| Eligibility |
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 non-small cell
lung cancer (NSCLC). Note: participants with a mixed histology including a significant
area of adenocarcinoma histology are eligible.
4. Cohort A only: Has disease progression on or after a prior platinum-containing
chemotherapy. Note: participants with Epidermal growth factor receptor (EGFR)
mutations or Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK) genomic rearrangements
must have documented disease progression on at least one licensed therapy for these
indications and may not have received platinum-containing chemotherapy.
5. Cohort B only:
1. Has received a maximum of one prior line of an anti-PD-(L)1 therapy
(monotherapy).
2. Must have had disease control (SD, PR or CR) for at least 6 months on most recent
treatment containing at least 2 doses of anti-PD-(L)1-therapy.
3. Has disease progression when entering screening 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: (i) Having
had two scan assessments completed at least 4 weeks apart, both showing
progression according to RECIST 1.1 or (ii) having had one scan assessment
completed showing disease progression according to standards used for previous
therapy combined with rapid disease progression / clinical progression.
6. Cohort C: Only
1. Has received a maximum of one prior line of an anti-PD-(L)1 therapy in
combination with a platinum-containing chemotherapy.
2. Must have had disease control containing at least 2 doses of anti-PD-(L)1
therapy. Disease control is defined as; (i) Stable disease (SD) for at least 12
weeks (date of first progression on anti-PD-(L)1 therapy) Or (ii). Confirmed
partial response or complete response (PR/CR) - confirmatory scan must be
performed >4 weeks from initial scan c) Has disease progression when entering
screening (first date of progression of disease is taken as end date of response
to previous anti-PD-(L)1 therapy) and this must be within 12 weeks of last dose
of treatment containing an anti-PD-(L)1 therapy. Progression should have been
confirmed in one of the following ways: (i) Having had two scan assessments
completed at least 4 weeks apart, both showing progression according to RECIST
1.12 or (ii) Having had one scan assessment completed showing disease progression
according to standards used for previous therapy combined with rapid disease
progression / clinical progression.
7. Measurable disease as defined by RECIST 1.1 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.
8. 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 Formalin fixed paraffin embedded [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).
See Section 5.3.13 for further details.
9. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1.
10. Life expectancy of at least 3 months.
11. Adequate organ function confirmed at Screening within 10 days of treatment initiation
- as evidenced by:
1. Platelet count =100,000 /mm3;
2. Hemoglobin =9.0 g/dL (=5.6 mmol/L);
3. Absolute neutrophil count (ANC) >1,500 /mm3;
4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =2.5 times
the upper limit of normal (ULN), or =5 times the ULN for participants with liver
metastases;
5. Total bilirubin =1.5 times the ULN or direct bilirubin <=ULN for participants
with total bilirubin levels >1.5 ULN.
6. Creatinine =1.5 times the ULN or calculated creatinine clearance 60 mL/min (by
Cockcroft Gault formula);
7. International Normalized Ratio (INR) or Prothrombin Time (PT) =1.5 times the ULN
and Activated Partial Thromboplastin Time (aPTT) =1.5 times the ULN. Note: If
participants is receiving anticoagulant therapy, then PT or Partial
thromboplastin time (PTT) must be within therapeutic range of intended use of
anticoagulants;
12. Female participants 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.
13. participants (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 participants. Female participants 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:
1. =45 years of age and has not had menses for more than 1 year;
2. Amenorrheic for >2 years without a hysterectomy and oophorectomy and a follicle
stimulating hormone (FSH) value in the postmenopausal range upon Screening
evaluation;
3. 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.
14. Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 or
less (except alopecia). If the participants 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. Has received more than 1 prior line of chemotherapy for advanced or metastatic
adenocarcinoma of the lung.
3. Cohort A: Has received prior therapy with an immunomodulatory agent; Cohort B: Has
received prior chemotherapy alone or in combination with immunotherapy in the
metastatic setting
4. Has a known additional malignancy that is progressing or requires active treatment.
Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of
the skin that has undergone potentially curative therapy or in situ cervical cancer.
5. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Note: participants with previously treated brain metastases may
participate provided they are stable (without evidence of progression by imaging
(using the identical modality for each assessment, either MRI or CT scan) for at least
4 weeks prior to the first dose of trial treatment and any neurological symptoms have
returned to baseline), have no evidence of new or enlarging brain metastases, and are
not using steroids for at least 7 days prior to trial treatment.
6. History of the following cardiac conditions:
1. Congestive cardiac failure of >Grade II severity according to the New York Heart
Association (NYHA) (Appendix C: defined as symptomatic at less than ordinary
levels of activity).
2. Ischemic cardiac event including myocardial infarction within 3 months prior to
first dose.
3. 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.
4. History or presence of sustained bradycardia (=55 BPM), left bundle branch block,
cardiac pacemaker or ventricular arrhythmia. Note: participants with a
supraventricular arrhythmia requiring medical treatment, but with a normal
ventricular rate are eligible.
5. Family history of long QTc syndrome; personal history of long QTc syndrome or
previous drug-induced QTc prolongation of at least Grade 3 (QTc >500ms).
7. Abnormal left ventricular ejection fraction on echocardiography or Multi Gated
Acquisition Scan (MUGA) (less than the lower limit of normal for a participants 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-lifes 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 AEs due to a previously administered agent. Note: Participants with
=Grade 2 alopecia are an exception to this criterion. If the participants 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 (AEs) 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. Note: Major surgery does not include
procedures for insertion of venous catheters or biopsies.
15. Received transfusion of blood products (including platelets or red blood cells) or
administration of colony stimulating factors (including Granulocyte-colony stimulating
factor [G-CSF], Granulocyte-macrophage colony-stimulating factor [GM-CSF] or
recombinant erythropoetin) within 4 weeks prior to the first dose of study treatment.
Note: Participants receiving stable dose of growth factors with a haemoglobin value
that meets Inclusion Criterion 9b may be included.
Note: Participants receiving stable dose of growth factors with a hemoglobin value
that meets Inclusion Criterion 9b may be included.
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.
Note: The use of physiologic doses of corticosteroids may be approved after
consultation with the Sponsor.
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).
Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
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., Hepatitis C virus (HCV) Ribonucleic acid (RNA) [qualitative] is detected).
Note: i) Participants with a history of hepatitis B infection are eligible provided
they are hepatitis B surface antigen negative ii) Participants with a history of
hepatitis C infection are eligible provided they have no evidence of hepatitis C RNA
using a quantitative polymerase chain reaction (qPCR) at least 6 months after
completing treatment for hepatitis infection.
20. Has received a live-virus vaccination within 30 days of planned treatment start. Note:
Seasonal flu vaccines that do not contain live virus are permitted.
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. Note: Participants receiving low doses prescribed to
maintain the patency of venous access devices may be included. Note: Factor Xa
antagonists are permitted.
27. Treatment with any of the following: histamine receptor 2 inhibitors, proton pump
inhibitors or antacids within 7 days of start of study treatment.
28. Treatment with any medication which is predominantly metabolized by CYP3A4 and has a
narrow therapeutic index.
29. Known hypersensitivity (>=Grade 3) to bemcentinib, pembrolizumab, 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 >30 Gy 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 participants
participation for the full duration of the trial, or means it is not in the best
interest of the participants 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. Cohort B only: Has an EGFR mutation or ALK genomic rearrangement.
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