Primary objective: To determine safety, feasibility, and the immune-activating capacity of short-term combined neo-adjuvant and adjuvant ipilimumab + nivolumab.Secondary objectives: To determine relapse free survival (RFS), any late adverse events,…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary readout will be the alteration in magnitude or breadth of the
neo-antigen specific T cell response in the time interval pre- to post-adjuvant
therapy in peripheral blood. To this purpose the immunogenic mutational load of
each patient*s melanoma will be determined by DNA and RNA sequencing from
baseline biopsies (3x14g, 5ug tumor DNA). Proteasomal degradation and peptide
presentation in HLA will be predicted in silico. MHC-tetramer staining
containing the predicted peptides will be done as described before.
In addition, we will analyze the effect of therapy on intratumoral T cell
responses to obtain better insight into the mode of action of therapy.
Identified neo-antigen specific T cells will be analyzed with respect to their
phenotype and immunologic function (intracellular cytokine staining, lytic
function as determined by CD107 staining, and coculture with APC presenting the
cognate antigen).
Safety and feasibility as measured by SUSARs and adherence to the timelines in
the study protocol.
Secondary outcome
RFS, as determined according to RECIST 1.1 criteria.
Rate and type of adverse events and late adverse events
Correlation between RFS and the delta of magnitude and/or breadth of
neo-antigen T cell population
Pharmacokinetics and pharmacodynamics of nivolumab and ipilimumab comparing the
two different treatment arms
Background summary
T cell checkpoint blockade by anti-CTLA and/or anti-PD1 is currently the most
promising therapy in late stage melanoma to induce long-term benefit or even
cure. Particularly the combination of ipilimumab and nivolumab induces high
response rates and promising response depth. This raises the question whether
ipilimumab and/or nivolumab could also become standard therapy in adjuvant
treatment of melanoma. Ipilimumab has been tested with promising results in
stage III melanoma, however due to short follow-up time (median 3 years) up-to
now, no melanoma specific survival (MSS) data could be analyzed or reported.
These results are expected by 2016.
In contrast to chemotherapeutic approaches, immunotherapeutic approaches depend
on sufficient activation of the immune system. To become fully activated, T
cells require two signals. The first signal is provided by the interaction of
the (tumor-) antigen presented in the major histocompatibility complex (MHC) on
the antigen-presenting cell (APC) to the T cell receptor (TCR) on the T cell
(signal 1). In parallel, a large number of co-inhibitory and co-stimulatory
interactions - so-called T cell checkpoints - modulate the outcome of the TCR -
pMHC interaction. Antibody-based interference with the T cell checkpoints
CTLA-4 and PD-1 has been shown to improve tumor-specific T cell responses and
to result in a significant clinical benefit in patients with melanoma and other
cancers.
The notion that T cell checkpoint inhibition is of greatest value at the moment
of TCR triggering has potentially significant consequences for the use of
checkpoint targeting antibodies as adjuvant therapies. Specifically, as the
amount of antigen that can provide this signal 1 will correlate with tumor
load, we postulate, that adjuvant immunotherapy will work most efficiently,
when adjuvant treatment is initiated prior to surgery.
Study objective
Primary objective: To determine safety, feasibility, and the immune-activating
capacity of short-term combined neo-adjuvant and adjuvant ipilimumab +
nivolumab.
Secondary objectives: To determine relapse free survival (RFS), any late
adverse events, pharmacokinetics/pharmacodynamics, and the correlation between
RFS and changes in neo-antigen specific T cell response
Study design
This is a two-arm phase 1b feasibility trial consisting of 20 patients
receiving the combination of ipilimumab+nivolumab, either adjuvant, or split
neo-adjuvant and adjuvant.
Intervention
Resectable stage III melanoma patients with palpable lymph nodes, naïve for
CTLA-4/PD-1/PD-L1 immunotherapy, will be treated either post-surgery for 12
weeks with the combination of ipilimumab+nivolumab or in a split design for 6
weeks upfront surgery and for 6 weeks post-surgery (10 patients per arm).
Medicine tested: Ipilimumab 3 mg/kg q3wks, Nivolumab 1 mg/kg q3wks
Lab testing (incl. PBMC, serum collection) will be performed during screening,
at baseline, direct post-surgery, at the indicated time points until week 18,
and subsequently every three months.
Tumor biopsies/material preservation is required at baseline and during
surgery.
CT scans will be required at baseline, week 6 (only neo-adjuvant arm), week 18,
and subsequently every 3 months up to 3 years.
Another PBMC, serum collection and tumor biopsies will be performed at the
timepoint of relapse.
Study burden and risks
Currently there is no standard adjuvant therapy for stage III melanomas.
Post-surgery adjuvant radiotherapy is commonly applied, because it has been
shown to marginally improve local disease control, but neither benefit in RFS,
nor overall survival (OS), can be achieved in this high-risk patient
population. High-dose interferon is currently the only systemic therapy for the
adjuvant treatment of melanoma that is approved in some countries. However,
questionable survival benefit (two out of three meta-analyses found no OS
benefit) and serious toxicity has led to the fact that interferon is not a
generally accepted adjuvant treatment in Europe. Adjuvant systemic
immunotherapy with ipilimumab is the only treatment so far to improve RFS in
stage III melanoma. However, OS benefit has not been shown thus far (possible
due to short follow-up period) and toxicity was high, mainly when applied
longer than four courses of ipilimumab (12 weeks).
Participants of this study will be exposed to two immunotherapeutic agents
(ipilimumab and nivolumab) known to induce immune related adverse events at a
high percentage when combined together. However, this exposure will be
restricted to 4 courses (12 weeks) in total.
In addition patients within this trial cannot be treated with local
radiotherapy, which bears the risk of reduced local tumor control. Considering
the fact that local irradiation only improves local tumor control, but does not
improve RFS or OS, participation in this trial might offer the chance for
improved recurrence free survival. This is based on the observation that
adjuvant ipilimumab has already shown this benefit in a prospective randomized
controlled phase 3 trial in stage III patients and the combination of
ipilimumab with nivolumab induces superior response rates as compared to
ipilimumab alone in stage IV melanoma.
Plesmanlaan 121
Amsterdam 1066CX
NL
Plesmanlaan 121
Amsterdam 1066CX
NL
Listed location countries
Age
Inclusion criteria
• Adults at least 18 years of age
• World Health Organization (WHO) Performance Status 0 or 1
• Histologically confirmed resectable stage III melanoma with palpable lymph node metastases and no history or active in-transit metastases within the last 6 months
• Patient willing to undergo triple tumor biopsies during screening and in case of disease progression
• No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1
• No immunosuppressive medications within 6 months prior study inclusion
• Presence of at least two of the defined HLA alleles
• Screening laboratory values must meet the following criteria: WBC >= 2.0x109/L, Neutrophils >=1.5x109/L, Platelets >=100 x109/L, Hemoglobin >=5.5 mmol/L, Creatinine <=1.5x ULN, AST <= 1.5 x ULN, ALT <= 1.5 x ULN, Bilirubin <=1.5 X ULN
• normal LDH
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should 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
• Women of childbearing potential 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 ipilimumab+nivolumab
• Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year Men who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product
• Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men do not require contraception
Exclusion criteria
• Distantly metastasized 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, except for subjects with vitiligo or resolved childhood asthma/atopy
• Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy
• Radiotherapy prior or post surgery within this trial
• Patients will be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection
• Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
• Allergies and Adverse Drug Reaction
- History of allergy to study drug components
- History of severe hypersensitivity reaction to any monoclonal antibody
• Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events;
• Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids;
• Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion
• Pregnant or nursing
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 | EUCTR2014-004764-38-NL |
| CCMO | NL51280.031.14 |