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

Primary To characterize the safety and tolerability of TNO155 in solid tumors and identify recommended regimen(s) and dose(s) for future studies Secondary  To evaluate the pharmacokinetic profile of TNO155  To assess the preliminary anti-tumor activity of TNO155  To assess pharmacodynamic response of SHP2 inhibition in tumors

TNO155

EGF816
TNO155

Hard Gelatin Capsule
capsule

1.5, 10, 50
25mg, 50mg

Primary Outcome Measures :
Number of participants with adverse events [ Time Frame: 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, cardiac imaging and ophthalmological assessments

Number of participants with dose limiting toxicities [ Time Frame: 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)


Secondary Outcome Measures :
Overall response rate [ Time Frame: From start of treatment for 60 months ]
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

pERK [ Time Frame: At screening and between Cycle 1 and Cycle 3 on treatment for 60 months ]
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

Area under the curve [ Time Frame: 60 months ]
Area under the plasma concentration time curve of TNO155

Cmax [ Time Frame: 60 months ]
highest observed plasma concentration of TNO155

tmax [ Time Frame: 60 months ]
Time of highest observed plasma concentration of TNO155

apparent terminal elimination half-life [ Time Frame: 60 months ]
terminal elimination half-life of TNO155

Area under the curve [ Time Frame: 60 months ]
Area under the plasma concentration time curve of TNO155 and EGF816 (nazartinib) when given in combination

Cmax [ Time Frame: 60 months ]
highest observed plasma concentration of TNO155 and EGF816 (nazartinib) when given in combination

tmax [ Time Frame: 60 months ]
Time of highest observed plasma concentration of TNO155 and EGF816 (nazartinib) when given in combination

apparent terminal elimination half-life [ Time Frame: 60 months ]
terminal elimination half-life of TNO155 and EGF816 (nazartinib) when given in combination

1. Able to understand and voluntarily sign the ICF and to comply with the study visit
schedule and the other protocol requirements. Written informed consent must be obtained
prior to any study specific procedures that are not part of standard of care. If consent
cannot be expressed in writing, it must be formally documented and witnessed, ideally via
an independent trusted witness.
For Japan only: written consent is necessary both from the patient and his/her legal
representative if he/she is under the age of 20 years.
2. Patient (male or female) ≥ 18 years of age
3. ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2
4. Patient must have a site of disease amenable to biopsy and be a candidate for tumor biopsy
according to the treating institution’s own guidelines and requirements for such procedure.
Patient must be willing to undergo a tumor biopsy at screening/baseline, and again during
therapy on this study.
5. Presence of at least one measurable lesion according to RECIST v1.1 (Appendix 1).
Target lesions in previously irradiated areas should not be selected unless there is clear
evidence of progression in such lesions since the irradiation.
6. Dose escalation part:
a. Advanced NSCLC harboring an activating EGFR mutation (e.g., exon 19 deletion,
L858R, exon 20 insertion/duplication), after progression on one or more SOC EGFR
TKI (e.g., gefitinib, erlotinib, afatinib, osimertinib), per local SOC guidelines, or for
whom no SOC EGFR-targeting TKI is available, and progression on or after, or
intolerance to, platinum-containing combination chemotherapy. EGFR TKIs may
include 1st through 3rd generation EGFR TKIs, as clinically indicated and available.
EGFR TKI therapy need not be the most recent prior therapy. The most recent
pathology report documenting the EGFR status of the NSCLC must be available in
the patient’s source documents.
b. Advanced HNSCC, after progression on or after, or intolerance to, platinumcontaining combination chemotherapy. This need not be the most recent prior
regimen.
c. Advanced GIST, after progression on SOC therapy per local guidelines, or for whom,
in the opinion of the Investigator, no effective standard therapy exists, is tolerated, or
is appropriate.
d. Advanced CRC, after progression on or intolerance to a fluoropyrimidine, oxaliplatin,
and irinotecan. These need not have been combined in a single regimen nor included
in the most recent prior regimen. Patients with CRC must have documented wild-type
status or G12C mutation of KRAS, and wild-type status of KRAS at codons 13 and
61 and of NRAS at codons 12, 13, and 61 and of BRAF at codon 600.
e. Advanced esophageal SCC, after progression on or after, or intolerance to, platinumcontaining combination chemotherapy. This need not be the most recent prior
regimen.
7. Dose expansion part:
a. Group 1: Advanced RAS/BRAF WT NSCLC harboring an activating EGFR mutation
(e.g., exon 19 deletion, L858R, exon 20 insertion/duplication), after progression on
one or more SOC EGFR TKI (e.g., gefitinib, erlotinib, afatinib, osimertinib), per local
SOC guidelines, or for whom no standard-of-care EGFR-targeting TKI is available,
and progression on or after, or intolerance to, platinum-containing combination
chemotherapy. EGFR TKIs may include 1st through 3rd generation EGFR TKIs, as
clinically indicated and available. EGFR TKI need not be the most recent prior
therapy.
b. Group 2: Advanced, RAS/BRAF WT HNSCC, after progression on or after, or
intolerance to platinum-containing combination chemotherapy. This need not be the
most recent prior regimen.
c. Group 3: Advanced RAS/BRAF WT other solid malignancy with documented RTKdependency. Patients must have had an objective response, per investigator
assessment, to a single-agent, non-investigational RTK inhibitor as their most recent
therapy, and then progressed. Exceptions to the above are possible on a case-by-case
basis after documented discussion with Novartis. Patients with NSCLC or HNSCC
must have progressed on or after, or been intolerant to, platinum-containing
combination therapy and patients with CRC must have progressed on or been
intolerant to a fluoropyrimidine, oxaliplatin, and irinotecan.
d. Group 4: Advanced RAS/BRAF WT other solid malignancy, after progression on
SOC therapy per local guidelines, or for whom, in the opinion of the Investigator, no
effective standard therapy exists, is tolerated, or is appropriate. Patients with NSCLC
or HNSCC must have progressed on or after, or been intolerant to, platinumcontaining combination therapy and patients with CRC must have progressed on or
been intolerant to a fluoropyrimidine, oxaliplatin, and irinotecan. Enrollment of any
single histological type of cancer to this group will be limited to a maximum of 5
patients; exceptions to this may be possible on a case-by-case basis after documented
discussion with Novartis.
e. Group 5: Advanced KRAS G12C-mutant NSCLC, after progression on or after, or
intolerance to, SOC per local guidelines including platinum-containing combination
chemotherapy. This need not be the most recent prior regimen.

1. Tumors harboring known activating KRAS, NRAS, HRAS, BRAF, or PTPN11 (SHP2)
mutations, with the exception of KRAS G12C-mutant CRC in dose escalation and KRAS
G12C-mutant NSCLC in dose expansion (pre-screening will be required for RAS and
BRAF mutations in the dose expansion part, either based on local testing at the clinical
site or at a Novartis designated central laboratory).
2. Treatment with any of the following anti-cancer therapies prior to the first dose of study
treatment within the stated timeframes:
a. ≤ 4 weeks for radiation therapy or limited field radiation for palliation within ≤ 2
weeks prior to the first dose of study treatment.
b. ≤ 4 weeks or ≤ 5 half-lives (whichever is shorter) for chemotherapy or biological
therapy (including monoclonal antibodies) or continuous or intermittent small
molecule therapeutics or any other investigational agent.
c. ≤ 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosoureas and
mitomycin C.
d. ≤ 6 weeks for immuno-oncologic therapy, such as CTLA4, PD-1, or PD-L1
antagonists
e. Patients who have undergone major surgery ≤ 4 weeks prior to first dose of study
treatment or who have not recovered from the surgical procedure.
2A. Patients who have not had resolution, except where otherwise stated in the
inclusion/exclusion criteria, of all clinically significant toxic effects of prior systemic
cancer therapy, surgery, or radiotherapy to Grade ≤1, except for alopecia.
2B. Malignant disease, other than that being treated in this study. Exceptions to this exclusion
include the following: malignancies that were treated curatively and have not recurred
within 2 years prior to study treatment; completely resected basal cell and squamous cell
skin cancers; any malignancy considered to be indolent and that has never required
therapy; and completely resected carcinoma in situ of any type.
3. Patients participating in additional parallel investigational drug or medical device studies.
4. History or current evidence of retinal vein occlusion (RVO) or current risk factors for
RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or
hypercoagulability syndromes).
5. Ongoing active diarrhea requiring medication (e.g., loperamide, bile acid sequestrant such
as cholestyramine) within 7 days.
6. Inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease) or impairment of
gastrointestinal (GI) function or GI disease that may significantly alter the absorption of
study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea,
malabsorption syndrome, small bowel resection).
7. All primary central nervous system (CNS) tumors or symptomatic CNS metastases which
are neurologically unstable or requiring increasing doses of steroids within the 4 weeks
prior to study entry to control their CNS disease. Note: Patients with controlled CNS
metastases may participate in this trial. The patient must have completed radiotherapy
and/or surgery for CNS metastases > 2 weeks prior to study entry. Patients must be
neurologically stable, having no new neurologic deficits on clinical examination, and no
new findings on CNS imaging. If patients require steroids for management of CNS
metastases, they must have been on a stable dose of steroids for 2 weeks preceding the
first dose of study treatment. If the corticosteroid dose is increased between the date of
imaging and the initiation of study treatment, a new baseline magnetic resonance imaging
(MRI)/ computed tomography (CT) is required.
8. 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. Any severe, acute, or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
treatment administration or that may interfere with the interpretation of study results and,
in the judgment of the investigator, would make the patient inappropriate for the study.
9. Inability to swallow capsules or a solution made with the capsule contents. When a
gastric tube-compatible formulation becomes available, this eligibility requirement will be
lifted and this will be communicated to Investigators via teleconference and meeting
minutes.
10. Clinically significant cardiac disease or risk factors at screening including any of the
following:
a. Any history of congestive heart failure
b. Left ventricular ejection fraction (LVEF) < 50% or below the institutional standard
lower limit, whichever is higher, as determined by multiple gated acquisition (MUGA)
scan or Trans-thoracic echocardiography (TTE)
c. Uncontrolled hypertension defined by blood pressure ≥ 140 /90 mmHg at rest (average
of 3 consecutive readings) despite medical treatment.
d. Troponin I/T or NT-pro-BNP above upper limit of normal
e. History or presence of clinically significant ventricular arrhythmias, atrial fibrillation,
resting bradycardia, conduction abnormality, transient ischemic attack or stroke.
f. Unstable angina pectoris or acute myocardial infarction ≤ 6 months prior to starting
study drug.
g. QTcF > 450 ms for males or > 460 ms for females on screening ECG (using triplicate
ECGs), history of Torsades de Pointes, or a history of congenital long QT syndrome.
h. Cumulative lifetime anthracycline exposure greater than 250 mg/m2
doxorubicin or
equivalent (see Appendix 3)
11. Patients requiring treatment with a prohibited concomitant medication (see Appendix 2)
12. Insufficient bone marrow function at screening:
a. Absolute Neutrophil Count (ANC) < 1.5 x 109
/L
b. Hemoglobin (Hgb) < 9.0 g/dL
c. Platelets < 75 x 109
/L
13. Insufficient hepatic or renal function at screening:
a. Serum total bilirubin > 1.5 x upper limit of normal (ULN). For patients with Gilbert’s
syndrome, total bilirubin > 3 x ULN
b. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN or >
5.0 x ULN if liver metastases are present
c. Serum creatinine > 1.5 x ULN OR creatinine clearance < 60 mL/min (calculated
using Cockcroft-Gault equation)
14. Patients who have the following laboratory values outside of the laboratory normal limits
and cannot be corrected to within normal limits with supplements (if applicable) during
screening:
a. Potassium
b. Magnesium
c. Phosphorus
d. Total calcium (corrected for serum albumin)
e. Fasting plasma glucose >175 mg/dL (>9.7 mmol/L)
15. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a positive
human chorionic gonadotropin (hCG) laboratory test.
16. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 30 days after stopping medication. Highly effective contraception
methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception
b. Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking
study treatment. In case of oophorectomy alone, only when the reproductive status of
the woman has been confirmed by follow up hormone level assessment
c. Male sterilization (at least 6 months prior to screening). The vasectomized male
partner should be the sole partner for that subject
d. Use of oral, injected or implanted hormonal methods of contraception or placement of
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal
contraception that have comparable efficacy (failure rate <1%), for example hormone
vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking study treatment. Women are considered post-menopausal
and not of child bearing potential if they have had at least 12 months of natural (spontaneous)
amenorrhea with an appropriate clinical profile (e.g., age appropriate [generally age at least 40
years], history of vasomotor symptoms [e.g., hot flush]) in the absence of other medical
justification or have had surgical bilateral oophorectomy (with or without hysterectomy), total
hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only
when the reproductive status of the woman has been confirmed by follow up hormone level
assessment is she considered not of child bearing potential.
17. Sexually active males unless they use a condom during intercourse while taking study
treatment and for 10 days after stopping study treatment. A condom is required to be used
by vasectomized men as well as during intercourse with a male partner in order to prevent
delivery of the drug via seminal fluid.
18. Japan only: patients with a history of drug- and/or non-drug-induced interstitial lung
disease (ILD) ≥ Grade 2.