Phase I Study of LXH254 in Patients With Advanced Solid Tumors Haboring MAPK Pathway Alterations

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT02607813

Collaborator

(none)

142

Enrollment

Locations

Arms

73.1

Actual Duration (Months)

7.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A Phase I Study of LXH254 in Patients With Advanced Solid Tumors That Harbor MAPK Pathway Alterations.

Condition or Disease	Intervention/Treatment	Phase
NSCLC Ovarian Cancer Melanoma Other Solid Tumors	Drug: LXH254 Drug: PDR001	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

142 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Dose Finding Study of Oral LXH254 in Adult Patients With Advanced Solid Tumors Harboring MAPK Pathway Alterations

Actual Study Start Date :

Jan 18, 2016

Actual Primary Completion Date :

Feb 18, 2022

Actual Study Completion Date :

Feb 19, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose escalation LXH254	Drug: LXH254 pan-RAF inhibitor
Experimental: Dose expansion LXH254: Group 1	Drug: LXH254 pan-RAF inhibitor
Experimental: Dose expansion LXH254: Group 2	Drug: LXH254 pan-RAF inhibitor
Experimental: Dose expansion LXH254: Group 3	Drug: LXH254 pan-RAF inhibitor
Experimental: Dose expansion: LXH254 + PDR001	Drug: LXH254 pan-RAF inhibitor Drug: PDR001 Biological: PDR001 anti-PD1 antibody
Experimental: Dose escalation LXH254 + PDR001	Drug: LXH254 pan-RAF inhibitor Drug: PDR001 Biological: PDR001 anti-PD1 antibody

Outcome Measures

Primary Outcome Measures

Safety and tolerability as assessed by incidence and severity of adverse events (AEs), dose interruptions, reductions, and dose intensity. [From Cycle 1 Day 1 until 30 days for LXH254 single agent and 150 days for LXH254 in combination with PDR001 post study treatment (expected duration approximately 12 months)]
cycle = 28 days
Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 single agent only) [28 days]
cycle = 28 days
Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 in combination with PDR001 only) [56 days]
cycle =28 days

Secondary Outcome Measures

Overall response rate (ORR) [Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months]
cycle = 28 days
Disease control rate (DCR) [Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months]
cycle = 28 days
Duration of response (DoR) [Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months]
cycle = 28 days
Progression-free survival (PFS) [Every 2 cycles after starting study treatment until disease progression; expected duration approximately 12 months]
cycle = 28 days
Overall survival (OS) - only for dose expansion [From time of start treatment until the date of death; expected duration approximately 12 months]
cycle = 28 days
Plasma concentrations of LXH254 [Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1]
cycle = 28 days
Derived PK parameters of LXH254: Area Under the Curve (AUC) [Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1]
cycle = 28 days
Derived PK parameters of LXH254: Peak Plasma Concentration (Cmax) [Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1]
cycle = 28 days
Derived PK parameters of LXH254: Time to Peak Plasma Concentration (Tmax) [Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1]
cycle = 28 days
Derived PK parameters of LXH254: half-life (T1/2) [Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1]
cycle = 28 days
Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor tissue and in blood [Cycle 1 day 1, 2, 3, 15, and 16; upon disease progression (expected duration approximately 12 months)]
cycle = 28 days
Plasma concentrations of PDR001 [Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1]
cycle = 28 days
Derived PK parameters of PDR001: Area Under the Curve (AUC) [Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1]
cycle = 28 days
Derived PK parameters of PDR001: Peak Plasma Concentration (Cmax) [Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1]
cycle = 28 days
Derived PK parameters of PDR001: Time to Peak Plasma Concentration (Tmax) [Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1]
cycle = 28 days
Derived PK parameters of PDR001: half-life (T1/2) [Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1]
cycle = 28 days

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

All patients participating in this clinical trial must have progressed following standard therapy, or for whom, in the opinion of the Investigator, no effective standard therapy exists, is tolerated or appropriate.
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
Presence of at least one measurable lesion according to RECIST v1.1.
Documented MAPK alteration

Additional inclusion criteria for the Dose Expansion part: LXH254 in combination with

PDR001:

Patients with confirmed KRAS-mutated NSCLC
Patients with confirmed NRAS-mutated melanoma (cutaneous melanoma only)

Exclusion Criteria:

Prior treatment with a BRAFi, MEKi and/or pan-RAF inihibitors for patients to be enrolled in the dose expansion part.

Exceptions may be made after documented agreement between Novartis and Investigator.

History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO.
Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
Patients receiving proton pump inhibitors which cannot be discontinued 3 days prior to the start study treatment and for the duration of the study.
Pregnant or nursing (lactating) women

Additional exclusion criteria for LXH254 in combination with PDR001

History of severe hypersensitivity reactions, which in the opinion of the investigator may cause in increased risk of serious infusion reaction.
Known human immunodeficiency virus (HIV).
Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
Active, known or suspected autoimmune disease.
Active infection requiring systemic antibiotic therapy
Patients requiring systemic steroid therapy or any immunosuppressive therapy (≥10mg/day prednisone or equivalent) which cannot be discontinued at least 7 days prior to first dose of study treatment.
Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.

Other inclusion/exclusion criteria as per protocol may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital MGH Cancer Center	Boston	Massachusetts	United States	02114
2	Memorial Sloan Kettering Cancer Center SC - LXH254X2101	New York	New York	United States	10065
3	UT M.D Anderson Cancer Center SC - LXH254X2101	Houston	Texas	United States	77030
4	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2C1
5	Novartis Investigative Site	Paris Cedex 10		France	75475
6	Novartis Investigative Site	Toulouse		France	31059
7	Novartis Investigative Site	Heidelberg		Germany	69120
8	Novartis Investigative Site	Milano	MI	Italy	20133
9	Novartis Investigative Site	Modena	MO	Italy	41124
10	Novartis Investigative Site	Napoli		Italy	80131
11	Novartis Investigative Site	Chuo ku	Tokyo	Japan	104 0045
12	Novartis Investigative Site	Seoul		Korea, Republic of	03080
13	Novartis Investigative Site	Groningen		Netherlands	9713 GZ
14	Medical Oncology, Erasmus MC	Rotterdam		Netherlands	3075 CE
15	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
16	Novartis Investigative Site	Madrid		Spain	28009
17	Novartis Investigative Site	Madrid		Spain	28046
18	Novartis Investigative Site	Zuerich		Switzerland	8091

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Novartis Pharmaceuticals

ClinicalTrials.gov Identifier:

NCT02607813

Other Study ID Numbers:

CLXH254X2101
2015-003421-33

First Posted:

Nov 18, 2015

Last Update Posted:

Mar 11, 2022

Last Verified:

Mar 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Novartis Pharmaceuticals

LXH254, CRAF, MAPK, solid tumor, PDR001

Additional relevant MeSH terms:

Spartalizumab

Study Results

No Results Posted as of Mar 11, 2022