Primary objective: To determine the MTD/highest studied dose determined to be safe, the safety and tolerability of INC280 as a single agent when administered orally to adult patients with c-MET dependent advanced solid malignancies.Secondary…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Escalation: Incidence, frequency, and category of DLT during the first cycle of
INC280 treatment.
Expansion: Safety by monitoring the frequency, duration, and severity of AEs,
changes in clinical laboratory findings, physical examinations, vital
signs, ECGs, EEGs and Brain MRI.
Expansion cohort NSCLC patients EGFRwt with high c-MET expression: Progression
free survival (PFS), duration of response (DOR), disease
control rate (DCR), and overall survival (OS)
Secondary outcome
Objective response.
Type, frequency, and severity of AEs, changes in hematology and blood chemistry
values, assessment of physical examinations, vital signs,
EEGs, ECGs, brain MRIs.
c-MET signaling inhibitory activity
Background summary
INC280 possesses potent inhibitory activity against the c-MET kinase.
The c-MET pathway is one of the most frequently dysregulated pathways
implicated in human cancers. Inappropriate signaling through the c-MET RTK
pathway occurs in multiple types of human cancers due to receptor
overexpression, gene amplification, gene mutation and/or ligand-dependent
activation and contributes to malignant progression through increased cell
proliferation, survival, invasion and metastasis. Aberrant c-MET signaling has
been documented in various tumor types, including most carcinomas and sarcomas,
as well as in many hematological malignancies. Using animal models, c-MET has
been shown to play a pivotal role in the development, maintenance and
dissemination of malignancies. Currently, several HGF and c-MET targeted agents
are being evaluated in clinical trials. These inhibitors have shown evidence of
early clinical benefit (e.g., objective responses, durable stable disease) in
various human cancers including lung, renal, breast, liver and gastric,
underscoring the potential of these agents in cancer treatment.
Study objective
Primary objective: To determine the MTD/highest studied dose determined to be
safe, the safety and tolerability of INC280 as a single agent when administered
orally to adult patients with c-MET dependent advanced solid malignancies.
Secondary objective: Preliminary anti-tumor activity of INC280, safety and
tolerability, c-MET inhibition and anti-tumor effect of INC280 by paired
pre-treatment and post-treatment tumor biopsies, PK.
Study design
Open-label phase I dose escalation and dose expansion study. Approximately 90
patients (max. 100).
Screening for c-MET mutation.
Determination of the MTD/highest studied dose of INC280. Cohorts of 3-6
patients. Cycles of 4 weeks. Dose-escalation decision after 1 cycle. Starting
dose 100 mg BID.
After the MTD/highest studied dose been determined, patients will be enrolled
to be treated with this dose.
Treatment until progression or unacceptable toxicity.
Protocol amendment 6: additional group in expansion cohort NSCLC patients
EGFRwt with high c-MET expression
Intervention
INC280 capsules for oral administration.
Strenght: 10 mg and 50 mg
Dosing schedule BID or QD
The starting dose for this study will be 100 mg BID
Protocol Amendment 5:
INC280 tablets 50mg and 100mg available and will replace INC280 hard gelatin
apsules
Study burden and risks
Risk: Adverse events of study medication.
Burden:
Cycles of 4 weeks.
Screening visit, 6 visits during cycle 1, 4 during cycle 2. Thereafter 1 visit
per cycle. Duration 1-4 h. 2 visits with duration of 8-10 h (PK samples). 2 end
of treatment/study visits.
Blood tests 7-50 ml/occasion.
Screening: Physical examination, blood tests, pregnancy test, ECG, MRI brain,
EEG, tumor measurements, tumor biopsy, skin biopsy.
Cycle 1: 5 x physical examination, 4 x blood tests, 2 long PK measurement days
0-24 h (8 samples per day of 3 ml), 3x ECG, 1x tumor biopsy, 1 x skin biopsy.
Cycle 2: 4 x physical examination, 4 x blood tests, MRI brain.
Following courses: Physical examination, blood tests, pregnancy test, tumor
measurements every 8 weeks, MRI brain (cycle 4).
End of treatment visit: Physical examination, blood tests, pregnancy test, ECG,
MRI brain, EEG, tumor measurements (unless performed <30 days).
Raapopseweg 1 1
Arnhem 6824 DP
NL
Raapopseweg 1 1
Arnhem 6824 DP
NL
Listed location countries
Age
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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-024101-12-NL |
| ClinicalTrials.gov | NCT01324479 |
| CCMO | NL43000.031.12 |