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

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

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

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

Intervention / Treatment
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* Drug: LTT462


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Escalation<br> | Drug: LTT462<br>* ERK Inhibitor<br>|
| Experimental: Expansion Group 1<br> | Drug: LTT462<br>* ERK Inhibitor<br>|
| Experimental: Expansion Group 2<br> | Drug: LTT462<br>* ERK Inhibitor<br>|
| Experimental: Expansion Group 3<br> | Drug: LTT462<br>* ERK Inhibitor<br>|
| Experimental: Expansion Group 4<br> | Drug: LTT462<br>* ERK Inhibitor<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LTT462, ERK, MAPK, solid tumor