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JOURNAL ONKOLOGIE – STUDIE

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

Rekrutierend

NCT-Nummer:
NCT04000529

Studienbeginn:
Juli 2019

Letztes Update:
07.05.2021

Wirkstoff:
TNO155, Spartalizumab, Ribociclib

Indikation (Clinical Trials):
Carcinoma, Squamous Cell Carcinoma of Head and Neck, Gastrointestinal Stromal Tumors, Carcinoma, Non-Small-Cell Lung, Esophageal Squamous Cell Carcinoma

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 1

Sponsor:
Novartis Pharmaceuticals

Collaborator:
-

Kontakt

Studienlocations
(3 von 9)

Novartis Investigative Site
50937 Koeln
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Novartis Investigative Site
2145 Westmead
AustraliaRekrutierend» Google-Maps
Novartis Investigative Site
1200 Bruxelles
BelgiumRekrutierend» Google-Maps
Novartis Investigative Site
104 0045 Chuo ku
JapanRekrutierend» Google-Maps
Novartis Investigative Site
119228 Singapore
SingaporeRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

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.

Ein-/Ausschlusskriterien

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).

Studien-Rationale

Primary outcome:

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:

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

Studien-Arme

  • Experimental: TNO155 in combination with spartalizumab
    TNO155 in combination with spartalizumab
  • Experimental: TNO155 in combination with ribociclib
    TNO155 in combination with ribociclib

Geprüfte Regime

  • TNO155:
    Capsule
  • Spartalizumab (PDR001):
    Concentrate for solution for infusion
  • Ribociclib (LEE011):
    Capsule and tablet

Quelle: ClinicalTrials.gov


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