| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced gastric or gastroesophageal cancer that progressed on or after at least one prior standard therapy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced gastric or gastroesophageal junction cancer that progressed on or after at least one prior standard therapy. |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10017760 |
| E.1.2 | Term | Gastric cancer NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10017767 |
| E.1.2 | Term | Gastric cancer stage IV with metastases |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10017768 |
| E.1.2 | Term | Gastric cancer stage IV without metastases |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066354 |
| E.1.2 | Term | Adenocarcinoma of the gastroesophageal junction |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Study objectives are the same for both Group 1 (CPI naïve) and Group 2 (CPI relapse).
- To assess the safety and tolerability of bavituximab in combination with pembrolizumab in patients with advanced gastric/GEJ cancer
- To assess the antitumor activity of the treatment combination based on Response Evaluation Criteria in Solid Tumors (RECIST) Guideline version 1.1
|
|
| E.2.2 | Secondary objectives of the trial |
- To further characterize the antitumor activity of the treatment combination based on additional assessments of clinical benefit
- To evaluate bavituximab concentrations when administered in combination with pembrolizumab
- To assess the potential immunogenicity bavituximab
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For Group 1 only (CPI naïve):
1. Progressed on and/or after at least 1 prior regimen for metastatic disease which includes a fluoropyrimidine and a platinum:
• Progression within 6 months of prior adjuvant or neoadjuvant chemotherapy will be deemed a rapid progressor and thus, equivalent to 1 advanced/metastatic disease treatment regimen.
• Changing from IV to oral fluoropyrimidine without noted progression is considered only 1 prior regimen.
• Human epidermal growth factor receptor 2 (HER2)-positive patients must have received prior anti-HER2 therapy and demonstrate PD or was ineligible for such therapy.
For Group 2 only (CPI relapse):
2. Patient achieved stable disease or better in two
consecutive scansachieved stable disease or better in two consecutive scans to PD-1/PD-L1 inhibition alone or in combination with chemotherapy and relapsed following PD-1/PD-L1 inhibition either alone or in combination with chemotherapy
• All patients must be immediate (defined by within 3 months) progressors of PD 1/PD-L1 inhbition with no intervening treatment with other agents such as chemotherapy alone.
For both Group 1 and Group 2:
3. Signed written informed consent obtained prior to performing any study procedure, including screening procedures.
4. Men and women ≥ 18 years old; ≥ 20 years old in South Korea and Taiwan.
5. Pathologically documented unresectable metastatic or locally advanced gastric or GEJ adenocarcinoma:
• Must be metastatic/unresectable at the time of enrollment into this study.
6. Willing and able to provide fresh (since most recent progression) formalin-fixed paraffin-embedded tissue tumor sample for screening of signature status prior to study treatment and to measure PD-1 status. An archival tissue sample should also be provided, if available.
7. Presence of at least one measurable lesion assessed by the Investigator per RECIST version 1.1.
8. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
9. Has adequate organ functions defined as listed in table in section 4.2 in the Protocol.
10. Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to start of study treatment.
11. Women must not be breastfeeding.
12. Women of childbearing potential defined as not surgically sterile or have not been free from menses for ≥ 2 years, must agree to follow instructions for highly effective method(s) of contraception. Patients or Partners of Patients of Reproductive Potential for the duration of treatment with study drug bavituximab and pembrolizumab plus 5 months post-treatment completion.
Males who are sexually active with women of childbearing potential must agree to follow instructions for highly effective method(s) of contraception or Partners of Patients of Reproductive Potentialfor the duration of treatment with study treatment plus 90 days post-treatment completion.
13. Has adequate treatment washout period before the start of study treatment, defined as:
• Major surgery ≥ 4 weeks; radiation therapy with abdominal radiation ≥ 4 weeks and have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.; palliative radiation without abdominal radiation, ≥ 2 weeks; chemotherapy ≥ 3weeks; biologic therapy ≥ 3 weeks |
|
| E.4 | Principal exclusion criteria |
For Group 1 only (CPI naïve):
1. Prior treatment with any checkpoint inhibitor or other therapies targeting T-cell control.
For Group 2 only (CPI relapse):
2. Primary refractory patients, defined as disease progression at first scan following initiation of PD-1/PD-L1 inhibitor treatment, or if best overall response to PD 1/PD L1 inhibition was disease progression
For both Group 1 and Group 2:
3. Received any form of anti-phosphatidylserine therapies.
4. Known microsatellite instability-high (MSI-H) gastric or GEJ adenocarcinoma
5. Medical history of myocardial infarction within 6 months before registration, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV;), troponin levels consistent with myocardial infarction as defined according to American College of Cardiologists (ACC) guidelines, unstable angina, or serious cardiac arrhythmia requiring treatment.
6. Experienced weight loss >10% over 2 months prior to first dose of study treatment.
7. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
8. Known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable without evidence of progression via imaging for at least four weeks prior to first dose of study, and no evidence of neurological symptoms. Carcinomatous meningitis is excluded regardless of clinical stability.
9. Known additional malignancy that is progressing or has required active treatment in within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
10. Active infection requiring systemic therapy.
11. Known human immunodeficiency virus (HIV) infection, or known acute hepatitis B or C infection.
12. Unresolved toxicities from previous cancer treatments (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Grade 2 toxicities may be eligible at the discretion of the Investigator after consultation with the Sponsor’s medical monitor.
13. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
14. Active autoimmune disease or history of chronic recurrent autoimmune disease, requiring systemic treatment for the past two years (i.e., disease modifying agents, corticosteroids, or immunosuppressive drugs).
• Replacement therapy (thyroxine, insulin, or physiological corticosteroid replacement for either adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
15. Severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.
16. History of infusion reactions to any component/excipient of bavituximab.
17. History of severe hypersensitivity reactions to mAbs.
18. Systemic steroid therapy (>10 mg daily prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment (note: topical, inhaled, nasal and ophthalmic steroids are permitted).
19. Received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
20. Prior organ transplantation including allogeneic or autologous stem-cell transplantation.
21. Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
22. Receipt of treatment with immunotherapy, biological therapies, or therapeutic doses of hormonal therapies within 3 weeks of scheduled C1D1 dosing.
23. Known psychiatric, substance abuse disorder, or geographical travel limitations that would interfere participant’s ability to cooperate with the requirements of the study.
24. Pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 5 months after the last dose of study treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Study endpoints are the same for both Group 1 (CPI naïve) and Group 2 (CPI relapse).
• Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0, including changes in clinical laboratory parameters
• Objective response rate (ORR) as assessed by the Investigator per RECIST version 1.1
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The safety and tolerability of study treatment will be evaluated based on AEs (incidence and severity), performance status, physical examinations, vital sign measurements, standard clinical laboratory safety evaluations. Laboratory abnormalities and AEs will be graded according to CTCAE v5.0. Immune-related reactions (IRRs) may occur with bavituximab and/or pembrolizumab. Detailed guidance for the handling of IRRs will be presented in the protocol. |
|
| E.5.2 | Secondary end point(s) |
• Duration of response (DoR), disease control rate (DCR) (as defined by ORR and stable disease rate at 6 weeks), progression-free survival (PFS), and overall survival (OS)
• Bavituximab concentrations before and after bavituximab infusions
• Presence of anti bavituximab antibodies (anti-drug antibodies [ADAs])
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Efficacy analysis will be performed on the full analysis set, and per protocol analysis set, including predefined biomarker subgroups (as below). Radiological and clinical tumor assessments will be evaluated based on RECIST version1.1. For patients with PD, a confirmatory scan will be performed at least 4 weeks later to confirm PD prior to removing the patient from study treatment. This confirmatory scan is recommended but not required, it is at the discretion of the treating physician. |
|
| 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 | Yes |
| 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
| 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 | No |
| 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 |
| Korea, Republic of |
| Taiwan |
| 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
|
| A maximum 12 months from the last patient receiving the last dose of study therapy or the time point when all patiens have discontinued the study, whichever is sooner. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 21 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 21 |
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