A phase Ib/II multi-center, open label, dose escalation study of WNT974, LGX818 and cetuximab in patients with BRAFV600-mutant KRAS wild-type metastatic colorectal cancer harboring Wnt pathway mutations

Patients with metastatic BRAF-mutant colorectal cancer (CRC) have a very poor
prognosis, with a median survival of only 10 months. Initial studies of BRAF
inhibitors in this disease have been disappointing, with few objective
responses. Based on pre-clinical data demonstrating the importance of an EGFR
feedback loop for BRAF inhibitor resistance as well as synergistic activity
with the combination of BRAF and EGFR inhibitors in BRAF-mutant CRC models,
clinical trials of BRAF inhibitors and EGFR antibodies were initiated.
Preliminary clinical efficacy data of LGX818 and cetuximab suggest promising
activity with 4 confirmed and 3 unconfirmed PRs of 27 evaluated patients (26%).
In addition to BRAFV600 mutations and EGFR activation, Wnt pathway alterations
(inactivating mutations in RNF43 and RSPO fusions) are likely to be important
oncogenic drivers in BRAF-mutant CRC. These alterations activate Wnt signals
and importantly, are markers for WNT974 sensitivity in preclinical models.
Preclinical studies of the triple combination of WNT974+LGX818+cetuximab in
BRAF-mutant, RNF43-mutant or RSPO-fusion positives, using CRC xenograft models
demonstrate increased anti-tumor activity as compared to double combinations of
LGX818 with cetuximab or LGX818 with WNT974.
These data suggest that the inhibition of the Wnt pathway in addition to
inhibition of BRAF and EGFR signals may offer additional clinical benefit to
patients with BRAF-mutant CRC.
Based on this rationale, the specific purpose of this Phase Ib/II study is to
1) identify safe and tolerable doses of WNT974+LGX818+cetuximab; and 2) explore
the anti-tumor activity of the triple combination.

Primary:
Phase Ib: To estimate the MTD(s) and/or RP2D(s) of the triple combination of
WNT974, LGX818 and
cetuximab in patients with BRAFV600-mutant CRC harboring Wnt pathway mutations.
Phase II: To estimate the preliminary anti-tumor activity of the RP2D(s) of
WNT974 in combination with LGX818 and cetuximab in patients with
BRAFV600-mutant CRC harboring Wnt pathway mutations.
Secondary: To assess additional parameters of clinical activity of WNT974 in
combination with LGX818 and cetuximab and to characterize the safety and
tolerability. To characterize pharmacokinetics of WNT974, its pharmacologically
active metabolite LHA333, and LGX818 when used in combination therapy with
cetuximab.

Multicenter phase 1b dose escalation study, for the triple combination of
WNT974, LGX818 and cetuximab, followed by a single arm phase II part.
The study treatment will be administered during 28-days cycles. WNT974 and
LGX818 will be administered daily orally. Cetuximab will be administered weekly
i.v., as recommended by the label.
Treatment period until disease progression or unacceptable side effects.
Patients who discontinue study treatment for any reason other than disease
progression will be followed up for progression of disease and all patients
will be followed for survival.
Approx. 60 patients.

Treatment with WNT974, LGX818 and cetuximab.

Risk: Adverse effects of the combination of combination of WNT974-LGX818 and
cetuximab. The adverse effects of this combination is not known.
The patient may receive no direct benefit from being in this study. Other
disadvantages are the inconveniences of the several tests such as extra blood
sampling, intravenous administration of cetuximab, eye exams and skin- and
tumorbiopsy.

Burden: The patient needs to go to the hospital more often and will undergo
more tests such as ECG, echocardiogram or MUGA, eye exams, more (frequent)
blood sampling and imaging scans. The visits may take more time (1-8
hours).Cycles of 4 weeks. Cycle 1: 6 visits, from cycle 2 onwards: 4 visits.
Duration mostly 1-4 hours. Some visits 8-9 hours.