Primary: 1. To determine the MTD and/or RDE of the combination ceritinib and nivolumab. 2. To assess the preliminary antitumor activity of the combination.Secondary: 1: To assess the safety profile of the ceritinib and nivolumab combination. 2: To…
ID
Source
Brief title
Condition
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
DLT, objective response rate.
Secondary outcome
Adverse events. DOR, DCR, TR, PFS, OS.
Background summary
Cisplatin or carboplatin in combination with other chemotherapy agents, with or
without bevacizumab is standard first-line treatment of locally advanced or
metastatic non-small cell lung cancer (NSCLC), unless a patient has a known
targetable gene mutation or aberration, and is therefore a candidate for a
targeted therapy.
Although chemotherapy has led to clinical improvements in patients with locally
advanced or metastatic NSCLC, the outcome of treatment in the first-line
setting remains poor, with median progression-free survival (PFS) and overall
survival (OS) of 5-7 months and 10-16 months, respectively.
A clinically relevant molecular subset of NSCLC is driven by the anaplastic
lymphoma kinase (ALK) translocation. It ALK is translocated, mutated, or
amplified, it plays a key role in the pathogenesis in several tumor types,
including NSCLC.
Metastatic ALK-positive NSCLC remains an incurable disease. Recent studies have
demonstrated the efficacy of ALK inhibitors in ALK-positive NSCLC and of
immunotherapy with PD-1 antibodies/blocking agents, such as nivolumab, in NSCLC
patients.
Ceritinib is an orally available potent ALK inhibitor. Ceritinib shows potent
antitumor activity in animal models. Efficacy was seen in the ongoing phase I
clinical trial in patients, which led to the approval of ceritinib by the FDA
for the treatment of patients with ALK-positive metastatic NSCLC who have
progressed on or are intolerant to crizotinib.
Harnessing the immune system to treat patients with NSCLC represents a novel
and exciting new treatment approach. The anti-PD-1 antibody Nivolumab has
demonstrated response rates of up to 20% in patients with NSCLC and has been
safely combined with several small molecules as well as chemotherapies.
The current study will investigate the combination of ceritinib and nivolumab
in adult patients with ALK-positive NSCLC. Combination therapy involving
targeted agents and immunotherapy may improve PFS and ultimately OS in NSCLC
patients. This study is intended to determine the MTD/recommended doses for
expansion (RDE) as well as to evaluate the safety and preliminary efficacy of
the ceritinib and nivolumab combination.
Study objective
Primary: 1. To determine the MTD and/or RDE of the combination ceritinib and
nivolumab. 2. To assess the preliminary antitumor activity of the combination.
Secondary: 1: To assess the safety profile of the ceritinib and nivolumab
combination. 2: To assess duration of response (DOR), disease control
rate(DCR), time to response(TTR), PFS, OS.
Study design
Multicenter phase IB open-label dose escalation and expansions study.
Starting dose ceritinib 450 mg orally per day and nivolumab IV infusion every 2
weeks (3 mg/kg).
Possible adjustments of ceritinib dose:
* 300 mg daily in case of safety or tolerability issues in first 6 weeks.
* 600 mg daily for next cohort if no safety or tolerability issues in first 6
weeks.
Treatment until disease progression or unacceptable side effects. Patients 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.
Approx. 18 subjects in dose escalation and 60 in expansion phase.
Intervention
Treatment with ceritinib and nivolumab.
Study burden and risks
Risk: Adverse effects of the combination of study drugs.
Burden: Cycles of 4 weeks. Cycle 1: 4 visits, cycle 2: 3 visits, from cycle 3
onwards: 2 visits. Duration mostly 1-4 hours. Some visits up to 8 hours.
2 infusions with nivolumab per cycle (approx. 200 ml).
Low-fat diet.
Physical examination: cycle 1-2: 2 times, from cycle 3 onwards once/cycle.
Blood tests (15 ml/occasion): every visit. PK; up to 12 ml/occasion extra.
Biomarkers: 25 ml/occasion extra.
Pregnancy test: once/cycle.
Tumor measurements: every 8 weeks for the 1st 12 cycles, every 12 weeks
thereafter.
ECG: cycle 1-2: twice, from cycle 3 onwards once/cycle.
Tumor biopsy: 1-2 times.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
* Female and male patients * 18 years of age.
* Relapsed locally advanced or metastatic NSCLC with an ALK-rearrangement.
* Measurable disease.
* Clinically and neurologically stable CNS metastases who have not required increasing doses of steroids or stable doses > 10 mg daily prednisone equivalent within 2 weeks prior to study entry to manage CNS symptoms.
* In the expansion phase, patients must have received prior treatment according to the following: Arm 1: ALK inhibitor-treated, ALK inhibitor: Yes, Chemotherapy: 0 or 1 prior courses, Prior treatment with any ALK inhibitor except ceritinib is allowed.
Arm 2: ALK inhibitor-naïve ALK inhibitor: No, Chemotherapy: 0 or 1 prior courses.
* WHO performance status 0 or 1.
Exclusion criteria
* Severe hypersensitivity reactions to other monoclonal antibodies.
* Prior treatment with anti-PD1/anti-PD-L1 agents.
* Chronic systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of start of treatment. Inhaled or topical steroids, and adrenal replacement steroid doses >10 mg daily prednisone equivalent, are permitted to enroll in the absence of active autoimmune disease.
* Clinically significant, uncontrolled heart disease and/or recent cardiac event. See protocol page 14 for details.
* (History of) interstitial lung disease.
* Comedications listed on page 14 of the protocol.
* Pregnancy, lactation, inadequate contraception (males and females). See protocol page 15 for details.
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 | EUCTR2014-005054-19-NL |
| ClinicalTrials.gov | NCT02393625 |
| CCMO | NL52443.078.15 |