MC# 20-03 - A Phase II Multi Center Study of BGB324 in Combination with Pembrolizumab in Patients with Previously Treated Advanced Adenocarcinoma of the Lung

  • Agent(s): BGB324
  • Disease Type(s): Lung-NSCLC
  • Phase(s): II
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): AKT, AXL, EGFR

Mechanism of Action

BGB324 is a potent selective small molecule inhibitor of Axl, a surface membrane protein kinase receptor.  Signaling through Axl stimulates a number of pro-survival pathways, some of which are mediated by AKT phosphorylation and up-regulation of the epithelial receptor kinase pathway.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of BGB324 when given in combination with Pembrolizumab
  • How much of BGB324 when given with Pembrolizumab is absorbed into the blood and how fast it is removed
  • How much of Pembrolizumab with given with BGB324 is absorbed into the blood and how fast it is removed
  • How proteins that indicate the status of your disease are affected with use of BGB324 when given in combination with Pembrolizumab
Inclusion Criteria
  1. Provision of signed informed consent
  2. Male and non-pregnant females who are aged 18 years or older at the time of provision of informed consent
  3. Histopathologically or cytologically documented Stage IV adenocarcinoma NSCLC
    • Cohort A: Has disease progression on or after a prior platinum-containing chemotherapy
    • Cohort B: Has received a maximum of two prior lines of therapy in the advanced setting, with the most recent treatment regimen containing an anti-PD-(L)1-therapy (as monotherapy or in combination)
      • Must have had disease control on most recent treatment containing at least 2 doses of anti-PD(L)1-therapy.  Disease control is defined as;
        • Stable disease (SD) for at least 12 weeks (date of first progression on anti- PD-(L)1 therapy) OR
        • Confirmed partial response or complete response (PR/CR) - confirmatory scan must be performed >4 weeks from initial scan)
      • Has disease progression when entering screening (first date of progression of disease is taken as end date of response to previous PD-(L)1 therapy) and this must be within 12 weeks of last dose of most recent treatment containing an anti-PD-(L)1-therapy. Progression should have been confirmed in one of the following ways:
        • Having had two scan assessments completed at least 4 weeks apart, both showing progression according to RECIST 1.12 or
        • Having had one scan assessment completed showing disease progression according to standards used for previous therapy combined with rapid disease progression / clinical progression
    • Cohort C: Has received a maximum of one prior line of therapy in the advanced setting containing an anti-PD(L)1-therapy in combination with a platinum-containing chemotherapy
      • Must have had disease control on most recent treatment containing at least 2 doses of anti-PD-(L)1-therapy.  Disease control is defined as;
        • Stable disease (SD) for at least 12 weeks (date of first progression on anti- PD-(L)1 therapy) OR
        • Confirmed partial response or complete response (PR/CR) - confirmatory scan must be performed >4 weeks from initial scan
      • Has disease progression when entering screening (first date of progression of disease is taken as end date of response to previous PD-(L)1 therapy) and this must be within 12 weeks of last dose of most recent treatment containing an anti-PD-(L)1 therapy.  Progression should have been confirmed in one of the following ways:
        • Having had two scan assessments completed at least 4 weeks apart, both showing progression according to RECIST 1.12 OR
        • Having had one scan assessment completed showing disease progression according to standards used for previous therapy combined with rapid disease progression / clinical progression
  4. Measurable disease as defined by RECIST 1.12 on computed tomography (CT) or magnetic resonance imaging (MRI) and as determined by the site study team.  Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
  5. Provision of suitable tumor tissue for the analysis of Axl kinase expression and PD-L1 expression.  Suitable tumor tissue must consist of a minimum of newly acquired (fresh) tumor tissue sample (as a FFPE block), together with either further newly acquired tumor tissue (i.e. further FFPE block) or an archival tumor tissue sample (as a further FFPE block or further 10 unstained slides).
  6. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1
  7. Life expectancy of at least 3 months
  8. Adequate organ function confirmed at Screening within 10 days of treatment initiation as evidenced by:
    • Platelet count ≥100,000 /mm3;
    • Hemoglobin ≥9.0 g/dL (≥5.6 mmol/L);
    • Absolute neutrophil count (ANC) >1,500 /mm3;
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times the upper limit of normal (ULN), or ≤5 times the ULN for patients with liver metastases;
    • Total bilirubin ≤1.5 times the ULN, or direct bilirubin <ULN for patients with total bilirubin levels >1.5 ULN;
    • Creatinine ≤1.5 times the ULN or calculated creatinine clearance 60 mL/min (by Cockcroft Gault formula);
    • International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times the ULN and Activated Partial Thromboplastin Time (aPTT) ≤1.5 times the ULN
  9. Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to the first dose of study treatment.  If urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  10. Patients (both male and female) of reproductive potential must be willing to practice highly effective methods of contraception throughout the study and for 120 days after the last dose of study medication.  Abstinence is acceptable if this is the usual lifestyle for the patient.  Female patients are considered NOT of childbearing potential if they have a history of surgical sterility or evidence of post-menopausal status defined as any of the following:
    • ≥45 years of age and has not had menses for more than 1 year;
    • Amenorrheic for <2 years without a hysterectomy and oophorectomy and a follicle stimulating hormone (FSH) value in the postmenopausal range upon Screening evaluation;
    • Post hysterectomy, oophorectomy or tubal ligation.  Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound.  Tubal ligation must be confirmed with medical records of the actual procedure.
  11. Have resolution of toxic effect(s) of the most recent prior cancer therapy to Grade 1 or less (except alopecia).  If subject received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
Exclusion Criteria
  1. Has disease suitable for local therapy administered with curative intent.
  2. Cohort A and Cohort C: Has received more than one prior line of chemotherapy for advanced or metastatic adenocarcinoma of the lung; Cohort B: Has received more than two prior lines of therapy for advanced or metastatic adenocarcinoma of the lung
  3. Cohort A: Has received prior therapy with an immunomodulatory agent
  4. Has a known additional malignancy that is progressing or requires active treatment
  5. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
  6. History of the following cardiac conditions:
    • Congestive  cardiac  failure  of  >Grade  II   severity   according   to   the NYHA
    • Ischemic cardiac event including myocardial infarction within 3 months prior to first dose
    • Uncontrolled cardiac disease, including unstable angina, uncontrolled hypertension (i.e. sustained systolic BP >160 mmHg or diastolic BP >90 mmHg), or need to change medication due to lack of disease control within 6 weeks prior to the provision of consent
    • History or presence of sustained bradycardia (≤55 BPM), left bundle branch block, cardiac pacemaker or ventricular arrhythmia
    • Family history of long QTc syndrome; personal history of long QTc syndrome or previous drug-induced QTc prolongation of at least Grade 3 (QTc >500 ms)
  7. Abnormal left ventricular ejection fraction on echocardiography or Multi Gated Acquisition Scan (MUGA) (less than the lower limit of normal for a patient of that age at the treating institution or <45%, whichever is lower)
  8. Current treatment with any agent known to cause Torsades de Pointes which cannot be discontinued at least five half-lives or two weeks prior to the first dose of study treatment
  9. Screening 12-lead ECG with a measurable QTc interval according to Fridericia’s correction >450 ms
  10. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of study treatment
  11. Has participated in a study involving any immune check point inhibitor other than currently approved immune check point inhibitors for their lung cancer
  12. Received chemotherapy or targeted small molecule therapy or radiation therapy within 2 weeks prior to starting study treatment or who has not recovered (i.e. ≤Grade 1 at baseline) from adverse events due to a previously administered agent.  If the patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  13. Received an anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first dose of study treatment or who has not recovered (i.e. ≤Grade 1 or baseline) from adverse events due to agents administered more than 4 weeks earlier
  14. Major surgery within 28 days prior to start of study treatment and failure to have recovered adequately from the toxicity and/or complications from the intervention prior to the first dose of study treatment
  15. Received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoetin) within 4 weeks prior to the first dose of study treatment
  16. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment
  17. Active autoimmune disease that has required systemic treatment in past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs)
  18. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  19. Has known active infection with Hepatitis B (e.g. HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected)
  20. Has received a live-virus vaccination within 30 days of planned treatment start
  21. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  22. Has a history of interstitial lung disease
  23. Inability to swallow or tolerate oral medication
  24. Existing gastrointestinal disease affecting drug absorption such as celiac disease or Crohn’s disease, or previous bowel resection which is considered to be clinically significant or could interfere with absorption
  25. Known lactose intolerance
  26. Requires vitamin K antagonists
  27. Treatment with any of the following: histamine receptor 2 inhibitors, proton pump inhibitors or antacids within 7 days of start of study
  28. Treatment with any medication which is predominantly metabolized by CYP3A4 and has a narrow therapeutic index
  29. Known severe hypersensitivity (Grade 3) to bemcentinib, pembrolizumab, and/or any of their excipients
  30. Any evidence of severe or uncontrolled systemic conditions (e.g. severe hepatic impairment) or current unstable or uncompensated respiratory or cardiac conditions, or ongoing
  31. Has active infection requiring systemic therapy (apart from cutaneous infections)
  32. Has received radiation to the lung of >30Gy within 6 months of first dose
  33. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient’s participation for the full duration of the trial, or means it is not in the best interest of the patient to participate, in the opinion of the Investigator
  34. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting from Screening through to 120 days after the last dose of study treatment
  35. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  36. Cohorts B and C: Has an EGFR mutation or ALK genomic rearrangement

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03184571

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Re: MC# 20-03