| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Gastric or Gastroesophageal Junction Adenocarcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Gastric or Gastroesophageal Junction Adenocarcinoma |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10017770 |
| E.1.2 | Term | Gastric carcinoma |
| 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 |
1. To evaluate PFS per RECIST 1.1 by blinded central radiologists' review of participants with PD-L1 positive expression with advanced gastric or
GEJ adenocarcinoma who have progressed on one previous line of therapy, when treated with pembrolizumab compared to paclitaxel.
2. To evaluate OS of participants with PD-L1 positive expression with advanced gastric or GEJ adenocarcinoma who have progressed on one
previous line of therapy, when treated with pembrolizumab compared to paclitaxel. |
|
| E.2.2 | Secondary objectives of the trial |
1. Of all participants with advanced gastric or GEJ adenocarcinoma who have progressed on 1 previous line of therapy, when treated with
pembrolizumab compared to paclitaxel, to evaluate: a. PFS per RECIST 1.1 by blinded central radiologists' review b. OS.
2) Among participants with PD-L1 positive expression and all participants, when treated with pembrolizumab compared to paclitaxel, to evaluate:
a) PFS per RECIST 1.1 by investigator assessment and PFS per irRECIST by blinded central radiologists' review
b) Time to Progression (TTP), Overall Response Rate (ORR), and Duration of Response (DOR), per RECIST 1.1 by blinded central radiologists' review/ by investigator assessment
3) Evaluate the safety and tolerability profile of pembrolizumab in participants with PD-L1 positive expression and all participants compared to paclitaxel. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Be willing and able to provide written informed consent/assent for the trial. The participant may also provide consent for Future Biomedical Research. However, the participant may participate in the main trial without participating in Future Biomedical Research.
2. Be 18 years of age on day of signing informed consent (or acceptable age according to local regulations, whichever is older).
3. Have histologically or cytologically-confirmed diagnosis of gastric or GEJ adenocarcinoma.
4. Have metastatic disease or locally advanced, unresectable disease.
5. Have measurable disease as defined by RECIST 1.1 as determined by investigator. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
6. Have a PS of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
7. Has experienced documented objective radiographic or clinical disease progression during or after first-line therapy containing any platinum/fluoropyrimidine doublet.
a. To be considered as second-line, the participant needs to have the documentation of disease progression on first-line treatment. The
disease progression can be confirmed by CT scan or by clinical evidence (such as cytology report from newly developed ascites and plural
effusion).
b. Any new or worsening malignant effusion (documented by ultrasound) may be confirmed by pathologic criteria (histology and/or
cytology) if appropriate.
c. A participant experiencing clinical disease progression during or within 6 months following the last dose of adjuvant or neo-adjuvant
therapy will be eligible for enrollment provided they received a platinum/fluoropyrimidine doublet as required.
d. To be eligible, the participant is required to have received at least one dose of platinum and fluoropyrimidine therapy.
8. Be willing to provide tissue for PD-L1 biomarker analysis and, based on the adequacy of the tissue sample quality for assessment of PD-L1 status, received permission for enrollment from the Core Lab. Repeat samples may be required if adequate tissue is not provided. Newly obtained biopsy specimens are preferred to archived samples and formalin-fixed, paraffin-embedded (FFPE) block specimens are preferred to slides. As of 20 MAR 2016, participants must be PD-L1 positive to be enrolled.
9. Participants with human epidermal growth factor receptor 2 (HER-2/neu) negative tumors are eligible. For participants with HER2/neu positive tumors or have an unknown tumor status, need to match the following:
a. If HER2/neu+ , participant must have documentation of disease progression on treatment containing trastuzumab.
b. Participants with unknown status must have their HER2/neu status determined locally. If HER2/neu -, the participant will be eligible. If
HER2/neu +, the participant must have documentation of disease progression on treatment containing trastuzumab.
10. Female participants of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from
heterosexual activity for the course of the study through 120 days after the last dose of study treatment for the pembrolizumab arm and through
180 days after the last dose of study treatment for the paclitaxel arm .Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study treatment for the pembrolizumab arm and through 180 days after the last dose of study treatment for the paclitaxel arm.
11. Demonstrate adequate organ function
12. Female participants of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
|
|
| E.4 | Principal exclusion criteria |
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 investigation device within 4 weeks of the first dose of treatment.
2. Has squamous cell or undifferentiated gastric cancer.
3. Has active autoimmune disease that has required systemic treatment in 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.
4. 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. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
5. Has had a prior anticancer mAb < 4 weeks prior to Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to agents administered > 4 weeks earlier.
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Note: Subjects with ≤ Grade 2 neuropathy or ≤ Grade 2 alopecia are an exception to this criterion and may qualify for the study.
a. If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
8. Has known central nervous system metastases and/or carcinomatous meningitis. Participants 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.
9. Has a history of (noninfectious) pneumonitis that required steroids or current pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the participant's participation for the full duration of the trial, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
13. Is pregnant or breastfeeding, or expecting to conceive or Father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of study Treatment for the pembrolizumab arm and through 180 days after the last dose of study treatment for the paclitaxel arm.
14. Has received prior immunotherapy including anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or if the participant has previously participated in Merck pembrolizumab (MK-3475) clinical trials.
15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C.
17. Has received a live vaccine within 30 days of planned start of study therapy.
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.
18. Known allergy or hypersensitivity to paclitaxel or any components used in the paclitaxel preparation or other contraindication for taxane therapy. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. PFS per RECIST 1.1 by blinded central radiologists' review in PDL1 positive participants
2. OS in PD-L1 positive participants |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
•IA Timing: To be performed after:
(1) enrollment is completed
(2) approximately 240 OS events have been observed among PD-L1 positive participants and
(3) a minimum of 260 PFS events have been observed among PD-L1 positive participants
Purpose: IA for OS and main efficacy analysis for PFS
•FA
Timing: at least 290 OS events have been observed among PD-L1 positive participants, or approximately 15 months after last patient
randomized, whichever is later.
Purpose: Main efficacy analysis for OS. |
|
| E.5.2 | Secondary end point(s) |
1. PFS per RECIST 1.1 by blinded central radiologists' review in all participants
2. OS in all participants |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•IA
Timing: To be performed after:
(1) enrollment is completed
(2) approximately 240 OS events have been observed among PD-L1 positive participants and
(3) a minimum of 260 PFS events have been observed among PD-L1 positive participants
Purpose: IA for OS and main efficacy analysis for PFS
•FA
Timing: at least 290 OS events have been observed among PD-L1 positive participants, or approximately 15 months after last patient
randomized, whichever is later.
Purpose: Main efficacy analysis for OS. |
|
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Chile |
| Colombia |
| Guatemala |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| Mexico |
| New Zealand |
| Philippines |
| Puerto Rico |
| Russian Federation |
| Singapore |
| South Africa |
| Taiwan |
| Turkey |
| United States |
| Belgium |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Ireland |
| Italy |
| Lithuania |
| Norway |
| Poland |
| Spain |
| United Kingdom |
| Argentina |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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