search
Back to results

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

Primary Purpose

Non-small Cell Lung Carcinoma, Head and Neck Squamous Cell Carcinoma, Esophageal SCC

Status
Active
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
TNO155
Spartalizumab
Ribociclib
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Non-small Cell Lung Carcinoma focused on measuring TNO155, spartalizumab, ribociclib, checkpoint inhibitor, SHP2, PD-1, CDK4/6, NSCLC, CRC, HNSCC, KRAS, esophageal SCC, GIST

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

  • Massachusetts General Hospital
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

TNO155 in combination with spartalizumab

TNO155 in combination with ribociclib

Arm Description

TNO155 in combination with spartalizumab

TNO155 in combination with ribociclib

Outcomes

Primary Outcome Measures

DLT incidence
Incidence of dose limiting toxicities (DLTs) during the first cycle of combination treatment during the dose escalation part
AE and SAE incidence
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) as per CTCAE v5.0, by treatment
Dose interruptions, reductions and dose intensity, by treatment
Dose tolerability

Secondary Outcome Measures

Pharmacokinetics (PK): Cmax
Cmax for TNO155, spartalizumab, and ribociclib
Pharmacokinetics (PK): Tmax
Tmax for TNO155, spartalizumab, and ribociclib
Pharmacokinetics (PK): AUClast
AUClast for TNO155, spartalizumab, and ribociclib
Pharmacokinetics (PK): AUCtau
AUCtau for TNO155, spartalizumab, and ribociclib
Efficacy measurements per RECIST v1.1: ORR
Overall response rate (ORR) per RECIST v1.1, by treatment
Efficacy measurements per RECIST v1.1: DCR
Disease control rate (DCR) per RECIST v1.1, by treatment
Efficacy measurements per RECIST v1.1: PFS
Progression-free survival (PFS) per RECIST v1.1, by treatment
Efficacy measurements per RECIST v1.1: DOR
Duration of response (DOR) per RECIST v1.1, by treatment
Efficacy measurements per iRECIST: ORR
Overall response rate (ORR) per iRECIST for TNO155 in combination with spartalizumab
Efficacy measurements per iRECIST: DCR
Disease control rate (DCR) per iRECIST for TNO155 in combination with spartalizumab
Efficacy measurements per iRECIST: PFS
Progression-free survival (PFS) per iRECIST for TNO155 in combination with spartalizumab
Efficacy measurements per iRECIST: DOR
Duration of response (DOR) per iRECIST for TNO155 in combination with spartalizumab
Overall Survival
Overall survival (OS) by treatment

Full Information

First Posted
June 24, 2019
Last Updated
September 19, 2023
Sponsor
Novartis Pharmaceuticals
search

1. Study Identification

Unique Protocol Identification Number
NCT04000529
Brief Title
Phase Ib Study of TNO155 in Combination With Spartalizumab or Ribociclib in Selected Malignancies
Official Title
A Phase Ib, Open-label, Multi-center Study to Characterize the Safety, Tolerability, and Preliminary Efficacy of TNO155 in Combination With Spartalizumab or Ribociclib in Selected Malignancies
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 30, 2019 (Actual)
Primary Completion Date
December 22, 2023 (Anticipated)
Study Completion Date
December 25, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Non-small Cell Lung Carcinoma, Head and Neck Squamous Cell Carcinoma, Esophageal SCC, Gastrointestinal Stromal Tumors, Colorectal Cancer
Keywords
TNO155, spartalizumab, ribociclib, checkpoint inhibitor, SHP2, PD-1, CDK4/6, NSCLC, CRC, HNSCC, KRAS, esophageal SCC, GIST

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
122 (Actual)

8. Arms, Groups, and Interventions

Arm Title
TNO155 in combination with spartalizumab
Arm Type
Experimental
Arm Description
TNO155 in combination with spartalizumab
Arm Title
TNO155 in combination with ribociclib
Arm Type
Experimental
Arm Description
TNO155 in combination with ribociclib
Intervention Type
Drug
Intervention Name(s)
TNO155
Intervention Description
Capsule
Intervention Type
Drug
Intervention Name(s)
Spartalizumab
Other Intervention Name(s)
PDR001
Intervention Description
Concentrate for solution for infusion
Intervention Type
Drug
Intervention Name(s)
Ribociclib
Other Intervention Name(s)
LEE011
Intervention Description
Capsule and tablet
Primary Outcome Measure Information:
Title
DLT incidence
Description
Incidence of dose limiting toxicities (DLTs) during the first cycle of combination treatment during the dose escalation part
Time Frame
1 year
Title
AE and SAE incidence
Description
Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) as per CTCAE v5.0, by treatment
Time Frame
3 years
Title
Dose interruptions, reductions and dose intensity, by treatment
Description
Dose tolerability
Time Frame
3 years
Secondary Outcome Measure Information:
Title
Pharmacokinetics (PK): Cmax
Description
Cmax for TNO155, spartalizumab, and ribociclib
Time Frame
3 years
Title
Pharmacokinetics (PK): Tmax
Description
Tmax for TNO155, spartalizumab, and ribociclib
Time Frame
3 years
Title
Pharmacokinetics (PK): AUClast
Description
AUClast for TNO155, spartalizumab, and ribociclib
Time Frame
3 years
Title
Pharmacokinetics (PK): AUCtau
Description
AUCtau for TNO155, spartalizumab, and ribociclib
Time Frame
3 years
Title
Efficacy measurements per RECIST v1.1: ORR
Description
Overall response rate (ORR) per RECIST v1.1, by treatment
Time Frame
3 years
Title
Efficacy measurements per RECIST v1.1: DCR
Description
Disease control rate (DCR) per RECIST v1.1, by treatment
Time Frame
3 years
Title
Efficacy measurements per RECIST v1.1: PFS
Description
Progression-free survival (PFS) per RECIST v1.1, by treatment
Time Frame
3 years
Title
Efficacy measurements per RECIST v1.1: DOR
Description
Duration of response (DOR) per RECIST v1.1, by treatment
Time Frame
3 years
Title
Efficacy measurements per iRECIST: ORR
Description
Overall response rate (ORR) per iRECIST for TNO155 in combination with spartalizumab
Time Frame
3 years
Title
Efficacy measurements per iRECIST: DCR
Description
Disease control rate (DCR) per iRECIST for TNO155 in combination with spartalizumab
Time Frame
3 years
Title
Efficacy measurements per iRECIST: PFS
Description
Progression-free survival (PFS) per iRECIST for TNO155 in combination with spartalizumab
Time Frame
3 years
Title
Efficacy measurements per iRECIST: DOR
Description
Duration of response (DOR) per iRECIST for TNO155 in combination with spartalizumab
Time Frame
3 years
Title
Overall Survival
Description
Overall survival (OS) by treatment
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Key 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: 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: Advanced solid malignancies with the exception of CRC or GIST, after progression on or intolerance to all SOC therapy per local guidelines. The exclusion of CRC applies only as of Protocol Amendment 4. 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 HNSCC, 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 Key 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 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 Symptomatic CNS metastases which are neurologically unstable Insufficient bone marrow function at screening: Absolute Neutrophil Count (ANC) < 1.5 x 109/L. Hemoglobin < 9.0 g/dL. Platelets < 75 x 109/L for TNO155 plus spartalizumab combination; < 100 x 109/L for TNO155 plus ribociclib combination. Insufficient hepatic or renal function at screening: 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. Creatinine clearance < 60 mL/min (calculated using Cockcroft-Gault equation). Pregnant or breast-feeding (lactating) women. Additional exclusion criteria for the TNO155 plus spartalizumab 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. Additional exclusion criteria for the TNO155 plus ribociclib combination 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).
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Novartis Investigative Site
City
Westmead
State/Province
New South Wales
ZIP/Postal Code
2145
Country
Australia
Facility Name
Novartis Investigative Site
City
Bruxelles
ZIP/Postal Code
1200
Country
Belgium
Facility Name
Novartis Investigative Site
City
Chengdu
State/Province
Sichuan
ZIP/Postal Code
610041
Country
China
Facility Name
Novartis Investigative Site
City
Koeln
ZIP/Postal Code
50937
Country
Germany
Facility Name
Novartis Investigative Site
City
Hong Kong
Country
Hong Kong
Facility Name
Novartis Investigative Site
City
Chuo ku
State/Province
Tokyo
ZIP/Postal Code
104 0045
Country
Japan
Facility Name
Novartis Investigative Site
City
Singapore
ZIP/Postal Code
119228
Country
Singapore
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
Facility Name
Novartis Investigative Site
City
Valencia
State/Province
Comunidad Valenciana
ZIP/Postal Code
46010
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

We'll reach out to this number within 24 hrs