Primary Objective:To investigate the pharmacodynamic activity of nivolumab, and nivolumab in combination with ipilimumab in the tumor environment and the periphery on biomarker measures such as circulating T cell subsets (activated and memory T…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
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Intervention
Outcome measures
Primary outcome
The primary objective relating to the pharmacodynamic activity of biomarkers
will be measured by changes from baseline in activated and memory T cells,
interferon inducible factors, and CD4 and CD8 T cell infiltration.
Secondary outcome
The secondary objective relates to safety and tolerability of nivolumab and
nivolumab in combination of ipilimumab in subjects with advanced melanoma.
These will be measured by the following endpoints:
Safety and tolerability of nivolumab and nivolumab in combination with
ipilimumab as measured by the incidence of adverse events (AEs), serious AEs,
death, laboratory test abnormalities, and changes in vital signs;
Antitumor activity of nivolumab and nivolumab in combination with ipilimumab as
measured by the objective response rate (ORR), duration of response, and
progression free survival (PFS);
Immunogenicity of nivolumab and nivolumab in combination with ipilimumab as
measured by the frequency of baseline positive subjects and the frequency of
ADA positive subjects
Association between PD-L1 and clinical efficacy will be measured by PDL1
expression levels clinical activity (ORR, PFS)
Background summary
Currently, the information regarding the mechanism of action of nivolumab in
the clinic is limited. Initial data from CA209003 (Phase 1 nivolumab
monotherapy) and CA209-006 (Phase 1 study combining nivolumab with a peptide
vaccine) have suggested key differences in the action of nivolumab from
ipilimumab on peripheral T cells. Specifically, nivolumab treatment does not
appear to increase absolute lymphocyte counts, nor increase the frequency of
activated CD4 and CD8 T cells. Both agents may be associated with an increase
in tumor antigen specific T cells.
This study aims to evaluate the immunomodulatory pharmacodynamic effects of
nivolumab and nivolumab in combination with ipilimumab in subjects with
melanoma. The goal is to gain an understanding of the how nivolumab and
nivolumab in combination with ipilimumab modulate the immune system to affect
an anti-tumor response. This will be accomplished through assessments of tumor
cells and tumor infiltrating lymphocytes and peripheral immunophenotyping,
serum cytokine and antibody measurements, as well as measures of T cell
function. The data collected and analyzed in this study will be utilized across
the nivolumab program, in order to inform the development of nivolumab for
other oncologic indications and for use in determining the best combination
therapies.
Study objective
Primary Objective:
To investigate the pharmacodynamic activity of nivolumab, and nivolumab in
combination with ipilimumab in the tumor environment and the periphery on
biomarker measures such as circulating T cell subsets (activated and memory T
cells populations by flow cytometry), interferon, interferon inducible factors
and T cell (CD4 and CD8) infiltration in tumor biopsy sections from subjects
with advanced melanoma.
Secondary Objectives:
• To further describe the safety and tolerability of nivolumab and nivolumab in
combination with ipilimumab in subjects with advanced melanoma
• To further describe the preliminary anti-tumor activity of nivolumab and
nivolumab in combination with ipilimumab in subjects with advanced melanoma
• To further investigate the immunogenicity of nivolumab and ipilimumab
• To assess the potential association between PD-L1 expression (by IHC) and
clinical efficacy measures
Exploratory Objectives:
• To describe the safety, tolerability and efficacy of nivolumab and nivolumab
in combination with ipilimumab in patients with brain metastases
• To investigate the potential association between selected biomarker measures
in peripheral blood and tumor tissue with safety and clinical efficacy measures
including overall survival (OS)
• To investigate the pharmacodynamic activity of nivolumab and nivolumab in
combination with ipilimumab in the peripheral blood and tumor tissue as
measured by other flow cytometry, immunohistochemistry and soluble factor assays
• To examine the effect of nivolumab and nivolumab in combination with
ipilimumab on gene expression as measured by microarray technology and
quantitative RT-PCR in peripheral blood and tumors tissue
• To study the effect of nivolumab and nivolumab in combination with ipilimumab
on the tumor antigen specific T cell responsiveness in the peripheral blood
• To analyze blood samples for immune-related single nucleotide polymorphisms
(SNPs) to support cross study analyses of the association of clinical activity
and safety measures with SNPs
• To characterize pharmacokinetics of nivolumab and nivolumab in combination
with ipilimumab, and explore the association between pharmacokinetics and
selected pharmacodynamic markers in peripheral blood and tumor tissue
• To investigate other potential predictive biomarkers of clinical response to
nivolumab or nivolumab in combination with ipilimumab by analyzing tumor
specimens for proteins involved in regulating immune responses (e.g. PD-1 and
PD-L2) and peripheral blood samples for immune cell populations, such as
myeloid derived suppressor cells
Study design
This is an exploratory, open-label, multicenter study of nivolumab and
nivolumab in combination with ipilimumab to evaluate the effect on cells of the
immune system, primarily activated T cells, B cells and monocytes.
Approximately 160 subjects with advanced melanoma (unresectable or metastatic)
will be treated in this study in four parts. The first part of this study will
have two cohorts consisting of approximately 40 patients each: cohort 1 will
consist of anti-CTLA4 therapy naive patients and cohort 2 will consist of
patients who have progressed on an anti-CTLA-4 regimen. Cohorts 1 and 2 will
be administered nivolumab at the 3mg/kg dose level every 2 weeks. In this part
of the study, patients will go through a screening period of no longer than 28
days and eligible patients will start the treatment period for a maximum of 2
years depending on their response. Nivolumab will be administered by IV
infusion every 14 days in 56 day cycles (on days 1, 15, 29 and 43 of each
cycle). This part of the study has now been completed and part 2, 3 and 4 will
be added per protocol amendment 4.
In the second part of this study, approximately 20 anti-CTLA4 therapy naive
patients with matched pre- and on-treatment tumor biopsies will be administered
nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg every 3 weeks for 4 doses
followed by nivolumab 3 mg/kg alone every 2 weeks (Arm A). This part of the
study is aimed at defining the optimal window for on-treatment biopsy with
concurrent nivolumab and ipilimumab therapy. Two groups of approximately 10
patients each will be enrolled sequentially with the first group assigned to an
on-treatment biopsy between Days 8 and 15 after the start of therapy and the
second group assigned to an on-treatment biopsy between Days 22 and 29 after
the start of therapy. Optimal biopsy timing will be defined as the biopsy
window with the greatest pharmacodynamic increase in intratumoral activated T
cells compared to the pre-treatment biopsy. The defined optimal on-treatment
biopsy window will be used in the third part of this study.
In the third part of this study, approximately 30 anti-CTLA4 therapy naive
patients will be randomized 2:1:1 and treated with one of the following:
• Arm A: nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV Q3W for 4
doses then nivolumab 3 mg/kg IV Q2W
• Arm B: nivolumab 3 mg/kg IV Q2W
In the fourth part of this study, approximately 20 anti-CTLA4 therapy naive
patients with brain metastases will be randomized 1:1 and treated with one of
the following:
• Arm D: nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV Q3W for 4
doses then nivolumab 3 mg/kg IV Q2W
• Arm E: nivolumab 3 mg/kg IV Q2W
In parts 2, 3 and 4 of this study, eligible subjects will receive study
treatment for a maximum of two years.
Subsequent to a maximum of 2 years of treatment, each patient will continue
follow-up consisting of office visits, lab work and tumor assessments for a
maximum period of up to 100 days; follow-up office visits 1 and 2 (40-60 days
and 101-120 days after the stop of study therapy).
All patients who have not completed 2 years of treatment will be followed for
overall survival assessment by telephone contact every 3 months from the last
follow-up office visit for the remainder of time left to complete 2 years from
the first dose of treatment.
Intervention
The medicinal interventions include nivolumab and nivolumab/ipilimumab
combination therapy. All of these compounds will be supplied by the sponsor.
Nivolumab monotherapy (Arm B and E) is given every 2 weeks for a maximum of 2
years or until disease progression.
Nivolumab/ipilimumab combination therapy (Arm A and D) will be given as 4 doses
every 3 weeks followed by nivolumab monotherapy for up to 2 years or until
disease progression.
All study drug will be given intravenously.
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits, where they will undergo physical examinations, 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 8 weeks, patients will undergo radiographic
assessment of their tumours (by CT or MRI) until disease progression or
treatment discontinuation whichever occurs later. Depending on the treatment
arm, subjects will have pre-treatment and on-treatment biopsies performed.
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. These procedures are conducted by medically trained
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 life threatening. Patients will be instructed when to contact their
treating physicians if side effects occur and are given a patient card with
detailed information.
Orteliuslaan 1000
Utrecht 3528 BD
NL
Orteliuslaan 1000
Utrecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
• Men and women >= 16 years of age
• Subjects must have ECOG performance status <= 1
• Subjects with advanced melanoma (unresectable or metastatic) who have received and either progressed or discontinued on no more than 3 prior treatment regimens or have refused standard therapy for treatment of metastatic melanoma.
• Subjects enrolled to Arm A, B, D and E (Part 2, 3 and 4) must never received anti-CTLA4 therapy
• Subjects must have histologic confirmation of advanced melanoma
• Subjects must have at least one measurable lesion at baseline by CT or MRI as per RECIST 1.1 criteria
• Subjects must have at least 1 tumor site that can be biopsied at acceptable clinical risk and must consent to pre- and on-treatment tumor biopsies
• Subjects enrolled to Arms D and E (Part 4)
o Must have at least one measurable index brain metastases > 0.5 cm and not larger than 3 cm that has not been previously irradiated
o Index brain lesions must not have sequela of prior therapy that would confound attribution of tumor response including edema or hemorrhage
o Must not have neurologic symptoms secondary to metastatic lesions
o Must not have received systemic corticosteroids within 14 days prior to initiation of study therapy
Exclusion criteria
• Active brain metastases within 28 days of study enrollment (Arms A and B - Part 2 & 3) within 28 days of study enrollment
• Subjects with known metastases must have a repeat imaging brain scan within 28 days of randomization/registration. If progression in prior lesion(s) or new lesion (s) is/are detected on repeat brain scan, patients are exluded from study (Arms A en B - Part 2 & 3)
• History of carcinomatous meningitis (Arms D and E - Part 4)
• Radiation within 14 days prior to initiation of study therapy, and the radiation field cannot have included the index brain lesion (Arms D and E - Part 4)
• Subjects with other concomitant malignancies, except basal cell or squamous cell skin cancers, superficial bladder cancer, or carcinoma in situ of the cervix or breast, are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period
• Subjects with active autoimmune disease, a history of known or suspected autoimmune disease or a history of a syndrome requiring systemic corticosteroids (> 10 mg daily prednisone equivalent), cytotoxic therapy or immunosuppressive medications with the exception of:
o Isolated vitiligo
o Resolved childhood atopy
o The history of positive ANA titer without associated symptoms or history of symptoms of an autoimmune disorder
o Controlled thyroid disorders
• Positive tests for HIV1/2 antibody or known acquired immunodeficiency syndrome (AIDS)
• History of any hepatitis
• Prior therapy with any antibody/drug that targets the T cell coregulatory proteins, including but not limited to, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-OX-40,and anti-CD40 antibodies
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 | EUCTR2012-001840-23-NL |
| ClinicalTrials.gov | NCT01621490 |
| CCMO | NL47500.031.14 |