This study has been transitioned to CTIS with ID 2024-513519-28-00 check the CTIS register for the current data. Primary objective • To compare the event-free survival (EFS) of neoadjuvant ipilimumab + nivolumab (followed by adjuvant nivolumab or…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
• EFS, defined as time from randomization to melanoma progression (irresectable
stage III or stage IV disease), melanoma recurrence, treatment-related death,
or melanoma-related death, whichever occurs first.
Secondary outcome
Key secondary endpoint
• OS, defined as time between date of randomization and date of death from any
cause;
Secondary endpoints:
• RFS, defined as time between date of surgery and date of melanoma recurrence,
treatment-related death or melanoma-related death, whichever occurs first;
• DMFS, defined as time between date of randomization and date of first distant
metastasis, treatment-related death or melanoma-related death, whichever occurs
first;
• EFS including new primary melanoma, defined as time from randomization to a
new primary melanoma (excluding melanoma in situ), melanoma progression
(irresectable stage III or stage IV disease), melanoma recurrence,
treatment-related death, or melanoma-related death, whichever occurs first;
• Pathologic response rate (categorized into pCR, near-pCR, MPR, pPR, pNR,
according to INMC criteria) in the neoadjuvant arm;
• Correlation of pathologic response in the neoadjuvant arm to RFS, DMFS, and
OS;
• Frequency and duration of all grade and grade 3-5 treatment-related adverse
events according to CTCAE 5.0;
• Surgical complication rates according to Clavien-Dindo surgical
classification;
• Quality of life as measured by EORTC QLQ C30, the Melanoma Subscale and
Melanoma Surgery Subscale of FACT-M, the Cancer Worry Scale, HADS
questionnaire, EQ-5D-5L, the immunotherapy-specific questionnaire, an
assessment of work performance, sexual health, and Amsterdam Cognition Scan;
• Performing health technology assessments comparing the neoadjuvant arm with
the standard adjuvant arm.
Background summary
Immunotherapy
Ipilimumab and nivolumab are antibodies (human proteins) that can help the
body's natural defenses (immune system) attack tumor cells. These agents are
also called "immunotherapy".
Adjuvant Immunotherapy
The standard treatment for patients with stage III melanoma (where there is
only metastasis to the lymph nodes) is surgery in which the lymph nodes are
removed, followed by one year of immunotherapy with nivolumab, pembrolizumab or
targeted treatment with dabrafenib + trametinib (in patients with BRAFV600E / K
melanoma).
By the time patients are diagnosed with stage III melanoma, they often already
have small metastases to other parts of the body that are so small that they
cannot be seen with scans. If you only performed an operation without
additional immunotherapy, this would allow the tumor to come back after the
operation in more than half of these patients. Immunotherapy after surgery
(also called "adjuvant" immunotherapy) can reduce the chance of disease
recurrence by 20%.
Neoadjuvant Immunotherapy
By administering the combination of ipilimumab and nivolumab prior to surgery
("neoadjuvant" immunotherapy), we hope to further reduce the chance that the
tumor will come back. In previous studies, led by the AvL, which were carried
out in the Netherlands (including the AVL) and Australia (the OpACIN and
OpACIN-neo study), melanoma patients with metastases to the lymph nodes only
were treated with immunotherapy prior to surgery for 6 years. weeks. These
studies showed that the risk of disease recurrence after surgery was greatly
reduced in patients who respond well to the immunotherapy (1 of 71 subjects got
the disease back). The correct dose of immunotherapy was also found that is
effective (in 61% of the subjects the immunotherapy had a good effect on the
tumor in 13% a partial effect) and thereby gives as little chance of side
effects as possible (20% of the subjects treated with this scheme developed one
or more more serious side effects).
This dose of the combination ipilimumab and nivolumab was subsequently tested
in a follow-up study (the PRADO study), in which an additional 99 subjects were
treated. This study confirmed the effectiveness and safety of the combination
immunotherapy; 61% of the subjects achieved a good effect and 11% a partial
effect on the combination ipilimumab and nivolumab and 22% of the subjects
developed one or more serious adverse reactions.
Additional treatment
The OpACIN and OpACIN-neo studies also showed that patients who do not respond
well to the neoadjuvant immunotherapy have a higher chance of the tumor coming
back. The PRADO study showed that patients who have partially responded to the
immunotherapy also have a higher chance of a tumor coming back, although this
is to a lesser extent than in patients who have not responded well.
If it appears in this study that your tumor has not or partially responded
well to the neoadjuvant immunotherapy prior to the operation, you will
therefore receive additional treatment after the operation in consultation with
your doctor. This is possible with nivolumab, which is currently the standard
treatment for your disease. Your tumor may also contain a BRAF mutation. BRAF
is a protein that can change (mutate) and is found in about 50% of patients
with melanoma. If your tumor contains a BRAF mutation, you will be treated with
the combination of dabrafenib and trametinib after surgery. You might also be
advised to have the operating area irradiated afterwards.
The administration of ipilimumab and nivolumab prior to surgery is still under
investigation and has not yet been approved as standard treatment. If other
treatments become available during the study, we will always look at what is
the best treatment for you at that time. Your doctor will tell you more about
this.
Study objective
This study has been transitioned to CTIS with ID 2024-513519-28-00 check the CTIS register for the current data.
Primary objective
• To compare the event-free survival (EFS) of neoadjuvant ipilimumab +
nivolumab (followed by adjuvant nivolumab or dabrafenib + trametinib in
patients not achieving a pathologic response) versus standard adjuvant
nivolumab.
Study design
This is an international (Australia, Europe, and USA) open-label two-arm
randomized phase 3 trial including 420 stage III (<=3 resectable in-transit
metastases allowed) cutaneous or unknown primary melanoma patients. Patients
will be randomized 1:1 to receive either 2 cycles of neoadjuvant ipilimumab 80
mg + nivolumab 240 mg every 3 weeks followed by a total lymph node dissection
(TLND) and, if applicable, resection of in-transit metastases (arm A) versus
standard upfront TLND +/- resection of in-transit metastases followed by 12
cycles adjuvant nivolumab 480 mg every 4 weeks (arm B). Patients in arm A
achieving only a pathologic partial response (10-50% viable tumor) or having no
response (>50% viable tumor) will receive additional adjuvant therapy: in case
of BRAF wildtype melanoma nivolumab 480 mg every 4 weeks for 46 weeks (11
cycles) and in case of BRAF V600E/K mutation-positivity, adjuvant dabrafenib
plus trametinib for 46 weeks. Patients will be treated in the study in both
arms until melanoma progression to irresectable stage III or stage IV disease,
disease recurrence, unacceptable toxicity, subject withdrawal of consent or
until end of study treatment.
Patients will be stratified according to BRAF status, continent, and the
presence/absence of in-transit metastases. An interim analysis will be
performed after 60 events have occurred. The data safety monitory board (DSMB)
will be ad hoc consulted when unexpected toxicities are reported. Patients will
be followed by 12 weekly CT scans until end of year 3 and then until year 5
according to the institute*s standards.
Intervention
In the NADINA trial, patients will be randomized to either neoadjuvant
ipilimumab 80 mg + nivolumab 240 mg q3w for 6 weeks (2 cycles), followed by
TLND (+ excision of in-transit metastases, if present), followed by 11 cycles
adjuvant nivolumab 480 mg q4w (BRAF wt) or dabrafenib 150 mg bid + trametinib 2
mg qd (BRAF V600E/K-mutated) for 46 weeks in patients not achieving a MPR (arm
A) or to TLND (+ excision of in-transit metastases) followed by standard
adjuvant nivolumab 480 mg q4w 12 cycles (arm B). In each arm 210 patients will
be included. After week 60 the patients will be followed every 12 weeks for the
first 2 years (year 2 and 3), and subsequently according to institute*s
standard in year 4 and 5.
Medication: 2 cycles ipilimumab 80 mg + nivolumab 240 mg q3w, followed by
adjuvant nivolumab 480 mg q4w (11 cycles) or dabrafenib 150 mg bid + trametinib
2 mg qd for 46 weeks in pathologic partial and non-responders (arm A) versus
adjuvant nivolumab 480 mg q4w for 52 weeks (12 cycles) (arm B).
Lab testing (including collection of serum, plasma and 1 vial of EDTA blood)
will be performed during screening. Lab testing (including collection of serum
and plasma) will be performed at baseline (week 0), week 3 (arm A only), week
6, week 9 (arm A only), at week 12 and every 12 weeks until end of year 3.
Tumor biopsies are required at baseline (4x14g: 1x FFPE, 2x fresh frozen, 1x
for tumor fragments (frozen in DSMO) or another fresh frozen sample according
to technique present at the study center). Surgical material should be
preserved as FFPE material, as fresh frozen (if lymph node >2cm) and as
fragments (if lymph node >5cm, in experienced centers (see Appendix D)).
Optionally, tumor biopsies (4x 14g: 2x fresh frozen, 1x FFPE, 1x for tumor
fragments (frozen in DMSO) or another fresh frozen sample) in week 2 for
translational research (window +/- 3 days).
CT scans will be required during screening and at week 6 and week 12.
Follow-up will start at week 12 with 12-weekly CT scans for patients achieving
a MPR in arm A. Adjuvant therapy should start no later than week 12 for
patients achieving no MPR in arm A and for all patients in arm B. During
adjuvant therapy radiologic evaluation will also be performed every 12 weeks.
Subsequent follow-up will be by CT scans in both arms every 12 weeks in year 2
and 3, and according to the institute*s standard follow-up schedules in year 4
and 5.
QoL (BL, week 6, 12, then every 12 weeks in year 1, and every half year in year
2 and 3), the Amsterdam Cognition Scan (ACS, BL, year 1 and year 2), and ePROs
with urgency algorithms (continuously) will be collected using the KAIKU app.
In case of recurrence, tumor biopsies (4x14g: 1x FFPE, 2x fresh frozen, 1x for
tumor fragments (frozen in DSMO) or another fresh frozen sample according to
technique present at the study center), serum and plasma collection are
required.
Study burden and risks
Recently, adjuvant systemic targeted therapy with dabrafenib and trametinib in
BRAFV600E/K mutation-positive patients has shown to improve RFS (significantly)
and OS (not significantly). Grade 3-4 toxicities were reported to occur in 41%
of the patients. Adjuvant systemic treatment with ipilimumab has been approved
by the FDA due to RFS and OS benefit, but was not filed for approval outside
the US due to the high grade of adverse events (41.6% grade 3-4 adverse events
in patients treated with ipilimumab 10 mg/kg adjuvant). Both anti-PD-1
antibodies nivolumab and pembrolizumab have been approved as adjuvant therapies
based on two phase 3 trials investigating pembrolizumab versus placebo and
nivolumab versus ipilimumab that showed RFS benefit in favor of the anti-PD-1
antibody, while OS benefit data are still pending. Treatment-related grade 3-4
adverse event rates were 14.7% and 14.4%, respectively.
Adjuvant nivolumab 240 mg q2w + ipilimumab 1 mg/kg q6w versus adjuvant
nivolumab in completely resected, stage IIIB/C/D or stage IV melanoma
(according to AJCC 8th edition) tested in the Checkmate 915 trial, failed to
achieve its primary objective. The IMMUNED trial that investigated adjuvant
placebo versus nivolumab versus standard dosing of ipilimumab 3 mg/kg +
nivolumab 1 mg/kg every 3 weeks for 4 cycles followed by nivolumab
consolidation up to 1 year in resectable stage IV melanoma patients already
showed a promising 24-months RFS of 70%. The grade 3-4 toxicity rate was high,
with 70.9% grade 3-4 adverse events for the combination treatment and 26.8% for
nivolumab monotherapy. These high toxicity rates combined with promising RFS
data support the idea of less systemic immune suppression in patients with low
tumor load, and result in the requirement of alternative lower dosing schemes
for combination therapy.
Participants of the NADINA trial will be exposed to two immunotherapeutic
agents (ipilimumab and nivolumab) known to induce immune-related adverse events
at a higher percentage when combined together. This has also been observed in
the OpACIN trial in which 90% of all patients receiving ipilimumab and
nivolumab at standard dosing developed grade 3-4 toxicities independent of
neoadjuvant or adjuvant application.
However, the OpACIN-neo trial that compared different dosing regimens,
identified two cycles of neoadjuvant ipilimumab 1 mg/kg + nivolumab 3 mg/kg as
dosing scheme that was effective (77% pRR, 57% pCR) and had a manageable
toxicity profile (20% grade 3-4 adverse events). Responding patients seem to
achieve long term benefit, as only one out of 71 responders in the OpACIN and
OpACIN-neo trial has recurrenced so far with a median follow-up of 48.0 and
24.6 months, respectively. These safety and efficacy data were confirmed in the
PRADO extension cohort that showed a pathologic response rate of 72%, a MPR of
61% and grade 3-4 adverse event rate of 22% for 2 cycles neoadjuvant ipilimumab
1 mg/kg + nivolumab 3 mg/kg (data update 10/2020).
These observations have led to the design of this phase 3 NADINA trial that
will test the dosing scheme of 2 cycles ipilimumab 80 mg + nivolumab 240 mg
flat-dose compared to standard adjuvant therapy.
Patients achieving no pathologic response upon neoadjuvant immunotherapy have a
high chance of early recurrence. To date, 16 out of 23 patients (69.6%) in the
OpACIN and OpACIN-neo trial without pathologic response recurred. Patients that
achieve a partial response may also be at risk for early recurrence, as in the
PRADO trial (and in contrast to the previous neoadjuvant trials where no
relapses were observed) 4 out of 11 partial responders (36,4%) had a recurrence
within the first two years. Interestingly, only 8 out of 21 non-responders
(38,1%) recurred, suggesting that the additional adjuvant therapy that
non-responders received in this trial, improves the outcome for this subgroup
with an initial poor prognosis (historic data from OpACIN-neo suggested 69,6%
relapses in non-responders). For patients achieving a partial or no response,
we hope to improve the RFS by adding adjuvant nivolumab or dabrafenib +
trametinib, and also allowing parallel adjuvant radiotherapy.
*
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Inclusion criteria
• Men and women, at least 16 years of age;
• World Health Organization (WHO) Performance Status 0 or 1;
• Cytologically or histologically confirmed resectable stage III melanoma of
cutaneous or unknown primary origin with one or more macroscopic lymph node
metastases (clinical detectable), that can be biopsied and a maximum of 3
additional resectable in-transit metastases. A concurrent resectable primary
melanoma is allowed. Clinical detectable lymph nodes are defined as either:
o a palpable node, confirmed as melanoma by pathology,or;
o a non-palpable but enlarged lymph node according to RECISTv1.1 (at least 15
mm in short axis), confirmed as melanoma by pathology, or;
o a PET scan positive lymph node of any size confirmed as melanoma by pathology;
• No other malignancies, except adequately treated and with a cancer-related
life-expectancy of more than 5 years;
• No prior immunotherapy targeting CTLA-4, PD-1, PD-L1 or LAG-3;
• No prior targeted therapy targeting BRAF and/or MEK;
• No immunosuppressive medications within 6 months prior study inclusion
(steroids equivalent to prednisolone <=10 mg are allowed);
• Screening laboratory values must meet the following criteria: WBC >=2.0x109/L,
neutrophils >=1.5x109/L, platelets >=100x109/L, hemoglobin >=5.5 mmol/L,
creatinine <=1.5xupper limit of normal (ULN), AST <=1.5x ULN, ALT <=1.5x ULN,
bilirubin <=1.5x ULN (except for subjects with Gilbert syndrome who must have a
total bilirubin <3.0 mg/dL);
• LDH level <1.5x ULN;
• Women of childbearing potential (WOCP) must use appropriate method(s) of
contraception, i.e. methods with a failure rate of <1% per year when used
consistently and correctly, to avoid pregnancy during and until 23 weeks post
last ipilimumab + nivolumab infusion;
• Males who are sexually active with WOCP are not required to use contraception
during treatment with nivolumab +/- ipilimumab, but must use appropriate
method(s) of contraception, i.e. methods with a failure rate of <1% per year
when used consistently and correctly, to avoid pregnancy during and until 17
weeks post last dabrafenib + trametinib administration;
• Patient willing and able to understand the protocol requirements and comply
with the treatment schedule, scheduled visits, electronic patient outcome
reporting, tumor biopsies and extra blood withdrawal during screening and in
case of relapse, and other requirements of the study;
• Patient has signed the Informed Consent document.
Exclusion criteria
• Distantly metastasized melanoma;
• Uveal/ocular or mucosal melanoma;
• Subjects with any active autoimmune disease or a documented history of
autoimmune disease, or history of syndrome that required systemic steroids or
immunosuppressive medications. Subjects with vitiligo, resolved childhood
asthma/atopy type I diabetes mellitus, residual hypothyroidism due to
autoimmune thyroiditis only requiring hormone replacement, skin disorders (such
as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are
permitted to enroll;
• Prior radiotherapy; targeting the affected lymph node region(s);
• Subjects will be excluded if they test positive for hepatitis B virus surface
antigen (HBsAg) or hepatitis C virus ribonucleic acid (HCV antibody),
indicating acute or chronic infection. Subjects treated and being at least one
year free from HCV are allowed to participate;
• Subjects will be excluded if they have known history of testing positive for
human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome
(AIDS);
• Subjects with history of allergy to study drug compononents or history of
severe hypersensitivity reaction to monoclonal antibodies.
• Subjects with underlying medical conditions or active infection that, in the
investigator's opinion, will make the administration of study drug hazardous or
obscure the interpretation of toxicity or adverse events;
• Women who are pregnant or breastfeeding;
• Concurrent medical condition requiring the use of immunosuppressive
medications, or immunosuppressive doses of systemic or absorbable topical
corticosteroids >10 mg prednisolone daily equivalent;
• Use of other investigational drugs before study drug administration 30 days
or 5 half-times before study inclusion;
• Psychological, familial, sociological, or geographical conditions that
potentially hamper compliance with the study protocol and follow-up schedule;
those conditions should be discussed with the subject before registration in
the trial.
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 |
|---|---|
| EU-CTR | CTIS2024-513519-28-00 |
| EudraCT | EUCTR2021-001492-16-NL |
| ClinicalTrials.gov | NCT04949113 |
| CCMO | NL76979.031.21 |