Clinical Trials /

BPI-7711 Capsule in Patients With EGFR Mutation T790M Positive Non-small Cell Lung Cancer

NCT03386955

Description:

Lung cancer has the highest incidence rate in China and is also a very common cancer in the world. BPI-7711 is a potential new drug developed for advanced or recurrent non-small cell lung cancer. The purpose of this study is to evaluate the safety, efficacy and how the drug is used by the body. The first part of the study will recruit 3~6 patients for different dose levels to evaluate safety. The dose will increase from the lowest level. In the first part, the study will also collect data on how the drug is used by the body to better decide how the drug should be taken. The second part of the study is the expansion part. Once efficacy is observed in the dose increasing process, additional 20~30 patients will be enrolled to further evaluate the anti-tumor efficacy of each dose level. Estimate 50~80 patients will be enrolled for both part. A recommended dose will be selected for Phase II study.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: BPI-7711 Capsule in Patients With EGFR Mutation T790M Positive Non-small Cell Lung Cancer
  • Official Title: An Open-label, Single Arm, Phase I Study to Evaluate Safety, Dose Escalation Tolerability, Pharmacokinetics and Antineoplastic Activity of the BPI-7711 Capsule in Patients With EGFR Mutation T790M Positive Advanced or Recurrent NSCLC

Clinical Trial IDs

  • ORG STUDY ID: BPI-7711-2015-001
  • NCT ID: NCT03386955

Conditions

  • Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
BPI-7711 CapsuleBPI7711, BPI-7711, BPI7711 CapsuleBPI-7711 treatment

Purpose

Lung cancer has the highest incidence rate in China and is also a very common cancer in the world. BPI-7711 is a potential new drug developed for advanced or recurrent non-small cell lung cancer. The purpose of this study is to evaluate the safety, efficacy and how the drug is used by the body. The first part of the study will recruit 3~6 patients for different dose levels to evaluate safety. The dose will increase from the lowest level. In the first part, the study will also collect data on how the drug is used by the body to better decide how the drug should be taken. The second part of the study is the expansion part. Once efficacy is observed in the dose increasing process, additional 20~30 patients will be enrolled to further evaluate the anti-tumor efficacy of each dose level. Estimate 50~80 patients will be enrolled for both part. A recommended dose will be selected for Phase II study.

Detailed Description

      This is an open label, single arm Phase I study, including a "dose escalation" part and a
      "dose extension" part. Dose extension will be initiated during the process of dose
      escalation: once a dose is found to be safe and effective (evaluated according to objective
      response rate [ORR]) during escalation, then that dose will be extended to enroll more
      patients; at the same time, dose escalation will further continue in order to find out a
      better dose.

      Dose escalation: on the basis of the traditional "3+3" dose escalation plan; single dose PK
      test is added. The subjects of each dose group will first be given a single dose, and blood
      samples be collected for PK analysis. 7 days (wash-out period) after single dose delivery, an
      additional 21 days of continuous multiple dose delivery will be given as a treatment cycle to
      evaluate the dose limiting toxicity (DLT). The initial dose will be 30 mg once a day. In the
      initial dose group, the second subject will be enrolled and administered with the study drug
      7 days after the first dosing (single dose) to the first subject. If there is no occurrence
      of serious or unexplainable safety event, the subsequent following-up subjects will be
      enrolled and receive the dose. If suspected safety event occurs, the investigator will
      discuss with the sponsor whether to delay dose delivery to the following-up subjects of the
      said group.

      Every dose escalation group will enroll 3 to 6 subjects. Dose adjustment will be based on the
      following scheme:

        -  If there is 0 case of DLT in 3 subjects of the initial dose group in the first treatment
           cycle, then the treatment dose of the subsequent 3 patients will be increased to level
           2.

        -  If there is 1 case of DLT in 3 subjects of the initial dose group in the first treatment
           cycle, then additional 3 patients will be enrolled in the group and accept the level 1
           dose treatment.

             -  If there is 0 case of DLT in the 3 new subjects, the dose will be increased to
                level 2.

             -  If there is ≥1 case of DLT in the 3 new subjects, the principal investigator and
                the sponsor will discuss to determine the next step dose scheme.

        -  If there are ≥2 cases of DLT in 3 subjects of the initial dose group, the principal
           investigator and the sponsor will meet to discuss the alternative dose delivery scheme.

      The same dose escalation rules shall be applicable to the following dose groups. Based on
      available tolerance, safety, and PK data, recommended Phase II dose (RP2D) will be selected.

      Dose extension group: If, in the dose escalation group, it is found that certain dose is safe
      and effective, then dose expansion will be initiated and about 20-30 additional subjects will
      be enrolled into this dose level and treated with 21 days as a cycle. The said dose extension
      group will be ended in advance (less than 30 subjects) if efficacy found to be unsatisfying
      after discussed by the investigator and the sponsor. There will be no DLT evaluation for
      subjects of the dose extension study.
    

Trial Arms

NameTypeDescriptionInterventions
BPI-7711 treatmentExperimentalPatients in dose escalation group will receive single dose of BPI-7711 capsule PO on day -7 and start receive the 21 days/cycle continuous treatment once a day after 7 day washout period. Patients in the extension group will receive BPI-7711 once a day with the selected doses.
  • BPI-7711 Capsule

Eligibility Criteria

        Inclusion Criteria:

          -  Subjects signs and dates the informed consent form before receiving any treatment or
             test sample collection related to the study.

          -  Male or female, ≥18 and ≤75 years of age when signing the informed consent.

          -  Locally advanced or metastatic non-small cell lung cancer (NSCLC) verified by
             histology or cytology, and no longer suitable for radical surgery or radiation
             therapy.

          -  ECOG scoring (PS) of physical conditions 0-1, and there is no deterioration 2 weeks
             before enrolled to the study. The expected survival is not less than 12 weeks.

          -  Disease progressed after EGFR-TKI treatment as proved by radiological evidence. For
             dose level which does not provide satisfying efficacy in the escalation group,
             patients must receive chemo therapy before enrolled into that dose, unless not
             suitable for chemotherapy judged by investigator. Patients must have documented
             radiological progression before enrolled into the study.

          -  At least 1 measurable lesion based on the RECIST1.1 criteria. If the subject has only
             1 measurable lesion, the baseline CT must be performed at 14 days after biopsy. The
             lesion received radiotherapy does not count as measurable lesion or a biopsy lesion
             unless it shows obvious progression after radiotherapy.

          -  Previous local test reports confirmed the tumor has EGFR positive gene mutation
             sensitive to EGFR-TKI treatment (including G719X, exon 19 loss, L858R, L861Q etc.).

          -  Central lab tissue tests confirm T790M positive for the biopsy samples collected after
             imaging examination with clear disease progression post last treatment. Subject should
             provide formalin fixed and paraffin embedded tumor tissue block or 5 pieces of 4-5µm
             thick undyed slices, or should agree to do tumor tissue biopsy.

          -  The clinical laboratory examination results shall meet the following criteria:

               1. Blood platelet ≥100×109/L

               2. Absolute neutrophil counting(ANC)≥1.5×109/L

               3. Hemoglobin(Hgb)≥90 g/L

               4. Total bilirubin (TBil) ≤1.5 times of upper normal limit(ULN)

               5. Alanine aminotransferase (ALT) and aspertate aminotransferase (AST) ≤3 times of
                  ULN (≤5 times of ULN is allowed if there is liver metastasis)

               6. Creatinine ≤1.5times of ULN or creatinine clearance≥50 mL/min.

               7. Mean resting corrected QT interval (QTc) ≤470 msec obtained from 3
                  electrocardiograms (ECGs).

               8. If the subject is not taking anticoagulants, the International Standardization
                  Ratio (INR) ≤1.5 and APTT ≤1.5 times of ULN. For patients who are being treated
                  with heparin anticoagulant therapy, if these indicators have no abnormality, and
                  then they can be enrolled. For subjects who are receiving warfarin anticoagulant
                  therapy, within 28 days before enrolled into the study, relating to INR, use
                  stable dose warfarin.

          -  Able to swallow the study drug.

          -  Female subjects should take effective contraceptive measures, should not be breast
             feeding and must have a negative pregnancy test prior to start of dosing if of
             child-bearing potential or must have evidence of non-child-bearing potential.

          -  Male patient subjects are willing to use barrier contraception.

          -  Except hair loss and stable below level 2 peripheral nerve toxicity, any clinical
             toxicity related to previous treatment before enrollment must restore to baseline or
             level 1.

        Exclusion Criteria:

          -  Anti-cancer treatment with EGFR-TKI (e.g., Icotinib, gefitinib or erlotinib) within 8
             days (approximately 5 times of half-life) before first dosing in the study.

          -  Received treatment targeted for T790M positive mutation, or participated in clinical
             trials for such types of drugs, e.g., AZD9291, CO-1686 and other third-generation TKI
             therapy.

          -  Any cytotoxic chemotherapy, investigational agents or anticancer drugs for the
             treatment of advanced NSCLC from a previous treatment regimen or clinical study within
             14 days prior to the first dose of study treatment.

          -  Any of the following cardiac criteria:

        Mean resting corrected QT interval (QTc) > 470 msec obtained from 3 electrocardiograms
        (ECGs); Any clinically important abnormalities in rhythm, conduction or morphology of
        resting ECG eg, complete left bundle branch block, third degree heart block, second degree
        heart block, PR interval >250 msec; Factors that may increase the risk of QTc prolongation
        or risk of arrhythmic events such as symptomatic heart failure - New York Heart Association
        (NYHA) Class II-IV, hypokalaemia, congenital long QT syndrome, family history of long QT
        syndrome or unexplained sudden death under 40 years of age in first degree relatives or any
        concomitant medication known to prolong the QT intervals.

          -  Past interstitial lung disease, drug induced interstitial lung disease, radiation
             pneumonia that needs steroid therapy, or any evidence of clinically. active
             interstitial lung disease.

          -  The known active infection, such as hepatitis B, hepatitis C and human
             immunodeficiency virus (HIV) infection. Patients with well-controlled hepatitis B can
             be enrolled to the study, and can receive antiviral treatment.

          -  Patients with other malignant tumor and still under treatment, or have recurrent or
             associated other malignant tumor within the last 5 years are not eligible. Cervical
             cancer in situ eradication therapy, non-melanoma skin cancer, superficial bladder
             tumor (noninvasive tumor), or carcinoma in situ with no recurrence, nor relevant
             treatment in 3 years after eradication treatment, may be eligible.

          -  Judged by investigators, clear digestive tract disorder which may interfere with
             BPI-7711 absorption (for example, obvious uncontrolled inflammatory gastrointestinal
             diseases, abdominal colostomy within 6 months or past history of gastrointestinal
             perforation, intestinal wide excision and the need for tube feeding or parenteral
             fluids/nutrition supplementation).

          -  Spinal cord compression, metastases of the meninges, and brain metastases with obvious
             symptoms. cannot be enrolled. The following cases of brain metastases without symptoms
             can be enrolled:

        Brain metastases without obvious symptoms diagnosed at screening visit, steroids and/or
        local treatment not required judged by investigator; Brain metastases without obvious
        symptoms after local treatment (such as radiotherapy), and steroids and/or antiepileptic
        therapy has stopped for at least 7 days before the first dosing of study drug.

          -  Local radiotherapy to alleviate the disease within 1 week before first dosing of the
             study drug; more than 30% bone marrow radiotherapy or with a wide field of
             radiotherapy within 4 weeks before first dosing of the study drug.

          -  ≤4 weeks before major surgery or ≤2 weeks before minor surgery before the first day of
             administration of the study drug.

          -  Any unstable factor or factors that may endanger the safety of the patients or affect
             the subjects' compliance to procedures and requirements of this study.

          -  Leukocyte-depleted whole blood transfusion within the 120 days before collecting
             genetic testing samples.

          -  Pregnant or breast-feeding women.

          -  Need of legal guardian to sign the informed consent on behalf of the subjects based on
             any reason. All subjects must have enough mental behavior ability, understand the
             nature and significance of the study, as well as the risks associated with this study,
             and be able to personally sign the informed consent.

          -  Drug abuse, alcoholic addiction, medical and mental illness and social barriers which
             may interfere the subjects' participation in the study or affect study result
             evaluation judged by investigator. Any factor that the investigator believes may make
             the candidates not suitable to receive study drug. The candidates are unwilling or
             unable to comply with the requirements of the study protocol.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients with dose limiting toxicity ( DLT).
Time Frame:From first dosing ( Day -7) to the last dosing of Cycle 1 ( Day 28).
Safety Issue:
Description:DLT to be evaluated according to NCI CTCAE V4.03

Secondary Outcome Measures

Measure:Maximum plasma concentration (Cmax) of BPI-7711 and its main metabolites.
Time Frame:Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.
Safety Issue:
Description:Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.
Measure:Peak Plasma Time (tmax) of BPI-7711 and its main metabolites after single dose.
Time Frame:Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.
Safety Issue:
Description:Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.
Measure:Area under the plasma concentration versus time curve (AUC) of BPI-7711 and its main metabolites after single dose.
Time Frame:Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.
Safety Issue:
Description:Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.
Measure:Clearance of BPI-7711 and its main metabolites after single dose.
Time Frame:Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.
Safety Issue:
Description:Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.
Measure:Half life of BPI-7711 and its main metabolites after single dose.
Time Frame:Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h, 48h, 72h, 120h, 144h post first dose on Day -7.
Safety Issue:
Description:Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Day-7~Day-1 at designated time points.
Measure:Blood concentration of BPI-7711 and its main metabolites after single dose under steady state.
Time Frame:Pre-dose of Cycle1 Day1, 8, 15. Pre-dose, 1h, 1.5h, 2h, 3h, 4h, 5h, 6h, 8h, 12h, 24h post dose on Cycle 2 Day1
Safety Issue:
Description:Collect and analyze the blood concentration data of BPI-7711 and its main metabolites on Cycle 1 Day1, Cycle Day 8, Cycle 1 Day 15 and Cycle 2 Day1 at designated time. points.
Measure:Objective response rate (ORR) of BPI-7711 capsule.
Time Frame:At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.
Safety Issue:
Description:Objective response rate evaluated by CT, MRI examination results according to RECIST 1.1.
Measure:Best objective response (BOR) of BPI-7711 capsule.
Time Frame:At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.
Safety Issue:
Description:Best objective response evaluated by CT, MRI examination results according to RECIST 1.1.
Measure:Disease control rate ( DCR) of BPI-7711 capsule.
Time Frame:At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.
Safety Issue:
Description:Disease control rate evaluated by CT, MRI examination results according to RECIST 1.1.
Measure:Duration of response ( DoR) of BPI-7711 capsule.
Time Frame:At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.
Safety Issue:
Description:Duration of response evaluated by CT, MRI examination results according to RECIST 1.1.
Measure:Progression free survival (PFS) of BPI-7711 capsule.
Time Frame:At screening, and every two cycles from the first multiple dose on Cycle 1 Day 1( 21 days as one cycle) until the date of first documented progression, death or withdrawal from study, whichever came first, assessed up to 20 months.
Safety Issue:
Description:Progression free survival evaluated by CT, MRI examination results according to RECIST 1.1.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Beta Pharma Shanghai

Trial Keywords

  • non-small cell lung cancer
  • NSCLC

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