A Phase I open-label dose escalation study with expansion to assess the safety and tolerability of INC280 in patients with c-MET dependent advanced solid tumors

Recruiting

Conditions: c-MET dependend solid tumors
10027656

Registration Number: NL-OMON43929

Lead Sponsor: ovartis

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Recruiting

Sex: Not specified

Target Recruitment: 16

Inclusion Criteria

- Advanced solid tumors with confirmed c-MET dysregulation and for whom no currently available therapy excists
- Previous anti-cancer and investigational therapy must be discontinued for at least 28 days before start study treatment, (6 weeks for GBM patients that received nitrosoureas), previous anti-body therapy for at least 60 days before start of study treatment and must have recovered fully from the adverse effects of such treatment before start study treatment.
- ECOG performance status <= 2
- Laboratory values:
Hemoglobin > 9 g/dL (5,58 mmol/l) without transfusion support or growth factors within 10 days of starting INC280
Platelet count >= 75 x 109/L
Absolute neutrophil count (ANC) >= 1.2 x 109/L without growth factor support
Total bilirubin <= 2 x upper limit of normal (ULN)
AST/SGOT and/or ALT/SGPT <= 2.5 x upper limit of normal (ULN) or <= 5.0 ULN if HCC is primary disease or liver metastases are present
Serum creatinine <= 2 x ULN
Asymptomatic serum amylase <= grade 2
Patients with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs and/or symptoms suggesting pancreatitis or pancreatic injury
Serum lipase <= ULN
Fasting serum triglyceride level <= 500 mg/dL
-Patients with GBM must have radiographic evidence of recurrent tumor and must be at least 12 weeks post radiation therapy (XRT).;Additional inclusion criteria for NSCLC patients EGFRwt with high c-MET expression:
a. Written documentation of EGFRwt NSCLC.
b. c-MET positivity as defined by c-MET IHC intensity score +3 in >= 50% of tumor cells performed through a Novartis designated central laboratory.
c.No more than three prior lines of antineoplastic therapy for NSCLC.;Other protocol-defined inclusion citeria may apply. See protocol page 49

Exclusion Criteria

- HCC with liver dysfunction greater than Child-Pugh A.
- Previous treatment with a c-MET inhibitor or HGF-targeting therapy.
- Symptomatic CNS metastases that are neurologically unstable or requiring increasing doses of steroids to control their CNS disease.
- Any CNS deficits. For patients with GBM, CNS symptoms grade 2 or greater.
- Receiving anti-epileptic drugs that are known to be strong inducers of CYP3A4.
- Prior or current anti-angiogenic therapy for patients with GBM.
- Radiation therapy within <= 4 weeks (<12 for GBM) or limited field radiotherapy within <=2 weeks (<12 weeks GBM) prior to the start of study treatment. Any persistent side effect of prior radiotherapy must be resolved to <= Grade 1 prior to the first dose of study drug. ;Additional exclusion criteria for patients of the expansion group with NSCLC EGFRwt and high c-MET expression :
a. Any unresolved toxicity (CTCAE grade > 1) from previous anti-cancer therapy or radiotherapy, except alopecia.
b. Anti-cancer therapies within the following time frames prior to the first dose of study treatment:
• Conventional cytotoxic chemotherapy: <=4 weeks (<=6 weeks for nitrosoureas and mitomycin-C)
• Biologic therapy (e.g., antibodies): <=4 weeks
• Non-cytotoxic small molecule therapeutics: <=5 half-lives or <=2 weeks (whichever is longer)
• Other investigational agents: <=4 weeks
• Radiation therapy (palliative setting is allowed.): <=4 weeks
• Major surgery: <=2 weeks;Other protocol-defined exclusion criteria may apply. See protocol page 50-51

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Escalation: Incidence, frequency, and category of DLT during the first cycle of<br /><br>INC280 treatment.<br /><br><br /><br>Expansion: Safety by monitoring the frequency, duration, and severity of AEs,<br /><br>changes in clinical laboratory findings, physical examinations, vital<br /><br>signs, ECGs, EEGs and Brain MRI.<br /><br><br /><br>Expansion cohort NSCLC patients EGFRwt with high c-MET expression: Progression<br /><br>free survival (PFS), duration of response (DOR), disease<br /><br>control rate (DCR), and overall survival (OS)</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Objective response.<br /><br><br /><br>Type, frequency, and severity of AEs, changes in hematology and blood chemistry<br /><br>values, assessment of physical examinations, vital signs,<br /><br>EEGs, ECGs, brain MRIs.<br /><br><br /><br>c-MET signaling inhibitory activity</p><br>