Description:
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.
Title
- Brief Title: Novartis PhII Ceritinib (LDK378) in R/R ALK+ Hem Malignancies
- Official Title: A Phase II Study of the ALK Inhibitor, Ceritinib (LDK378), in Relapsed/Refractory ALK+ Hematologic Malignancies
Clinical Trial IDs
- ORG STUDY ID:
Pro00056623
- NCT ID:
NCT02343679
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| ceritinib | LDK378 | Ceritinib for ALK + patients |
Purpose
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.
Detailed Description
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
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Ceritinib for ALK + patients | Experimental | all ALK + hematologic malignancies patients will receive ceritinib | |
Eligibility Criteria
Inclusion Criteria:
- Alk+R/R hematologic malignancy including but not limited to ALK+ALCL or ALK+LBCL > 1
prior standard cytotoxic regimen
- Age >18
- ECOG performance status <2
- Evidence of measurable or evaluable disease
- Toxicities ≤ grade 2 due to prior therapies Exception: any grade alopecia
- Platelets >75 x 109/L
- ANC>1.5 x 109/L
- AST/ALT<3.0 x ULN, except liver involvement by their lymphoma, include if AST/ALT<5 x
ULN.
- Total Bilirubin<1.5 x ULN, (includes gilbert's syndrome if total bilirubin <3.0 x ULN
and direct bilirubin <1.5 x ULN)
- Potassium, magnesium, total calcium and phosphorous > lower limits of normal
- Calculated or measured CrCl> 30ml/min
- Ability to provide written informed consent
- Willing/able to comply with scheduled visits, treatment plans, laboratory tests and
other procedures
- Women/men of reproductive potential must agree to use effective birth control during
study and for 3 months after receiving study drug.
- Must have existing tissue available for correlative studies
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:
- Basal or squamous cell carcinoma of the skin
- In situ malignancy - completely resected.
- Prostate cancer treated with prostatectomy or radiotherapy > 2 years before Day 1
of protocol therapy and PSA is undetectable
- In situ malignancy - completely resected
- 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:
- Medication with a significant known risk of prolonging the QT interval or
inducing Torsades de Pointes
http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm
- Strong inhibitors or strong inducers of CYP3A4/5
http://medicine.iupui.edu/flockhart/table.htm or
http://www.druginteractioninfo.org
- Therapeutic doses of warfarin sodium (Coumadin) or coumadin-derived
anti-coagulant.
- Enzyme-inducing anticonvulsive agents
- Herbal supplements
- Pregnant or nursing (lactating) women
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Overall Response Rate (ORR) |
| Time Frame: | 5 years |
| Safety Issue: | |
| Description: | ORR defined as CR + PR. Stable disease of at least 3 months will also be reported. |
Secondary Outcome Measures
| Measure: | Progression Free Survival (PFS) |
| Time Frame: | 5 years |
| Safety Issue: | |
| Description: | Calculate the median time until disease progression or death in patients treated with ceritinib |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Withdrawn |
| Lead Sponsor: | Anne Beaven, MD |
Last Updated
February 1, 2017
