Non-Small Cell Lung Cancer (NSCLC)

To determine the MTD/RP2D of the LEE011 and ceritinib combination and evaluate whether the combination is safe and has beneficial effects in ALK-positive advanced non-small cell lung cancer patients.

LEE011, LDK378 (ceritinib)

LDK378 (ceritinib)
LEE011

capsule

50, 150
50, 200

Efficacy assessments
Tumor response assessment as per RECIST version 1.1
Progression free survival
Duration of response
Time to response
Disease control rate
Overall survival

Safety assessments
Physical examination
Vital signs
Laboratory evaluations
Cardiac monitoring (12-lead ECG)
Frequency, duration and severity of adverse events

Other assessments
LEE011 and ceritinib pharmacokinetics assessments
Baseline molecular status in tumor tissue of potential predictive markers. Retrospective Rb expression analysis.

Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patients must be diagnosed with ALK-positive advanced NSCLC. The tumor must be ALK-positive as determined by ALK rearrangement in ≥15% of cells (as measured by FISH using the Vysis break-apart ALK probe) or by using the Ventana ALK IHC test. The analysis may be performed locally.
2. Age 18 years or older.
3. Patients must have disease that can be evaluated by RECIST v1.1; measurable disease is required for patients enrolled in the dose expansion part.
4. Performance status (WHO) 0-2
5. Availability of tumor sample:
For ALK inhibitor naïve patients:
• A representative tumor sample must be submitted. An archival tumor specimen is acceptable
For patients after progression on an ALK inhibitor:
• A new tumor biopsy is required unless a biopsy performed after progression on the patient’s most recent ALK inhibitor is available for submission
For all patients a newly obtained tumor specimen must be submitted if no appropriate archival sample is available. In the event that no sample is available and a new biopsy cannot be obtained, enrollment may be considered after discussion with the sponsor.
6. Written informed consent before any study specific screening procedures.

Patients eligible for this study must not meet any of the following criteria:
1. For Phase Ib part:
• Patients who have progressed on ceritinib cannot be enrolled in the escalation part of the study until a combination drug dose with clinically active ceritinib exposure is determined. Prior therapy with other ALK inhibitors is allowed.
2. For Phase II part:
• Group A: prior therapy with an ALK inhibitor is not permitted.
• Group B: progression following an ALK inhibitor other than ceritinib is required and the last dose of the ALK inhibitor must be no more than 60 days prior to the first dose of study drug. Prior ceritinib is not permitted.
• Group C: progression following ceritinib is required and the last dose of ceritinib must be no more than 60 days prior to the first dose of study drug. Patients must have tolerated a dose of ceritinib of 600 mg QD, or greater.
• Groups B2 and C2: if the result of the interim analysis is negative, patients with known G1202R status at screening will be excluded from the study.
3. Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of steroids or local CNS-directed therapy (such as radiotherapy, surgery or intrathecal chemotherapy) to control their CNS disease
Note: Patients with controlled CNS metastases, or asymptomatic CNS metastases that do not require local antineoplastic therapy, such as radiotherapy or surgery, may be permitted to participate in this trial after discussion with the sponsor.
4. History of cytologically proven carcinomatous meningitis
5. Prior treatment with any CDK 4/6 inhibitor therapy
6. Patients with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate).
7. Impaired cardiac function or any clinically significant cardiac disease, including any of the following:
• Clinically significant heart disease such as CHF requiring treatment (NYH grade ≥ 2), unstable angina pectoris or myocardial infarction within the past 3 months, or left ventricular ejection fraction (LVEF) < 45% or less than the institution lower limit of normal as determined by multiple gated acquisition scan (MUGA) or echocardiogram (ECHO).
• QT corrected with Fridericia’s (QTcF) >450 ms screening ECG or congenital long QT syndrome or family history of unexpected sudden cardiac death.
• Any other clinically significant heart disease such as unstable arrhythmia, symptomatic resting bradycardia, left bundle branch block, bifascicular block, or any heart disease that requires the use of a cardiac pacemaker ≤ 3 months prior to starting study drug
8. Patients with the following laboratory values during screening and on day 1 of pre-dose:
Hematology (transfusion before the study start to reach inclusion criteria is not acceptable)
• Absolute neutrophil count (ANC) < 1.5 x 109/L
• Platelet count < 100 x 109/L
• Hemoglobin (Hgb) < 9 g/dL
Biochemistry
• Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 50 mL/min
• Total bilirubin > 1.5 x ULN, except for patients with known Gilbert syndrome, who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN.
• Alanine aminotransferase (ALT) > 3 x ULN, except for patients that have tumor involvement of the liver, who are excluded if > 5 x ULN
• Aspartate aminotransferase (AST) > 3 x ULN, except for patients that have tumor involvement of the liver, who are excluded if > 5 x ULN
• Potassium, magnesium or calcium abnormality > CTCAE grade 1 (despite oral supplementation)
• Phosphate abnormality > CTCAE grade 2 (despite oral supplementation)
9. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of ceritinib or LEE011 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome)
10. Evidence of active viral hepatitis, including Hepatitis A, B or C (testing for viral hepatitis is not mandatory)
11. Presence of ≥ CTCAE grade 2 toxicity (except alopecia and ototoxicity) due to prior cancer therapy
12. Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively more than 3 years prior to study entry and have not recurred; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy or has been treated with curative intent; and completely resected carcinoma in situ of any type
13. History of interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis (i.e., affecting activities of daily living or requiring therapeutic intervention).
14. Any medical condition that would, in the investigator’s judgement, prevent the patient’s participation in the clinical study due to safety concerns or compliance with clinic study procedures. Any severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that would increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the the judgment of the investigator, would make the patient inappropriate for the study.
15. Systemic anticancer therapy within 2 weeks of the first dose of study drug(s). Patients whose immediate prior treatment was an ALK inhibitor or another TKI may start treatment with study drug 1 week after the last dose of that inhibitor.
16. Radiotherapy to lung within 4 weeks prior to the first dose of study drug or patients who have not recovered from radiotherapy-related toxicities. For all other anatomic sites radiotherapy within 2 weeks prior to the first dose of study drug.
17. Major surgery within 2 weeks of the first dose of study drug (mediastinoscopy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery).
18. Patient receiving treatment with 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 LEE011 and for the duration of the study:
• Strong inhibitors and inducers of CYP3A4/5.
• Substrates of CYP3A4/5 or CYP2C9 with a narrow therapeutic index
• Substrates primarily metabolized by CYP3A4/5 or CYP2C9.
• Medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
19. Patients who are currently receiving treatment with warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants.
20. Patients receiving 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.
21. 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.
22. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study and for 3 months after stopping treatment. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 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 with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female patients on the study the vasectomized male partner should be the sole partner for that patient.
• Use of a combination of any two of the following (a+b or a+c, or b+c):
a. 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.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. 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 ago. 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.
23. Sexually active males must use a condom during intercourse while taking the study drugs and for 3 months after stopping ceritinib and LEE011 treatment and 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.