| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. To determine the safety and tolerability of pembrolizumab administered at 200 mg Q3W dosing as monotherapy and in combination with cisplatin and 5-fluorouracil or cisplatin and capecitabine.
2. To estimate the Objective Response Rate (ORR) per RECIST 1.1 assessed by central imaging vendor in all subjects and in PD-L1 positive subjects.
3. To estimate the ORR per RECIST 1.1 assessed by central imaging vendor review. |
|
| E.2.2 | Secondary objectives of the trial |
* To estimate by central imaging vendor:
- DOR per RECIST 1.1. Supportive analyses for this objective and primary objective include ORR and DOR per irRECIST as well as DCR, PFS and OS per RECIST 1.1 and ir RECIST in all subjects and in PD-L1 positive subjects.
- Anti-tumor activity of pembrolizumab in combination with cisplatin and 5-fluorouracil or cisplatin and capecitabine, by ORR per RECIST 1.1. Supportive analyses for this objective include ORR per irRECIST as well as DOR, DCR, PFS and OS per RECIST 1.1 and ir RECIST in all subjects and in PD-L1 positive subjects.
- DOR per RECIST 1.1 in PD-L1 positive subjects. Supportive analyses for this objective and primary objective include ORR and DOR per irRECIST as well as DCR, PFS and OS per RECIST 1.1 and ir RECIST in PD-L1 positive subjects.
* To evaluate the relationship between PD-L1 status and efficacy endpoints in subjects receiving pembrolizumab (as monotherapy or in combination with chemotherapy) with gastric cancer.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
|
|
| E.3 | Principal inclusion criteria |
For potential subjects in Cohort 1 (3L+ cohort):
1.Have received, and progressed on, at least two prior chemotherapy regimens. For the purposes of this study, perioperative, neoadjuvant, adjuvant chemotherapy regimens will not count as a prior regimen, unless the subject progressed while receiving adjuvant therapy or within 6 months of receiving adjuvant treatment. The date of progression and how progression was determined must be known with documentation available confirming progression on or after treatment. Previous treatment regimens must have included a fluoropyrimidine and platinum doublet (as part of either a line of therapy or adjuvant treatment.
2.Be HER-2/neu negative, or, if HER2/neu positive, must have previously received treatment with trastuzumab (Note: If HER2/neu status was previously determined, that result is acceptable but documentation of status must be available; subjects with unknown status will have their HER2/neu status determined locally. Documentation of previous treatment with trastuzumab must also be provided.)
For potential subjects in Cohorts 2 or 3 (1L cohorts):
3.Is HER2/neu negative
4.Have not received prior systemic anti-cancer therapy for their metastatic or advanced gastric or gastroesophageal junction adenocarcinoma. For the purposes of this study, perioperative, neoadjuvant, adjuvant chemotherapy regimens will not count as a prior regimen, unless disease progression has occurred during or within 6 months of adjuvant chemotherapy.
For all potential subjects:
5.Be willing and able to provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
6.Be ≥18 years of age on day of signing informed consent.
7.Have histologically or cytologically-confirmed recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma that is considered incurable by local therapies.
8.Be willing to provide newly-obtained or archived tissue for PD-L1 biomarker analysis
and, based on the adequacy of the tissue sample quality for assessment of PD -L1 status,
have received notice of eligibility prior to non-random allocation. Newly-obtained tissue
will be from the stomach and/or gastroesophageal junction (endoscopic tumor biopsy) or a metastatic location IF obtained as part of normal clinical practice. Repeat samples may
be required if adequate tissue is not provided.
9.Be PD-L1 positive, if the subject is being allocated to a cohort which, at the time of enrollment, is only enrolling PD-L1 positive subjects.
10.Have measurable disease based on RECIST 1.1 as determined by central imaging vendor. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
11.Have a performance status of 0 or 1 on the ECOG Performance Scale within 3 days prior to the first dose of study therapy.
12. Life expectancy of at least 3 months.
13.Female subjects 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 or 180 days after the last dose of study medication (Reference Section 5.7.2). Duration of use will be determined when the subject is assigned to treatment. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year.
Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 or 180 days after the last dose of study therapy. Duration of use will be determined when the subject is assigned to treatment. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
14.Demonstrate adequate organ function.
15.Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
|
|
| E.4 | Principal exclusion criteria |
1. Experienced weight loss >10% over 2 months prior to first dose of study therapy.
2. Has clinical evidence of ascites by physical exam.
3. 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.
4. 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.
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. The use of physiologic doses of corticosteroids (prednisone 10 mg or
equivalent) may be approved after consultation with the Sponsor.
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
7. 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.
8. 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 that has undergone potentially curative therapy or in situ cervical cancer.
9. 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.
10. Has known history of, or any evidence of active, non-infectious pneumonitis.
11. Has an active infection requiring systemic therapy.
12. Has a history or current evidence of any condition (e.g. known deficiency of the enzyme dihydropyrimidine dehydrogenase [DPD]), 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 (e.g. any contraindication to the use of cisplatin, 5-FU, or capecitabine for subjects in Japan, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
14. 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 or 180 days after the last dose of trial treatment. Duration of use will be determined when the subject is assigned to treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or if the subject has previously participated in Merck MK-3475 clinical trials.
16.Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known chronic or acute Hepatitis B (e.g., HBsAg reactive) or Hepatitis C infection
(e.g., HCV RNA [qualitative] is detected).
18. Has received a live vaccine within 30 days of planned start of study therapy.
19. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy objective of this study is to evaluate the anti -tumor activity of
pembrolizumab in subjects with advanced gastric cancer. Objective Response rates per RECIST 1.1 as assessed by the central imaging vendor will be used as the primary response rate efficacy endpoint. Objective response rate will also be used as the primary endpoint due to the single-arm design of this study.
RECIST 1.1 will be used by the local site for treatment decisions. However RECIST 1.1 will
be adapted to account for the unique tumor response profile seen with immunotherapies such as pembrolizumab. Refer to Section 7.1.2.7.3 for details.
The primary safety objective of this trial is to characterize the safety and tolerability of
pembrolizumab and pembrolizumab in combination with cisplatin+5-FU or
cisplatin+capecitabine in subjects with gastric cancer. The primary safety analysis will be
based on subjects who experienced toxicities as defined by CTCAE criteria .
Safety will be assessed by quantifying the toxicities and grades experienced by subjects who have received pembrolizumab and pembrolizumab in combination with cisplatin+5-FU or cisplatin+capecitabine, including serious adverse events (SAEs) and events of clinical
interest (ECIs). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety and Response will be assessed throughout the entire study. The first protocol defines response assessment is scheduled for Week 9, with additional assessments following at 6 week intervals. |
|
| E.5.2 | Secondary end point(s) |
| A secondary objective of this trial is the evaluation of the relationship between PD-L1 biomarker status as assessed by immunohistochemistry and response to pembrolizumab. This objective will be evaluated using data from both the 3L+ and the 1L monotherapy cohorts. The data obtained in this trial with regard to the biomarker will inform the performance of PD-L1 assessment by IHC, and may determine if the definition of PD-L1 positivity should be modified for future trials or specific populations. Fresh biopsies are currently used for PD-L1 assessment, although in this study archival biopsies will also be obtained to compare the performance of the PD-L1 IHC assay in archived versus fresh biopsies so that it may be possible to use archival biopsies in future studies. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| A fresh tumor sample is required at screening. Archival tumor sample may be provided at any time. The timing of response assessments is detailed in Section E.5.1.1 |
|
| 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 | 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 | No |
| 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 | 3 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Canada |
| Chile |
| Colombia |
| Estonia |
| France |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Lithuania |
| Peru |
| Portugal |
| Romania |
| Russian Federation |
| United Kingdom |
| United States |
|
| 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
|
| The overall trial ends when the last subject completes the last study-related phone-call or trial visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator). |
|
| 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 |
Print
