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

A Phase I Dose Finding Study of Oral LTT462 in Adult Patients With Advanced Solid Tumors Harboring MAPK Pathway Alterations.

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

Study Overview

• Status: Terminated
• Conditions: Melanoma; Ovarian Neoplasms; Non-Small-Cell Lung Carcinoma; Other Solid Tumors
• Intervention / Treatment: Drug: LTT462

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Essen, Germany, 45147
    • Novartis Investigative Site
• Japan
  • Tokyo
    • Chuo ku, Tokyo, Japan, 104 0045
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 169610
    • Novartis Investigative Site
• Spain
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Switzerland
  • Bellinzona, Switzerland, 6500
    • Novartis Investigative Site
• United States
  • New York
    • New York, New York, United States, 10065
      • Novartis Investigative Site
  • Texas
    • Houston, Texas, United States, 77030-4009
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Escalation	Drug: LTT462; ERK Inhibitor
Experimental: Expansion Group 1	Drug: LTT462; ERK Inhibitor
Experimental: Expansion Group 2	Drug: LTT462; ERK Inhibitor
Experimental: Expansion Group 3	Drug: LTT462; ERK Inhibitor
Experimental: Expansion Group 4	Drug: LTT462; ERK Inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	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.	Up to 2.8 years
Percentage of Participants With Dose Limiting Toxicities (DLTs)	Percentage of participants with dose limiting toxicity were reported.	Up to 2.8 years
Percentage of Participants With at Least One Dose Reduction	Percentage of participants with at least one dose reduction were reported.	Up to 2.8 years
Percentage of Participants With at Least One Dose Interruptions	Percentage of participants with at least dose interruptions were reported.	Up to 2.8 years
Dose Intensity Received by Participants	Dose intensity of LTT462 received by treatment group was reported.	Up to 2.8 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Overall Response Rate (ORR)	Percentage of participants with overall response rate were reported.	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)
Percentage of Participants With Disease Control Rate (DCR)	Percentage of participants with disease control rate were reported.	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)
Duration of Response (DOR)	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.	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)
Progression Free Survival (PFS)	Median time for progression free survival was reported.	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)
Overall Survival (OS) - Only for Dose Expansion Phase	Median time for overall survival, only for dose expansion phase was reported.	Every 2 cycles after starting LTT462 treatment until end of treatment (Up to 2.8 years)
The Maximum (Peak) Observed Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Cmax) After Single Dose Administration of LTT462	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.	day 1, day 15
Area Under the Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of LTT462	AUClast is the area under the curve from time zero to the last measurable concentration sampling time calculated by mass * time *volume^-1	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
The Time to Reach Maximum (Peak) Plasma, Blood, Serum, or Other Body Fluid Drug Concentration (Tmax) After Single Dose Administration of LTT462	Tmax is the time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration.	day 1, day 15
Elimination Half-life (T1/2) of LTT462	T1/2 is the Elimination half-life.	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
The Area Under the Curve Calculated to the End of a Dosing Interval (Tau) at Steady-state (AUCtau) of LTT462	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	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
Accumulation Ratio (Racc) of LTT462	Racc is the accumulation ratio calculated by AUCtau ratio Day 15 versus Day 1.	Cycle 1 Days 1, 2, 3, 8, 15 and 16; Cycle 2 day 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1
Changes From Baseline in Relative Quantity (RQ) of Dual Specificity Phosphatase 6 (DUSP6) in Tumor Tissue and in Blood	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.	Cycle 1 Days 1, 2, 3, 15 and 16

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2016
• Primary Completion (Actual): November 21, 2018
• Study Completion (Actual): November 21, 2018

Study Registration Dates

• First Submitted: February 16, 2016
• First Submitted That Met QC Criteria: March 11, 2016
• First Posted (Estimate): March 17, 2016

Study Record Updates

• Last Update Posted (Actual): September 19, 2019
• Last Update Submitted That Met QC Criteria: August 15, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: solid tumor; ERK; MAPK; LTT462
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Ovarian Neoplasms
• Other Study ID Numbers: CLTT462X2101; 2015-003614-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No