Clinical Trials /

Selumetinib in Combination With Gefitinib in NSCLC Patients

NCT02025114

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Selumetinib in Combination With Gefitinib in NSCLC Patients
  • Official Title: A Phase IB/II, Open Label, Multicenter Study of Selumetinib Administered Orally in Combination With Gefitinib in Patients With EGFR-mutated Non-small Cell Lung Cancer Who Have Developed Acquired Resistance of EGFR Inhibitor Treatment

Clinical Trial IDs

  • ORG STUDY ID: 201312070MIPC
  • NCT ID: NCT02025114

Conditions

  • Non-small Cell Lung Cancer (NSCLC)

Interventions

DrugSynonymsArms
selumetinibCapsule

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
CapsuleExperimentalThe starting dose of selumetinib in combination with the standard dose of gefitinib (250mg QD) on a continuous dosing schedule will be 50mg QD. Total 3 doses of selumetinib will be tested (50mg QD, 50mg BID and 75mg BID).
  • selumetinib

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:20 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine the MTD and/or RP2D
Time Frame:an expected average of 18 weeks
Safety Issue:
Description:Frequency and characteristics of DLTs to the selumetinib and gefitinib combination using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v.4.0. (an expected average of 18 weeks) If one patient experiences a DLT in a group of 3 or more evaluable patients, then the cohort will be expanded to include 6 evaluable patients. If only one DLT is observed in the complete cohort of 6 evaluable patients, then dose escalation may occur.

Secondary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:Patients will be followed up for 2 years(post disease progression)
Safety Issue:
Description:to estimate overall clinical activity of selumetinib combined with gefitinib in EGFR-mutated NSCLC patients who have acquired resistance to EGFR TKIs

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Taiwan University Hospital

Trial Keywords

  • NSCLC, EGFR mutation

Last Updated

September 10, 2017