| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Previously Treated Advanced Adenocarcinoma of the Lung |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001160 |
| E.1.2 | Term | Adenocarcinoma lung |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess anti-tumor activity of the combination of bemcentinib and pembrolizumab |
|
| E.2.2 | Secondary objectives of the trial |
To assess the safety of bemcentinib and pembrolizumab when given in combination
To further assess the anti-tumor activity of the combination of bemcentinib and pembrolizumab
To evaluate the pharmacokinetic profile of bemcentinib when given with pembrolizumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Provision of signed informed consent.
2.Male and non-pregnant females aged 18 years or older
3.Histopathologically or cytologically documented Stage IV adenocarcinoma non-small cell lung cancer (NSCLC). Note: Patients with a mixed histology inc a significant area of adenocarcinoma histology are eligible.
4.Cohort A: Has disease progression on or after a prior platinum containing chemotherapy.
Cohort B: a) Has received a maximum of one prior line of anti-PD (L)1 therapy (as monotherapy).
b) Must have had disease control containing at least 2 doses of an anti-PD-(L)1 therapy.
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 must be within 12 weeks of last dose of most recent treatment containing an anti-PD-(L)1 therapy.
Cohort C: a) Has received a maximum of one prior line of anti-PD(L)1 therapy in combination with a platinum-containing chemotherapy.
b) Must have had disease control containing at least 2 doses of anti-PD-(L)1 therapy.
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 must be within 12 weeks of last dose of treatment containing an anti-PD-(L)1 therapy.
5.Measurable disease as defined by RECIST 1.12 on CT or 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.
6.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).
7.Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1 [Appendix A].
8.Life expectancy of at least 3 months.
9.Adequate organ function confirmed at Screening within 10 days of treatment initiation - as evidenced by:
a. Platelet count ≥100,000 /mm3; b. Hemoglobin ≥9.0 g/dL (≥5.6 mmol/L); c. Absolute neutrophil count (ANC) >1,500 /mm3; d. 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; e. Total bilirubin ≤1.5 times the ULN. f. Creatinine ≤1.5 times the ULN or calculated creatinine clearance 60 mL/min (by Cockcroft Gault formula; see Appendix B);
g.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 patient is receiving anticoagulant therapy, then PT or Partial thromboplastin time (PTT) must be within therapeutic range of intended use of anticoagulants;
10.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.
11.Patients (both male and female) of reproductive potential must be willing to practice highly effective methods of contraception (as described in Section 6.14) throughout the study and for 120 days after the last dose of study medication.
12.Have resolution of toxic effect(s) of the most recent prior cancer therapy to Grade 1 or less (except alopecia). If the patient received major surgery or radiation therapy of > 30 Gy, they must have recovered |
|
| E.4 | Principal exclusion criteria |
1. Has disease suitable for local therapy administered with curative intent.
2. Has received more than one 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.
5. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
6. History of cardiac conditions as described in the protocol.
7. Abnormal left ventricular ejection fraction on echocardiography or 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 AEs due to a previously administered agent.
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 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.
15. Received transfusion of blood products or administration of colony stimulating factors 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
18. Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
19. Has known active infection with Hepatitis B or Hepatitis C.
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 treatment.
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 >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 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.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohort A : A 2-stage, single arm, Simon’s 2-stage design1 with one (null hypothesis for futility) interim and a final analysis will be utilized.
The interim analysis will be conducted when 22 patients are evaluable for Objective Response Rate.
Recruitment will be halted whilst the Stage 1 interim analysis is conducted and recommence if the decision is made to continue to the maximum of 48 evaluable patients.
Cohorts B and C:
A single arm, Simon’s 2-stage design with one (null hypothesis for futility) interim and a final analysis. The interim analysis will be conducted when 13 patients are evaluable for Objective Response Rate. When at least 1 patient has an observed response at the interim analysis, up to a further 16 patients may be evaluated, for a total of 29 evaluable patients |
|
| E.5.2 | Secondary end point(s) |
•The number and frequency of adverse events; assessment of safety laboratory parameters, vital signs and ECGs
•To include Disease Control Rate, Duration of Response; Progression-free Survival; 12-month Overall Survival
•Assessment of pharmacokinetic variables including Cmax, AUC, t½
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cohort A : A 2-stage, single arm, Simon’s 2-stage design1 with one (null hypothesis for futility) interim and a final analysis will be utilized.
The interim analysis will be conducted when 22 patients are evaluable for Objective Response Rate.
Recruitment will be halted whilst the Stage 1 interim analysis is conducted and recommence if the decision is made to continue to the maximum of 48 evaluable patients.
Cohorts B and C:
A single arm, Simon’s 2-stage design with one (null hypothesis for futility) interim and a final analysis. The interim analysis will be conducted when 13 patients are evaluable for Objective Response Rate. When at least 1 patient has an observed response at the interim analysis, up to a further 16 patients may be evaluated, for a total of 29 evaluable patients |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 13 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Norway |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
DRC recommends early termination following the review of the ORR and risk: benefit at
- Interim analysis
Or
Study will complete and the final analysis will occur after planned 106 evaluable patients have had the potential to be followed for at least 24 weeks. If there are patients continuing on study treatment at the date of LPLV, the study will be closed once all patients have completed their last dose of study drug or discontinued study drug and have completed their post treatment visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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