Ceritinib + Trametinib in Patients With Advanced ALK-Positive Non-Small Cell Lung Cancer (NSCLC)

  • STATUS
    Recruiting
  • End date
    Jun 20, 2022
  • participants needed
    69
  • sponsor
    University of California, San Francisco
Updated on 25 January 2021
calcium
tyrosine
measurable disease
brigatinib
lipase
potassium
kinase inhibitor
metastasis
neutrophil count
ROS1
cancer chemotherapy
alopecia
crizotinib
lung carcinoma
secondary malignant neoplasm of liver
proto-oncogene tyrosine-protein kinase ros
alectinib

Summary

This is a phase I/II study of ceritinib and trametinib in Stage IIIB or IV anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC). The Phase I portion will investigate the safety and tolerability of the combination of ceritinib and trametinib in ALK or ROS-1 rearranged NSCLC. The Phase II portion will investigate the clinical efficiency of the combination of ceritinib and trametinib in 3 single arm cohorts: ALKi (ALK inhibitor) nave patients; post-crizotinib progressed disease (PD) patients; and PD second line ALK tyrosine kinase inhibitor (TKI) patients.

Description

This is a phase I/II study of ceritinib and trametinib in Stage IIIB or IV ALK rearranged NSCLC.

The phase I portion is a standard 3+3 dose escalation study starting at dose level 1 and will be open to any patient with ALK-rearranged, or ROS-1 rearranged NSCLC.

The phase II portion will consist of 3 single arm cohorts in ALK-rearranged NSCLC:

  • Cohort A (ALKi Nave): 20 evaluable patients
  • Cohort B (Post-crizotinib PD): 21 evaluable patients
  • Cohort C (PD second line ALK TKI (e.g., alectinib, ceritinib, PF-06463922 or - AP21163): 10 evaluable patients.

The aim will be to enroll up to 69 patients. Patients may continue treatment for up to 24 months from the time of study entry, and will receive 12 months of follow-up following completion of the drugs.

Details
Condition Non-Small Cell Lung Cancer, nsclc
Treatment Trametinib, Ceritinib
Clinical Study IdentifierNCT03087448
SponsorUniversity of California, San Francisco
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have Non-Small Cell Lung Cancer?
Do you have any of these conditions: nsclc or Non-Small Cell Lung Cancer?
Age 18 years old or older
Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization and agree to use effective contraception, throughout the treatment period, and for 4 months after the last dose of study treatment
Patients must have histologically or cytological confirmed stage IIIB or IV non-small cell lung cancer
Documented ALK-rearrangement (or ROS1 rearrangement for phase I only) break-apart fluorescence in situ hybridization (FISH) (in at least 15% of tumor cells), or next generation sequencing assay performed on tumor sample or cell-free DNA in Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory
Measurable disease defined by RECIST 1.1 criteria
Eastern Cooperative Oncology Group (ECOG) Performance status of 0-2
Life expectancy of at least 3 months
Resolution of all acute toxic effects of prior chemotherapy, immunotherapy, radiotherapy or surgical procedures to grade 2 (CTCAE v 4.0). Exception to this criterion: patients with any grade of alopecia are allowed to enter the treatment
The following laboratory criteria have been met
Absolute neutrophil count (ANC) 1.5 x 109/L
Hemoglobin (Hgb) 9 g/dL
Platelets 75 x 109/L
Prothrombin time (PT) / international normalized ratio (INR) and Partial thromboplastin time (PTT) 1.5 x upper limit of normal (ULN)
Serum creatinine 1.5 mg/dL and /or calculated creatinine clearance (using Cockcroft-Gault formula) 30 mL/min
Albumin 2.5 g/dL
Total bilirubin 1.5 x 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) 2.5 x ULN; alanine transaminase (ALT) 2.5 x ULN, except for patients with liver metastasis, who are only included if AST and ALT < 5 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
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 + trametinib
Potassium
Magnesium
Phosphorus
Total calcium (corrected for serum albumin) 12. Left Ventricular Ejection fraction (LVEF) lower limit of normal (LLN) by echocardiogram (ECHO) or multigated acquisition scan (MUGA) 13. Patient has the ability to understand and provide signed informed consent. 14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedure. 15. Specific inclusion criteria for the phase II dose expansion cohorts
Documented ALK-rearranged stage IIIB or IV NSCLC and
Cohort A: No prior ALK inhibitor therapy (prior chemotherapy or immunotherapy is allowed)
Cohort B: Prior treatment with crizotinib and documented disease progression by RECIST 1.1 criteria
Cohort C: Prior treatment with 2nd generation ALKi (e.g. ceritinib, alectinib, loratinib, or brigatinib) and documented disease progression by RECIST 1.1 criteria

Exclusion Criteria

Patients with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate)
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)
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
Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) within the last 3 weeks, or chemotherapy without delayed toxicity within the last 2 weeks preceding the first dose of the combination. Prior systemic treatment in the adjuvant setting is allowed
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
electrocardiogram (ECG)
\. Patient has impairment of gastrointestinal (GI) function or GI disease
that may significantly alter the absorption of orally administered medication
(e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or
malabsorption syndrome)
\. 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 (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 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, dose must have been stabilized (or decreasing) for at least 5 days before first dose of study treatment
Enzyme-inducing anticonvulsive agents
Herbal supplements 10. 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 human Chorionic Gonadotropin (hCG) laboratory test. 11. 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 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)
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
\. Sexually active males unless they use a condom during intercourse while
taking drug and 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
\. Patient has a history of pancreatitis or history of increased amylase or
lipase that was due to pancreatic disease
\. 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
\. 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
\. History of another malignancy. Exception: Subjects who have been disease-
free for 3 years, or subjects with a history of completely resected non-
melanoma skin cancer and/or subjects with indolent (early stage breast cancer
or prostate cancer) second malignancies are eligible after discussion with the
study principle investigator (PI)
\. History of retinal vein occlusion (RVO)
\. Symptomatic brain metastases or leptomeningeal (LM) disease requiring
corticosteroids for symptom management. Asymptomatic brain metastases or LM
will be allowed on study
\. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or
Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of
cleared HBV and HCV infection will be permitted)
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