A Phase I, open-label, dose escalation study of oral LGK974 in patients malignancies dependent on Wnt ligands

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 33

Inclusion Criteria

1. Diagnosis of locally advanced or metastatic cancer that has progressed
despite standard therapy or for which no effective standard therapy exists and
histological confirmation of one of the following diseases indicated below:
• Single agent LGK974- Dose escalation part: documented B-RAF mutant
colorectal cancer; or pancreatic adenocarcinoma. In addition, tumors of any
histological origin with previously documented genetic alterations upstream in
the Wnt signaling pathway, such as gene fusions in RSPOs and mutations in
RNF43, are eligible with prior agreement with Novartis
• Single Agent LGK974 -Dose expansion part: documented B-RAF mutant colorectal
cancer with documented RNF43 mutation and/or RSPO fusion of pancreatic
adenocarcinoma with documented RNF43 mutation. In addition, patients with
tumors of any histological origin with documented genetic alterations upstream
in the Wnt signaling pathway, such as gene fusions in RSPOs and mutations in
RNF43, are eligible with prior agreement with Novartis• LGK974 with PDR001:
Dose escalation: patients with the following cancers that were previously
treated with anti-PD-1 therapy and whose best response on that therapy was
progressive disease (i.e., primary refractory): melanoma, lung SCC, HNSCC.
Patients with esophageal SCC, cervical SCC or TNBC who are either naive or
primary refractory to prior anti-PD-1 therapy.
• LGK974 with PDR001: Dose expansion: patients with pancreatic cancer, or TNBC,
or melanoma, or head and neck squamous cell cancer.
• Patients with cancers of squamous cell histology must have had progression on
or after, or intolerance to, a prior platinum-containing chemotherapy regimen-
WHO performance status of 0-2
eker(s)

Exclusion Criteria

1.Patients with a primary central nervous system tumor or with uncontrolled,
symptomatic brain metastases that have not been adequately treated. Patients
with symptomatic brain metastases that have been adequeatly treated, such as
with radiotherapy or resection, are not excluded if any associated symptoms are
stable, and do not require ongoing glucocorticoid therapy.
2: Impaired cardiac function including any one of the following:
- Corrected QT interval (QTc) > 480 milliseconds on baseline ECG.
- Clinically significant, uncontrolled heart disease (e.g. unstable angina,
congestive heart failure, uncontrolled hypertention, ventricular or atrial
arrhythmias)
- Myocardial infarction (MI) within the prior 3 months.
3.Patients with any of the following laboratory values at baseline:
- Absolute neutrophil count (ANC) < 1.0 109/L
- Platelets < 75 109/L
- Hemoglobin < 9.0 g/dL
- Calculated or measured creatinine clearance (using Cockcroft-Gault formula) <
50 ml/min
- Bilirubin > 1.5 x ULN
- Aspartate transaminase (AST) and alanine transaminase (ALT) > 3.0 x ULN,
except for patients with liver metastasis who are excluded if AST and ALT > 5.0
x ULN.
4. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of oral LGK974 (e.g., ulcerative diseases,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel
resection).
5. Presence of >CTCAE Grade 2 toxicity (except alopecia) due to prior therapy.
6.Malignant disease other than that being treated in this study.

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Incidence rate of dose limiting toxicities (DLTs) during the first cycle of<br /><br>LGK974 and during the first 2 cycles of LGK974 in combination with PDR001.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>- Safety: Frequency and severity of (serious) adverse events. Changes in<br /><br>laboratory values, assessments of physical examinations, vital signs and<br /><br>electrocardiograms.<br /><br>- Pharmacokinetics: PK parameters.<br /><br>- Pharmacodynamics: Post-treatment change from baseline in certain biomarkers.<br /><br>Correlation between plasma exposure parameters of LGK974 and biomarkers.<br /><br>- Efficacy: Overall response rate (ORR), complete response (CR) or partial<br /><br>response (PR) rate and duration of response (DOR) defined according to RECIST.</p><br>