PRIMARY OBJECTIVES:
I. Determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of
ceritinib in combination with gemcitabine (gemcitabine hydrochloride) alone,
gemcitabine/nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) and
gemcitabine/cisplatin in patients with advanced solid malignancies.
SECONDARY OBJECTIVES:
I. Characterize the safety profile of ceritinib in combination with gemcitabine based
chemotherapy in advanced solid malignancies.
II. Determine the pharmacokinetic profile of ceritinib, gemcitabine, nab-paclitaxel,
cisplatin and their metabolites when administered in combination in patients with advanced
solid tumors.
III. Determine the preliminary efficacy of the study combinations.
TERTIARY OBJECTIVES:
I. Explore potential biomarkers of efficacy to the study combination.
OUTLINE: This is a dose-escalation study of ceritinib. Patients are assigned to 1 of 3
treatment arms.
ARM 1 (ceritinib MTD then with gemcitabine alone):
Dose Escalation Cohort 1: Patients with advanced solid tumors for whom gemcitabine
hydrochloride-based therapy is clinically appropriate receive ceritinib orally (PO) once
daily (QD) on days 1-28 and gemcitabine hydrochloride intravenously (IV) over 30 minutes on
days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.
Expansion Cohort 1E: Once the MTD of ceritinib has been determined, an additional 10 patients
with anaplastic lymphoma kinase positive (ALK-positive) advanced solid tumors who previously
progressed on gemcitabine hydrochloride-based therapy receive ceritinib and gemcitabine
hydrochloride as in the dose escalation cohort 1. Courses repeat every 28 days in the absence
of disease progression or unacceptable toxicity.
ARM 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel):
Dose Escalation Cohort 2: Patients with advanced pancreatic cancer receive ceritinib PO QD on
days 1-28, gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15, and paclitaxel
albumin-stabilized nanoparticle formulation IV over 30 minutes on days 1, 8, and 15. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Expansion Cohort 2E: Once the MTD of ceritinib has been determined, patients with
ALK-positive advanced solid tumors receive ceritinib, gemcitabine hydrochloride, and
paclitaxel albumin-stabilized nanoparticle formulation as in the dose escalation cohort 2.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
ARM 3 (ceritinib MTD then with gemcitabine and cisplatin):
Dose Escalation Cohort 3: Patients with advanced solid tumors for whom gemcitabine
hydrochloride and cisplatin-based therapy is clinically appropriate receive ceritinib PO QD
on days 1-28, gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, and cisplatin IV
on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable
toxicity.
Expansion Cohort 3E: Once the MTD of ceritinib has been determined, an additional 10 patients
with ALK-positive advanced solid tumors receive ceritinib, gemcitabine hydrochloride, and
cisplatin as in the dose escalation cohort 3. Courses repeat every 21 days in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for at least 4 weeks.
Inclusion Criteria:
- Arm 1: histologically or cytologically confirmed solid tumors that are advanced that
gemcitabine-based treatment is considered a clinically appropriate option
- Arm 2: histologically or cytologically confirmed adenocarcinoma of the pancreas that
is locally advanced or metastatic
- Arm 3: histologically or cytologically confirmed solid tumors that are advanced that
gemcitabine plus cisplatin treatment is considered a clinically appropriate option
- Arms 1E, 2E and 3E: solid tumor that demonstrate anaplastic lymphoma kinase (ALK)
positivity; ALK positivity can be assessed using the assays below, and documentation
of ALK positivity using one of the tests below is required
- Fluorescence in situ hybridization (FISH) test for ALK positivity using the Food
and Drug Administration (FDA)-approved FISH test (Abbott Molecular Inc), using
Vysis breakapart probes (defined as 15% or more positive tumor cells); OR
- Harboring a confirmed ALK positivity, as determined by positivity to the Ventana
immunohistochemistry (IHC) assay
- Arms 1E: previously treated with and progressed on gemcitabine-containing therapy
- Arms 1, 2, 3: patients should have clinically measurable or evaluable malignant
disease
- Arms 1E, 2E, 3E: patients with at least one measurable site of disease as defined by
Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1 that have
not been previously irradiated
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- Life expectancy >= 3 months
- Absolute neutrophil count (ANC) >= 1,500 cells/mm^3 (system international [SI] units
1.5 x 10^9/L)
- Platelets >= 100,000 cells/mm^3 (SI units 100 x 10^9/L)
- Hemoglobin >= 9 g/dL (SI units 90 g/L) (in the absence of transfusion within 24 hours
prior to dosing)
- Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and
alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3 x
upper limit of normal (ULN); in patients with known hepatic involvement, AST and ALT
=< 5 x ULN are allowed
- Total bilirubin =< 1.5 x ULN
- Calculated or measured creatinine clearance (CrCL) >= 60 mL/min using modified
Cockcroft and Gault formula
- Serum lipase =< 2 x ULN
- Serum amylase =< 2 x ULN
- International normalized ratio (INR) =< 1.5; (anticoagulation is allowed if target INR
=< 1.5 on a stable dose of warfarin or on a stable dose of low molecular weight [LMW]
heparin for > 2 weeks at the first dose of study agent)
- If urinalysis shows proteinuria, 24 hour urine collection is to be performed and the
24 hour urine protein is to be < 2 grams to be eligible
- Willing and able to comply with scheduled visits, treatment plan and laboratory tests
- Ability to understand and willingness to sign a written informed consent; a signed
informed consent must be obtained prior to any study specific procedures
- Patient must consent to the use of their archival tumor tissue for protocol use if
available
Exclusion Criteria:
- Arms 2, 2E, 3, 3E: patients who previously received > 2 lines of systemic chemotherapy
for advanced or metastatic disease
- Previous pelvic radiation affecting >= 25% of the bone marrow; patients who received
whole pelvic radiation are excluded
- Patients who have received the last administration of an anti-cancer therapy including
chemotherapy, immunotherapy, hormonal therapy and monoclonal antibodies (but excluding
nitrosourea, mitomycin-C, targeted therapy and radiation) =< 4 weeks prior to starting
study drug
- Patients who have received the last administration of nitrosourea or mitomycin-C =< 6
weeks prior to starting study drug
- Patients who have had radiotherapy =< 4 weeks prior to starting study drug, or =< 2
weeks prior to starting study drug in the case of localized radiotherapy (e.g., for
analgesic purpose or for lytic lesions at risk of fracture)
- Patients who have received targeted therapy (e.g., sunitinib, sorafenib, pazopanib),
except ALK inhibitors, =< 2 weeks prior to starting study drug
- Patients who have residual toxicity(-ities) from previous anti-cancer treatment(s)
that is/are clinically significant or > grade 1 are excluded; those whose
toxicity(-ities) improved to grade 1 or better will be eligible
- The patient is less than 5 half-lives from prior ALK inhibitor or targeted therapy
(for adequate wash-out) without recovery from treatment toxicities to < grade 1 or to
their pre-treatment levels
- Patients with known history of extensive disseminated bilateral interstitial fibrosis
or interstitial lung disease, including a history of pneumonitis, hypersensitivity
pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and clinically
significant radiation pneumonitis (i.e., affecting activities of daily living or
requiring therapeutic intervention)
- Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or
intra-pelvic), open biopsy or significant traumatic injury =< 4 weeks prior to
starting study drug, or patients who have had minor procedures, percutaneous biopsies
or placement of vascular access device =< 1 week prior to starting study drug, or who
have not recovered from side effects of such procedure or injury
- Known hypersensitivity or infusion reaction to cisplatin and gemcitabine
- Patients with known hypersensitivity to any of the excipients of ceritinib
(microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and
magnesium stearate)
- Receiving medications that meet one of the following criteria and that cannot be
discontinued at least 1 week prior to the start of treatment with ceritinib and for
the duration of participation:
- Medication with a known risk of prolonging the QT interval or inducing torsades
de pointes
- Strong inhibitors or strong inducers of cytochrome P450, family 3, subfamily A,
polypeptide 4 (CYP3A4)/5
- Medications with a low therapeutic index that are primarily metabolized by
CYP3A4/5, cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and/or
cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9)
- Therapeutic doses (defined as doses need to achieve target INR > 1.5) of warfarin
sodium (Coumadin) or any other Coumadin-derived anti-coagulant; anticoagulants
not derived from warfarin are allowed (e.g., dabigatran, rivaroxaban, apixaban)
- Unstable or increasing doses of corticosteroids
- Enzyme-inducing anticonvulsive agents
- Herbal supplements
- Any of the following concurrent severe and/or uncontrolled medical conditions which
could compromise participation in the study; impaired cardiac function or clinically
significant cardiac diseases, including any of the following:
- Unstable angina within 6 months prior to screening
- Myocardial infarction within 6 months prior to screening
- History of documented congestive heart failure (New York Heart Association
functional classification III - IV)
- Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg
and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without
antihypertensive medication
- Initiation or adjustment of antihypertensive medication(s) is allowed prior to
screening
- Ventricular arrhythmias; supraventricular and nodal arrhythmias not controlled
with medication
- Other cardiac arrhythmia not controlled with medication
- Corrected QT (QTc) > 450 msec using Fridericia correction on the screening
electrocardiogram (ECG)
- Any active gastrointestinal (GI) impairment which, in the opinion of the investigator,
would impair or alter the absorption of ceritinib (e.g., ulcerative colitis, or
Crohn's disease)
- Ongoing GI adverse events > grade 2 (e.g., nausea, vomiting, or diarrhea) at the start
of the study
- History of alcoholism, drug addiction, or any psychiatric or psychological condition
which, in the opinion of the investigator, would impair study compliance
- Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g.,
active or uncontrolled infection) that could cause unacceptable safety risks or
compromise compliance with the protocol
- Pregnant or breast-feeding women
- Women of child-bearing potential, defined as sexually mature women who have not
undergone a hysterectomy or who have not been naturally postmenopausal for at least 12
consecutive months (e.g., who has had menses any time in the preceding 12 consecutive
months), must have a negative serum pregnancy test =< 3 days prior to starting study
treatment
- Women of child-bearing potential, who are biologically able to conceive, not employing
2 forms of highly effective contraception; male not using at least at least one form
of highly effective contraception will be excluded; highly effective contraception
(e.g. male condom with spermicide, diaphragm with spermicide, intra-uterine device)
must be used by both sexes during the study and must be continued for 3 months after
the end of study treatment; oral, implantable, or injectable contraceptives may be
affected by cytochrome P450 interactions, and are therefore not considered effective
for this study
- Patients with untreated brain metastases or who have signs/symptoms attributable to
brain metastases and have not been assessed with radiologic imaging to rule out the
presence of brain metastases; patients with brain metastases that have been
definitively treated and on stable or decreasing dose of steroid within 4 weeks of
starting study treatment will be eligible
