Primary objective:To characterize safety and tolerability of each treatment arm tested and identify recommended doses (RD) and regimens for future studies, by assessing the incidence and severity of AEs and SAEs; including changes in laboratory…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Incidence and severity of AEs and SAEs, including changes in laboratory values,
vital signs, and ECGs
Incidence and nature of DLTs in the first cycle (dose escalation only)
Dose interruptions, reductions, and dose intensity
Secondary outcome
Tumor MAPK pathway suppression (change from baseline) within combination
treatment arms
Tumor mutational changes throughout treatment course
Tumor immune phenotyping within combination treatment arms (e.g. CD8, PD-L1)
BOR per RECIST v1.1
For individual investigational drug, compare the PK in combination regimen vs.
as a single agent
Background summary
The purpose of this study is to inhibit the MAPK pathway in BRAF V600
colorectal cancer by leveraging the potential for approved and novel agents to
uniquely target mechanisms of intrinsic and acquired resistance in BRAF
V600-driven cancer cells. Furthermore, targeted MAPK inhibition in tumor immune
cells may complement the mechanism of action of anti-PD-1 antibodies in
mismatch-repair deficient CRC, thereby potentially increasing anti-cancer
immunomodulation. Therefore, RAF and ERK inhibition will be combined with the
anti-PD-1 antibody spartalizumab in CRC harboring concurrent activated BRAF and
microsatellite instability, with the future potential to explore targeted
immune approaches in the mismatch repair proficient setting as well.Given the
number of potentially active agents and the inability to predict which
combination may be most beneficial for patients, this trial will investigate
the safety, tolerability, and preliminary anti-tumor effect using an adaptive
platform design to improve efficiency
Study objective
Primary objective:
To characterize safety and tolerability of each treatment arm tested and
identify recommended doses (RD) and regimens for future studies, by assessing
the incidence and severity of AEs and SAEs; including changes in laboratory
values, vital signs, and ECGs; the incidence and nature of DLTs in the first
cycle (dose escalation only); and by assessing dose interruptions, dose
reductions, and dose intensity
Secondary objective:
To characterize the PK of each investigational drug within each treatment arm
by assessing serum/plasma concentrations and PK parameters of individual
investigational drugs within combination treatments.
To evaluate preliminary anti-tumor activity of each treatment arm by assessing
best overall response (BOR), progression free survival (PFS), overall response
rate (ORR), and disease control rate (DCR) per RECIST v1.1.
To evaluate PD effect in their respective combinations in tumor by assessing
the change from baseline of the PD marker DUSP6 in tumor tissue (dose
escalation only)
Study design
This is a phase Ib, multi-center, open-label study with multiple treatment
arms. The open platform design of this study is adaptive to allow removal of
combination treatment arm(s) based on emerging data and facilitate introduction
of new candidate combinations. The study is comprised of a dose escalation part
and may be followed by a dose expansion part for any combination treatment arm.
The study will initially enroll subjects into the dabrafenib + LTT462 treatment
arm.
The dose escalation of the triplet combination treatment arms will start after
the first dose level of the dabrafenib + LTT462 treatment arm has been
determined to be safe and tolerable. This will be when at least two cycles of
therapy have been received by patient at the first dose level, and writen
confirmation has been received by the investigators that the second dose level
has been evaluated. Dabrafenib + LTT462 will be used as the initial backbone
doublet to which partner investigational drugs will be added to comprise
triplet combination treatment arms. It is possible that planned combination
treatment arm(s) may not be initiated based on emerging clinical data.
Multiple triplet combination treatment arms may enroll in parallel during dose
escalation. Those treatment arms that reach a maximum tolerated dose
(MTD)/recommended dose (RD) may, but are not required to, proceed to dose
expansion to further explore safety, tolerability, and preliminary anti-tumor
activity. Another possibility is that a triplet combination treatment arm
reaching an MTD/RD could be studied as a new backbone regimen to which other
investigational drugs would be added by protocol amendment to generate
quadruplet treatment arms. In the case that all dose levels of a given
combination treatment arm are not considered tolerable, then no MTD/RD for that
treatment arm will be defined, and enrollment in that treatment arm will be
discontinued
Intervention
Dabrafenib (DRB436), LTT462, trametinib (TMT212), LXH254, TNO155, spartalizumab
(PDR001), tislelizumab (VDT482) in various combinations.
Study burden and risks
Risks and side-effects associated with the treatment provided.
Risks associated with the study assessments such as blooddraws, imaging and
tumor biopsy.
Burdens: 4 week cycles. Cycle 1: 5-6 visits depending on schedule. C2: 2-3
visits depending on schedule.
From Cycle 3 onward: 1 visit. Duration of visits: usually 1-2 hours unless
blooddraws for farmacokinetic profiling is planned. Depending on the given
combination therapy a visit may extend from minimally 2 to max 9 hours.
Assessments during visits, depending on combination therapy and type of visit:
physical exam, blooddraws, ECG's / vital signs, imaging, pregnancy testing,
tumor biopsy.
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
Patients must be >= 18 years of age.
ECOG performance status <= 1.
Patients must have a site of disease amenable to biopsy, and be a candidate for
tumor biopsy according to the treating institution*s guidelines.
All patients must have a BRAF V600 mutation confirmed by local assessment.
Patients with unresectable advanced/metastatic BRAF V600 cancer of the colon or
rectum with measurable disease as determined by RECIST v1.1
See for more details protocol section 5.1
Exclusion criteria
Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of study drugs
Patients with CNS tumor involvement, unless > 2 weeks after completion of
CNS-therapy, stable with respect to CNS-involvement, not receiving steroids or
on stable dose of < 10 mg/day for two weeks.
Out of range laboratory values:
Hemoglobin (Hgb) < 9.0 g/dL
Platelets < 75 x 109/L
Serum total bilirubin > 1.5 x upper limit of normal (ULN),
Asparate aminotransferase (AST) > 3 x ULN
Alanine aminotransferase (ALT) > 3 x ULN
Serum creatinine > 1.5 x ULN OR Creatinine Clearance < 60 mL/min
Other exclusion criteria may apply, please see protocol section 5.2
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 | EUCTR2019-004688-27-NL |
| CCMO | NL73014.031.20 |