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

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ClinicalTrials.gov Identifier: NCT04000529
Recruitment Status : Recruiting
First Posted : June 27, 2019
Last Update Posted : November 3, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.


Condition or disease Intervention/treatment Phase
Non-small Cell Lung Carcinoma Head and Neck Squamous Cell Carcinoma Esophageal SCC Gastrointestinal Stromal Tumors Colorectal Cancer Drug: TNO155 Drug: Spartalizumab Drug: Ribociclib Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 126 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : July 30, 2019
Estimated Primary Completion Date : September 13, 2022
Estimated Study Completion Date : September 13, 2022


Arm Intervention/treatment
Experimental: TNO155 in combination with spartalizumab
TNO155 in combination with spartalizumab
Drug: TNO155
Capsule

Drug: Spartalizumab
Concentrate for solution for infusion
Other Name: PDR001

Experimental: TNO155 in combination with ribociclib
TNO155 in combination with ribociclib
Drug: TNO155
Capsule

Drug: Ribociclib
Capsule and tablet
Other Name: LEE011




Primary Outcome Measures :
  1. DLT incidence [ Time Frame: 1 year ]
    Incidence of dose limiting toxicities (DLTs) during the first cycle of combination treatment during the dose escalation part

  2. AE and SAE incidence [ Time Frame: 3 years ]
    Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) as per CTCAE v5.0, by treatment

  3. Dose interruptions, reductions and dose intensity, by treatment [ Time Frame: 3 years ]
    Dose tolerability


Secondary Outcome Measures :
  1. Pharmacokinetics (PK): Cmax [ Time Frame: 3 years ]
    Cmax for TNO155, spartalizumab, and ribociclib

  2. Pharmacokinetics (PK): Tmax [ Time Frame: 3 years ]
    Tmax for TNO155, spartalizumab, and ribociclib

  3. Pharmacokinetics (PK): AUClast [ Time Frame: 3 years ]
    AUClast for TNO155, spartalizumab, and ribociclib

  4. Pharmacokinetics (PK): AUCtau [ Time Frame: 3 years ]
    AUCtau for TNO155, spartalizumab, and ribociclib

  5. Efficacy measurements per RECIST v1.1: ORR [ Time Frame: 3 years ]
    Overall response rate (ORR) per RECIST v1.1, by treatment

  6. Efficacy measurements per RECIST v1.1: DCR [ Time Frame: 3 years ]
    Disease control rate (DCR) per RECIST v1.1, by treatment

  7. Efficacy measurements per RECIST v1.1: PFS [ Time Frame: 3 years ]
    Progression-free survival (PFS) per RECIST v1.1, by treatment

  8. Efficacy measurements per RECIST v1.1: DOR [ Time Frame: 3 years ]
    Duration of response (DOR) per RECIST v1.1, by treatment

  9. Efficacy measurements per iRECIST: ORR [ Time Frame: 3 years ]
    Overall response rate (ORR) per iRECIST for TNO155 in combination with spartalizumab

  10. Efficacy measurements per iRECIST: DCR [ Time Frame: 3 years ]
    Disease control rate (DCR) per iRECIST for TNO155 in combination with spartalizumab

  11. Efficacy measurements per iRECIST: PFS [ Time Frame: 3 years ]
    Progression-free survival (PFS) per iRECIST for TNO155 in combination with spartalizumab

  12. Efficacy measurements per iRECIST: DOR [ Time Frame: 3 years ]
    Duration of response (DOR) per iRECIST for TNO155 in combination with spartalizumab

  13. Overall Survival [ Time Frame: 3 years ]
    Overall survival (OS) by treatment



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04000529


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Michael Cournoyer    617-726-5276    mcournoye@mgh.harvard.edu   
Principal Investigator: Jessica Lin         
Australia, New South Wales
Novartis Investigative Site Recruiting
Westmead, New South Wales, Australia, 2145
Belgium
Novartis Investigative Site Recruiting
Bruxelles, Belgium, 1200
China, Sichuan
Novartis Investigative Site Recruiting
Chengdu, Sichuan, China, 610041
Germany
Novartis Investigative Site Recruiting
Koeln, Germany, 50937
Hong Kong
Novartis Investigative Site Recruiting
Hong Kong, Hong Kong
Japan
Novartis Investigative Site Recruiting
Chuo ku, Tokyo, Japan, 104 0045
Singapore
Novartis Investigative Site Recruiting
Singapore, Singapore, 119228
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08035
Sponsors and Collaborators
Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04000529    
Other Study ID Numbers: CTNO155B12101
First Posted: June 27, 2019    Key Record Dates
Last Update Posted: November 3, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
TNO155, spartalizumab, ribociclib, checkpoint inhibitor, SHP2, PD-1, CDK4/6, NSCLC, CRC, HNSCC, KRAS, esophageal SCC, GIST
Additional relevant MeSH terms:
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Carcinoma
Squamous Cell Carcinoma of Head and Neck
Gastrointestinal Stromal Tumors
Carcinoma, Non-Small-Cell Lung
Esophageal Squamous Cell Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Carcinoma, Squamous Cell
Neoplasms, Squamous Cell
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Lung Diseases
Respiratory Tract Diseases
Head and Neck Neoplasms
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Carcinoma, Bronchogenic
Bronchial Neoplasms
Esophageal Neoplasms
Esophageal Diseases