A Phase I Clinical Study With Investigational Compound LTT462 in Adult Patients With Specific Advanced Cancers.

Phase 1

Terminated

Conditions: Ovarian Neoplasms
Non-Small-Cell Lung Carcinoma
Melanoma
Other Solid Tumors

Interventions: Drug: LTT462

Registration Number: NCT02711345

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: A phase I study of LTT462 in patients with advanced solid tumors that harbor MAPK pathway alterations.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 65

Inclusion Criteria

Patient (male or female) ≥12 years of age
ECOG (Eastern Cooperative Oncology Group) performance status ≤1
Must have progressed following standard therapy, or for whom, in the opinion of the Investigator, no effective standard therapy exists, is tolerated or appropriate.
Patients must be willing and able to undergo study required biopsies.
Presence of at least one measurable lesion according to RECIST v1.1.
Documented MAPK pathway alteration

Exclusion Criteria

Prior treatment with ERK inhibitors.
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 malignant disease other than that being treated in the study.
Clinically significant cardiac disease.

Other protocol-defined exclusion criteria may apply.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Escalation	LTT462	-
Expansion Group 1	LTT462	-
Expansion Group 3	LTT462	-
Expansion Group 4	LTT462	-
Expansion Group 2	LTT462	-

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	Up to 2.8 years	An adverse events is defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions that occur after participant's signed informed consent has been obtained. A SAE is described as any adverse event that leads to death, is life threatening, causes or prolongs hospitalization, results in a congenital anomaly, or any other important medical event not described above.
Percentage of Participants With Dose Limiting Toxicities (DLTs)	Up to 2.8 years	Percentage of participants with dose limiting toxicity were reported.
Percentage of Participants With at Least One Dose Reduction	Up to 2.8 years	Percentage of participants with at least one dose reduction were reported.
Percentage of Participants With at Least One Dose Interruptions	Up to 2.8 years	Percentage of participants with at least dose interruptions were reported.
Dose Intensity Received by Participants	Up to 2.8 years	Dose intensity of LTT462 received by treatment group was reported.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Overall Response Rate (ORR)	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)	Percentage of participants with overall response rate were reported.
Percentage of Participants With Disease Control Rate (DCR)	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)	Percentage of participants with disease control rate were reported.
Duration of Response (DOR)	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)	DOR is defined as the time between the date of the first documented response (complete response \[CR\] or partial response \[PR\]) and the date of progression.
Progression Free Survival (PFS)	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)	Median time for progression free survival was reported.
Overall Survival (OS) - Only for Dose Expansion Phase	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)	Median time for overall survival, only for dose expansion phase was reported.
The Time to Reach Maximum (Peak) Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Tmax) After Single Dose Administration of LTT462	day 1, day 15	Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration.
Elimination Half-life (T1/2) of LTT462	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1	T1/2 is the Elimination half-life.
The Area Under the Curve Calculated to the End of a Dosing Interval (Tau) at Steady-state (AUCtau) of LTT462	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1	AUCtau is the area under the curve calculated to the end of a dosing interval (tau) at steady-state calculated by formula amount \time \ volume\^-1
The Maximum (Peak) Observed Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Cmax) After Single Dose Administration of LTT462	day 1, day 15	Cmax is the maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after single dose administration expressed in mass x volume-1.
Area Under the Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of LTT462	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1	AUClast is the area under the curve from time zero to the last measurable concentration sampling time calculated by mass \* time \*volume\^-1
Accumulation Ratio (Racc) of LTT462	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1	Racc is the accumulation ratio calculated by AUCtau ratio Day 15 versus Day 1.
Changes From Baseline in Relative Quantity (RQ) of Dual Specificity Phosphatase 6 (DUSP6) in Tumor Tissue and in Blood	Cycle 1 Days 1, 2, 3, 15 and 16	Assessment of Pharmacodynamic (PD) effects of LTT462 in tumor, pre- and post- treatment tumor biopsies were examined for expression of DUSP6. For assessment of PD effects in blood, levels of DUSP6 were measured in blood samples.