This is an open-label, non-randomized, multicenter phase Ib/II study, which is composed of a
phase Ib dose escalation part and a phase II dose expansion part. Patients will receive
selumetinib in combination with gefitinib 250mg daily. This study will enroll EGFR-mutated
NSCLC patients who have developed acquired resistance to EGFR TKI treatment.
he primary objective of the dose escalation part is to determine the MTD and/or RP2D of
selumetinib in combination with gefinitib. Once MTD and/or RP2D has been determined in the
phase Ib dose escalation phase, study drug selumetinib with combination of 250mg QD dose of
gefitinib will be further evaluated in a phase II dose expansion phase of the study. The
purpose of the dose expansion phase is to evaluate the efficacy of selumetinib in combination
of gefitinib and to further characterize the safety, and tolerability of the combination.
20 patients will be required in the phase II period. In the expansion phase, 10 patients with
T790M and 10 patients without T790M will be enrolled. It is assumed that 20% response rate is
the target of clinical interest. If the true response rate is 20%, the probability of
observing no responses in a random sample of 10 patients is 0.107. The false negative rate
for detecting a true 20% response rate in each cohort is approximately 10%. Each cohort will
be enrolled 10 patients to evaluate the efficacy; therefore 20 patients will be enrolled in
dose expansion part. Patients treated at the MTD and/or RP2D during the phase Ib will be
considered as part of the required number of patients in the phase II. Patients at the MTD or
RP2D cannot contribute to the 20 patients require for phase II part.
Inclusion Criteria:
1. Written informed consent obtained prior to any screening procedures.
2. ≥20 years of age.
3. Must have discontinued any previous anti-cancer and investigational therapy (excluding
EGFR TKI) for at least 28 days or radiotherapy ≥14 days before study treatment
administration, and must have recovered to Grade 1 from the adverse effects of such
treatment before starting study treatment.
4. Life expectancy ≥3months.
5. ECOG performance status: 0-1.
6. Female patients of child-bearing potential should have a negative pregnancy test.
7. Required baseline laboratory status:
(1) Hemoglobin>9g/dL. (2) Platelet count≥100x109/L. (3) Absolute neutrophil count
(ANC)≥1.5x109/L without growth factor support. (4) Total bilirubin 1.5x upper limit of
normal (ULN). (5) AST/SGOT and/or ALT/SGPT 2.5x ULN. (6) Serum creatinine clearance >50
ml/min, by either Cockcroft-Gault formula or by 24-hour urine collection analysis.
8. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
9. In phase Ib part, lung cancer patients with disease progression after EGFR TKI and at
least one line of chemotherapy. If less than 70 years of age, a platinum-based regimen must
be included.
10. In phase II part, patients must be willing to perform a re-biopsy of the tumor at the
time of study entrance and meet definition of acquired resistance criteria of Jackman's as
follows:
(1) Previous treatment with EGFR TKI (gefitinib, erlotinib, afatinib, dacomitinib, AZD9291,
or any EGFR TKI under investigation).
(2) Either or both of the followings:
1. A tumor harboring an EGFR mutation known to be associated with drug sensitivity (ie,
exon 19 deletion , L858R, L861Q, G719X etc.).
2. Objectively clinical benefit from treatment with EGFR TKI as defined by either:
Documented partial or complete response (RECIST or WHO) or Significant and durable(≥
6months) clinical benefit (stable disease as defined by RECIST or WHO) after
initiation of EGFR TKI.
(3) Systemic progression of disease (RECIST or WHO) while on continuous treatment with
EGFR TKI within the last 30 days.
(4) No intervening systemic therapy between cessation of EGFR TKI and initiation the
study treatment.
Exclusion Criteria:
1. Unable or unwilling to swallow capsules once or twice daily.
2. Patients who had discontinued previous gefitinib treatment due to intolerance of
side effects (such as diarrhea ≥CTCAE Grade 2, intolerable skin rash, ILD or
AST/ALT elevation ≥ CTCAE Grade 3).
3. Previous treatment of MEK, Ras, or Raf inhibitors or history of hypersensitivity
to selumetinib, or any excipient agents.
4. Symptomatic CNS metastases which are neurologically unstable or requiring
increasing doses of steroids to control the CNS condition.
5. Radiation therapy within 4 weeks prior to the first dose of study drug or limited
field radiotherapy within 2 weeks prior to the start of study treatment. Any
persistent side effect of prior radiotherapy must be resolved to Grade 1 prior to
the first dose of study treatment.
6. Any unresolved toxicity from previous anticancer therapy > Grade 1.
7. Currently receiving any prohibited medications including vitamins supplements,
and herbal supplements. Refer to Table 6.5 for a list of excluded medication.
8. Unable to undergo an MRI or contrast CT procedures.
9. Active HBV or HCV infection, HBV carrier can be enrolled if HBV DNA titer is low
under antiviral treatment.
10. Known history of HIV seropositivity. HIV testing is not required as part of this
study.
11. Undergone a bone marrow or solid organ transplant.
12. Another malignancy diagnosed or treated within 5 years, except carcinoma in situ
or skin cancer.
13. Major surgery within 4 weeks prior to initiating study treatment, excluding the
placement of vascular access.
14. Cardiac conditions as follows:
1. Uncontrolled hypertension (BP ≥150/95 mmHg despite medical therapy).
2. Left ventricular ejection fraction <55% measured by echocardiography.
3. Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest.
4. Symptomatic heart failure (NYHA grade II-IV), see Appendix A.
5. Prior or current cardiomyopathy.
6. Severe valvular heart disease.
7. Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical
therapy), see Appendix A.
8. Acute coronary syndrome within 6 months prior to starting treatment". 15.
Ophthalmological conditions as follows:
1. Intra-ocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of
intra-ocular pressure).
2. Current or past history of central serous retinopathy or retinal vein occlusion.
16. Past medical history of interstitial lung disease, drug-induced interstitial
disease, radiation pneumonitis which required steroid treatment, pre-existing
idiopathic pulmonary fibrosis or any evidence of clinically active interstitial lung
disease.
17. Pregnant or 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 (>5mIU/mL).
18. Women of child-bearing potential, defined as all women physically capable of
becoming pregnant, unless they are using highly effective methods of contraception
during dosing and for 30 more days after stopping study drug.
19. Women are considered post-menopausal and not of child baring 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.
20. Sexually active males must use a condom during intercourse while taking the drug
and for 30 more days after stopping study drug and should not father a child in this
period. A condom is required to be used also by a vasectomized men in order to prevent
delivery of the drug via seminal fluid.
21. Any other condition that would, in the Investigator's judgment, contraindicate
patient's participation in the clinical study due to safety concerns or compliance
with clinical study procedures, e.g. infection/inflammation, intestinal obstruction,
unable to swallow medication, social/psychological issues, etc.
