| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
HER2-positive locally Advanced unresectable or metastatic solid tumors in Phase 1
HER2+ breast cancer and subjects with HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma in Phase 2a.
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066896 |
| E.1.2 | Term | HER2 positive gastric cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10084871 |
| E.1.2 | Term | Gastroesophageal junction cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
- To assess the safety and tolerability profile of BI-1607 in combination with trastuzumab in subjects with HER2+ advanced solid tumors.
- Phase 1: To identify DLTs, determine the MTD or maximum administered dose of BI-1607, and propose a recommended Phase 2 dose (RP2D) for evaluation of BI-1607 in combination with trastuzumab in subjects with HER2+ advanced solid tumors |
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| E.2.2 | Secondary objectives of the trial |
- To assess the PK profile of BI-1607 when administered every 3 weeks in combination with trastuzumab in subjects with HER2+ advanced solid tumors.
- To assess the immunogenicity of BI-1607 when administered in combination with trastuzumab.
- To assess the CD32b receptor occupancy (RO) of BI-1607 on B cells when administered in combination with trastuzumab.
- To assess possible antitumor activity of BI-1607 in combination with trastuzumab. |
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| 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 |
| Genetic assessment (DNA analysis) |
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| E.3 | Principal inclusion criteria |
Phase 1 and Phase 2a:
1. Is willing and able to provide written informed consent for the trial;
2. Is ≥18 years of age on day of signing informed consent;
3. Can attend the clinical site for administration of the experimental treatment;
4. Has a HER2+ locally advanced unresectable or metastatic solid tumor and has received standard of care or is intolerant to standard of care antineoplastic therapy. Subjects who are intolerant to trastuzumab cannot be enrolled in the study;
5. Has at least 1 measurable disease lesion as defined by RECIST 1.1 criteria;
6. Has a locally confirmed HER2+ tumor (according to 2018 ASCO/CAP HER2 test guideline) by an accurate and validated assay (according to Herceptin® or Trazimera® SmPC/PI). This can be from the most recent archival tissue sample or new tissue material from a recently obtained surgical or diagnostic biopsy. Tissue obtained for the biopsy must not have been previously irradiated. Subjects who do not have an archival or new tissue sample at Screening may still be enrolled in the study provided HER2 positivity can be established.
7. Must have progressive disease after the last line of treatment. In addition, subjects must have received the following previous lines of treatment:
a. Prior lines of treatment including trastuzumab and chemotherapy.
b. At least one prior line of treatment with an antibody-drug conjugate (ADC) (eg, trastuzumab-emtansine [TDM-1, or trastuzumab-deruxtecan]) if it is part of the standard of care.
8. Has left ventricular ejection fraction ≥50%.;
9. Has a life expectancy of ≥12 weeks;
10.Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
11. Has adequate organ function confirmed by laboratory values.
Phase 2a Only:
12. Cohort 1 (HER2+ locally advanced or metastatic breast cancer):
a. Has histologically confirmed breast adenocarcinoma that is un-resectable loco-regional, or metastatic.
b. Must have received a minimum of 1 and a maximum of 3 prior anti–HER2-based regimens with documented progression on the most recent regimen.
13. Cohort 2 (HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma):
a. Has histologically confirmed metastatic gastric or gastroesophageal adenocarcinoma.
b. Must have received a minimum of 1 and a maximum of 2 prior anti–HER2-based regimens with documented progression on the most recent regimen.
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| E.4 | Principal exclusion criteria |
1. Needs doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) while on the trial other than as premedication;
2. Has known active CNS metastases and/or carcinomatous meningitis;
3. Has known or suspected hypersensitivity or contraindication to trastuzumab, BI-1607, or any of their excipients. Previous isolated IRRs are not to be considered a reason for exclusion unless Grade 4 inintensity;
4. Has cardiac or renal amyloid light-chain amyloidosis;
5. Has received the following:
a. Chemotherapy or small molecule products within 2 weeks of first dose of BI- 1607.
b. Radiotherapy within 2 weeks of first dose of BI-1607.
c. Immunotherapy or biological therapy within 4 weeks or 5 half-lives of the respective drug, whichever is longer before the first dose of BI-1607.
6. Has not recovered from AEs to at least Grade 1 by NCI CTCAE v5.0 due to prior anticancer therapies;
7. Has had clinically significant lung disease requiring systemic corticosteroid treatment within the last 6 months of enrollment or who are suspected to have these diseases by imaging at screening period or severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy;
8. Has an active, known or suspected autoimmune disease;
9. Is a female subject and has the ability to become pregnant (or already pregnant or lactating/breastfeeding). Subjects should not breastfeed during treatment and for 7 months after the last dose of study treatment. However, those female subjects who have a negative serum or urine pregnancy test before enrollment and agree to use a highly effective method of birth control for 4 weeks before entering the trial, during the trial, and for 12 months after last dose of BI-1607 are considered eligible;
10. Is a male subject with partner(s) of childbearing potential (unless he agrees to use a barrier method of contraception [condom plus spermicidal gel] with the female partner(s) who is using one highly effective method of contraception during the trial and for 12 months after completing treatment). Men with pregnant or lactating partners should be advised to use barrier method contraception (condom plus spermicidal gel) to prevent exposure to the fetus or neonate. All males should refrain from sperm donation for 12 months after last dose of study drug;
11. Has had major surgery from which the subject has not yet recovered;
12. Is at high medical risk because of nonmalignant systemic disease including severe active infections on treatment with antibiotics, antifungals, or antivirals;
13. Has presence of chronic graft versus host disease;
14. Has had an allogenic tissue/solid organ transplant;
15. Has evidence of chronic active hepatitis B virus (HBV) infection or chronic active hepatitis C virus (HCV) infection or known history of HIV;
16. Has received a live vaccine within 30 days before the first dose of study treatment;
17. Has uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:
a. Myocardial infarction or stroke/transient ischemic attack within the past 6 months.
b. Uncontrolled angina within the past 3 months.
c. Any history of clinically significant arrhythmias.
d. QT interval prolongation >480 msec.
e. History of other significant heart disease.
18. Has a known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the study;
19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
20. Is participating or planning to participate in another interventional clinical trial, or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks or 5 half-lives of the
respective drug, whichever is longer before first dose of study drug. Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks or 5 half-lives of the respective drug, whichever is longer after the last dose of the previous investigational agent. Participation in an observational trial is acceptable.
21. Has a known additional malignancy of another type, except for adequately treated cone-biopsied carcinoma in situ (eg, breast carcinoma, cervical cancer in situ), adequately controlled superficial bladder cancer and basal or squamous cell carcinoma of the skin.
22. Has a diagnosis of primary or acquired immunodeficiency disorder or is taking any other form of immunosuppressive therapy within 7 days or 5 half-lives of the respective drug, whichever is longer before the first dose of study drug.
Refer to protocol for exhaustive exclusion criteria |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• AEs and serious adverse events (SAEs) (graded according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) and their causality in relation to BI-1607 or to the combination with trastuzumab
• Occurrence of DLTs. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
• PK parameters for BI-1607 during the treatment period. The PK parameters will include area under the serum concentration-time curve (AUC), maximum concentration (Cmax), time to Cmax (tmax), and terminal half-life (t½)
• Anti-drug antibody response to BI-1607 in blood serum
• RO on circulating B lymphocytes.
• Best tumor response, objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, PFS, time to objective response, duration of objective response (DOR), and OS |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Dose escalation in Phase 1, Expansion cohorts in Phase 2a |
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| 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 | 1 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| 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 |
| United States |
| Germany |
| Spain |
| United Kingdom |
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| 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
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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 | 4 |
| 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 | 4 |
| 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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