Phase Ib Study of TNO155 in Combination With Spartalizumab or Ribociclib in Selected Malignancies

  • STATUS
    Recruiting
  • End date
    Sep 24, 2024
  • participants needed
    185
  • sponsor
    Novartis Pharmaceuticals
Updated on 11 April 2022
cancer
measurable disease
KRAS
combination chemotherapy
progressive disease
EGFR
solid tumors
cancer chemotherapy
solid tumour
targeted therapy
squamous cell carcinoma of head and neck
ki-ras
tno155

Summary

This study is a Phase Ib, multi-center, open-label study of TNO155 in combination with spartalizumab or ribociclib with a dose escalation part followed by a dose expansion part in adult subjects with advanced solid tumors.

These two treatment arms will enroll subjects in parallel to characterize the safety, tolerability, PK, PD and preliminary antitumor activity.

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.

Description

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.

Details
Condition Non-small Cell Lung Carcinoma, Head and Neck Squamous Cell Carcinoma, Esophageal SCC, Gastrointestinal Stromal Tumors, Colorectal Cancer
Treatment Ribociclib, TNO155, spartalizumab
Clinical Study IdentifierNCT04000529
SponsorNovartis Pharmaceuticals
Last Modified on11 April 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Signed informed consent must be obtained prior to participation in the study
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
ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1
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
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)
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
therapy per local guidelines
local guidelines
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
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
Patients must have a site of disease amenable to biopsy

Exclusion Criteria

Prior treatment with a MAPK pathway inhibitor
Clinically significant cardiac disease or risk factors
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)
History or current evidence of retinal vein occlusion (RVO) or current risk factors
for RVO
Symptomatic CNS metastases which are neurologically unstable
Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or impairment
Insufficient bone marrow function at screening
of gastrointestinal (GI) function or GI disease that may significantly alter the
Absolute Neutrophil Count (ANC) < 1.5 x 109/L
absorption of study drugs
Hemoglobin < 9.0 g/dL
Insufficient hepatic or renal function at screening
Platelets < 75 x 109/L for TNO155 plus spartalizumab combination; < 100 x 109/L
Creatinine clearance < 60 mL/min (calculated using Cockcroft-Gault equation)
for TNO155 plus ribociclib combination
Pregnant or breast-feeding (lactating) women
Additional exclusion criteria for the TNO155 plus spartalizumab combination
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
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
Additional exclusion criteria for the TNO155 plus ribociclib combination
History of severe hypersensitivity reactions to other mAbs
Active, known or suspected autoimmune disease
History of or current interstitial lung disease or pneumonitis grade ≥ 2
Human Immunodeficiency Virus (HIV) infection, unless the patient is on antiviral
therapy and has undetectable viral load
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
Systemic chronic steroid therapy
Patients who discontinued prior anti-PD-1 therapy due to an anti-PD-1-related
toxicity
Systolic Blood Pressure (SBP) < 90 mmHg
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)
History of HIV infection (testing not mandatory)
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
Previous treatment with a CDK4/6 inhibitor
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)
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