Primary Objectives - To compare Overall Survival (OS) and Progression free survival (PFS) of nivolumab monotherapy to ipilimumab monotherapy and that of nivolumab combined with ipilimumab to ipilimumab monotherapy in subjects with previously…
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Condition
- Skin neoplasms malignant and unspecified
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Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective will be measured by the co-primary endpoints of overall
surival (OS) and Progression Free Survival (PFS) in all randomized subjects.
OS is defined as the time between the date of randomization and the date of
death due to any cause. OS will be censored on the last date a subject was
known to be alive. OS data will be collected continuously while subjects are on
study medication and every 3 months via in-person or phone contact after
discontinuation of study medication.
PFS is defined as the time between the date of randomization and the first date
of documented progression, as determined by the investigator, or death due to
any cause, whichever occurs first. Subjects who die without a reported
progression will be considered to have progressed on the date of their death.
Subjects who did not progress or die will be censored on the date of their last
evaluable tumor assessment. Subjects who did not have any on study tumor
assessments and did not die will be censored on their date of randomization.
Subjects who started anti-cancer therapy without a prior reported progression
will be censored on the date of their last evaluable tumor assessment prior to
the initiation of subsequent anti-cancer therapy. Tumor assessments are
scheduled to be performed at Week 12, every 6 Weeks up to Week 49 and then
every 12 to 24 Weeks until disease progression.
Secondary outcome
The first secondary objective (to compare ORR between the experimental arms and
the control group) will be measured by the endpoint of ORR. The ORR is defined
as the number of subjects with a BOR of CR or PR divided by the number of
randomized subjects for each treatment group. The BOR is defined as the best
response designation, as determined by the investigator, recorded between the
date of randomization and the date of objectively documented progression per
RECIST 1.1 or the date of subsequent anti-cancer therapy, whichever occurs
first. For subjects without documented progression or subsequent therapy, all
available response designations will contribute to the BOR assessment. Tumor
assessments are scheduled to be performed at Week 12, every 6 Weeks up to Week
49 and then every 12 to 24 Weeks until disease progression. The second
secondary objective (to evaluate differences in OS, PFS, and ORR between the
two experimental arms) and will be measured by the endpoints of OS, PFS, and
ORR. The third secondary objective (to evaluate PD-L1 expression as a
predictive biomarker) will be measured by the endpoint OS based on PD-L1
expression level. PD-L1 expression will be evaluated in tumor specimens
collected prior to randomization. The forth secondary objective (to evaluate
HRQoL) will be measured by mean changes from baseline in the EORTC-QLQ-C30
global health status/QoL composite scale and by mean changes from baseline in
the remaining EORTC QLQ-C30 scales. HRQoL will be evaluated per Section 5.1 of
the protocol.
Background summary
The lifetime risk of developing invasive melanoma has been dramatically
increasing and the overall mortality from melanoma continues to rise. Although
in 2011, two new agents, ipilimumab and vemurafenib, were approved for advanced
melanoma there is still a large unmet need for patients with previously
untreated,unresectable or metastatic melanoma.
Approximately 50% of cutaneous melanoma is BRAF mutation positive, and
vemurafenib is indicated for the treatment of BRAF V600E mutation positive
advanced melanoma. Vemurafenib is a potent inhibitor of mutation positive BRAF
and has demonstrated an increased overall survival benefit compared to
dacarbazine with a hazard ratio for death of 0.62 with a median overall
survival of 13.2 months versus 9.6 months for vemurafenib and dacarbazine,
respectively. Besides these two agents, no other agent has demonstrated an
overall survival benefit in a Phase 3 randomized study.
Ipilimumab at 3 mg/kg was chosen as the comparator because it is the only FDA
approved treatment of previously untreated, unresectable or metastatic melanoma
without restriction to BRAF status that has demonstrated overall survival
benefit in a Phase 3 randomized trial (Ipilimumab monotherapy at 3 mg/kg has
been shown to increase 2-year survival compared to a vaccine control (26% vs.
14%) in previously treated subjects with metastatic melanoma). In a
retrospective analysis of a Phase 2 ipilimumab clinical trial in unresectable
and metastatic melanoma, CA184004, rates of objective responses and stable
disease in patients with BRAF-V600E mutation positive tumors were comparable to
those in patients with the wildtype gene. Given 3 mg/kg of ipilimumab has not
been evaluated in a phase 3 trial of previously untreated, unresectable or
metastatic melanoma, the median overall survival has been estimated to be 14
months (as calculated in section 1.4.4.2 of the protocol - page 23).
Nivolumab monotherapy has demonstrated clinical activity across several tumor
types, including advanced prior treated melanoma, with objective response rates
of 20 - 41% in 106 melanoma subjects treated at various dose levels in
CA209003. Nivolumab has also demonstrated a manageable safety profile. The most
common AEs included fatigue, rash, pruritis, diarrhea, and nausea.
The combination of nivolumab and ipilimumab has the potential for increased
benefit compared to both ipilimumab monotherapy and nivolumab monotherapy.
Preliminary analysis of the evaluable CA209004 subjects revealed that
approximately 33% of the subjects had >80% tumor reductions in target lesions
by week 12. This compares favorably to < 2% for 3 mg/kg ipilimumab monotherapy
based on the CA184020 (N=540) and <3% for nivolumab monotherapy based on the
CA209003. However, the combination of nivolumab and ipilimumab also has the
potential for increased frequencies of adverse events. The most common
(reported at > 10% incidence) treatment related AEs are fatigue, rash,
pruritus, diarrhea, lipase increased, pyrexia, ALT increase, AST increased,
amylase increased and vitiligo. Although the preliminary
data suggests an increase in adverse event frequency of nivolumab combined with
ipilimumab compared to ipilimumab monotherapy or nivolumab monotherapy, there
were no unexpected adverse events noted in the combination of nivolumab and
ipilimumab. In addition, many of the Grade 3-4 adverse events associated with
the nivolumab combined with ipilimumab were laboratory in nature, without
clinical sequalae and adverse events have been manageable and reversible
following intervention dose delays or with systemic steroid treatment.
Evaluating both nivolumab monotherapy and the combination of nivolumab and
ipilimumab will provide clinical data allowing clinicians to select the
appropriate treatment for each patient based on the individual risk-benefit
ratio. The robust clinical activity demonstrated by nivolumab
monotherapy and the promising clinical activity of nivolumab combined with
ipilimumab in subjects with advanced melanoma in combination with the
manageable safety profile and the lack of approved survival-prolonging agents
for a large segment of the previously untreated
population supports the further development of nivolumab and nivolumab combined
with ipilimumab in subjects with previously untreated, unresectable or
metastatic melanoma.
Study objective
Primary Objectives -
To compare Overall Survival (OS) and Progression free survival (PFS) of
nivolumab monotherapy to ipilimumab monotherapy and that of nivolumab combined
with ipilimumab to ipilimumab monotherapy in subjects with previously
untreated, unresectable or metastatic melanoma.
Secondary Objectives -
To compare ORR of nivolumab monotherapy to ipilimumab monotherapy and that of
nivolumab combined with ipilimumab to ipilimumab monotherapy in subjects with
unresectable or metastatic melanoma
- To evaluate differences in OS, PFS, and ORR between nivolumab combined with
ipilimumab and nivolumab monotherapy in subjects with unresectable or
metastatic melanoma
- To evaluate whether PD-L1 expression is a predictive biomarker for PFS and OS
- To evaluate Health Related Quality of Life (HRQoL) as assessed by the
European Organisation for Research and Treatment of Care (EORTC) QLQ-C30
Exploratory Objectives - To evaluate duration of and time to objective response
of nivolumab monotherapy, nivolumab combined with ipilimumab, and ipilimumab in
subjects with unresectable or metastatic melanoma - To assess the overall
safety and tolerability of nivolumab monotherapy, nivolumab combined with
ipilimumab, and ipilimumab monotherapy in subjects with unresectable or
advanced melanoma - To characterize pharmacokinetics of nivolumab and
ipilimumab administered alone or in combination with nivolumab - To
characterize the immunogenicity of nivolumab and nivolumab combined with
ipilimumab - To evaluate pharmacokinetic drug-drug interaction between
nivolumab and ipilimumab - To explore potential biomarkers associated with
clinical efficacy (ORR, PFS and OS) of nivolumab and/or nivolumab combined with
ipilimumab by analyzing biomarker measures within the tumor microenvironment
and periphery (eg, blood, serum, PBMCs) in comparison to clinical outcomes. -
To assess the effects of natural genetic variation (SNPs) in select genes
including, but not limited to, PD-1, PD-L1, PD-L2, and CTLA-4 on clinical
endpoints and/or on the incidence of adverse events - To assess changes in
health status and work and activity impairment in treatment groups using the
EuroQoL EQ-5D and the Work Productivity and Activity Impairment questionnaire
(WPAI-GH) respectively - To describe the quality of survival in patients after
treatment discontinuation using the EuroQoL EQ-5D .
Study design
This is a Phase 3, randomized, double-blind study of nivolumab monotherapy or
nivolumab combined with ipilimumab versus ipilimumab monotherapy in adult (less
than or equal to 18 years) subjects with previously untreated unresectable or
metastatic melanoma. Subjects must have stage III (unresectable) or stage IV
melanoma, as per the American Joint Committee on Cancer (AJCC) staging system,
and must not have received prior therapy for the treatment of unresectable or
metastatic melanoma. Prior adjuvant or neoadjuvant therapy is allowed in the
setting of completely resectable disease. PD-L1 status will be obtained by
immunohistochemical (IHC) staining of PD-L1 protein prior to
randomization. Subjects will be randomized 1:1:1 and stratified by PD-L1 status
(positive vs.negative/indeterminate), BRAF Status (BRAF mutation positive, BRAF
wildtype), and AJCC M stage (M0/M1a/M1b vs. M1c). One cycle of treatment is
defined as six weeks. Subjects will be treated with one of the following:
- Arm A: nivolumab 3 mg/kg IV every 2 weeks + ipilimumab-placebo on weeks 1, 4
and nivolumab-placebo on weeks 4 for cycles 1 and 2
- Arm B: nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks
for 4 doses then nivolumab 3 mg/kg IV Q2W + nivolumab-placebo on weeks 3 and 5
for cycles 1 and 2.
- Arm C: ipilimumab 3mg/kg IV every 3 weeks for a total of 4 doses +
nivolumab-placebo on weeks 1, 3, 4 and 5 for cycles 1 and 2 then every 2 weeks.
This study will consist of 3 phases: screening (up to 28 days), treatment and
follow-up. Treatment will continue until documented disease progression, there
is discontinuation due to toxicity, withdrawal of consent or the study ends.
Subjects will be followed every 3 months for survival after completion of the
follow-up visits. Subjects in Arm C who were receiving nivolumab - placebo
will enter the follow-up phase upon unblinding of the study.
Intervention
The medical interventions for this trial include both Nivolumab and Ipilimumab.
All compounds will be supplied by the Sponsor company.
One cycle of treatment is defined as six weeks. Subjects will be treated with
one of the following:
- Arm A: nivolumab 3 mg/kg IV every 2 weeks + ipilimumab-placebo on weeks 1, 4
and nivolumab-placebo on weeks 4 for cycles 1 and 2
- Arm B: nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV every 3 weeks
for 4 doses then nivolumab 3 mg/kg IV Q2W + nivolumab-placebo on weeks 3 and 5
for cycles 1 and 2.
- Arm C: ipilimumab 3mg/kg IV every 3 weeks for a total of 4 doses +
nivolumab-placebo on weeks 1, 3, 4 and 5 for cycles 1 and 2 then every 2 weeks.
Beyond the first 2 cycles (12 weeks), subjects will be receiving infusions
(Nivolumab for arm A and B and Nivolumab macthing placebo for arm C) every 2
weeks for 60 minites.
Subjects in Arm C who were receiving nivolumab - placebo will enter the
follow-up phase upon unblinding of the study.
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinationd, vital sign measurements
including oxygen saturation levels, blood tests for safety assessment,
pregnancy testing (for females of child bearing potential) and monitoring for
adverse events. In addition, every 6 weeks (from week 12 up until the 1st
year), patients will undergo radiographic assessment of their tumours (by CT or
MRI) until disease progression of treatment discontinuation whichever occurs
later. Beyond year one, the radiographic assessment of their tumours (by CT or
MRI) will be every 12 to 24 weeks. Blood will also be collected at certain
visits for research purposes (PK, immunogenicity and biomarker studies). The
frequency of visits and number of procedures carried out during this trial
would typically be considered over and above standard of care. There procedures
are carried out by trained medical professionals and every effort will be made
to minimise any risks or discomfort to the patient. Treatment for cancer often
has side effects, including some that are lift threatening. An independent Data
Monitoring Committee (DMC) will be utilised in this trial.
Orteliuslaan 1000
Utrecht 3528 BD
NL
Orteliuslaan 1000
Utrecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
1. Signed Written Informed Consent
a) Subjects 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 subject care
b) Subjects must be willing and able to comply with scheduled visits, treatment
schedule, laboratory testing, and other requirements of the study
2. Target Population
a) Histologically confirmed unresectable Stage III or Stage IV melanoma, as per
AJCC staging system.
b) Eastern Cooperative Oncology Group (ECOG) performance status of * 1 (Refer
to Appendix 2)
c) Treatment naïve subjects (ie, no prior systemic anticancer therapy for
unresectable or metastatic melanoma). Note that prior adjuvant or neoadjuvant
melanoma therapy is permitted if it was completed at least 6 weeks prior to
randomization, and all related adverse events have either returned to baseline
or stabilized.
d) Measurable disease by CT or MRI per RECIST 1.1 criteria.5.4.3.1
e) Tumor tissue from an unresectable or metastatic site of disease must be
provided for biomarker analyses. In order to be randomized, a subject must be
classified as PD-L1 positive, PD-L1 negative, or PD-L1 indeterminate. If an
insufficient amount of tumor tissue from an unresectable or metastatic site is
available prior to the start of the screening phase, subjects must consent to
allow the acquisition of additional tumor tissue for performance of biomarker
analyses.
f) Subjects must have known BRAF V600 mutation status or consent to BRAF V600
mutation testing per local institutional standards during the Screening Period
g) Prior radiotherapy must have been completed at least 2 weeks prior to study
drug administration.
Screening laboratory values must meet the following criteria and should be
obtained
within 14 days prior to randomization:
- WBC greater than or equal to 2000/µL
- Neutrophils greater than or equal to 1500/µL
- Platelets greater than or equal to 100 x103/µL
- Hemoglobin > 9.0 g/dL
- Serum creatinine less than or equal to 1.5 x ULN or creatinine clearance
(CrCl) greater than or equal to 40 mL/min (using the Cockcroft-Gault formula):
- AST/ALT less tha or equal to 3 x ULN
- Total Bilirubin less than or equal to 1.5 x ULN (except subjects with Gilbert
Syndrome, who can have total bilirubin < 3.0 mg/dL).
i) Subject 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 randomized / has not been treated) after obtaining agreement from the
medical monitor prior to re enrolling a subject. If re-enrolled, the subject
must be re-consented.
3. Age and Reproductive Status
a) Men and women, less than or equal to 18 years of age
b) Women of childbearing potential (WOCBP) must use method(s) of contraception
as indicated in Appendix 5. For a teratogenic study drug and/or when there is
insufficient information to assess teratogenicity (preclinical studies have not
been done), a highly effective method(s) of contraception (failure rate of less
than 1% per year) is required. The individual methods of contraception and
duration should be determined in consultation with the investigator. WOCBP must
follow instructions for birth control when the half life of the investigational
drug is greater than 24 hours, contraception should be continued for a period
of 30 days plus the time required for the investigational drug to undergo five
half lives. The half life of BMS- 936558 and ipilimumab is up to 25 days and 18
days, respectively. Given the blinded nature of this study, WOCBP should
therefore use an adequate method to avoid pregnancy for 23 weeks (30 days plus
the time required for nivolumab to undergo five half lives) after the last dose
of investigational drug.
c) Women must have a negative serum or urine pregnancy test (minimum
sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the
start of investigational product.
d) Women must not be breastfeeding
e) Men who are sexually active with WOCBP must use any contraceptive method
with a failure rate of less than 1% per year The investigator shall review
contraception methods and the time period that contraception must be followed.
Men that are sexually active with WOCBP must follow instructions for birth
control when the half life of the investigational drug is greater than 24
hours, contraception should be continued for a period of 90 days plus the time
required for the investigational drug to undergo five half lives. The half-life
of nivolumab and ipilimumab is up to 25 days and 18 days, respectively. Given
the blinded nature of the study, men who are sexually active with WOCBP must
continue contraception for 31 weeks (90 days plus the time required for
nivolumab to undergo five half lives) after the last dose of investigational
drug.
f) Women who are not of childbearing potential (ie, who are postmenopausal or
surgically sterile; see Section 3.3.3 for the definition of WOCBP) and
azoospermic men do not require contraception.
Exclusion criteria
1. Target Disease Exceptions
a) Active brain metastases or leptomeningeal metastases. Subjects with brain
metastases are eligible if these have been treated and there is no magnetic
resonance imaging (MRI) evidence of progression for at least 8 weeks after
treatment is complete and within 28 days prior to first dose of study drug
administration. There must also be no requirement for immunosuppressive doses
of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2
weeks prior to study drug administration.
b) Ocular melanoma
2. Medical History and Concurrent Diseases
a) Any participation in a Phase 3 ipilimumab trial
b) Any serious or uncontrolled medical disorder that, in the opinion of the
investigator, may increase the risk associated with study participation or
study drug administration, impair the ability of the subject to receive
protocol therapy, or interfere with the interpretation of study results.
c) Prior malignancy active within the previous 3 years except for locally
curable cancers that have been apparently cured, such as basal or squamous cell
skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate,
cervix, or breast.
d) Subjects with active, known or suspected autoimmune disease. Subjects with
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external
trigger are permitted to enroll.
e) Subjects with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days of study drug administration.
Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily
prednisone equivalents are permitted in the absence of active autoimmune
disease.
f) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4
antibody, or any other antibody or drug specifically targeting T-cell
costimulation or immune checkpoint pathways.
3. Physical and Laboratory Test Findings
a) Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C
virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
b) Known history of testing positive for human immunodeficiency virus (HIV) or
known acquired immunodeficiency syndrome (AIDS).
4. Allergies and Adverse Drug Reaction
a) History of allergy to study drug components.
b) History of severe hypersensitivity reaction to any monoclonal antibody.
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.
6. 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 | EUCTR2012-005371-13-NL |
| ClinicalTrials.gov | NCT01844505 |
| CCMO | NL44310.031.13 |