Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors

Phase 1TerminatedNCT03114319

Novartis Pharmaceuticals227 enrolled

Overview

The purpose of this first in human (FIH) trial was to characterize the safety and tolerability of the SHP2 inhibitor TNO155 alone and in combination with EGF816 (nazartinib) and identify a recommended dose for future studies in adult patients with advanced solid tumors in selected indications.

This study has been designed as a Phase I, open-label, dose finding study with a dose escalation part and a dose expansion part in adult patients with selected advanced solid tumors. The study treatment, TNO155 alone or in combination with EGF816 (nazartinib), was taken until the patient experienced unacceptable toxicity, progressive disease and/or treatment was discontinued at the discretion of the investigator or the patient or due to withdrawal of consent.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

227

Conditions

Advanced EGFR Mutant Non Small Cell LungCancer (NSCLC)KRAS G12-mutant NSCLC Esophageal Squamous Cell Cancer (SCC)

Eligibility

Sex: ALLMin age: 18 YearsMax age: 99 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Able to understand and voluntarily sign the ICF and able to comply with the study visit schedule and the other protocol requirements. 2. Patient (male or female) ≥18 years of age willing to agree to not father a child/become pregnant and comply with effective contraception criteria. 3. Must have progressed following standard therapy, or for whom, in the opinion of the Investigator, no effective standard therapy exists, is tolerated or is appropriate. 4. ECOG (Eastern cooperative oncology group) performance status ≤2 Additional criteria only appying to TNO155 in combination with EGF816 (nazartinib): 5. Patients must be screened for Hepatitis B virus and Hepatitis C virus Exclusion Criteria: 1. Tumors harboring known activating KRAS, NRAS, HRAS, BRAF or PTPN11 (SHP2) mutations. (Exceptions are KRAS G12-mutant NSCLC's) 2. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO. 3. Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures. 4. Clinically significant cardiac disease. 5. Active diarrhea or inflammatory bowel disease 6. Insufficient bone marrow function 7. Insufficient hepatic and renal function. Additional criteria only appying to TNO155 in combination with EGF816 (nazartinib): 8. Patients with a known history of human immunodeficiency virus (HIV) seropositivity. 9. Patients receiving concomitant immunosuppressive agents or chronic corticosteroids use at the time of study entry. 10. Patients who have undergone a bone marrow or solid organ transplant 11. Patients with a history or presence of interstitial lung disease or interstitial pneumonitis 12. Bullous and exfoliative skin disorders at screening of any grade 13. Presence of clinically significant ophthalmological abnormalities that might increase the risk of corneal epithelial injury

Locations (18)

H Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, United States

Dana Farber Cancer Center

Boston, Massachusetts, United States

Memorial Sloane Ketterin Cancer Ctr

New York, New York, United States

Sarah Cannon Research Institute

Nashville, Tennessee, United States

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Kobe, Japan

Novartis Investigative Site

Rotterdam, South Holland, Netherlands

Novartis Investigative Site

Amsterdam, Netherlands

Novartis Investigative Site

Singapore, Singapore

...and 8 more locations

Outcomes

Primary Outcomes

Number of participants with adverse events and serious adverse events

All patients participating in this study will be assessed for incidence and severity of adverse events (AEs) and serious AEs, including changes in laboratory values, vital signs, electrocardiograms and cardiac biomarkers

Time frame: up to 5 years; at least once per treatment cycle

Number of participants with dose limiting toxicities

Incidence and nature of dose limiting toxicities (DLTs) in the dose escalation part. A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first treatment cycle (either 21 days or 28 days, depending on the cohort's treatment schedule) with TNO155 or with TNO155 in combination with EGF816 (nazartinib)

Time frame: up to 28-day cycle

Number of participants with dose interruptions and reductions

Assessment of tolerability. For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments may be permitted in order to allow patients to continue the study treatment

Time frame: Up to 5 years

Dose intensity of study drugs

Dose intensity is computed as the ratio of actual cumulative dose received to actual duration of exposure

Time frame: Up to 5 years

Secondary Outcomes

Overall response rate (ORR) per RECIST v1.1

ORR is the proportion of patients with a best overall response of Complete Response (CR) or Partial response (PR)

Time frame: From start of treatment for 60 months

Disease control rate (DCR) per RECIST v1.1

DCR is the proportion of patients with a best overall response of CR or PR or stable disease (SD)

Time frame: From start of treatment for 60 months

Progression-free survival (PFS) per RECIST v1.1

PFS is the time from date start of treatment to the date of event defined as the first documented progression or death due to any cause

Time frame: Up to 5 years

Duration of response (DOR) per RECIST v1.1

DOR is the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause

Time frame: Up to 5 years

Change from baseline in DUSP6 in tumor samples

Dual Specificity Phosphatase 6 (DUSP6) mRNA levels assessed in paired tumor biopsy samples by quantitative polymerase chain reaction (qPCR)

Time frame: At screening and between Cycle 1 and Cycle 3. One cycle=either 21 days or 28 days, depending on the cohort's treatment schedule.

Area under the plasma concentration-time curve (AUC) of study drugs

Pharmacokinetic (PK) parameters calculated based on the plasma concentrations versus time profiles by using non-compartmental methods

Time frame: From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule.

Peak plasma concentration (Cmax) of study drugs

PK parameters calculated based on the plasma concentrations versus time profiles by using non-compartmental methods

Time frame: From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule.

Time to reach peak plasma concentration (Tmax) of study drugs

PK parameters calculated based on the plasma concentrations versus time profiles by using non-compartmental methods

Time frame: From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule.

Apparent terminal elimination half-life of study drugs

PK parameters calculated based on the plasma concentrations versus time profiles by using non-compartmental methods

Time frame: From pre-dose up to 48 hours post-dose on Cycle 1 Day 1 and from pre-dose up to 24 hours post-dose on Cycle 1 Day 14. One cycle=21 days or 28 days, depending on the dosing schedule.

Dose Finding Study of TNO155 in Adult Patients With Advanced Solid Tumors

Overview

Conditions

Interventions

Eligibility

Locations (18)

Outcomes

Primary Outcomes

Secondary Outcomes