Clinical trial NCT03114319: Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors
Official title: An Open-label, Multi-center, Phase I, Dose Finding Study of Oral TNO155 in Adult Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: 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
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2017-04-14
Enrollment: 227
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of participants with adverse events and serious adverse events
timeFrame: up to 5 years; at least once per treatment cycle
measure: Number of participants with dose limiting toxicities
timeFrame: up to 28-day cycle
measure: Number of participants with dose interruptions and reductions
timeFrame: Up to 5 years
measure: Dose intensity of study drugs
timeFrame: Up to 5 years
Secondary outcomes:
measure: Overall response rate (ORR) per RECIST v1.1
timeFrame: From start of treatment for 60 months
measure: Disease control rate (DCR) per RECIST v1.1
timeFrame: From start of treatment for 60 months
measure: Progression-free survival (PFS) per RECIST v1.1
timeFrame: Up to 5 years
measure: Duration of response (DOR) per RECIST v1.1
timeFrame: Up to 5 years
measure: Change from baseline in DUSP6 in tumor samples
timeFrame: At screening and between Cycle 1 and Cycle 3. One cycle=either 21 days or 28 days, depending on the cohort's treatment schedule.
measure: Area under the plasma concentration-time curve (AUC) of study drugs
timeFrame: 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.
measure: Peak plasma concentration (Cmax) of study drugs
timeFrame: 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.
measure: Time to reach peak plasma concentration (Tmax) of study drugs
timeFrame: 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.
measure: Apparent terminal elimination half-life of study drugs
timeFrame: 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.
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloane Ketterin Cancer Ctr
state: New York
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Kobe-shi
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
state: Zuid Holland
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: