To evaluate the efficacy of each combination arm, as measured by confirmed objective response rate (ORR)
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Confirmed ORR using RECIST v1.1, per local assessment
Secondary outcome
DoR using RECIST v1.1, per local assessment
PFS and DCR, assessed using RECIST v1.1, per local assessment
Overall survival (OS)
Incidence and severity of AE including changes in laboratory values, vital
signs and cardiac assessment.
Dose interruptions, reductions, and permanent discontinuations of study
treatments
Anti-drug antibodies (ADA) prevalence at baseline and ADA incidence on treatment
Proportion of subjects with a favorable biomarker profile (pFBP)
Background summary
Melanoma is the most aggressive form of all skin cancers. Worldwide, it is
expected that over
232,000 people are diagnosed with cutaneous melanoma each year and more than
55,000 people
are expected to die of this disease annually. Usually melanoma is diagnosed at
an early stage in
which surgical excision is curative in most cases. The management of patients
with unresectable or
metastatic melanoma is more difficult
Patients who do not respond to, or progress on, the approved treatments have
very
limited treatment options, and there is no established standard of care.
Guidelines recommend
enrollment in a clinical trial, treatment with ipilimumab (anti-CTLA-4),
chemotherapy, or highdose
interleukin-2 (IL-2) for selected patients .
Based on retrospective data from 47 patients treated in the pivotal phase III
study KEYNOTE-006,
single-agent checkpoint inhibitor therapy with ipilimumab has limited
anti-tumor activity following
failure of pembrolizumab (anti-PD-1) with a reported objective response rate
(ORR) of 16%
(Zimmer et al 2017). As a result, most patients are enrolled in clinical
studies as there is an urgent
need for new treatment options for patients who failed the available standard
therapies.
Patients enrolled in this study have failed previous therapies including immune
checkpoint
inhibitors. The mechanisms of primary and acquired resistance to checkpoint
inhibitors treatment
are not well understood and are mainly due to a combination of intrinsic or
extrinsic resistance
mechanisms (see Section 2.1). The combinations tested in this study aim to
alter the tumor and/or
microenvironment in favorable way to overcome treatment resistance and restore
T cell function.
Study objective
To evaluate the efficacy of each combination arm, as measured by confirmed
objective response rate (ORR)
Study design
randomized, open-label, phase II, open platform study with novel treatment
combinations
Intervention
All participants will be treated with :
- PDR001 400 mg once every 4 weeks; administered via intravenous infusion over
30 minutes
- one of the treatments as specified in the protocol:
* LAG525 600 mg once every 4 weeks; administered via intravenous infusion over
30 minutes
* INC280 400 mg BID (total daily dose 800 mg), administered orally
* ACZ885 300 mg once every 4 weeks; administrated via subcutaneous injection
* LEE011 600 mg QD on days 1 to 21 of a 28-day cycle, administered orally
Study burden and risks
RISK: adverse events of treatment with PDR001 and INC280, LAG525 or ACZ885
Burden: Cycles of 4 weeks, Cycle 1: 4 visits, cycle 3: 3 visit, cycle 2, and
3,4,5 etc : 1 visit
Physical examination: once per cycle.
Blooddraws :1-2 per visit, One PK days more frequent (C1D15: 6-7 draws)
ECG:during cycle 1 and 3: two ECGs taken in triplicate (thus total 6); once in
triplicate (thus 3) duiring C2 and EOT
CT-/MRI-scan: during screening, in week 12, 20, 28, 36, 44 and week 52, from
week 52 every 12 weeks,
Brain MRI : once during screening, if applicable following the CT/MRI schema
Skin photographs : if applicable, following the CT/MRI schema
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
- Male or female must be >= 18 years
- Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV
melanoma
- Previously treated for unresectable or metastatic melanoma. Subjects must
have at least received the following treatments.
-- V600BRAF wild type patients: must have received anti-PD-1/PD-L1
single-agent, or in combination with anti-CTLA-4 therapy
--V600BRAF mutant patients: must have received prior anti-PD-1/PD-L1
single-agent, or in combination with anti-CTLA-4 therapy. In addition, subjects
must have received prior V600BRAF inhibitor therapy, either single-agent or in
combination with a MEK inhibitor
-. ECOG performance status 0-2
-. At least one measurable lesion per RECIST v1.1
-. At least one lesion, suitable for sequential mandatory tumor biopsies
on non-randomized arm (1A)
- Subjects must have baseline tumor sample that is positive for LAG-3 per
central assessment at the Novartis-designated laboratory
Exclusion criteria
- Presence of clinically active or unstable brain metastasis.
- Active, known or suspected autoimmune disease or a documented history of
autoimmune disease.
- Active infection requiring systemic antibiotic therapy., - Known history or
current interstitial lung disease or non-infectious pneumonitis
- Known history of testing positive for Human Immunodeficiency Virus (HIV)
infection
- Active hepatitis B virus (HBV) infection (HBsAg positive).
- Subjects with positive test for hepatitis C virus (HCV) RNA
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 | EUCTR2018-000610-38-NL |
| ClinicalTrials.gov | NCT03484923 |
| CCMO | NL65729.031.18 |