E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Malignancies Associated with EphA2 Expression |
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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 |
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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 | 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 |
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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 |
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 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 a recommended Phase II dose 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 in patients with selected adenocarcinoma non small cell lung cancer (NSCLC), or other tumor subtype(s) identified as positive for EphA2 tumor expression as a monotherapy (Part B-1) and in combination with nivolumab (Part B-2) using RECIST 1.1 |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the escalation (Parts A-1 and A-2) this study are: • 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 pharmacokinetic parameters of BT5528 and MMAE (as appropriate) • To determine incidence of anti-drug antibody development
The secondary objectives of the expansions (Parts B-1 and B-2) study are: • To assess safety, tolerability of BT5528 in patients with selected adenocarcinoma NSCLC, or other tumor subtype(s) identified as positive for EphA2 tumor expression indications as a monotherapy (Part B-1) and in combination with nivolumab (Part B-2) • To determine PK parameters of BT5528 and MMAE (as appropriate) • To determine incidence of anti-drug antibody development |
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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. Availability of archived tumor samples or willingness to provide fresh tumor biopsy during screening for EphA2 assessment. 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, 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 4 or later for the Part A-1 monotherapy, or enrolling in Cohort 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 cancer enrolling in Cohort 4 or later for the Part A-1 monotherapy, or enrolling in Cohort 3 or later for the Part A-2 combination therapy may be enrolled without prior confirmation of EphA2 expression. The SRC may review the requirement for EphA2 expression prior to starting therapy where individual tumor types or subtypes have already demonstrated signs of efficacy.
Additional Inclusion Criteria – Part B 1.Patients with metastatic recurrent disease histologically confirmed to be an adenocarcinoma subtype of NSCLC (adeno-NSCLC), or other tumor subtype(s) are eligible and must have exhausted all appropriate treatment options per local guidelines including progression on or after platinum-based chemotherapy; or must not have been a candidate for or must have received any other approved therapies including appropriate treatment for driver mutation disease, if applicable; 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, patients who received prior immunotherapy, the last dose must have been at least 28 days prior to the first dose of BT5528 study treatment. 2. Patients must have tumor tissue (fresh or archived), except where the SRC has waived this requirement, submitted for assessment by central laboratory with confirmation of positive EphA2 tumor expression prior to initiation of BT5528 study treatment. At least 6 patients per expansion cohort must have at least 1 tumor lesion amenable to biopsy and must be willing to submit tumor tissue for research purposes including the screening tumor sample collected prior to first dose of BT5528 and undergo additional post dose biopsy of tumor tissue and normal tissue (e.g. skin) collected 4 hours – 7 days following any dose of BT5528 within Cycle 1 is preferred, or if not feasible then any later cycle is allowed. A normal tissue (e.g. skin) biopsy is required on the same day, preferably collected as close as possible to the same time as tumor tissue is collected. |
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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 shorter. If NSCLC with EGFRmt, osimertinib or other TKI treatments or cytotoxic chemotherapy within 14 days prior to first dose of study treatment. Prior toxicities must have resolved to grade 1 per CTCAE v 5.0 (except alopecia which must be no greater than Grade 2). For immunotherapy, including immune checkpoint inhibitors, 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. Current treatment with strong inhibitors or inducers of CYP3A4 or strong inhibitors of P-gp including herbal- or food-based. 4. Known sensitivity to any of the ingredients of investigational product or MMAE. 5. 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. 6. 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 7. Receipt of live vaccine within 30 days of study treatment 8. Uncontrolled, symptomatic brain metastases (must have stable neurologic status following local therapy for at least 4 weeks without use of steroids or on stable or decreasing dose of less than or equal to 10 mg daily prednisone or equivalent and must be without neurologic dysfunction that would confound evaluation of neurologic and other AEs.) 9. Patients with uncontrolled hypertension (systolic BP ≥139 mmHg; diastolic BP ≥89 mmHg) prior to first dose of BT5528 study treatment (must have been in stable control for at least 3 months) 10. 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 including but not limited to: - Patients with history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of NYHA Class III-IV documented within 6 months prior to first dose of BT5528 or: i. Mean resting QTcF >470 msec ii. Any factors that increase risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age, or any concomitant medication known to prolong the QT interval iii. Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block 11. Known HIV or AIDS 12. 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 13. 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. 14. 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. 15. 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). 16. Systemic anti-infective treatment or fever within the last 14 days prior to first dose of BT5528 study treatment. 17. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures
Additional Exclusion Criteria Part A-2 and B-2 Nivolumab Combination Cohorts: 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 8. History of interstitial lung disease |
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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-1 and B-2 (expansions): 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 |
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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) |
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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-1 and B-2 (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. |
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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 ) |
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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 | 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 | 4 |
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 | 20 |
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 |
United Kingdom |
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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
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 4 |