) Screening laboratory values must meet the following criteria prior
to commencement of treatment:
(1) WBCs >= 2000/µL
(2) Neutrophils >=1500/µL
(3) Platelets >= 100 x 10³/µL
(4) Hemoglobin >= 9.0 g/dL
(5) Serum creatinine of <= 1.5 X ULN or creatinine clearance > 40
mL/minute (using Cockcroft/Gault formula)
(a) Female CrCl= [(140- age in years) x weight in kg x 0.85) ÷(72 x
serum creatinine in mg/ dL)]
(b) Male CrCl= [(140- age in years) x weight in kg x 1.00) ÷(72 x serum
creatinine in mg/ dL)]
(6) AST <= 3 X ULN
(7) ALT <= 3 X ULN
(8) Total bilirubin <= 1.5x ULN (except patients with Gilbert Syndrome
who must have total bilirubin < 3.0 mg/dL)
xiv) Patients with a known history of Grades 3-4 adverse reactions
during anti-CTLA-4 therapy will be allowed to participate if all toxicities
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before
administration of nivolumab (minimum of 40 patients)
xv) Patients must have evaluable disease by CT or MRI per RECIST 1.1
criteria (radiographic tumor assessment performed within 6 weeks of
first dose of study drug)
or clinically apparent disease that the investigator can follow for
response.
xvi) Patient Re-enrollment: This study permits the re-enrollment of a
subject that has
discontinued the study as a pre-treatment failure (ie, subject has not
been treated). If
re-enrolled, the subject must be re-consented.
For Other Inclusion Criteria please refer to Protocol
Exclusion criteria
1. Target Disease Exceptions
a) As of Amendment 02, this criterion is no longer applicable.
b) Patients with untreated, symptomatic CNS metastases are excluded
2. Medical History and Concurrent Diseases
a) As of Amendment 03, this criterion is not applicable.
b) Patients with a condition requiring systemic treatment with either
corticosteroids (>10 mg daily prednisone equivalent) or other
immunosuppressive medications within 14 days of study drug
administration. Inhaled or topical steroids and adrenal replacement
steroid doses > 10 mg daily prednisone equivalent are permitted in the
absence of active autoimmune disease.
c) Patients with previous malignancies (except non-melanoma skin
cancers, in situ bladder cancer, gastric or colon cancers, cervical
cancers/dysplasia or breast carcinoma in situ) are excluded unless a
complete remission was achieved at least 2 years prior to study entry
and no additional therapy is required or anticipated to be required
during the study period
d) Any serious or uncontrolled medical disorder or active infection that,
in the opinion of
the investigator, may increase the risk associated with study
participation, study drug
administration, or would impair the ability of the patient to receive
protocol therapy
e) Any treatment in a BMS-sponsored, interventional nivolumab trial or
ipilimumab trial
f) Known drug or alcohol abuse
3. Physical and Laboratory Test Findings
a) Any positive test for hepatitis B virus or hepatitis C virus indicating
acute or chronic
infection
b) Positive test for HIV
4. Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity reactions to other monoclonal
antibodies
b) History of allergy or intolerance (unacceptable adverse event) to
study drug components or Polysorbate-80-containing infusions.
c) As of Amendment 02, this criterion is no longer applicable.
5. Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding
b) Women with a positive pregnancy test at enrollment or prior to
administration of study medication
c) Women treated with ORAL hormone replacement therapy (HRT) are to
be excluded
unless the oral replacement therapy was stopped by investigator's
discretion at least 4
weeks prior to screening and was changed to other contraception
method.
6. As of Amendment 02, this criterion is no longer applicable
7. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a
psychiatric or physical (eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure
the safety of the study subjects and that the results of the study can be
used. It is imperative that subjects fully meet all eligibility criteria.
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 | EUCTR2014-001286-28-NL |
| ClinicalTrials.gov | NCT02156804 |
| CCMO | NL50000.028.14 |