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About
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.
Full description
This is a single-arm, open-label, multicenter, phase II study of ceritinib in adult patients with ALK- and ROS1 activated colorectal, cholangiocarcinoma, pancreatic, hepatic, gastric, or esophageal adenocarcinoma. An estimated 500 patients will be screened for ALK and ROS1 by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) per institutional standard of care (SOC), and/or ALK/ROS1 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.
Enrollment
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Inclusion criteria
Histologically or cytologically confirmed diagnosis of inoperable colorectal adenocarcinoma, pancreatic, hepatocellular, cholangiocarcinoma, small bowel, gastric or esophageal adenocarcinoma that carries an activated ALK or ROS1 pathway
Age 18 years or older at the time of informed consent.
Patients must have received at least 1 line of cytotoxic chemotherapy
Patients must have archival tissue sample available, collected either at the time of diagnosis or any time since.
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.
Cohort Expansion Phase: Patient must have measurable lesions as defined by RECIST version 1.1 criteria.
ECOG performance status 0-2
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.
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
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.
Serum amylase ≤ 2 x ULN and serum lipase ≤ 1 x ULN
Fasting plasma glucose ≤175 mg/dL (≤9.8 mmol/L)
Patient must have the following laboratory values or have the following laboratory values corrected with supplements to be within normal limits at screening:
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.
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:
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.
Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
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.
Patients with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
Prior therapy with ceritinib or other ALK or ROS1 inhibitor agents
Patients who are currently receiving treatment with warfarin sodium (Coumadin®) or any other coumarin-derivative anti-coagulants.
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.
Impairment of GI function or GI disease that may significantly alter the absorption of ceritinib
History of pancreatitis or history of increased amylase or lipase that was due to pancreatic disease.
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).
Cardiac conditions as follows:
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:
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.
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.
Known inability to swallow up to five LDK378 capsules daily.
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.
Primary purpose
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Interventional model
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4 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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