Clinical Trials /

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

NCT04000529

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
  • Esophageal Squamous Cell Carcinoma
  • Gastrointestinal Stromal Tumor
  • Head and Neck Squamous Cell Carcinoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: CTNO155B12101
  • NCT ID: NCT04000529

Conditions

  • Non-small Cell Lung Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Esophageal SCC
  • Gastrointestinal Stromal Tumors
  • Colorectal Cancer

Interventions

DrugSynonymsArms
TNO155TNO155 in combination with spartalizumab
SpartalizumabPDR001TNO155 in combination with spartalizumab
RibociclibLEE011TNO155 in combination with ribociclib

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
TNO155 in combination with spartalizumabExperimentalTNO155 in combination with spartalizumab
  • TNO155
  • Spartalizumab
TNO155 in combination with ribociclibExperimentalTNO155 in combination with ribociclib
  • TNO155
  • Ribociclib

Eligibility 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.

             a. 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 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 esophageal SCC after progression on or intolerance to
             platinum-containing combination chemotherapy.

             iv. 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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:DLT incidence
Time Frame:1 year
Safety Issue:
Description:Incidence of dose limiting toxicities (DLTs) during the first cycle of combination treatment during the dose escalation part

Secondary Outcome Measures

Measure:Pharmacokinetics (PK): Cmax
Time Frame:3 years
Safety Issue:
Description:Cmax for TNO155, spartalizumab, and ribociclib
Measure:Pharmacokinetics (PK): Tmax
Time Frame:3 years
Safety Issue:
Description:Tmax for TNO155, spartalizumab, and ribociclib
Measure:Pharmacokinetics (PK): AUClast
Time Frame:3 years
Safety Issue:
Description:AUClast for TNO155, spartalizumab, and ribociclib
Measure:Pharmacokinetics (PK): AUCtau
Time Frame:3 years
Safety Issue:
Description:AUCtau for TNO155, spartalizumab, and ribociclib
Measure:Efficacy measurements per RECIST v1.1: ORR
Time Frame:3 years
Safety Issue:
Description:Overall response rate (ORR) per RECIST v1.1, by treatment
Measure:Efficacy measurements per RECIST v1.1: DCR
Time Frame:3 years
Safety Issue:
Description:Disease control rate (DCR) per RECIST v1.1, by treatment
Measure:Efficacy measurements per RECIST v1.1: PFS
Time Frame:3 years
Safety Issue:
Description:Progression-free survival (PFS) per RECIST v1.1, by treatment
Measure:Efficacy measurements per RECIST v1.1: DOR
Time Frame:3 years
Safety Issue:
Description:Duration of response (DOR) per RECIST v1.1, by treatment
Measure:Efficacy measurements per iRECIST: ORR
Time Frame:3 years
Safety Issue:
Description:Overall response rate (ORR) per iRECIST for TNO155 in combination with spartalizumab
Measure:Efficacy measurements per iRECIST: DCR
Time Frame:3 years
Safety Issue:
Description:Disease control rate (DCR) per iRECIST for TNO155 in combination with spartalizumab
Measure:Efficacy measurements per iRECIST: PFS
Time Frame:3 years
Safety Issue:
Description:Progression-free survival (PFS) per iRECIST for TNO155 in combination with spartalizumab
Measure:Efficacy measurements per iRECIST: DOR
Time Frame:3 years
Safety Issue:
Description:Duration of response (DOR) per iRECIST for TNO155 in combination with spartalizumab
Measure:Overall Survival
Time Frame:3 years
Safety Issue:
Description:Overall survival (OS) by treatment

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • TNO155, spartalizumab, ribociclib, checkpoint inhibitor, SHP2, PD-1, CDK4/6, NSCLC, CRC, HNSCC, KRAS, esophageal SCC, GIST

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