To compare the overall survival of ipilimumab monotherapy at doses of 3 mg/kg versus 10 mg/kg in subjects with previously treated or untreated unresectable Stage III or Stage IV melanoma
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Study Assessments and Primary Endpoint: Safety Assessments: All subjects who
receive at least one dose of study treatment (ipilimumab) will be evaluated for
safety parameters.
Primary Endpoint: All randomized subjects will be evaluated for efficacy
analyses. Overall survival (OS) will be defined as the time from the date of
randomization until the date of death. For those subjects who have not died, OS
will be censored on the last date the subject was known to be alive.
Secondary outcome
Secondary Objectives:
Efficacy:
* To compare progression-free survival between doses of 3 mg/kg and 10 mg/kg by
mWHO criteria
* To compare best overall response rate between doses of 3 mg/kg and 10 mg/kg
by mWHO criteria
* To compare disease control rate between doses of 3 mg/kg and 10 mg/kg by mWHO
criteria
* To evaluate duration of response and stable disease for the of 3 mg/kg and 10
mg/kg dose groups by mWHO criteria
* To evaluate the OS in each of the two dosing groups in the subset of subjects
with brain metastases
Background summary
Ipilimumab is approved for use in the US (metastatic melanoma) and in the EU
(for previously treated metastatic melanoma). The currently approved dose is 3
mg/kg every 3 weeks for up to 4 doses. A dose effect was observed in Phase 2
with an acceptable safety profile for 10 mg/kg, suggesting that the higher dose
may be more appropriate. However, 2 randomized Phase 3 studies demonstrated
comparable increments in overall survival (OS) relative to their respective
controls. The first Phase 3 study, MDX010-20, examined ipilimumab (3 mg/kg
monotherapy) vs a melanoma vaccine in previously treated subjects. The second
Phase 3 study, CA184024, compared ipilimumab + DTIC to DTIC alone in
treatment-naïve subjects. In light of the meaningful differences in Phase 3
study designs, a cross-study comparison of the 2 doses is difficult to
interpret. The current study offers direct comparison of 3 vs 10 mg/kg
monotherapy in a well-sized, randomized Phase 3 study in order to more clearly
define the relative risk:benefit of each dose.
Study objective
To compare the overall survival of ipilimumab monotherapy at doses of 3 mg/kg
versus 10 mg/kg in subjects with previously treated or untreated unresectable
Stage III or Stage IV melanoma
Study design
Study Design: This is a randomized, multicenter, double-blind Phase 3 study.
Subjects aged * 18 years of age with untreated or previously treated
unresectable Stage III or Stage IV (metastatic) melanoma who have not received
a B-Raf inhibitor or prior immune checkpoint modulatory therapy (see
eligibility criteria) will be randomly assigned to be treated with ipilimumab
at a dose of either 3 mg/kg or 10 mg/kg by intravenous infusion every 3 weeks x
4 doses. After initial response (or stable disease for at least 3 months)
followed by subsequent progression and in the absence of intolerable toxicity,
subjects are eligible to receive re-induction therapy using the same dose and
schedule as used for induction. Re-induction may be provided at the discretion
of the investigator using the same criteria.
When the analysis for the primary endpoint of overall survival has been
conducted, all subjects, including subjects in the Re-induction phase, will no
longer be treated on this study and will revert to commercial supplies of
ipilimumab where available as per local labels. Subjects will continue to be
followed for long term survival.The study will be double-blinded and subjects
will be randomized in a 1:1 ratio between the two treatment arms. Randomization
will be stratified by:
1) M substage: M0+M1a+M1b versus M1c without brain metastases versus M1c with
brain metastases
2) Prior treatment for metastatic melanoma: yes versus no
3) ECOG Performance Status: 0 versus 1
This study is divided into the following phases: Screening, Induction,
Re-induction, Progression Follow-up, and Survival Follow-up.
Intervention
Study Population: Men and women, * 18 years of age, with previously treated or
untreated unresectable Stage III or IV histologically or cytologically
confirmed melanoma, ECOG Performance Status 0 or 1, and who have not received a
B-Raf inhibitor or prior CTLA-4 or PD-1antagonists, or PD-L1 or CD137 agonists
are eligible. Subjects with brain metastases who are free of neurologic
symptoms related to metastatic brain lesions and who do not require or receive
systemic corticosteroid therapy in the 10 days prior to beginning ipilimumab
therapy are eligible. Subjects with a history of or current active autoimmune
diseases (see eligibility criteria) or current uncontrolled infectious disease
will be excluded. Subjects must provide a baseline blood sample for biomarker
testing.
Study burden and risks
This trial can cause the following side effects,
A). Common Side Effects Considered to be Related to the Infusion: hypotension
(low blood pressure), fever,chills, nausea and/or vomiting, flushing, fatigue
diarrhea, skin rash, skin itchiness, abdominal pain, loss of appetite , local
reaction at the site of injection, headache.
B). Immune*related side effects associated with administration of ipilimumab:
* The most common stomach/intestinal side effect is diarrhoea, constipation,
blood in stool and abdominal pain.
* Rash: Rashes on the skin and or together with itching.
* Inflammation in the various parts of the eye or with pigment (colour) changes
in the retina (back wall of the eye). In rare cases, double vision occurred as
a result of muscle weakness.
* Serious problems with particular glands (a gland is a group of cells or an
organ that secretes a substance) such as the pituitary gland, the thyroid or
the adrenal gland. Symptoms that may be associated with problems of the
pituitary gland or adrenal gland include tiredness, confusion, weight loss,
impotence (inability to perform sexually) and headache.
* Inflammation of the liver which can be life threatening.
C). Risks Associated with Study Procedures:
* Risks associated with taking blood or putting a needle in a vein might
include pain from the puncture, bruising, bleeding, infection, or fainting.
* During a CT and MRI scan it is know that there are rare occurrences of
allergic reactions to the contrast dyes injected into a vein during the scan.
Such allergic reactions can involve itching, rash, or in severe cases,
difficulty in breathing and dangerous lowering of blood pressure or other
general symptoms.
D). Men, pregnant women and women that are breastfeeding are at risk because it
not known if the study medication can cause potential damage to the sperm,
foetus and baby.
E). In rare occasions there are side effects that occur in patients who use
Ipilimumab such as
* In more than one organ alike such as the liver, kidney, heart, lungs and
cardiovascular system (body system consisting of the heart, blood vessels and
blood circulation)
* Meningitis (inflammation of the membrane surrounding the spinal cord and
brain). This can cause headache, feeling sick and vomiting, stiff neck and
sensitivity of your eyes to light.
* Inflammation of the nerves that control muscles
* Inflammation of the kidneys (Nephritis).
* Vitiligo, a condition where the skin loses pigment and turns white.
Blistering and peeling of the top layer of skin resembling that of a severe
burn have been rarely reported.
* Symptoms associated with immune-based reactions against other parts of the
body such as joints
Vijzelmolenlaan 9
3440 AM Woerden
NL
Vijzelmolenlaan 9
3440 AM Woerden
NL
Listed location countries
Age
Inclusion criteria
Inclusion Criteria
1) Signed Written Informed Consent
a) Willing and able to give written informed consent;
2) Target Population
a) Histologically or cytologically confirmed diagnosis of malignant melanoma;
b) Previously-treated or untreated unresectable Stage III or Stage IV melanoma (AJCC 2010) (regardless of B-Raf mutation status or HLA type);
c) Prior adjuvant melanoma therapy is permitted; any number of previous treatments for melanoma are permitted except for prior B-Raf inhibitors, CTLA-4 antagonists or PD-1 antagonists, or PD-L1 or CD137 agonists;
d) Measurable/evaluable disease, within 28 days of first dose of study drug;
e) Subjects with brain metastases who are free of neurologic symptoms related to metastatic brain lesions and who do not require or receive systemic corticosteroid therapy in the 10 days prior to beginning ipilimumab therapy are eligible;
f) ECOG performance status of 0 or 1;
g) Subjects must have the complete set of baseline (ie, screening) digital radiographic images of lesions and anatomic regions limited to brain, chest, and abdomen within 28 days of first dose of study drug;
h) Provision of baseline DNA samples from peripheral blood for testing of:
* CD86 and CTLA-4 polymorphisms, and
* genome-wide association analysis to identify genetic determinants of immune-related adverse events;
i) Adequate hematologic, renal and hepatic function, specifically:
* WBC * 2500/uL, ANC * 1000/uL,
* Platelets * 75 x 10^3/uL,
* Hemoglobin * 9 g/dL,
* Creatinine * 2.5 x ULN,
* AST/ALT * 3 x ULN for subjects without liver metastasis; * 5 x ULN for subjects with liver metastasis,
* Total bilirubin * 3 x ULN, (except subjects with Gilbert*s Syndrome, who must have a total bilirubin less than 3.0 mg/dL);
j) Accessible for treatment and Follow-up;
3) Age and Reproductive Status
a) Men and women * 18 years of age
b) Women of childbearing potential (WOCBP) and men must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product] in such a manner that the risk of pregnancy is minimized. See Section 3.3.4 for the definition of WOCBP.
c) WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of investigational product.
d) Women must not be breastfeeding
e) Sexually active fertile men must use effective birth control if their partners are WOCBP.
Exclusion criteria
Exclusion Criteria
1) Target Disease Exceptions
a) Primary ocular melanoma;
b) Active brain metastases with symptoms or requiring corticosteroid treatment;
2) Medical History and Concurrent Diseases
a) Any other malignancy from which the subject has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix;
b) History of or current active autoimmune diseases, including but not limited to inflammatory bowel diseases, rheumatoid arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis (scleroderma and variants), systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies (eg, Guillain-Barre syndrome). Vitiligo is NOT excluded;
c) Uncontrolled infectious diseases * requires negative tests for clinically suspected HIV, HBV and HCV. If positive results are not indicative of true active or chronic infection, the subject may enter the study after discussion and agreement between the Investigator and the Medical Monitor;
d) History of or current immunodeficiency disease, splenectomy or splenic irradiation;
e) Prior allogeneic stem cell transplantation;
f) Any underlying medical or psychiatric condition, which in the opinion of the Investigator, will make the administration of study drug hazardous or obscure the interpretation of AEs, such as a condition associated with frequent diarrhea;
3) Physical and Laboratory Test Findings
a) Not applicable; defined in Inclusion criteria
4) Prohibited Therapies and/or Medications
a) Prior therapy with a B-Raf inhibitor, CTLA-4 or PD-1 antagonists, or PD-L1 or CD137 agonists;
b) Concomitant therapy with any anti-cancer agent, potent immunosuppressive agents, surgery or radiotherapy or other investigational anti-cancer therapies or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses);
c) Prior anti-cancer therapy < 4 weeks prior to randomization;
d) Prior therapies with systemic immunosuppressive agents within prior 2 years (excluding episodic low dose corticosteroids, eg, for treatment of allergic dermatologic conditions); prior therapies with cytotoxic or investigational drugs within 4 weeks of randomization;
e) Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 4 weeks prior to or after any dose of ipilimumab);
f) Treatment with any other investigational products within 4 weeks prior to randomization into this study;
g) Any psychological or medical condition which may interfere with the ability to provide informed consent;
h) Any psychological, familial, cultural/sociological or geographical condition which could potentially hamper compliance with study schedule, procedures and testing;
5) Allergies and Adverse Drug Reaction
a) History of allergic reaction to parenteral administered recombinant protein product;
6) Sex and Reproductive Status
a) Sexually active fertile men not using effective birth control if their partners are WOCBP
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
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 | EUCTR2011-0044029-2-NL |
| ClinicalTrials.gov | NCT01515189 |
| CCMO | NL39470.029.12 |