A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02974725

Collaborator

(none)

241

Enrollment

Locations

Arms

Anticipated Duration (Months)

6.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To characterize safety and tolerability and identify a recommended dose and regimen for the LXH254 in combination with LTT462 or trametinib or ribociclib.

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer Melanoma	Drug: LXH254 Drug: LTT462 Drug: Trametinib Drug: LXH254 Drug: Ribociclib	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

241 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase Ib, Open-label, Multicenter Study of Oral LXH254-centric Combinations in Adult Patients With Advanced or Metastatic KRAS or BRAF Mutant Non-Small Cell Lung Cancer or NRAS Mutant Melanoma

Actual Study Start Date :

Feb 24, 2017

Anticipated Primary Completion Date :

Apr 25, 2023

Anticipated Study Completion Date :

Apr 25, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LXH254+LTT462	Drug: LXH254 LXH254 will be supplied as tablet for oral use. Drug: LTT462 LTT462 will be supplied as hard gelatin capsule for oral use.
Experimental: LXH254+Trametinib	Drug: Trametinib Trametinib will be supplied as film-coated tablet for oral use Drug: LXH254 Trametinib will be supplied as film-coated tablet for oral use
Experimental: LXH254+Ribociclib	Drug: Ribociclib Ribociclib will be supplied in tablets and hard gelatin capsules.

Arm

Intervention/Treatment

Experimental: LXH254+LTT462

Drug: LXH254

LXH254 will be supplied as tablet for oral use.

Drug: LTT462

LTT462 will be supplied as hard gelatin capsule for oral use.

Experimental: LXH254+Trametinib

Drug: Trametinib

Trametinib will be supplied as film-coated tablet for oral use

Drug: LXH254

Trametinib will be supplied as film-coated tablet for oral use

Experimental: LXH254+Ribociclib

Drug: Ribociclib

Ribociclib will be supplied in tablets and hard gelatin capsules.

Outcome Measures

Primary Outcome Measures

Number of participants with Adverse Events (AEs) as a measure of safety and tolerability [up to 5 years]
Dose limiting toxicities (DLTs) (dose escalation only) [up to 3 years]
Tolerability measured by the number of subjects who have interruptions/reductions of study treatment and reason for interruptions/reductions [up to 5 years]
Tolerability measured by the dose intensity of study drug, Relative Dose intensity for subjects with non-zero duration of exposure is computed as the ratio of dose intensity and planned dose intentity [Up to 5 years]

Secondary Outcome Measures

Overall Response Rate (ORR) [Up to 5 years]
Duration of response (DOR) [Up to 5 years]
Disease Control Rate (DCR) [Up to 5 years]
Progression Free Survival (PFS) [Up to 5 years]
Overall Survival (OS) - (dose expansion part only) [Up to 6 years]
Derived PK parameter (Cmax) for LXH254 & LTT462: [Up to 5 years]
Derived PK parameter (AUC) for LXH254 & LTT462 [Up to 5 years]
Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor samples [up to 5 years]
Derived PK parameter (Cmax) for LXH254 & trametinib [up to 5 years]
Derived PK parameter (AUC) for LXH254 & trametinib [Up to 5 years]
Derived PK parameter (Cmax) for LXH254 & ribociclib [Up to 5 years]
Derived PK parameter (AUC) for LXH254 & ribociclib [Up to 5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have advanced or metastatic NSCLC or cutaneous melanoma
Presence of KRAS or BRAF mutation (NSCLC) or NRAS mutation (cutaneous melanoma) in tumor tissue
All patients participating in this clinical trial must have progressed following standard therapy or, in the opinion of the Investigator, no effective standard therapy exists, is tolerated, appropriate or is considered equivalent to study treatment.
ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2

Exclusion Criteria:

-Dose expansion - KRAS or NRAS mutant patients groups: Prior treatment with a RAFi (including any BRAFi and pan-RAFi), MEKi and/or ERKi. (Patients with KRAS mutant NSCLC with prior G12C inhibitor treatments are also excluded in the LXH254+trametinib expansion part). BRAF mutant patients group: Prior treatment with any EGFR, ALK, ROS1, KRAS, RAF (both BRAFV600 selective and pan-RAF), MEK1/2 and/or ERK1/2 inhibitors (for patients with BRAF V600 mutant NSCLC, prior treatments with BRAF and MEK1/2 inhibitors are allowed).

Patients who have received more than 3 lines of anti-cancer therapy are excluded.

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 (PPI) which cannot be discontinued 3 days prior to the start study treatment and for the duration of the study.
Patients with Gilbert's syndrome or other heritable diseases of bile processing.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego	San Diego	California	United States	92103
2	UCSF Medical Center	San Francisco	California	United States	94143
3	Massachusetts General Hospital SC	Boston	Massachusetts	United States	02114
4	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
5	Sarah Cannon Research Institute Tennessee Oncology	Nashville	Tennessee	United States	37203
6	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
7	Novartis Investigative Site	Westmead	New South Wales	Australia	2145
8	Novartis Investigative Site	Melbourne	Victoria	Australia	3000
9	Novartis Investigative Site	Prahran	Victoria	Australia	3181
10	Novartis Investigative Site	Leuven		Belgium	3000
11	Novartis Investigative Site	Lyon Cedex		France	69373
12	Novartis Investigative Site	Paris Cedex 10		France	75475
13	Novartis Investigative Site	Villejuif Cedex		France	94800
14	Novartis Investigative Site	Dresden		Germany	01307
15	Novartis Investigative Site	Essen		Germany	45147
16	Novartis Investigative Site	Frankfurt		Germany	60590
17	Novartis Investigative Site	Heidelberg		Germany	69120
18	Novartis Investigative Site	Koeln		Germany	50937
19	Novartis Investigative Site	Ramat Gan		Israel	52621
20	Novartis Investigative Site	Tel Aviv		Israel	6423906
21	Novartis Investigative Site	Milano	MI	Italy	20133
22	Novartis Investigative Site	Milano	MI	Italy	20162
23	Novartis Investigative Site	Rozzano	MI	Italy	20089
24	Novartis Investigative Site	Aviano	PN	Italy	33081
25	Novartis Investigative Site	Verona	VR	Italy	37126
26	Novartis Investigative Site	Napoli		Italy	80131
27	Novartis Investigative Site	Seoul		Korea, Republic of	03080
28	Novartis Investigative Site	Seoul		Korea, Republic of	06351
29	Novartis Investigative Site	Warszawa		Poland	02 781
30	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
31	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
32	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
33	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46010
34	Novartis Investigative Site	Pamplona	Navarra	Spain	31008
35	Novartis Investigative Site	Madrid		Spain	28034
36	Novartis Investigative Site	Stockholm		Sweden	171 76