Primary objective:To estimate the efficacy of adjuvant nivolumab monotherapy in completely resected MCC patients; i.e. the primary endpoint is Disease-free survival (DFS) in arm A at 12 months, defined as the number of patients alive and free of…
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Brief title
Condition
- Neoplastic and ectopic endocrinopathies
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary objective is of the study is to estimate the efficacy of adjuvant
nivolumab monotherapy in completely resected MCC patients; i.e. the primary
endpoint is Disease-free survival (DFS) in arm A at 12 months, defined as the
number of patients alive and free of disease at 12 months after randomization
compared to DFS in arm B.
Secondary outcome
The secondary objectives of the study are to assess safety and additional
efficacy parameters of the nivolumab treatment in MCC, as well as to
characterize potential biomarkers; secondary endpoints are:
(i) Adverse events according to CTCAE, Version 4.0 criteria, that are
definitely, probably, or possibly related to the administration of nivolumab,
(ii) Overall survival rate at 12 months, defined as the number of patients
alive at 12 months after randomization divided by the total number of patients
randomized.
(iii) DFS rate at 12 months, defined as the number of patients alive and free
of disease at 12 months after randomization divided by the total number of
patients randomized.
The patients having received ipilimumab will be analyzed in a purely
descriptive manner.
In addition, the exploratory objectives are:
(iv) Disease free and overall survival
(v) Identify and validate prognostic/predictive biomarkers such as immune
status, kinetics of the absolute lymphocyte count (ALC), or tumor
microenvironment characteristics
Background summary
Merkel cell carcinoma (MCC) is a rare, highly aggressive skin cancer and has a
high mortality rate after initial diagnosis. This high mortality rate is
largely due to the fact that to date there is no established adjuvant therapy
for completely resected MCC and none of the currently available therapeutic
interventions is able to improve overall survival of patients suffering from
metastatic disease. Consequently, new therapeutic strategies both for the
adjuvant as well as the palliative setting are needed.
As compared to most other cancers, MCC is particularly linked to immune
suppression.
Two major causative factors for MCC have been identified: ultraviolet (UV)
light and the Merkel-cell polyomavirus (MCPyV), whose large T antigen is
expressed in tumor cells and inactivates Rb. Approximately 80% of Merkel-cell
carcinomas are associated with MCPyV, and these patients often have MCPyV
T-antigen-specific T cells in their peripheral blood. Virus-associated
Merkel-cell carcinomas carry extremely low mutational burdens, in contrast to
UV-induced, MCPyV-negative Merkel-cell carcinomas are characterized by a
mutational load that is comparable to UV-induced squamous cell carcinoma.
Several studies have shown that approximately 50% of MCCs express PD-L1 on
tumor cells or infiltrating macrophages. Indeed, recent reports indicate that
MCC is particular receptive to immune therapy PD-1/PD-L1 blocking antibodies.
Almost half of the patients with completely resected MCC will relapse with
loco-regional or distant metastases within the first two years after initial
diagnosis of this highly immunogenic cancer. Consequently, an immune modulating
therapy with ipilimumab (Yervoy) or nivolumab (Opdivo®) is likely to improve
the disease-free survival as well as the overall survival of MCC patients if
given in an adjuvant setting.
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
CA209-003. The reported benefit of PD-1/PDL-1 blockade in metastatic MCC
suggest, that this can be anticipated for nivolumab as well.
In the initial trial design, the immune modulating treatment was based on
CTLA-4 blockade by ipilimumab; however, the advent of PD-1/PD-L1 blockade in
the palliative treatment of MCC dramatically changed the treatment environment
to an extent that applying treatments other than by PD-1/PD-L1 blockade had
become very difficult. Moreover, the side effects of PD-1/PD-L1 blocking are
far less frequent than side effects of ipilimumab. Consequently, randomization
into the previous Ipilimumab treatment arm A was stopped. New patients will be
randomized to nivolumab treatment instead.
Study objective
Primary objective:
To estimate the efficacy of adjuvant nivolumab monotherapy in completely
resected MCC patients; i.e. the primary endpoint is Disease-free survival (DFS)
in arm A at 12 months, defined as the number of patients alive and free of
disease at 12 months after randomization compared to DFS in arm B.
Secondary objectives:
To assess safety and additional efficacy parameters of the nivolumab treatment
in MCC, as well as to characterize potential biomarkers; secondary endpoints
are:
(i) Adverse events according to CTCAE, Version 4.0 criteria, that are
definitely, probably, or possibly related to the administration of nivolumab,
(ii) Overall survival rate at 12 months, defined as the number of patients
alive at 12 months after randomization divided by the total number of patients
randomized.
(iii) DFS rate at 12 months, defined as the number of patients alive and free
of disease at 12 months after randomization divided by the total number of
patients randomized.
Exploratory objectives:
(iv) Disease free and overall survival
(v) Identify and validate prognostic/predictive biomarkers such as immune
status, kinetics of the absolute lymphocyte count (ALC), or tumor
microenvironment characteristics
The biology and the immunology of MCC are only partially understood, thus it
appears mandatory to implement a comprehensive translational research program
in order to establish the means to identify the group of patients most likely
to benefit from therapy. This translational research program will focus on the
immune monitoring of the MCC patients treated in the phase II trial, as well as
aim at the discovery of predictive and/or surrogate biomarkers for a successful
immune therapy of MCC. The randomized design of the study allows distinguishing
predictive from prognostic biomarkers. To reach this goal, sampling for
translational research studies (tumor tissue, peripheral blood mononuclear
cells (PBMC), plasma, serum) will be done as described in the study protocol.
These studies include: *
* Prognostic/predictive value of the presence of tumor infiltrating lymphocytes
in MCC lesions prior to therapy *
* Expression of immune modulatory molecules in the tumor *
* Presence of immune modulatory cells in the tumor *
* Association with MCPyV *
* Detection of circulating free MCC-specific DNS/microRNA in plasma and serum
Study design
This is a national, open-label, randomized, multicenter phase II study to
assess the efficacy of adjuvant nivolumab therapy in completely resected MCC
patients. In the initial trial design, the immune modulating treatment was
based on CTLA-4 blockade by ipilimumab; however, the advent of PD-1/PD-L1
blockade in the palliative treatment of MCC (presented at AACR, ASCO and ESMO)
dramatically changed the treatment environment to an extent that applying
treatments other than by PD-1/PD-L1 blockade had become very difficult.
Moreover, the side effects of PD-1/PD-L1 blocking are far less frequent than
side effects of ipilimumab.
Consequently, randomization into the previous Ipilimumab treatment arm A was
stopped. New patients will be randomized to nivolumab treatment instead.
Patients randomized already into the Ipilimumab-arm will be evaluated
descriptively for efficacy and safety. Patients already randomized into the
observation arm (arm B) will be evaluated together with the newly randomized
arm B-patients.
A total of 177 patients with completely resected MCC will be enrolled over a
recruitment period of 36 months into this trial, and randomized 2:1 to be
treated with the PD-1 antibody nivolumab (118 patients) as adjuvant therapy or
just observed (59 patients). Patients will be stratified by gender, age, and
stage of disease, i.e. stage I/II versus stage III/IV with no evidence of
disease (NED).
Intervention
Patients with completely resected MCC will be randomized 2:1 to be treated with
nivolumab as adjuvant therapy or just observed. Patients will be stratified by
gender, age, and stage of disease, i.e. stage I/II versus stage III/IV with no
evidence of disease (NED).
Nivolumab will be applied at a flat dose of 480mg by IV infusion every 4 weeks
for a maximum of 13 doses i.e. for up to one year. Treatment may be
discontinued prematurely in case of drug-related AEs, progressive disease or
wish of patient.
Laboratory evaluations will be performed and the results examined before
administration of each drug dose. Tumor assessment will be performed every 12
weeks during treatment phase. The same methods of assessment (e.g.
ultrasonography, CT or MRI scans) used at baseline will be used during
treatment phase.
Study burden and risks
The time and events schedule summarizes the frequency and timing of the various
measurements can be found in the protocol (Table 4, pages 33 and 34).
At study entry, the following procedures and assessments will be performed:
informed consent, collection of demographic data, medical and surgical history,
opthalmological examination (if clinically indicated), central confirmation of
histological diagnosis of MCC, ECG, full physical examination, blood sampling,
test for hepatitis B/C and HIV, urinalysis, tumor evaluation and blood sampling
for translational research project.
The assessment of the subject's eligibility to participate will be conducted as
determined by the inclusion/exclusion criteria.
For patients randomized into the treatment arm, Nivolumab will be applied at a
flat dose of 480mg by IV infusion every 4 weeks for a maximum of 13 doses i.e.
for up to one year. Treatment may be discontinued prematurely in case of
drug-related AEs, progressive disease or wish of patient.
Laboratory evaluations will be performed and the results examined before
administration of each drug dose. Tumor assessment will be performed every 12
weeks during treatment phase. The same methods of assessment (e.g.
ultrasonography, CT or MRI scans) used at baseline will be used during
treatment phase. The subjects will be evaluated every 4 weeks: physical
examinations and vital signs, urinalysis will be performed. The subjects will
be asked to complete a questionnaire (quality of life assessment) every 3
months during the treatment period. Tumor tissue will be collected at the end
of the study therapy for translational research project.
The disease will be assessed at baseline and 12 weeks after first
administration of nivolumab (treatment arm) or after randomization (observation
arm). Thereafter, the disease will be assessed every 12 weeks in the absence of
PD until end of study with a maximum of 2 years after first treatment dose
(treatment arm) or after randomization (observation arm) for each patient
according to the current German and European guidelines for the management of
MCC patients.
The same methods of assessment (e.g. ultrasonography, CT or MRI scans) used at
baseline will be used during follow up. In addition, survival will be assessed
every 12 weeks after end of treatment.
The follow-up period will last for a maximum of 2 years for all randomized
patients.
For patients randomized into the observation arm, follow-up starts with date of
randomization up to a maximum of 2 years or until withdrawal of informed
consent, loss to follow-up, death or end of study, whichever occurs first.
Follow-up period will start for patients randomized into the treatment arm
after application of last dose of investigational product until withdrawal of
informed consent, loss to follow-up, death or end of study, whichever occurs
first.
No patient diaries will need to be completed.
Hufeland Str. 55
Essen 45122
DE
Hufeland Str. 55
Essen 45122
DE
Listed location countries
Age
Inclusion criteria
1. The patient is willing and able to give written informed consent.
2. Central histological confirmation of diagnosis of Merkel cell carcinoma
(MCC).
3. All MCC manifestations have been completely resected by surgery within 12
weeks before enrolment.
4. No currently present metastases (as confirmed by standard imaging studies
(e.g. suggested by S2k guidelines).
5. No previous systemic therapy for MCC.
6. Required values for initial laboratory tests: *
WBC >= 2000/uL *
ANC >= 1000/uL *
Platelets >= 75 x 103/uL *
Hemoglobin >= 8 g/dL (>= 80 g/L) *
Creatinine <= 2.0 x ULN *
AST/ALT <= 2.5 x ULN *
Total Bilirubin <= 2.0 x ULN (except patients with Gilbert*s Syndrome, who must
have a total bilirubin less than 3.0 mg/dL)
7. ECOG performance status of 0 or 1.
8. No active or chronic infection with HIV, Hepatitis B or C.
9. Men and women, >= 18 years of age.
10. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception (Pearl-Index < 1) to avoid pregnancy during treatment phase and
for additional 5 months after the last dose of nivolumab, in such a manner that
the risk of pregnancy is minimized. WOCBP include any female who has
experienced menarche and who has not undergone successful surgical
sterilization (hysterectomy, bilateral tubal ligation, or bilateral
oophorectomy) or is not post-menopausal. WOCBP must have a negative serum or
urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG)
within 72 hours before the start of nivolumab.
11. Men of fathering potential must be using an adequate method of
contraception to avoid conception during treatment phase and for additional 7
months after the last dose of nivolumab) in such a manner that the risk of
pregnancy is minimized.
Exclusion criteria
1. Autoimmune disease: Patients with a history of inflammatory bowel disease,
including ulcerative colitis and Crohn*s Disease, are excluded from this study,
as are patients with a history of symptomatic disease requiring systemic
steroids (e.g., rheumatoid arthritis, systemic progressive sclerosis, systemic
lupus erythematosus, autoimmune vasculitis); autoimmune motor neuropathy.
2. Other serious illnesses, e.g., serious infections requiring i.v.
antibiotics.
3. The patient is known to be positive for Human Immunodeficiency Virus (HIV)
or other chronic infections (HBV, HCV) or has another confirmed or suspected
immunosuppressive or immune deficient condition.
4. Any underlying medical or psychiatric condition, which in the opinion of the
investigator will make the administration of nivolumab hazardous or obscure the
interpretation of AEs, such as a condition associated with frequent diarrhea.
5. Any non-oncology vaccine therapy for up to 1 month before or after any dose
of nivolumab.
6. A history of prior or current treatment with a T cell potentiating agent
(e.g. IL-2, interferon, anti-CTLA-4, anti-CD137, anti-PD1, anti-PD-L1, or
anti-OX40 antibody).
7. Chronic use of immunosuppressive agents or systemic corticosteroids.
8. Women of childbearing potential (WOCBP), defined above in Section 5.1, who:
*
are unwilling or unable to use an acceptable method of contraception to avoid
pregnancy during treatment phase and for additional 5 months after the last
dose of investigational product *
have a positive pregnancy test at baseline *
are pregnant or breastfeeding.
9. The patient has psychiatric or addictive disorders that may compromise
his/her ability to give informed consent or to comply with the trial
procedures.
10. Prisoners or subjects who are compulsorily detained (involuntarily
incarcerated) for treatment of either a psychiatric or physical (e.g.,
infectious) illness.
11. Men of reproductive potential unwilling to use an adequate method to avoid
pregnancy during treatment phase and for additional 7 months after the last
dose of investigational product.
12. Use of any investigational or non-registered product (drug or vaccine)
other than the study treatment.
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 | EUCTR2013-000043-78-NL |
| ClinicalTrials.gov | NCT02196961 |
| CCMO | NL67336.031.19 |