Clinical Trials /

Ceritinib and Combination Chemotherapy in Treating Patients With Advanced Solid Tumors or Locally Advanced or Metastatic Pancreatic Cancer

NCT02227940

Description:

This phase I trial studies the side effects and best dose of ceritinib and combination chemotherapy in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) or pancreatic cancer that has spread from where it started to nearby tissue or lymph nodes (locally advanced) or has spread to other places in the body (metastatic). Ceritinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle formulation, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ceritinib and more than one drug (combination chemotherapy) may be a better treatment for solid tumors or pancreatic cancer.

Related Conditions:
  • Malignant Solid Tumor
  • Pancreatic Adenocarcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Ceritinib</span> and <span class="go-doc-concept go-doc-intervention">Combination Chemotherapy</span> in Treating Patients With Advanced Solid Tumors or Locally Advanced or Metastatic <span class="go-doc-concept go-doc-disease">Pancreatic Cancer</span>

Title

  • Brief Title: Ceritinib and Combination Chemotherapy in Treating Patients With Advanced Solid Tumors or Locally Advanced or Metastatic Pancreatic Cancer
  • Official Title: A Phase I Study of Ceritinib (LDK378), a Novel ALK Inhibitor, in Combination With Gemcitabine-Based Chemotherapy in Patients With Advanced Solid Tumors
  • Clinical Trial IDs

    NCT ID: NCT02227940

    ORG ID: I 248813

    NCI ID: NCI-2014-01766

    Trial Conditions

    Adult Solid Neoplasm

    Metastatic Pancreatic Adenocarcinoma

    Pancreatic Adenocarcinoma

    Stage III Pancreatic Cancer

    Stage IV Pancreatic Cancer

    Trial Interventions

    Drug Synonyms Arms
    Ceritinib LDK 378, LDK378, Zykadia Arm 1 (ceritinib MTD then with gemcitabine alone), Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel), Arm III (ceritinib MTD then with gemcitabine and cisplatin)
    Cisplatin Abiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone's Chloride, Peyrone's Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, Platosin Arm III (ceritinib MTD then with gemcitabine and cisplatin)
    Gemcitabine Hydrochloride dFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011 Arm 1 (ceritinib MTD then with gemcitabine alone), Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel), Arm III (ceritinib MTD then with gemcitabine and cisplatin)
    Paclitaxel Albumin-Stabilized Nanoparticle Formulation ABI 007, ABI-007, Abraxane, Albumin-bound Paclitaxel, Albumin-Stabilized Nanoparticle Paclitaxel, nab-paclitaxel, Nanoparticle Albumin-bound Paclitaxel, Nanoparticle Paclitaxel, protein-bound paclitaxel Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel)

    Trial Purpose

    This phase I trial studies the side effects and best dose of ceritinib and combination
    chemotherapy in treating patients with solid tumors that have spread to other places in the
    body and usually cannot be cured or controlled with treatment (advanced) or pancreatic
    cancer that has spread from where it started to nearby tissue or lymph nodes (locally
    advanced) or has spread to other places in the body (metastatic). Ceritinib may stop the
    growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in
    chemotherapy, such as gemcitabine hydrochloride, paclitaxel albumin-stabilized nanoparticle
    formulation, and cisplatin, work in different ways to stop the growth of tumor cells, either
    by killing the cells, by stopping them from dividing, or by stopping them from spreading.
    Giving ceritinib and more than one drug (combination chemotherapy) may be a better treatment
    for solid tumors or pancreatic cancer.

    Detailed Description

    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.

    Trial Arms

    Name Type Description Interventions
    Arm 1 (ceritinib MTD then with gemcitabine alone) Experimental Dose Escalation Cohort 1: Patients with advanced solid tumors for whom gemcitabine hydrochloride-based therapy is clinically appropriate receive ceritinib PO (QD on days 1-28 and gemcitabine hydrochloride 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 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. Ceritinib, Gemcitabine Hydrochloride
    Arm 2 (ceritinib MTD then with gemcitabine and nab-paclitaxel) Experimental 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. Ceritinib, Gemcitabine Hydrochloride, Paclitaxel Albumin-Stabilized Nanoparticle Formulation
    Arm III (ceritinib MTD then with gemcitabine and cisplatin) Experimental 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. Ceritinib, Cisplatin, Gemcitabine Hydrochloride

    Eligibility Criteria

    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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    MTD and RP2D of ceritinib in combination with gemcitabine hydrochloride alone, defined as the highest dose level at which < 2 of 6 patients experience treatment-related dose limiting toxicity (DLT) (Arms 1 and 1E)

    MTD and RP2D of ceritinib in combination with gemcitabine hydrochloride and cisplatin, defined as the highest dose level at which < 2 of 6 patients experience treatment-related DLT (Arms 3 and 3E)

    MTD and RP2D of ceritinib in combination with gemcitabine hydrochloride and paclitaxel albumin-stabilized nanoparticle formulation, defined as the highest dose level at which < 2 of 6 patients experience treatment-related DLT (Arms 2 and 2E)

    Secondary Outcome Measures

    Incidence of adverse events of ceritinib in combination with gemcitabine hydrochloride based chemotherapy in advanced solid malignancies according to NCI CTCAE v4.0

    Pharmacokinetic parameters of ceritinib and gemcitabine hydrochloride when administered in combination in patients with advanced solid tumors (Arms 1 and 1E)

    Pharmacokinetic parameters of ceritinib, gemcitabine hydrochloride, and paclitaxel albumin-stabilized nanoparticle formulation when administered in combination in patients with advanced solid tumors (Arms 2 and 2E)

    Pharmacokinetic parameters of paclitaxel albumin-stabilized nanoparticle formulation, and cisplatin when administered in combination in patients with advanced solid tumors (Arms 3 and 3E)

    Progression free survival

    Response rate as assessed by the RECIST 1.1

    Trial Keywords