| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with HER2-overexpressing advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma that has progressed on or after a prior HER2-directed agent and fluoropyrimidine- or platinum-containing chemotherapy (2nd-line or 3rd-line). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with advanced gastric cancers who have failed prior treatment regimens. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 2
• To assess the effect and contribution of ALX148 plus trastuzumab, ramucirumab, and paclitaxel on objective response rate (ORR), compared to a historical control with a combination of ramucirumab and paclitaxel, in patients with metastatic HER2-overexpressing gastric/GEJ adenocarcinoma that has progressed on or after a prior HER2-directed agent and fluoropyrimidine- or platinum-containing chemotherapy.
Phase 3
• To assess the effect of ALX148 plus trastuzumab, ramucirumab, and paclitaxel versus ramucirumab and paclitaxel on overall survival (OS) in patients with metastatic HER2-overexpressing gastric/GEJ adenocarcinoma that has progressed on or after a prior HER2-directed agent and fluoropyrimidine- or platinum-containing chemotherapy. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 2
• To assess the effect of ALX148 plus trastuzumab, ramucirumab, and paclitaxel on objective response rate (ORR) using blinded independent central review (BICR).
• To assess secondary measures of efficacy for ALX148 administered in combination with trastuzumab, ramucirumab, and paclitaxel versus trastuzumab, ramucirumab, and paclitaxel.
• To assess the safety and tolerability of ALX148 administered in combination with trastuzumab, ramucirumab, and paclitaxel versus trastuzumab, ramucirumab, and paclitaxel.
• To characterize the pharmacokinetics (PK) and evaluate the immunogenicity of ALX148.
Phase 3 (in addition to above)
• To assess the impact of ALX148 administered in combination with trastuzumab, ramucirumab, and paclitaxel versus ramucirumab and paclitaxel on patient reported outcomes of quality of life. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age ≥18 years (except in regions in which the minimum age for subject participation is >18 years).
Patients with HER2-overexpressing advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma that has progressed on or after a prior HER2-directed agent and fluoropyrimidine- or platinum-containing chemotherapy (2nd-line or 3rd-line).
Phase 2: HER2 overexpression determined by an FDA-approved test for gastric/GEJ cancer in the most recent tissue sample. If safe and feasible, it is recommended that patient eligibility be based on a biopsy obtained after prior trastuzumab treatment.
Phase 3: HER2 overexpression (in a tissue sample taken after the patient’s most recent HER2-directed therapy) determined by HER2 protein overexpression and/or HER2 gene amplification in tumor specimens assessed with FDA-approved (and local regulatory authority-approved) tests specific for gastric cancer. (HER2 positivity will be centrally assessed for eligibility in Phase 3.)
Patients must have at least one measurable lesion as defined by RECIST version 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
Adequate bone marrow, renal, liver, cardiac (via ECG), clotting (INR/PT and PTT) function.
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) must be 0 or 1.
Resolved acute effects of any prior therapy.
Patients of childbearing potential must be non-pregnant and must agree to use a highly effective method of contraception throughout the study.
Consent to the study and study procedures.
|
|
| E.4 | Principal exclusion criteria |
Patients with known symptomatic CNS metastases or leptomeningeal disease requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry, have discontinued corticosteroid treatment for these metastases and are clinically stable off anticonvulsants for at least 4 weeks and are neurologically stable before enrollment.
Prior radiotherapy within 2 weeks of start of study treatment. Note: Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
Prior treatment with anti-CD47 or anti-SIRPĪ± agent or ramucirumab or any other systemic anticancer therapy within 4 weeks of starting study treatment.
Any Grade 3-4 GI bleeding or history of deep vein thrombosis (DVT), pulmonary embolism (PE), arterial thrombosis or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered “significant”) within 3 months prior to first dose of Cycle 1 Day 1.
Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.
Prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 2
• Objective response rate (ORR; CR or PR using the Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 for solid tumors) based on investigator assessment. Dropouts will be analyzed as non-responders.
Phase 3
• Overall survival (OS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 2
• Date of first documentation of progression. Scans will continue every 8 weeks (±7 days) for the first 18 months on study or until death, or until starting a new treatment for the disease under study, or withdrawal of consent
Phase 3
• Date of Death |
|
| E.5.2 | Secondary end point(s) |
Phase 2
•Objective response rate (ORR; CR or PR using the Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 for solid tumors) based on blinded independent central review (BICR).
• Duration of response (DoR), disease control rate (DCR), time to tumor progression (TTP) based on investigator and BICR assessment.
• Progression-free survival (PFS) based on investigator and BICR assessment., and overall survival (OS).
• Adverse Events as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v. 5.0), timing, seriousness, and relationship to study therapy;
• Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 5.0) and timing;
• Pharmacokinetic exposure of ALX148 such as trough (pre-infusion) and peak (post-infusion) serum ALX148 concentrations;
• Immunogenicity characterized by the presence or absence of serum anti-ALX148 antibodies.
Phase 3
• Objective response rate (ORR), Disease control rate (DCR), duration of response (DoR), and time to tumor progression (TTP) based on both blinded independent central review and investigator assessment.
• Progression-free survival (PFS) based on both blinded independent central review and investigator assessment.
• Adverse Events as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v. 5.0), timing, seriousness, and relationship to study therapy;
• Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 5.0) and timing;
• Pharmacokinetic exposure of ALX148 such as trough (pre-infusion) and peak (post-infusion) serum ALX148 concentrations;
• Immunogenicity characterized by the presence or absence of serum anti-ALX148 antibodies.
• Quality of life measurements as characterized by the EORTC QLQ-C30 and QLQ-STO22 questionnaires. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the study and based on study assessments and procedures
as stated in the protocol sections 6 and 7. |
|
| 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 | 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) | 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase 2 portion is Open label whereas Phase 3 portion is Double blinded. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Korea, Republic of |
| Singapore |
| Taiwan |
| United States |
| Belgium |
| Czechia |
| France |
| Italy |
| Spain |
| United Kingdom |
|
| 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
|
For each country, the trial is considered complete either after all study
objectives have been met or all subjects within the country have
discontinued and 36 month follow up (to obtain OS data) has occurred. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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