Advanced EGFR Mutant Non Small Cell LungCancer (NSCLC), KRAS G12-mutant NSCLC, Esophageal Squamous Cell Cancer (SCC), Head/Neck SCC, Melanoma, Advanced Gastrointestinal Stromal Tumors (GIST), Advanced NRAS/BRAFT wt Cutaneous Melanoma
Conditions
Keywords
TNO155, SHP2, advanced solid tumor, NSCLC, HNSCC, Esophageal SCC, Melanoma, EGFR, KRAS G12C, GIST, PTPN11, cancers with a mass, bulky tumor, nodule, lump, advanced solid malignancies
Brief summary
The purpose of this first in human (FIH) trial was 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
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), was taken until the patient experienced unacceptable toxicity, progressive disease and/or treatment was discontinued at the discretion of the investigator or the patient or due to withdrawal of consent.
Interventions
DRUGTNO155
TNO155 for oral administration
DRUGTNO155 in combination with EGF816 (nazartinib)
TNO155 for oral administration; EGF816 (nazartinib) for oral administration
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Able to understand and voluntarily sign the ICF and able to comply with the study visit schedule and the other protocol requirements. 2. Patient (male or female) ≥18 years of age willing to agree to not father a child/become pregnant and comply with effective contraception criteria. 3. 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. 4. ECOG (Eastern cooperative oncology group) performance status ≤2 Additional criteria only appying to TNO155 in combination with EGF816 (nazartinib): 5. Patients must be screened for Hepatitis B virus and Hepatitis C virus
Exclusion criteria
1. Tumors harboring known activating KRAS, NRAS, HRAS, BRAF or PTPN11 (SHP2) mutations. (Exceptions are KRAS G12-mutant NSCLC's) 2. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO. 3. 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. 4. Clinically significant cardiac disease. 5. Active diarrhea or inflammatory bowel disease 6. Insufficient bone marrow function 7. Insufficient hepatic and renal function. Additional criteria only appying to TNO155 in combination with EGF816 (nazartinib): 8. Patients with a known history of human immunodeficiency virus (HIV) seropositivity. 9. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry. 10. Patients who have undergone a bone marrow or solid organ transplant 11. Patients with a history or presence of interstitial lung disease or interstitial pneumonitis 12. Bullous and exfoliative skin disorders at screening of any grade 13. Presence of clinically significant ophthalmological abnormalities that might increase the risk of corneal epithelial injury
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with adverse events and serious adverse events | up to 5 years; at least once per treatment cycle | 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 and cardiac biomarkers |
| Number of participants with dose limiting toxicities | up to 28-day cycle | 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) |
| Number of participants with dose interruptions and reductions | Up to 5 years | Assessment of tolerability. For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments may be permitted in order to allow patients to continue the study treatment |
| Dose intensity of study drugs | Up to 5 years | Dose intensity is computed as the ratio of actual cumulative dose received to actual duration of exposure |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from baseline in DUSP6 in tumor samples | At screening and between Cycle 1 and Cycle 3. One cycle=either 21 days or 28 days, depending on the cohort's treatment schedule. | Dual Specificity Phosphatase 6 (DUSP6) mRNA levels assessed in paired tumor biopsy samples by quantitative polymerase chain reaction (qPCR) |
| Area under the plasma concentration-time curve (AUC) of study drugs | From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule. | Pharmacokinetic (PK) parameters calculated based on the plasma concentrations versus time profiles by using non-compartmental methods |
| Overall response rate (ORR) per RECIST v1.1 | From start of treatment for 60 months | ORR is the proportion of patients with a best overall response of Complete Response (CR) or Partial response (PR) |
| Time to reach peak plasma concentration (Tmax) of study drugs | From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule. | PK parameters calculated based on the plasma concentrations versus time profiles by using non-compartmental methods |
| Apparent terminal elimination half-life of study drugs | From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule. | PK parameters calculated based on the plasma concentrations versus time profiles by using non-compartmental methods |
| Peak plasma concentration (Cmax) of study drugs | From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule. | PK parameters calculated based on the plasma concentrations versus time profiles by using non-compartmental methods |
| Disease control rate (DCR) per RECIST v1.1 | From start of treatment for 60 months | DCR is the proportion of patients with a best overall response of CR or PR or stable disease (SD) |
| Progression-free survival (PFS) per RECIST v1.1 | Up to 5 years | PFS is the time from date start of treatment to the date of event defined as the first documented progression or death due to any cause |
| Duration of response (DOR) per RECIST v1.1 | Up to 5 years | DOR is the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause |
Countries
Canada, Italy, Japan, Netherlands, Singapore, South Korea, Spain, Taiwan, United States
Outcome results
None listed