The objective of this study is to test the safety, tolerability and anti-tumor activity of the combination of the investigational products epacadostat and pembrolizumab, compared to pembrolizumab as mono therapy, in patients with unresectable or…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The dual primary endpoints are PFS and OS.
* Progression-free survival, defined as the time from date of randomization
until the
earliest date of disease progression, as determined by independent central
review of
objective radiographic disease assessments per RECIST 1.1, or death from any
cause,
whichever comes first.
* Overall survival, defined as the time from date of randomization to date of
death due to
any cause.
The study is considered to have met its study objective if the combination is
superior to
pembrolizumab and placebo in either PFS or OS.
Secondary outcome
Objective response rate, defined as the proportion of subjects who have best
response as
complete response (CR) or partial response (PR). Responses are based on
independent
central review using RECIST 1.1.
Duration of response (DOR) determined by disease assessment defined as the time
from
the earliest date of qualifying response until earliest date of disease
progression or death
from any cause, whichever comes first. Response will be determined by
independent
central review using RECIST 1.1.
Background summary
Melanoma is the most serious form of skin cancer and exists in adults of all
ages. In the EU alone, 41000 new cases are diagnosed every year and yearly,
approximately 11000 patients within the EU die from the disease. Average 5-year
survival for advanced melanoma is a mere 15% and therefore an important medical
need exists to identify new, effective treatments. Surgical excision with a
wide margin is the standard of care for early-stage melanoma, and most patients
with in situ melanoma or early-stage melanoma will be cured by primary excision
alone. Metastatic melanoma, however, is very unlikely to be curable wby surgery
because of the likelihood of micrometastases too small to be found by CT, MRI
or PET imaging. Therefore, an adjuvant treatment is indicated. Radiation
therapy plays a role in the treatment strategy, in particular after resection
of primary melanomas that are associated with a high rate of local recurrence,
and in patients with positive excision margins. Secondly, blockade of
immuno-inhibitory pathways are currently in focus as important therapeutic
strategy for cancer treatment. Proof of this is observed in the clinical
response to therapy with antibodies targeted against CTLA-4 and PD-1/PD-L1.
Pembrolizumab is a potent and highly selective monoclonal antibody that
directly blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.
Even though these agents show anti-tumor activity in a monotherapeutic setting,
there are more immuno-inhibitory mechanisms present in the tumor microclimate.
This suggests that combination therapies might have a more optimal therapeutic
effect. Recent research has focused on the role of indoleamine 2,3-dioxygenase
(IDO1) as a mechanism inducing tolerance to the malignity. IDO1 activity
results in a strong inhibition of the T-cell mediated immune respons by
blocking T-cell activation and inducing T-cell apoptosis. Additionally, IDO1
activity induces the differentiation of naive T-cells to cells with a
regulatory phenotype (Treg). Studies showed that an elevated Treg activity
promotes tumor growth. In reverse, Treg depletion showed to induce an antitumor
immune response. Within the context of cancer, there are a number of
indications that IDO1 is an important regulator of immunosuppressive mechanisms
at the basis of the evasion of the immune response by tumors. It is expected
that combined inhibition of the IDO1 and the PD-1 pathway will have a
complimentary therapeutic effect and will lead to a greater suppression of
antitumor immunity.
Study objective
The objective of this study is to test the safety, tolerability and anti-tumor
activity of the combination of the investigational products epacadostat and
pembrolizumab, compared to pembrolizumab as mono therapy, in patients with
unresectable or metastatic melanoma.
Study design
This is a randomised, double blind, placebo controlled phase 3 trial of
pembrolizumab in combination with epacadostat or placebo.
Intervention
Both treatment groups will receive pembrolizumab (200 mg per IV over 30 mins),
on day 1 of every 3-week treatment cycle.
Additionally, patients will receive 100 mg epacadostat, bid, orally, or
placebo. See also C16.
Study burden and risks
Treatment cycles will take three weeks, of which pembrolizumab will be
administered on day 1 and epacadostat will be taken orally twice daily. At
every visit, a physical examination will be performed, vital signs will be
measured, ECGs made and blood samples will be collected. At some selected
sites, additional ECGs (day 1 of cycli 1 and 2 as well as additional PK
sampling is planned. Subjects who consent to these additional PK samples will
have to remain in the hospital for an extended period of time, as these are
taken 4-10 hours after administration of pembrolizumab. These additional PK
samples are optional and trial subjects will be specifically asked for their
consent for this, in the consent form.
The subjects will also be asked to complete questionnaires on their health and
symptoms (EuroQol EQ-5D-3L [Health], EORTC QLQ-C30 [Quality of Life], WPAI:
Melanoma [Work productivity and activity impairment].
There will be a tumor biopsy at screening (this can be omitted in case there is
adequate tumor tissue available). If the subject consents, a tumor biopsy may
be performed at week 12 and week 24, and after disease progression. At several
timepoints during the study, photographs are taken of the skin lesions.
Trial subjects may experience physical and/or psychological discomfort with
some of the study procedures, such as blood sampling, administration of the IV
line, ECGs, CT/MRI scans, and tumor biopsy. The main side effects reported with
the trial medication include fatigue, itching, rash, frequent or irregular
bowel movements, pain in joints, muscles, or bones, stomach ache and nausea.
Augustine Cut-Off 1801
Wilmington DE 19803
US
Augustine Cut-Off 1801
Wilmington DE 19803
US
Listed location countries
Age
Inclusion criteria
- Have histologically or cytologically confirmed melanoma.
- Have unresectable Stage III or Stage IV melanoma, not amenable to local therapy.
- Have been untreated for advanced or metastatic disease - with exceptions as outlined in the protocol.
- Have documentation of V600-activating BRAF mutation status or consent to BRAF V600 mutation testing during the screening period.
- Have laboratory parameters within Protocol-defined range.
- Have the presence of at least one measurable lesion by CT or MRI per RECIST 1.1 criteria.
- Provide a baseline tumor biopsy
- Have resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia).
- Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
subject.
Exclusion criteria
- Has received prior systemic treatment for unresectable or metastatic melanoma (except therapy as noted in inclusion criteria #3).
- Has received prior therapy with an anti*PD-1, anti*PD-L1, anti*PD-L2, anti*CD137, or IDO1 inhibitor or any other antibody or drug specifically targeting checkpoint pathways other than anti-CTLA-4 which is permitted in the adjuvant setting.
- Has received prior adjuvant therapy, monoclonal antibody, chemotherapy or an investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) before administration of study drug or not recovered (* Grade 1 or at baseline) from AEs due to previously administered agents. Exception to this rule would be use of denosumab, which is not excluded.
Note: Subjects with * Grade 2 neuropathy are an exception and may enroll.
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of study treatment.
- Has a known additional malignancy that is progressing or requires active treatment. Exceptions are described in the protocol.
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
- Has ocular melanoma.
- Has an active autoimmune disease that has required systemic treatment in past 2 years.
- Has an active infection requiring systemic therapy.
- Has known history of human immunodeficiency virus (HIV)
- Has known history of or is positive for Hepatitis B or Hepatitis C
- Has history of (noninfectious) pneumonitis that required steroids, or current pneumonitis.
- Has received prior radiotherapy within 2 weeks of therapy. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
- Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study.
- Has received live vaccine within 30 days before the first dose of study treatment.
- Has received monoamine oxidase inhibitors within the 21 days prior to starting study treatment.
- Has any history of Serotonin Syndrome after receiving serotonergic drugs.
- Has presence of a gastrointestinal condition that may affect drug absorption.
- Has a history or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful.
- Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, New York Heart Association Class III or IV congestive heart failure, and arrhythmia requiring therapy. Medically controlled arrhythmia would be permitted.
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 | EUCTR2015-004991-31-NL |
| CCMO | NL56546.056.16 |