The primary objective is to evaluate the antitumor activity of ceritinib in patients with ALK-positive NSCLC metastatic to the brain and/or toleptomeninges based on whole body overall response rate (ORR), defined as the proportion of patients with a…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall response rate (ORR), defined as the proportion of patients with a best
overall confirmed response of
complete response (CR) or partial response (PR) in the whole body as assessed
per RECIST 1.1 by the investigator.
Secondary outcome
Disease Control Rate (DCR)
And
1. To evaluate intracranial tumor-response related endpoints (Arms 1-4).
2. To evaluate extracranial tumor-response related endpoints (Arms 1-4).
3. To evaluate whole body tumor-response related endpoints (Arms 1-4).
4. To evaluate overall survival (OS)
5. To evaluate safety
6. To characterize the PK of ceritinib in this patient population
Background summary
Lung cancer has been among the most common cancers in the world for several
decades. In 2008, there were an estimated 1.61 million new cases, representing
12.7% of all new cancers worldwide. It has been the most common cause of death
from cancer, with 1.38 million deaths
Ten to 35% of the patients newly diagnosed with NSCLC presents with synchronous
BM. It is estimated that 40 to 50% of all patients with NSCLC will develop BM
at any stage of the treatment of their disease.
The role of systemic therapies in the treatment of BM remains unclear to date.
For decades, systemic chemotherapies were believed to be of limited benefit.
Guidelines for the treatment of NSCLC patients with BM, still recommend
localized treatment of the brain disease prior to initiating systemic treatment
for advanced incurable patients.
ALK rearrangements serve as a key strong oncogenic driver for NSCLC and
represent a critical therapeutic target susceptible to targeted ALK kinase
inhibition.
Crizotinib, an orally available small-molecule inhibitor of ALK and MET
tyrosine kinases, is the first tyrosine kinase inhibitor to target ALK to have
demonstrated a clinical activity and to be approved in the US and EU as
treatment of metastatic ALK-positive NSCLC.
Studies with crizotinib in BM showed: Overall Intracranial Response Rate
(CR+PR) in a subgroup of 109 patients with untreated BM was 7% (95%CI: 3-14)
compared to an extracranial Response Rate of 53% (95% CI: 43-63).
There is a medical need for more effective treatment for patients with
ALK-positive NSCLC metastatic to the CNS before and after failure to crizotinib.
Ceritinib is an orally available ALK inhibitor with efficacy seen in the
ongoing Phase I and Phase II. The Phase I clinical trial in patients (with
and without previous crizotinib therapy) has led to the approval of ceritinib
by the FDA and EMA. A total of 14 patients out of the 246 patients included in
the 750 mg dose group had brain metastases at baseline considered to be target
lesions by the investigator per RECIST 1.0. In these 14 patients, the OIRR was
50% (95% CI: 23.0, 77.0) (1 patient with confirmed CR in the brain and 6
patients with a confirmed PR in the brain).
Additional research is needed in Brain metastases patients to confirm the
efficacy data.
Study objective
The primary objective is to evaluate the antitumor activity of ceritinib in
patients with ALK-positive NSCLC metastatic to the brain and/or to
leptomeninges based on whole body overall response rate (ORR), defined as the
proportion of patients with a best overall confirmed response of
complete response (CR) or partial response (PR) in the whole body as assessed
per RECIST 1.1 by the investigator.
The key secondary objective is to evaluate whole body Disease Control Rate
(DCR) in patients with ALK-positive NSCLC metastatic to the brain
and/or to leptomeninges based on investigator assessment per RECIST 1.1
Study design
A Phase II, multi-center, open-label, five-arm study to evaluate the efficacy
and safety of oral ceritinib treatment for patients with ALK-positive non-small
cell lung cancer (NSCLC) metastatic to the brain and/or to leptomeninges
Approximately 125 patients diagnosed with ALK-positive metastatic NSCLC and
active lesions in the included in the study, approximately 30 patients in each
of the Arms 1 to 4 and approximately 5 patients in Arm 5.
Treatment until disease progression or unacceptable side effects. Patient who
discontinue study treatment for any reason other than disease progression will
be followed up for progression of disease and all patients will be followed for
survival.
Intervention
Drug: LDK378 (ceritinib) 750 mg daily oral intake.
Study burden and risks
Risk: Adverse effects of study drug.
Burden: Cycle of 28 days. 3 visits in cycle 1. 1 visit from cycle 2. usually
takes 2 hours. 1 visit is 5- 8 hours.
Physical and neurological examination: course 1: 2 times. cycle 2: 1 time.
Blood tests: (10-15 ml / times): Each visit. PK (9 times): 2 mL extra.
Cerebro-spinal fluid (total 15 patients): 2 x 2mL.
Pregnancy test: 1x per treatment.
Tumor measurements every 2 cycles.
ECG: 3 visits in cycle 1. Up to 10x max
Tumor Biopsy: 0-2 times (1st is required if no archival material available, 2nd
optional)
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
- Female and male patients of 18 years older or older
- Stage IV ALK-positive NSCLC. Pre-treated and treatment naive. See protocol 01 page 45 for details.
- At least one extracranial measurable lesion
- Able to swallow medication and neurological stable within 1 week before first dose.
- WHO performance status 0-2
- Brain metastases or leptomenigeal carcinomatosis
Exclusion criteria
- Patient with a history of treatment with ceritinib
- Patients who need whole brain radiation to control the brain metastases
- In case active brain lesions (single or not) require local treatment
- Patient who has received thoracic radiotherapy to lung fields * 4 weeks prior to starting
the study treatment
- Patient with a concurrent malignancy or history of a malignant disease other than NSCLC
- Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event
- Patient has impairment of GI function or GI disease that influence drup uptake
- Concomittent therapy as defined on page 133 of protocol am. 1
- Patient is pregnant or nursing
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 |
|---|---|
| Other | clinicaltrials.gov NCT02336451 |
| EudraCT | EUCTR2014-000578-20-NL |
| CCMO | NL53760.031.15 |