Clinical trial NCT01351103: A Study of LGK974 in Patients With Malignancies Dependent on Wnt Ligands
Official title: A Phase I, Open-label, Dose Escalation Study of Oral LGK974 in Patients With Malignancies Dependent on Wnt Ligands
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pancreatic Cancer
BRAF Mutant Colorectal Cancer
Melanoma
Triple Negative Breast Cancer
Head and Neck Squamous Cell Cancer
Cervical Squamous Cell Cancer
Esophageal Squamous Cell Cancer
Lung Squamous Cell Cancer
Keywords: LGK974
pancreatic adenocarcinoma
BRAF mutant colorectal cancer
RNF43 mutation
RSPO fusion
melanoma
triple negative breast cancer
PDR001
immunotherapy
head and neck scc
cervical scc
esophageal scc
lung scc
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-05-10
Enrollment: 185
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study was to find the recommended dose of LGK974 as a single agent and in combination with PDR001 that can be safely given to adult patients with selected solid malignancies that had progressed despite standard therapy or for which no effective standard therapy existed.

Detailed description: This open-label multicenter phase 1 dose escalation study was the first to administer LGK974 as a single agent or in combination with PDR001 in humans.

The study comprised of 2 parts: a dose escalation of LGK974 as a single agent, followed by a safety expansion in specific disease indications; and a dose escalation of LGK974 in combination with PDR001, followed by a safety expansion in cutaneous melanoma.

Eligibility criteria: Inclusion Criteria:

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 Dose escalation part:documented B-RAF mutant colorectal cancer or pancreatic adenocarcinoma. In addition, tumors of any histological origin with documented genetic alterations upstream in the Wnt signaling pathway are eligible with prior agreement with Novartis.

Single Agent Dose expansion part: documented B-RAF mutant colorectal cancer with documented RNF43 mutation and/or RSPO fusion or 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 (e.g. RNF43 or RSPO fusion) 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 naïve or primary refractory to prior anti-PD-1 therapy.

LGK974 with PDR001: Dose expansion: patients with:

* cutaneous melanoma that was primary refractory to prior anti-PD-1 therapy, defined as a best response of progressive disease or stable disease for \<= 4 months, or disease recurrence with the first 6 months of adjuvant therapy. Patients with BRAF V600-mutant melanoma must have also received and been failed by prior systemic therapy with BRAF V600 inhibitor, with or without a MEK inhibitor.
* Cutaneous melanoma with acquired resistance to prior anti-PD-1 therapy, defined as progressive disease following response (PR or CR) or following stable disease for \> 4 months. Patients with BRAF V600-mutant melanoma must have also received and been failed by prior systemic therapy with a BRAF V600 inhibitor, with or without a MEK inhibitor.

Exclusion Criteria:

* Impaired cardiac function
* Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of LGK974 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
* Brain metastases that have not been adequately treated
* Malignant disease other than that being treated in this study
* Laboratory abnormalities as specified in the protocol
* Osteoporosis, osteopenia
* Bone fractures within the past year
* Pathologic bone fracture
* Active, known or suspected autoimmune disease or severe hypersensitivity reactions to other monoclonal antibodies

Other protocol-defined inclusion/exclusion criteria may apply

Primary outcomes:
measure: Incidence of dose limiting toxicities (DLTs) during the first cycle of LGK974 treatment and during the first 2 cycles of LGK974 in combination with PDR001
timeFrame: 28 days (LGK974 single agent) and 56 days (LGK974 in combination with PDR001)
Secondary outcomes:
measure: Type and category of study drug related adverse events (AE)
timeFrame: 61 months
measure: Absorption and plasma concentrations of LGK974
timeFrame: 61 months
measure: PD related to the Wnt pathway
timeFrame: 61 months
measure: Overall response rate of tumor
timeFrame: 61 months
measure: Absorportion and plasma concentrations of PDR001
timeFrame: 61 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA School of Medicine
state: California
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute SC-7
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center Onc Dept.
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute Wayne St
state: Michigan
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center MD Anderson 2
state: Texas
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
state: Zuid Holland
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Rodon J, Argiles G, Connolly RM, Vaishampayan U, de Jonge M, Garralda E, Giannakis M, Smith DC, Dobson JR, McLaughlin ME, Seroutou A, Ji Y, Morawiak J, Moody SE, Janku F. Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours. Br J Cancer. 2021 Jul;125(1):28-37. doi: 10.1038/s41416-021-01389-8. Epub 2021 May 3.