A Phase II Study of the ALK Inhibitor, Ceritinib (LDK378), in Relapsed/Refractory ALK+ Hematologic Malignancies
A Phase II Study of the ALK Inhibitor, Ceritinib (LDK378), in Relapsed/Refractory ALK+ Hematologic Malignancies
This is a phase II, single arm, unblinded study of ceritinib in patients with rel/ref hematologic malignancies. Up to 24 evaluable subjects will be enrolled with an interim analysis for efficacy after the first 9 subjects are enrolled. Any subject who takes at least one dose of study drug will be evaluable for safety. Only subjects who complete at least 1 cycle of study drug and have clear progression on physical exam or have had at least one restaging study will be considered evaluable for response. Each subject will receive the same dose of 750mg po daily at the study entry. Subjects with stable disease or better will be allowed to continue study drug until disease progression or until intolerable adverse events or patient or physician decision. Intrapatient dose reductions will be allowed for adverse events. This is a multicenter study with Duke as the lead site. Blood and tissue samples, will be collected and used for exploratory analysis.
This is a phase II, single arm, unblinded study of ceritinib in patients with rel/ref hematologic malignancies. Up to 24 evaluable subjects will be enrolled with an interim analysis for efficacy after the first 9 subjects are enrolled. Any subject who takes at least on dose of study drug will be evaluable for safety. Only subjects who complete at least 1 cycle of study drug and have clear progression on physical exam or have had at least one restaging study will be considered evaluable for response. Each subject will receive the same dose of 750mg po daily at the study entry. Subjects with stable disease or better will be allowed to continue study drug until disease progression or until intolerable adverse events or patient or physician decision. Intrapatient dose reductions will be allowed for adverse events. Blood and tissue samples, will be collected and used for exploratory analysis.
Dose Level 0 (starting dose) 750mg/day Dose level -1 600mg/day Dose level -2 450mg/day
Baseline evaluations are to be conducted within 30 days prior to start of protocol therapy unless otherwise noted in the time to events table. Scans and x-rays must be performed within six weeks prior to the start of therapy. Bone marrow biopsy must be performed within twelve weeks prior to starting therapy. In the event that the patient's condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the next cycle of therapy. All the labs have to be within the study eligibility range prior to the start of study treatment.
All visits should occur within 3 days before or after the scheduled day of the visit. An early or late visit will not shorten or extend the duration of that cycle - all cycles will be 28 days.
If study drug is held for any reason then the missed days should still be counted as a day in the cycle. However, if the study drug is on hold when a 28 day cycle ends, then day 1 of the next cycle and the necessary evaluations should not be started until drug is restarted. Therefore, the cycle during which a drug is held could potentially have more than 28 days.
Patients will be followed for up to 2 years after completion of therapy or until progression of disease or death, whichever comes first. In follow up, patients will be seen every 3 months for physical exam, lab draws for the first two years after completing all study drugs or until alternative therapy is begun or until progression of disease or death-whichever comes first. Radiographic imaging will be performed every 6 months for the first two years after study drug is completed.
Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event and will continue to be followed until progression of disease or death. Unacceptable adverse events are those that lead to stopping of a study drug and for which there is no resolution of drug related toxicity after a 6 week washout period so that the subject is removed from study as defined in section 6.
Patients removed from the study due to progressive disease will be followed until resolution or stabilization of any adverse events due to the agents, after which their follow up will be completed.
At a minimum, all patients who discontinue ceritinib treatment, including those who refuse to return for a final visit, will be contacted for safety evaluations during the 30 days following the last dose of treatment
Inclusion Criteria:
Exclusion Criteria:
No chemotherapy, radiation or surgical resection of malignancy < 3 weeks before start of study drug
Prior therapy with other ALK inhibitor investigational agents except crizotinib
Active, uncontrolled, serious infection or medical or psychiatric illness likely to interfere with trial
Known HIV infection
Extensive disseminated bilateral interstitial fibrosis or interstitial lung disease, (history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis or clinically significant radiation pneumonitis) i.e. affecting daily living or requiring ongoing therapeutic intervention.
Symptomatic CNS metastases and neurologically unstable or increasing doses of steroids < 2 weeks prior to study entry
Major surgery 4 weeks before initiating protocol therapy.
Hypersensitivity to microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide, magnesium stearate
Diagnosis or treatment for malignancy other than NHL < 3 years before Day 1 of protocol therapy. Exceptions:
Current treatment with another investigational agent < 14 days before enrollment. Other non-treatment studies allowed if it won't interfere with study participation.
Myocardial infarction or unstable angina 6 months before enrollment or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
o QTcF>450msec
Oral steroids > 4mg dexamethasone or equivalent/day excluding steroids used for adrenal insufficiency
Impaired GI function from significant small bowel resection or gastric bypass surgery or inability to swallow up to five ceritinib capsules daily
Ongoing GI adverse events > grade 2 (e.g. nausea, vomiting, or diarrhea) at start of study.
Receiving medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to start of treatment and for the duration of participation:
Pregnant or nursing (lactating) women