| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| untreated patients with adenocarcinoma of the lung of advanced stage |
|
| E.1.1.1 | Medical condition in easily understood language |
| untreated patients with adenocarcinoma of the lung of advanced stage |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
The objectives of this study are to determine DNA methylation as well as expression of CTAs in lung adenocarcinoma patients whose tumor cells do express PD-L1 (≥ 1%) as well as in
patients whose tumor cells do not express PD-L1. These results will be compared with the outcome of the patients after treatment with the combination of chemotherapy and
pembrolizumab. In addition, expression of selected CTAs will be investigated in serum samples from these patients.
We hypothesize that in lung adenocarcinomas expression of CTAs may be upregulated by loss of DNA methylation which may result in an enhanced immune response and finally in an
enhanced tumor response and in a better clinical outcome of some patients. |
|
| E.2.2 | Secondary objectives of the trial |
To investigate expression of CTAs in tumor samples (with ≥ 1% PD-L1 expression on tumor cells versus without PD-L1 expression on tumor cells) of lung adenocarcinoma patients obtained before treatment with the combination of chemotherapy and pembrolizumab
• To determine the response rate (complete and partial remission, stable disease; measured by computertomography; RECIST 1.1 criteria) at 6 months after start of treatment
• To analyse the distribution of PFS (time from start of treatment to radiologically confirmed progressive disease or death due to any cause) of patients
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have an untreated lung adenocarcinoma of advanced stage.
2. Be willing and able to provide written informed consent/assent for the trial.
3. Be ≥ 18 years of age on day of signing informed consent.
4. Have measurable disease based on RECIST 1.1.
5. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1.
6. Have a performance status of 0 or 1 on the ECOG Performance Scale.
7. Demonstrate adequate organ function as defined in
8. Table 1, all screening labs should be performed within 10 days of treatment initiation.
Table 1 Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥ 1,500 /mcL
Platelets
≥ 100,000 / mcL
Hemoglobin
≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)
Renal
Serum creatinine OR
Measured or calculateda creatinine clearance
(GFR can also be used in place of creatinine or CrCl)
≤ 1.5 X upper limit of normal (ULN) OR
≥ 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN
Hepatic
Serum total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastases
Albumin
> 2.5 mg/dL
Coagulation
International Normalized Ratio (INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT)
≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
≤ 1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or PTT is within therapeutic range of intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
10. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 – Contraception, for the course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
11. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
|
|
| E.4 | Principal exclusion criteria |
The subject must be excluded from participating in the trial if the subject:
1. 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 treatment.
2. Has received radiotherapy within 14 days before the first dose of study treatment or received lung radiation therapy of > 30 Gy within 6 months before the first dose of study treatment.
3. Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
4. Has had an allogeneic tissue/solid organ transplant.
5. 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 trial treatment.
6. Has a known history of active TB (Bacillus Tuberculosis)
7. Hypersensitivity to pembrolizumab or any of its excipients.
8. Has had prior chemotherapy, targeted small molecule therapy or therapy with an anticancer monoclonal antibody.
9. Has had radiation therapy within 2 weeks prior to study Day 1.
10. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
11. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic 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. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
12. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 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.
13. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
14. Has an active infection requiring systemic therapy.
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
16. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
20. Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of study therapy. Administration of killed vaccines is allowed.
21. Evidence of interstitial lung disease.
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Response rate according to RECIST 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Progression-free survival at 6 and 12 months
Expression and DNA methylation of CTAs in tumor samples
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| after 30 month of treatment |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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