| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| unresectable or recurrent gastric or gastroesophageal junction adenocarcinoma |
|
| 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 | PT |
| E.1.2 | Classification code | 10017761 |
| E.1.2 | Term | Gastric cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate and compare the efficacy of GS-5745 in combination with nivolumab versus nivolumab alone in subjects with recurrent gastric or GEJ adenocarcinoma |
|
| E.2.2 | Secondary objectives of the trial |
To characterize and compare safety and tolerability of GS-5745 in combination with nivolumab versus nivolumab alone in subjects with recurrent gastric or GEJ adenocarcinoma
To characterize the pharmacokinetics (PK) of GS-5745 in combination with nivolumab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Age ≥18 years
2) Histologically confirmed inoperable locally advanced or metastatic adenocarcinoma of the stomach or GEJ which have progressed on at least 1 prior systemic therapy or line of treatment for unresectable/metastatic disease
3) Eastern Cooperative Oncology Group (ECOG) ≤ 1
4) Measurable disease according to RECIST v1.1
5) Tumor sites that can be accessed for repeat biopsies
6) Archival tumor tissue, preferably from the most recent available biopsy; there must be adequate tissue for a PD-L1 stratification test, as assessed by central pathologist
7) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to grade 1 (NCI CTCAE version 4) or baseline
8) Subjects not receiving anticoagulant medication must have an international normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin (aPTT) ≤ 1.5 x upper limit of normal (ULN). The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard in the institution) and the subject has been on stable dose of anticoagulants for at least 1 week at the time of randomization
9) Adequate hematologic function
a) neutrophils ≥ 1.5 x 10^9/L
b) platelets ≥ 100 x 10^9/L
c) hemoglobin ≥ 9 g/dL
10) Adequate hepatic function
a) Direct or total bilirubin ≤ 1.5 x ULN
b) ALT and AST ≤ 2.5 x ULN
11) Creatinine clearance (CLcr) ≥ 60 mL/min, estimated based on the Cockroft-Gault formula or measured based on 24 hour urine collection or other reliable method
12) For female subjects of childbearing potential, willingness to use a protocol-recommended method of contraception from the screening visit throughout the study treatment period, for 90 days following the last dose of GS-5745 and at least 5 months after the last dose of nivolumab, unless the subject chooses continuous heterosexual abstinence as a lifestyle-choice (see Appendix 4 of the protocol)
13) For male subjects of reproductive potential having intercourse with females of childbearing potential, willingness to use a protocol recommended method of contraception and to refrain from sperm donation from the start of study drug, throughout the study treatment period, and for 90 days after administration of the last dose of GS-5745 or nivolumab (see Appendix 4 of the protocol)
14) Breastfeeding females must agree to discontinue nursing before study drug administration
15) In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current disease status, medical condition, and the potential benefits and risks of alternative treatments for the subject’s cancer
16) Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions
17) Evidence of a signed informed consent prior to implementation of any protocol specific procedure |
|
| E.4 | Principal exclusion criteria |
1) Subjects who have received only neoadjuvant or adjuvant therapy for gastric adenocarcinoma
2) Radiotherapy within 28 days of randomization; subjects given palliative radiotherapy to peripheral sites (eg, bone metastasis) may enter the study before 28 days have elapsed provided the radiated sites do not contain lesions which may be used to evaluate response, and must have recovered from any acute, reversible effects
3) Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, active gastrointestinal bleeding, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements as judged by treating physician
4) History of a concurrent or second malignancy except for adequately treated local basal cell or squamous cell carcinoma of the skin; cervical carcinoma in situ; superficial bladder cancer; asymptomatic prostate cancer without known metastatic disease, with no requirement for therapy or requiring only hormonal therapy, and with normal prostate-specific antigen for ≥ 1 year prior to randomization; adequately treated Stage 1 or 2 cancer currently in complete remission; or any other cancer that has been in complete remission for ≥ 5 years
5) Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (ie, larger than what is required for placement of central venous access, percutaneous feeding tube, or biopsy), within 28 days of first dose of study drug
6) Known positive status for human immunodeficiency virus (HIV)
7) Known acute or chronic-active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
8) Chronic daily treatment with oral corticosteroids (dose of > 10 mg/day prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled steroids and short courses of oral steroids for anti-emesis or as an appetite stimulant are allowed
9) Known or suspected central nervous system metastases
10) Known alcohol or drug abuse or any other medical or psychiatric condition which contraindicates participation in the study
11) Documented myocardial infarction or unstable/uncontrolled cardiac disease (ie, unstable angina, congestive heart failure [New York Heart Association > Class II]) within 6 months of randomization
12) Serious systemic fungal, bacterial, viral, or other infection that is not controlled or requires intravenous antibiotics
13) Pregnant or breastfeeding women (pregnancy needs to be excluded by testing of beta-human chorionic gonadotropin [β-hCG])
14) Experimental medical treatment within 28 days prior to randomization
15) Known hypersensitivity to GS-5745 or nivolumab or excipients or to Chinese hamster ovary cell products or to recombinant human or humanized antibodies
16) Prior treatment with anti-CTLA-4 agents (ipilimumab), anti-PD-1 or anti-PD-L1 agents (pembrolizumab, nivolumab), anti-PD-L2 agents, anti-MMP agents, or other immunomodulatory therapies
17) Previous severe hypersensitivity reaction to treatment with another monoclonal antibody Therapy
18) Subject is expected to require any other form of systemic or localized antineoplastic therapy while on study
19) Prior therapy with anti-tumor vaccines or other immuno-modulatory antitumor agents
20) Current or history of pneumonitis or interstitial lung disease
21) Active known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
22) History of bone marrow, stem cell, or allogeneic organ transplantation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective Response Rate; ORR will be determined from the subjects’ best response during treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Laboratory/clinic visits will occur every 2 weeks through week 96, at EOT and EOS visits and 30-day safety follow-up visit.
Adverse events will be assessed at each clinic visit from screening up to and including the 30-day safety follow-up visit or EOS visit whichever is later.
Tumor evaluation by CT or MRI will be performed during screening and approximately every 8 weeks regardless of visit week or dose interruption. |
|
| E.5.2 | Secondary end point(s) |
• Progression free survival, defined as the interval from the date of randomization to the earlier of the first documentation of definitive disease progression or death from any cause.
• Overall survival, defined as the interval from date of randomization to death from any cause.
• Duration of response, defined as the interval from the date of the first response (CR or PR) is achieved to the earlier of the first documentation of definitive disease progression or death from any cause.
• Occurrence of adverse events and laboratory abnormalities during treatment. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Laboratory/clinic visits will occur every 2 weeks through week 96, at EOT and EOS visits and 30-day safety follow-up visit.
Adverse events will be assessed at each clinic visit from screening up to and including the 30-day safety follow-up visit or EOS visit whichever is later.
Tumor evaluation by CT or MRI will be performed during screening and approximately every 8 weeks regardless of visit week or dose interruption. |
|
| 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 | No |
| 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 | Yes |
| 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 | 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 | No |
| 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 | 35 |
| 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 |
| Belgium |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
| 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
|
|
| 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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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