Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this first in human (FIH) trial is to characterize the safety and tolerability of the SHP2 inhibitor TNO155 alone and in combination with EGF816 (nazartinib) and identify a recommended dose for future studies in adult patients with advanced solid tumors in selected indications.

Detailed Description
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This study has been designed as a Phase I, open-label, dose finding study with a dose escalation part and a dose expansion part in adult patients with selected advanced solid tumors. The study treatment, TNO155 alone or in combination with EGF816 (nazartinib), will be taken until the patient experiences unacceptable toxicity, progressive disease and/or treatment is discontinued at the discretion of the investigator or the patient or due to withdrawal of consent. Some patients will be participating in a food effect investigation as an exploratory objective.

Official Title
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An Open-label, Multi-center, Phase I, Dose Finding Study of Oral TNO155 in Adult Patients With Advanced Solid Tumors

Conditions
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Advanced EGFRmutant NonSmallSellLungCancer (NSCLC),KRAS G12-mutant NSCLC,Esophageal SquamousCellCancer (SCC),Head/Neck SCC,Melanoma

Intervention / Treatment
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* Drug: TNO155
* Drug: TNO155 in combination with EGF816 (nazartinib)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to understand and voluntarily sign the ICF and able to comply with the study visit schedule and the other protocol requirements. Patient (male or female) ≥18 years of age willing to agree to not father a child/become pregnant and comply with effective contraception criteria. Must have progressed following standard therapy, or for whom, in the opinion of the Investigator, no effective standard therapy exists, is tolerated or is appropriate. ECOG (Eastern cooperative oncology group) performance status ≤2 Additional criteria only appying to TNO155 in combination with EGF816 (nazartinib): Patients must be screened for Hepatitis B virus and Hepatitis C virus Exclusion Criteria: Tumors harboring known activating KRAS, NRAS, HRAS, BRAF or PTPN11 (SHP2) mutations. (Exceptions are KRAS G12-mutant NSCLC's) 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. Clinically significant cardiac disease. Active diarrhea or inflammatory bowel disease Insufficient bone marrow function Insufficient hepatic and renal function. Additional criteria only appying to TNO155 in combination with EGF816 (nazartinib): Patients with a known history of human immunodeficiency virus (HIV) seropositivity. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry. Patients who have undergone a bone marrow or solid organ transplant Patients with a history or presence of interstitial lung disease or interstitial pneumonitis Bullous and exfoliative skin disorders at screening of any grade Presence of clinically significant ophthalmological abnormalities that might increase the risk of corneal epithelial injury

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TNO155<br>TNO155 for oral administration | Drug: TNO155<br>* TNO155 for oral administration<br>|
| Experimental: TNO155 in combination with EGF816 (nazartinib)<br>TNO155 in combination with EGF816 (nazartinib) in patients with advanced EGFR mutant NSCLC | Drug: TNO155 in combination with EGF816 (nazartinib)<br>* TNO155 for oral administration; EGF816 (nazartinib) for oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events | All patients participating in this study will be assessed for incidence and severity of adverse events (AEs) and serious AEs, including changes in laboratory values, vital signs, electrocardiograms, cardiac imaging and ophthalmological assessments | up to 5 years; at least once per treatment cycle | 
| Number of participants with dose limiting toxicities | Incidence and nature of dose limiting toxicities (DLTs) in the dose escalation part. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first treatment cycle (either 21 days or 28 days, depending on the cohort's treatment schedule) with TNO155 or with TNO155 in combination with EGF816 (nazartinib) | up to 28-day cycle | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | To evaluate the preliminary anti-tumor activity of TNO155 or of TNO155 in combination with EGF816 (nazartinib), e.g., overall response rate per RECIST 1.1 | From start of treatment for 60 months | 
| pERK | On treatment versus baseline comparison of pharmacodynamic markers e.g., pERK (Phosphorylated form of Extracellular signal-regulated kinase) on newly obtained tumor samples by IHC | At screening and between Cycle 1 and Cycle 3 on treatment for 60 months | 
| Area under the curve | Area under the plasma concentration time curve of TNO155 | 60 months | 
| Cmax | highest observed plasma concentration of TNO155 | 60 months | 
| tmax | Time of highest observed plasma concentration of TNO155 | 60 months | 
| apparent terminal elimination half-life | terminal elimination half-life of TNO155 | 60 months | 
| Area under the curve | Area under the plasma concentration time curve of TNO155 and EGF816 (nazartinib) when given in combination | 60 months | 
| Cmax | highest observed plasma concentration of TNO155 and EGF816 (nazartinib) when given in combination | 60 months | 
| tmax | Time of highest observed plasma concentration of TNO155 and EGF816 (nazartinib) when given in combination | 60 months | 
| apparent terminal elimination half-life | terminal elimination half-life of TNO155 and EGF816 (nazartinib) when given in combination | 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, TNO155, SHP2, advanced solid tumor, NSCLC, HNSCC, Esophageal SCC, EGFR, KRAS G12C, GIST, PTPN11, cancers with a mass, bulky tumor, nodule, lump, advanced solid malignancies