Ceritinib in Combination With Stereotactic Ablative Radiation Metastatic Lung Adenocarcinoma

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Brief Title

Ceritinib in Combination With Stereotactic Ablative Radiation Metastatic Lung Adenocarcinoma

Official Title

Phase II Trial of Ceritinib in Combination With Stereotactic Ablative Radiation in ALK-rearranged Metastatic Lung Adenocarcinoma

Brief Summary

      The purpose of this study is to see if Ceritinib can target ALK in non-small cell lung cancer
      and slow down cancer growth and prevent it from spreading.
    

Detailed Description

      This is an, open-label, two-cohort protocol designed to evaluate the activity of targeted
      therapy and SABR in ALK positive lung adenocarcinoma.

      Cohort A will evaluate the combination in ALK-inhibitor naïve patients. Cohort B will
      evaluate the combination in patients who have received treatment with one prior ALK
      inhibitor.

      Ceritinib will be administered to the patient until disease progression by RECIST 1.1,
      unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other
      reason including death.

      The primary focus of this protocol is identifying response in ALK+ lung cancer patients.
      Patients with Ventana assay and Vysis FISH probe positive tumors will be treated. Evidence of
      ALK gene rearrangement will also be considered eligible for the trial.

      Primary Objective:

      Cohort A: Superiority of ceritinib + SABR median PFS compared to historical control of 10
      months (expected to be 20 months)

      Endpoint:

      Cohort A Median PFS defined as time from initiation of ceritinib until disease progression by
      RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for
      any other reason including death.

      Primary:

      Cohort B: Superiority of ceritinib + SABR median PFS compared to historical control of 7
      months.

      Endpoint:

      Cohort B: Median PFS defined as time from initiation of ceritinib until disease progression
      by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial
      for any other reason including death.

      Secondary:

        -  Report Overall survival Overall survival

        -  Report Time to 2nd SABR Time from start of systemic therapy to first day of second
           course of SABR

        -  Report Time to 3rd SABR Time from start of therapy to first day of third course of SABR

        -  Report proportion of patients CR/PR/stable disease at 6 and12 months Number of patients
           with CR/PR/stable disease for 6 and 12 months after initiation

      Safety:

      -Demonstrate safety of ceritinib followed by SABR Describe toxicity and adverse events (CTCAE
      v.4) compared to historical controls.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Progression Free Survival

Secondary Outcome

 Time to subsequest Stereotactic Ablative Radiation

Condition

ALK-positive Non-small Cell Lung Cancer

Intervention

Ceritinib

Study Arms / Comparison Groups

 ALK-inhibitor naive patients
Description:  Patients will receive ceritinib at a dose of 750 mg (150 mg capsules times 5 capsules once a day) for 10 weeks. Patient will stop taking Ceritinib 72 hours before SABR (Stereotactic ablative body radiation). They could get 1, 3 ,or 5 treatments on consecutive days with 18 hours between each treatment or every other day (doctor's determination). The patient may start taking Ceritinib again 72 hours after radiation is complete. Patient will continue to take certinib for up to 8 months. At Follow-Up treatment, patients will be contacted every 3 months for 9 months.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

33

Start Date

November 2015

Completion Date

August 2021

Primary Completion Date

August 2020

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or cytologically confirmed diagnosis of lung adenocarcinoma that
             demonstrates ALK rearrangement as detected by the approved FISH test (Abbott Molecular
             Inc), using Vysis breakapart probes (defined as 15% or more positive tumor cells); or
             the Ventana IHC test. Evidence of rearrangement by gene sequencing tests such as
             FoundationOne or Caris will also be seen as evidence of ALK abnormality and meeting
             eligibility requirement.

          2. Patients with no prior ALK-inhibitor therapy will be placed in cohort A, those treated
             with one prior line of ALK-inhibitor (at any time) will enter cohort B.

          3. Patients will not have any other curative therapeutic option, such as radiation or
             surgery.

          4. WHO performance status 0-2.

          5. Age ≥18 years.

          6. Patients must have recovered from all toxicities related to any prior anticancer
             therapies to ≤ Grade 2 (CTCAE v 4.03), provided that any concomitant medication is
             given prior to initiation of treatment with ceritinib. Exception to this criterion:
             patients with any grade of alopecia are allowed to enter the treatment.

          7. Adequate organ function: the following laboratory criteria have been met:

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               -  Hemoglobin (Hgb) ≥ 8 g/dL

               -  Platelets ≥ 75 x 109/L

               -  Serum creatinine <1.5 mg/dL and /or calculated creatinine clearance (using
                  Cockcroft-Gault formula) ≥30 mL/min

               -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN), except for patients with
                  Gilbert's syndrome who may be included if total bilirubin ≤ 3.0 x ULN or direct
                  bilirubin ≤ 1.5 x ULN

               -  Aspartate transaminase (AST) < 2.0 x ULN, except for patients with liver
                  metastasis, who are only included if AST < 3 x ULN; alanine transaminase (ALT) <
                  2.0 x ULN, except for patients with liver metastasis, who are only included if
                  ALT < 3 x ULN

               -  Alkaline phosphatase (ALP) ≤5.0 x ULN

               -  Fasting plasma glucose ≤175 mg/dL (≤9.8 mmol/L)

               -  Serum amylase ≤ 2 x ULN

               -  Serum lipase ≤ ULN

          8. Patient must have the following laboratory values or have the following laboratory
             values corrected with supplements to be within normal limits before the first dose of
             ceritinib:

               -  Potassium

               -  Magnesium

               -  Phosphorus

               -  Total calcium (corrected for serum albumin)

          9. Written informed consent for the protocol must be obtained prior to any screening
             procedures.

         10. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
             tests and other procedures.

        Exclusion Criteria:

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

          2. History of carcinomatous meningitis.

          3. Prior therapy with ceritinib.

          4. Presence or history of a malignant disease other than lung adenocarcinoma that has
             been diagnosed and/or required therapy within the past year and is undergoing active
             anticancer treatment. Exceptions to this exclusion include the following: completely
             resected basal cell and squamous cell skin cancers, and completely resected carcinoma
             in situ of any type.

          5. Patient has history of interstitial lung disease or interstitial pneumonitis,
             including clinically significant radiation pneumonitis (i.e., affecting activities of
             daily living or requiring therapeutic intervention).

          6. Patient who has received thoracic radiotherapy to lung fields ≤4 weeks prior to
             starting the study treatment or patients who have not recovered from
             radiotherapy-related toxicities. For all other anatomic sites (including radiotherapy
             to thoracic vertebrae and ribs) radiotherapy ≤2 weeks prior to starting the study
             treatment or has not recovered from radiotherapy-related toxicities. Palliative
             radiotherapy for bone lesions ≤2 weeks prior to starting study treatment is allowed.

          7. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac
             event (within 6 months), such as:

               -  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 (QTcF) >470 ms using Fridericia's correction on the screening ECG

          8. Impaired GI function or GI disease that may alter absorption of ceritinib or inability
             to swallow up to five ceritinib capsules daily. Although, patients unable to swallow
             capsules will be allowed to participate in this study, by following the specific
             instructions on making a slurry of the medication.

          9. Patient has impairment of GI function or GI disease that may significantly alter the
             absorption of ceritinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting,
             diarrhea, or malabsorption syndrome).

         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 ceritinib and for
             the duration of participation (see Appendix 1 Tables):

               -  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, CYP2C8 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 coumadin-derived
                  anti-coagulant. Anticoagulants not derived from warfarin are allowed (eg,
                  dabigatran, rivaroxaban, apixaban).

               -  Unstable or increasing doses of corticosteroids; If patients are on
                  corticosteroids for endocrine deficiencies or tumor-associated symptoms
                  (non-CNS), dose must have been stabilized (or decreasing) for at least 5 days
                  before first dose of study treatment.

               -  Enzyme-inducing anticonvulsive agents

               -  Herbal supplements

         11. 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.

         12. Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using highly effective methods of contraception
             during dosing and agree to continue for 3 months after the last dose of study
             treatment. 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):

                    1. 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.

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

                    3. 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.

         13. Sexually active males unless they agree to use a condom during intercourse while
             taking drug and agree to continue for 3 months after the last dose of study treatment.
             Male patients for 3 months should not father a child in this period. A condom is
             required to be used also by vasectomized men in order to prevent delivery of the drug
             via seminal fluid.

         14. Patient has a history of pancreatitis or history of increased amylase or lipase that
             was due to pancreatic disease.

         15. Patient has other severe, acute, or chronic medical conditions including uncontrolled
             diabetes mellitus or psychiatric conditions or laboratory abnormalities that, in the
             opinion of the investigator, may increase the risk associated with study participation
             or may interfere with the interpretation of study results.

         16. Patient has had major surgery (e.g., intra-thoracic, intra-abdominal or intra-pelvic)
             within 4 weeks prior to starting study treatment or has not recovered from side
             effects of such procedure. Video-assisted thoracic surgery (VATS) and mediastinoscopy
             will not be counted as major surgery and patients can receive study treatment ≥1 week
             after these procedures.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Saad Khan, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02513667

Organization ID

STU 042015-076


Responsible Party

Sponsor

Study Sponsor

University of Texas Southwestern Medical Center

Collaborators

 Novartis Pharmaceuticals

Study Sponsor

Saad Khan, MD, Principal Investigator, UT Southwetern Medical Center-Oncology


Verification Date

May 2020