| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Malignancies Associated with EphA2 Expression |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer tumors that have recurred after or did not respond to standard of care treatments |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
The primary objectives of the escalation (Parts A-1 and A-2) are:
• To assess safety and tolerability of BT5528 in patients with advanced solid tumor malignancies associated with EphA2-expression and/or specified tumors identified as positive for EphA2 tumor expression as a monotherapy (Part A-1) and in combination with nivolumab (Part A-2)
• To define the maximum tolerated dose of BT5528, if observed, and determine one or more recommended Phase II dose/s as a monotherapy (Part A-1) and in combination with nivolumab (Part A-2)
The primary objectives of the expansions (Parts B-1 and B-2) are:
• To assess the clinical activity of BT5528 as monotherapy in patients with solid tumors historically known for high expression of EphA2
(Cohort B-1: urothelial cancer, Cohort B-2: ovarian cancer, Cohort B-3: non-small cell lung cancer [NSCLC], Cohort B-4: head and neck cancer,
Cohort B-5: triple negative breast cancer (TNBC), and Cohort B-6: gastric/upper gastrointestinal cancer [GI]) |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the escalation (Parts A-1 and A-2) :
• To assess preliminary signals of anti-tumor activity achieved with BT5528 administration in patients with advanced solid tumor malignancies associated with EphA2-expression and/or specified tumors identified as positive for EphA2 tumor expression as a monotherapy (Parts A-1) and in combination with nivolumab (Parts A-2)
• To determine PK parameters of BT5528 and MMAE (as appropriate)
• To determine incidence of ADA development
The secondary objectives of the expansion cohorts (Part B):
• To assess safety and tolerability of BT5528 as monotherapy in patients with tumors historically known for high expression of EphA2
• To investigate whether tumor EphA2 expression levels are predictive of clinical activity with BT5528 monotherapy in patients with tumors
historically known for high expression of EphA2
• To determine PK parameters of BT5528 and MMAE (as appropriate)
• To determine incidence of ADA development |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent; at least 18 years of age
2. ECOG Performance Status score of 0 or 1; measurable disease per RECIST v1.1
3. Acceptable organ function:
- Creatinine clearance ≥50 mL/min by Cockcroft-Gault equation or 24-hour urine collection
- Total bilirubin ≤1.5 × ULN
- Serum albumin ≥2.5 g/dL
- AST ≤2.5 × ULN or ≤5 × ULN in presence of liver metastases
- ALT ≤2.5 × ULN or ≤5 × ULN in presence of liver metastases
- INR <1.3 or ≤ institutional ULN
4. Acceptable hematologic function (no red blood cell or platelet transfusions or growth factors allowed within 4 weeks of first dose of BT5528):
- Hemoglobin ≥9 g/dL
- ANC ≥1500 cells/mm3
- Platelet count ≥75,000 cells/mm3
5. Negative pregnancy test for women of childbearing potential. Male patients with female partners of childbearing potential and female patients of childbearing potential must follow highly effective contraception (oral and hormonal contraceptives allowed) at least as conservative as Clinical Trial Facilitation Group recommendations for less than 1% failure rate during participation in the study and for 6 months after last dose of study drug. Male patients must refrain from donating sperm during study participation and for 6 months after last dose of study drug and women must not breastfeed or donate eggs.
6. All patients must have tumor tissue (fresh or archived) available for analysis of EphA2 tumor expression and other biomarkers. In the absence of available tumor tissue, patients must be willing to undergo a biopsy to provide fresh tumor samples.
7. Life expectancy ≥12 weeks 10. Willing and able to comply with protocol and study procedures.
Additional Inclusion Criteria – Part A
1. Patients with metastatic recurrent histologically confirmed malignant solid tumor who must have exhausted all appropriate treatment options per local guidelines and must have failed at least one prior line of therapy with evidence of radiographic progression on the most recent line of therapy. If applicable, for patients who received prior immunotherapy, the last dose must have been at least 28 days prior to the first dose of BT5528 study treatment. Patients with pancreatic cancer are allowable but are planned for less than 50% of total patients enrolled in each escalation cohort. The Sponsor or SRC may decide to require enrollment of specific tumor types or subtypes at any point during the escalation if it is felt necessary to enrich the evaluation of biomarkers, safety or PK in a specific tumor type.
2.Patients enrolling in Cohort A1-4 or later for the Part A-1 monotherapy, or enrolling in Cohort A2-3 or later for the Part A-2 combination therapy, must have tumor tissue (fresh or archived) submitted to central laboratory with confirmation of positive EphA2 tumor expression prior to initiating study treatment. Patients with Ovarian or urothelial cancer enrolling in Cohort A1-4 or later for the Part A-1 monotherapy, or enrolling in Cohort A2-3 or later for the Part A-2 combination therapy must have tumor tissue (fresh or archived) available for central laboratory for retrospective analysis of EphA2 tumor expression but may be enrolled without prior confirmation of EphA2 expression.
Additional Inclusion Criteria – Part B
1. Patients with metastatic recurrent disease histologically confirmed to be non-small cell lung cancer (NSCLC), ovarian cancer, triple-negative breast cancer (TNBC), gastric/upper gastrointestinal (GI) cancer, head and neck (H&N) cancer, or urothelial cancer are eligible; and must have failed or are ineligible for all appropriate treatment options per local guidelines; and must have evidence of radiographic progression on the most recent line of therapy.
2. Patients with urothelial cancer who have previously received treatment with enfortumab vedotin (EV) are eligible to the study. Patients who received EV and showed disease progression within 6 months of treatment start are planned for less than 50% of total patients enrolled in the cohort. |
|
| E.4 | Principal exclusion criteria |
1. Chemotherapy treatments within 14 days prior to first dose of study treatment. For other anticancer treatments, treatment within 28 days or 5 half-lives, whichever is shorter. For immunotherapy, including immune checkpoint inhibitors, treatment within 28 days prior to the first dose of study treatment.
2. Experimental treatments within 4 weeks of first dose of BT5528 study treatment.
3. Prior toxicities must have resolved to Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 (except alopecia which can be Grade 2).
4. Current treatment with strong inhibitors or inducers of CYP3A4 or strong inhibitors of P-gp including herbal- or food-based.
5. Known sensitivity to any of the ingredients of investigational product or MMAE.
6. Significant medical condition, life-threatening illness, active uncontrolled infection or organ system dysfunction (such as ascites, coagulopathy, encephalopathy), or other reasons which could compromise patient’s safety, or interfere with or compromise study outcome integrity including consideration of gastrointestinal, skin and pulmonary co-morbidities and including review of screening chest CT to ensure no clinically significant co-morbidities.
7. Major surgery (excluding placement of vascular access) within 4 weeks of first dose of BT5528 study treatment and must have recovered adequately prior to starting study therapy
8. Receipt of live vaccine within 30 days of study treatment
9. Untreated CNS metastases. Subjects with treated CNS metastases are permitted on study if all the following are true:
a. CNS metastases have been clinically stable for at least 6 weeks prior to screening
b. If requiring steroid treatment for CNS metastases, the subject is on a stable or decreasing dose of ≤20 mg/day of prednisone or equivalent for at least 2 weeks
c. Baseline scans show no evidence of new or enlarged brain metastasis
d. Subject does not have leptomeningeal disease
e. Subject must be without neurologic dysfunction that would confound the evaluation of neurologic and other AEs.
10. Uncontrolled hypertension (systolic BP ≥160 mmHg; diastolic BP ≥100 mmHg that is responsive to intervention) at screening or prior to initiation of study drug.
11. History or current evidence of any condition, therapy or laboratory abnormality that might confound study results , interfere with patient’s participation, or is not in the best interest of the patient to participate
12. Known HIV or AIDS
Note: Well controlled HIV will be allowed if the patient meets all the following criteria at inclusion:
a) CD4+ T-cell (CD4+) counts ≥350 cells/uL;
b) HIV viral load <400 copies/mL
c) Without a history of opportunistic infection within the last 12 months.
d) On established antiretroviral therapy (ART) for at least 4 weeks. Use of anti-retroviral therapy is permitted, but should be discussed with the Medical Monitor on a case-by-case basis.
13. Patients with a positive hepatitis B surface antigen and/or anti-hepatitis B core antibody. Patients with a negative PCR assay are permitted with appropriate antiviral therapy
14. Active hepatitis C infection with positive viral load if hepatitis C virus antibody positive (if antibody is negative then viral load not applicable). Patients who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of ≥12 weeks.
15. Thromboembolic events and/or bleeding disorders within 3 months (e.g., deep vein thrombosis or pulmonary embolism) prior to the first dose of BT5528 study treatment.
16. Prior history of pneumonitis with presence of residual symptoms.
17. History of another malignancy within 3 years before the first dose of BT5528, or any evidence of residual disease from a previously diagnosed malignancy (excluding adequately treated with curative intent basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia/cervical carcinoma in situ or melanoma in situ or ductal carcinoma in situ of the breast).
18. Systemic anti-infective treatment or fever within the last 14 days prior to first dose of BT5528 study treatment.
Additional Exclusion Criteria Part A-2 Combination Cohort:
1. Prior intolerance to immune checkpoint inhibitor
2. Known hypersensitivity to checkpoint inhibitor therapy
3. Prior organ transplant (including allogeneic)
4. Diagnosis of clinically relevant immunodeficiency
5. Active systemic infection requiring therapy
6. More than 10 mg daily prednisone equivalent or other strong immunosuppressant
7. History of autoimmune disease except alopecia or vitiligo
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Part A-1 and A-2 (escalations): Treatment-emergent adverse events (TEAEs), laboratory, ECG and vital sign abnormalities using CTCAE v5.0 criteria
2. Part A-1 and A-2 (escalations): Dose-limiting toxicities as defined in the protocol
3. Part B (expansion): Objective response rate (ORR), duration of response (DOR), clinical benefit rate (CR + PR + SD ≥4 months), time to tumor progression (TTP), progression-free survival time (PFS), rate of PFS at 6 mos., rate of OS at 12 mos. all assessed per RECIST v1.1 criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From Cycle 1 Day 1 (each cycle is 28 days) until 30 days post last dose, safety reported as incidence of treatment-emergent adverse events
2. At the end of Cycle 1
3. PFS time: From Cycle 1 Day 1 until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months)
PFS at 6 months: From Cycle 1 Day 1 until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months)
Rate of OS at 12 months: From Cycle 1 Day 1 until death or loss of follow-up or withdrawal of consent (assessed every 3 months for up to 1 year) |
|
| E.5.2 | Secondary end point(s) |
1. Part A-1 and A-2 (escalations): Objective response rate (ORR), duration of response (DOR), clinical benefit rate (CR + PR + SD ≥4 months), time to tumor progression (TTP), progression-free survival time (PFS), rate of PFS at 6 mos., rate of OS at 12 mos. all assessed per RECIST v1.1 criteria
2. Part B (expansions): Treatment-emergent adverse events (TEAEs), laboratory, ECG and vital sign abnormalities using CTCAE v5.0 criteria
3. All Parts: Plasma concentrations of BT5528 and MMAE with appropriate pharmacokinetic derivations such as Cmax, Cmin, AUC, and elimination t½
4. All Parts: Measurement of ADA. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From Cycle 1 Day 1 (each cycle is 28 days) until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months then every 16 weeks up to 12 months)
PFS at 6 months: From Cycle 1 Day 1 until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed every 8 weeks up to 6 months)
Rate of OS at 12 months: From Cycle 1 Day 1 until death or loss of follow-up or withdrawal of consent (assessed every 3 months up to 12 months)
2. From Cycle 1 Day 1 until 30 days post last dose
3. From Cycle 1, and end of each cycle until disease progression or death or new anti-cancer therapy or withdrawal of consent (assessed up to 12 months ) |
|
| 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 | Yes |
| 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) | 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 | 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
| 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 | 9 |
| 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 |
| United States |
| Belgium |
| Spain |
| United Kingdom |
|
| 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
|
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | 4 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 4 |
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