Clinical Trials /

Study of Oral Ceritinib in Patients With ALK and ROS1 Activated Gastrointestinal Malignancies

NCT02638909

Description:

The available data indicate that Ceritinib has substantial anti-tumor activity in patients with anaplastic lymphoma kinase (ALK) and ROS1 rearranged non-small cell lung cancer (NSCLC). This trial will investigate the potential of Ceritinib in patients with advanced gastrointestinal malignancies with ALK and ROA1 rearrangement, and for whom there is no available therapeutic option.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Cholangiocarcinoma
  • Colorectal Carcinoma
  • Esophageal Carcinoma
  • Gastric Carcinoma
  • Hepatocellular Carcinoma
  • Pancreatic Carcinoma
  • Small Intestinal Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Study of Oral <span class="go-doc-concept go-doc-intervention">Ceritinib</span> in Patients With <span class="go-doc-concept go-doc-biomarker">ALK</span>-Activated Gastrointestinal Malignancies

Title

  • Brief Title: Study of Oral Ceritinib in Patients With ALK-Activated Gastrointestinal Malignancies
  • Official Title: A Phase II, Multicenter, Single-Arm Study of Oral Ceritinib in Adult Patients With ALK-Activated Gastrointestinal Malignancies
  • Clinical Trial IDs

    NCT ID: NCT02638909

    ORG ID: NOV-ALK-01

    Trial Conditions

    Colorectal Adenocarcinoma

    Cholangiocarcinoma

    Pancreatic Adenocarcinoma

    Hepatocellular Adenocarcinoma

    Gastric Adenocarcinoma

    Esophageal Adenocarcinoma

    Trial Interventions

    Drug Synonyms Arms
    ceritinib Zykadia

    Trial Purpose

    The available data indicate that Ceritinib has substantial anti-tumor activity in patients
    with anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC). This
    trial will investigate the potential of Ceritinib in patients with advanced gastrointestinal
    malignancies with ALK rearrangement, and for whom there is no available therapeutic option.

    Detailed Description

    This is a single-arm, open-label, multicenter, phase II study of Ceritinib in adult patients
    with ALK -activated colorectal, cholangiocarcinoma, pancreatic, hepatic, gastric, or
    esophageal adenocarcinoma. An estimated 500 patients will be screened for ALK by
    fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) per institutional
    standard of care (SOC), and/or ALK by next-generation sequencing (NGS). At least 30
    identified patients will be treated with ceritinib per protocol. Treatment with ceritinib
    will continue until patient experiences unacceptable toxicity that precludes further
    treatment, discontinues treatment at the discretion of the investigator or patient, starts a
    new anticancer therapy and/or dies.

    Male and female patients aged 18 or over that have colorectal adenocarcinoma,
    cholangiocarcinoma, pancreatic, hepatocellular, gastric or esophageal adenocarcinoma that
    contain an activated ALK gene due to rearrangement, mutation, amplification, translocation
    or other mechanisms. Patients must have been pretreated with cytotoxic chemotherapy.

    Trial Arms

    Name Type Description Interventions

    Eligibility Criteria

    Inclusion Criteria:

    1. Histologically or cytologically confirmed diagnosis of inoperable colorectal
    adenocarcinoma, pancreatic, hepatocellular, cholangiocarcinoma, small bowel, gastric
    or esophageal adenocarcinoma that carries an activated ALK pathway

    2. Age 18 years or older at the time of informed consent.

    3. Patients must have received at least 1 line of cytotoxic chemotherapy

    4. Patients must have archival tissue sample available, collected either at the time of
    diagnosis or any time since.

    - If archival tissue is unavailable, patient must be eligible and willing to undergo
    a fresh tissue biopsy

    5. Patients must have recovered from all toxicities related to prior anticancer
    therapies to grade 2 (CTCAE v 4.03) provided that concomitant medication is given
    prior to initiation of treatment with LDK378, except for patients with grade 2
    nausea/vomiting and/or grade 2 diarrhea despite optimal supportive therapy who will
    not be allowed to participate in the study. Additionally, patients with any grade of
    alopecia are allowed on treatment.

    6. Cohort Expansion Phase: Patient must have measurable lesions as defined by RECIST
    version 1.1 criteria.

    7. ECOG performance status 0-2

    8. Patients must have normal organ and marrow function as defined below: Bone marrow
    function defined as the following: An absolute neutrophil count (ANC) 1,500/mcl.
    Platelets 75,000/mcl. Hemoglobin 8 g/dl.

    9. Renal function defined as the following: Serum creatinine less than or equal to 1.5 x
    institutional upper limit normal (ULN). Calculated or measured creatinine clearance
    (CrCL) 30 mL/min

    10. Hepatic function defined as the following: Serum total bilirubin < 1.5 x ULN. AST
    (SGOT), ALT (SGPT), and alkaline phosphatase 3.0 x ULN. Serum albumin 2.5 g/dl.
    If liver involvement, AST, ALT, and alkaline phosphatase 5.0 x ULN.

    11. Serum amylase 2 x ULN and serum lipase 1 x ULN

    12. Fasting plasma glucose 175 mg/dL (9.8 mmol/L)

    13. Patient must have the following laboratory values or have the following laboratory
    values corrected with supplements to be within normal limits at screening:

    - Potassium lower limit of normal (LLN)

    - Magnesium LLN

    - Phosphorus LLN

    - Total calcium (corrected for serum albumin) LLN

    14. A male subject of fathering potential must use an adequate method of contraception to
    avoid conception throughout the study [and for up to 12 weeks after the last dose of
    study drug] to minimize the risk of pregnancy. If the partner is pregnant or
    breastfeeding, the subject must use a condom. A condom is required to be used also by
    vasectomized men in order to prevent delivery of the drug via seminal fluid.

    15. Women of childbearing potential (WOCBP) must be using an adequate method of
    contraception to avoid pregnancy throughout the study and for up to 12 weeks after
    the last dose of study drug to minimize the risk of pregnancy. WOCBP must have a
    negative serum or urine pregnancy test within 72 hours before the start of the
    investigational product. Highly effective contraception methods include:

    - Total abstinence (when this is in line with the preferred and usual lifestyle of
    the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
    post-ovulation methods) and withdrawal are not acceptable methods of
    contraception.

    - Female sterilization (have had surgical bilateral oophorectomy with or without
    hysterectomy) or tubal ligation at least six weeks before taking study
    treatment. In case of oophorectomy alone, only when the reproductive status of
    the woman has been confirmed by follow up hormone level assessment.

    - Male sterilization (at least 6 months prior to screening) with the appropriate
    post-vasectomy documentation of the absence of sperm in the ejaculate. For
    female subjects on the study the vasectomized male partner should be the sole
    partner for that subject.

    - Combination of any two of the following (a+b or a+c or b+c):

    - Use of oral, injected or implanted hormonal methods of contraception or other
    forms of hormonal contraception that have comparable efficacy (failure rate <
    1%), for example hormone vaginal ring or transdermal hormone contraception.

    - Placement of an intrauterine device (IUD) or intrauterine system (IUS).

    Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
    cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.

    In case of use of oral contraception, women should have been stable on the same pill
    for a minimum of 3 months before taking study treatment.

    Women are considered post-menopausal and not of child bearing potential if they have
    had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
    profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical
    bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six
    weeks prior to screening. In the case of oophorectomy alone, only when the
    reproductive status of the woman has been confirmed by follow up hormone level
    assessment is she considered not of child bearing potential.

    16. Ability to understand and the willingness to sign a written informed consent
    document.

    Exclusion Criteria:

    1. Patients who have had chemotherapy or radiotherapy within 3 weeks (4 weeks for
    radiotherapy to the lung fields and 6 weeks for nitrosoureas or mitomycin C) prior to
    entering the study or those who have not recovered from adverse events due to agents
    administered more than 4 weeks earlier.

    2. Patients with known hypersensitivity to any of the excipients of ceritinib
    (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and
    magnesium stearate)

    3. Prior therapy with ceritinib or other ALK inhibitor agents

    4. Patients who are currently receiving treatment with warfarin sodium (Coumadin) or
    any other coumarin-derivative anti-coagulants.

    5. Patients with symptomatic CNS metastases who are neurologically unstable or have
    required increasing doses of steroids within the 1 week prior to study entry to
    manage CNS symptoms.

    6. Impairment of GI function or GI disease that may significantly alter the absorption
    of ceritinib

    7. History of pancreatitis or history of increased amylase or lipase that was due to
    pancreatic disease.

    8. 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).

    9. Cardiac conditions as follows:

    - Active coronary artery disease, unstable or newly diagnosed angina or myocardial
    infarction less than 6 months prior to first study drug administration.

    - Class II-IV New York Heart Association (NYHA) congestive heart failure.

    - Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers
    or digoxin

    - QTc (Frederica) prolongation > 470 msec.

    - Subjects with valvular heart disease CTCAE (Version 4.0) Grade 2.

    - Known left ventricular ejection fraction (LVEF) < 50%.

    - Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) 160 mm Hg
    and/or Diastolic Blood Pressure (DBP) 100 mm Hg, with or without
    anti-hypertensive medication

    10. 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 LDK378 and for the
    duration of participation:

    - Medication with a known risk of prolonging the QT interval or inducing Torsades
    de Pointes (please refer to
    http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm)

    - Strong inhibitors or strong inducers of CYP3A4/5 (please refer to
    http://medicine.iupui.edu/flockhart/table.htm or
    http://www.druginteractioninfo.org)

    - Medications with a low therapeutic index that are primarily metabolized by
    CYP3A4/5, and/or CYP2C9 (please refer to
    http://medicine.iupui.edu/flockhart/table.htm or
    http://www.druginteractioninfo.org)

    - Therapeutic doses of warfarin sodium (Coumadin) or any other coumarin-derived
    anti-coagulant. Anti-coagulants not derived from warfarin are allowed (e.g.,
    dabigatran, rivaroxaban, apixaban).

    - Unstable or increasing doses of corticosteroids

    - Enzyme-inducing anti-convulsive agents

    - Herbal supplements

    11. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
    infection, symptomatic congestive heart failure, unstable angina pectoris (Canadian
    Cardiovascular Society grade II-IV despite medical therapy), cardiac arrhythmia,
    active bleeding diatheses, or psychiatric illness/social situations that would limit
    compliance with study requirements.

    12. Major surgical procedure, open biopsy, or significant traumatic injury less than 4
    weeks or those who receive minor surgical procedures (e.g. core biopsy or fine needle
    aspiration) within 1 week from first dose of first study drug administration.

    13. Known inability to swallow up to five LDK378 capsules daily.

    14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
    female after conception and until the termination of gestation, confirmed by a
    positive hCG laboratory test.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Clinical Benefit Rate (CBR) of ceritinib, as defined as the percentage of patients who have achieved complete response, partial response, and stable disease at 2 months per RECIST 1.1) to ceritinib by investigator assessment

    Secondary Outcome Measures

    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0

    Objective tumor response based on computed tomography scans (or magnetic resonance imaging if patients are allergic to iodinated contrast) per RECIST 1.1 criteria

    Trial Keywords

    Gastrointestinal malignancies