Rationale The purpose of this study is to evaluate the safety, tolerability, and preliminary
efficacy of the combination of TNO155 with spartalizumab and of TNO155 with ribociclib, and
to identify dosing regimens for further study. Data from preclinical models have demonstrated
anti-tumor activity for the combinations of TNO155 with spartalizumab and of TNO155 with
ribociclib that is superior to the activity observed with each of the drugs as single agents.
These data suggest that these combinations may provide clinical benefit to patients with
advanced malignancies.
Study Design This study is a Phase Ib, multi-center, open-label study with a dose escalation
part followed by a dose expansion part in adult subjects with advanced solid tumors to
characterize the safety and tolerability TNO155 in combination with spartalizumab and of
TNO155 in combination with ribociclib and to identify the MTD and/or recommended regimen
(dose and schedule) for each combination. The study treatment will be administered until the
subject experiences unacceptable toxicity, progressive disease, and/or has treatment
discontinued at the discretion of the Investigator or the subject, or due to withdrawal of
consent.
Objectives
Primary objective:
To characterize the safety and tolerability TNO155 in combination with spartalizumab and of
TNO155 in combination with ribociclib, and to identify the MTD and/or recommended regimen
(dose and schedule) for each combination.
Secondary objectives:
- To characterize the pharmacokinetic (PK) profile of TNO155, spartalizumab and ribociclib
when administered as a combination of TNO155 plus spartalizumab or of TNO155 plus
ribociclib.
- To evaluate the preliminary anti-tumor activity of TNO155 in combination with
spartalizumab and of TNO155 in combination with ribociclib.
Key Inclusion Criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. Age ≥ 18 years. 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.
3. ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1.
4. Dose escalation part: Patients with advanced solid tumors, with evaluable disease as
determined by RECIST version 1.1, and fit into one of the following groups:
a. For TNO155 plus spartalizumab combination: i. Advanced EGFR WT, ALK WT NSCLC, after
progression on or intolerance to platinum-containing combination chemotherapy and
after progression on anti-PD-1 or anti-PD-L1 therapy.
ii. Advanced HNSCC or esophageal SCC, after progression on or intolerance to
platinum-containing combination chemotherapy.
iii. Advanced CRC, after progression on or intolerance to all standard-of-care (SOC)
therapy per local guidelines.
b. For TNO155 plus ribociclib combination: i. Advanced NSCLC, after progression on or
intolerance to platinum-containing combination chemotherapy and anti-PD-1 or
anti-PD-L1 therapy.
ii. Advanced HNSCC or esophageal SCC after progression on or intolerance to,
platinum-containing combination chemotherapy and anti-PD-1 or anti-PD-L1 therapy,
where such therapy is available and considered standard of care.
iii. Advanced CRC or GIST, after progression on or intolerance to all SOC therapy per
local guidelines.
5. Dose expansion part: Patients with advanced solid tumors, with at least one measurable
lesion as determined by RECIST version 1.1, who fit into one of the following groups:
a. For TNO155 plus spartalizumab combination: i. Advanced EGFR WT, ALK WT, KRAS G12C
NSCLC after progression on or intolerance to platinum-containing combination
chemotherapy and after progression on anti-PD-1 or anti-PD-L1 therapy.
ii. Advanced EGFR WT, ALK WT, KRAS WT NSCLC, after progression on or intolerance to
platinum-containing combination chemotherapy and after progression on anti-PD-1 or
anti-PD-L1 therapy.
iii. Advanced HNSCC, after progression on or intolerance to, platinum-containing
combination chemotherapy.
b. For TNO155 plus ribociclib combination: i. Advanced EGFR WT, ALK WT, KRAS WT NSCLC,
after progression on or intolerance to platinum-containing chemotherapy and anti-PD-1
or anti-PD-L1 therapy ii. Advanced CRC harboring a KRAS codon 12, 13, or 61 mutation,
after progression on or intolerance to all SOC per local guidelines
6. Patients with NSCLC whose tumors harbor genomic aberrations for which SOC targeted
therapies exist and are locally approved and available must have had progression on or
after, or intolerance to, the SOC targeted therapy/therapies as indicated
7. Patients must have a site of disease amenable to biopsy
Key Exclusion Criteria:
1. Prior treatment with a MAPK pathway inhibitor
2. Clinically significant cardiac disease or risk factors
3. Use of any agent known to prolong the QT interval unless it can be permanently
discontinued for the duration of study (see list in Section 6.2.2).
4. History or current evidence of retinal vein occlusion (RVO) or current risk factors
for RVO
5. 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
6. Symptomatic CNS metastases which are neurologically unstable
7. Insufficient bone marrow function at screening:
1. Absolute Neutrophil Count (ANC) < 1.5 x 109/L.
2. Hemoglobin < 9.0 g/dL.
3. Platelets < 75 x 109/L for TNO155 plus spartalizumab combination; < 100 x 109/L
for TNO155 plus ribociclib combination.
8. Insufficient hepatic or renal function at screening:
1. Serum total bilirubin > upper limit of normal (ULN) or, for TNO155 plus
spartalizumab combination only, if liver metastases are present at baseline,
serum total bilirubin > 1.5 x ULN. An exception for either combination is for
patients with Gilbert's syndrome, who are excluded if total bilirubin > 3.0 x ULN
or direct bilirubin > 1.5 x ULN
2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x ULN for
TNO155 plus spartalizumab combination or > 2.5 x ULN for TNO155 plus ribociclib
combination, or > 5 x ULN for either combination if liver metastases are present.
3. Creatinine clearance < 60 mL/min (calculated using Cockcroft-Gault equation).
9. Pregnant or breast-feeding (lactating) women.
Additional exclusion criteria for the TNO155 plus spartalizumab combination
10. History of severe hypersensitivity reactions to other mAbs.
11. Active, known or suspected autoimmune disease.
12. History of or current interstitial lung disease or pneumonitis grade ≥ 2.
13. Human Immunodeficiency Virus (HIV) infection, unless the patient is on antiviral
therapy and has undetectable viral load.
14. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
15. Systemic chronic steroid therapy
16. Patients who discontinued prior anti-PD-1 therapy due to an anti-PD-1-related
toxicity.
Additional exclusion criteria for the TNO155 plus ribociclib combination
17. Systolic Blood Pressure (SBP) < 90 mmHg.
18. International Normalized Ratio (INR) > 1.5 (unless the patient is receiving
anticoagulants and the INR is within the therapeutic range of intended use for that
anticoagulant within seven days prior to the first dose of study drug).
19. History of HIV infection (testing not mandatory)
20. Currently receiving any of the following substances and cannot be discontinued seven
days prior to Cycle 1 Day 1:
- Concomitant medications or herbal supplements, that are strong inducers or
inhibitors of CYP3A4/5,
- Medications that have a narrow therapeutic window and are predominantly
metabolized through CYP3A4/5.
21. Previous treatment with a CDK4/6 inhibitor.
22. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks
prior to starting study drug, or who have not fully recovered from side effects of
such treatment.
Note: The following uses of corticosteroids are permitted: single doses, topical
applications (e.g., for rash), inhaled sprays (e.g., for obstructive airways diseases), eye
drops or local injections (e.g., intra-articular).
