| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nectin-4 Expressing Advanced Malignancies. |
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| E.1.1.1 | Medical condition in easily understood language |
| Advanced cancer of a type that has an abundance of surface receptors called Nectin-4 on the tumour cells. |
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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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
| 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 clinical study will investigate BT8009 given alone and given in combination with Opdivo (nivolumab). The primary objectives are:
1. To assess the safety and tolerability of BT8009 given alone to patients with advanced solid tumor malignancies or given in combination with Opdivo.
2. To define the maximum tolerated dose (MTD) of BT8009 given alone and in combination with Opdivo, and to determine a recommended dose for the next phase of clinical studies.
3. Assess the clinical activity of BT8009 in patients with solid tumor associated with Nectin-4 expression as a monotherapy and in combination with nivolumab.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the clinical study are:
1. To assess preliminary signals of anti-tumor activity achieved with BT8009 administration in patients with advanced solid tumor malignancies as a monotherapy and in combination with nivolumab.
2. To determine the maximum concentration of BT8009 (given alone and in combination with Opdivo) in blood and the rate at which the drug is metabolized. The sponsor will also assess the incidence of development of antibodies to BT8009.
3. To assess safety and tolerability of BT8009 in patients with advanced solid tumor malignancies when given alone and in combination with Opdivo.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. At least 18 years old at the time informed consent is given.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
3. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
4. Acceptable organ function, as evidenced by the following laboratory data:
a) Renal function: creatinine clearance of ≥50 mL/min by the Cockcroft-Gault equation or equivalent.
b) Total bilirubin ≤1.5 × ULN (upper limit of normal)
c) Serum albumin ≥2.5 g/dL
d) Aspartate aminotransferase (AST) ≤2.5 × ULN or ≤5 × ULN in the presence of liver metastases
e) Alanine aminotransferase (ALT) ≤2.5 × ULN or ≤5 × ULN in the presence of liver metastases
f) International normal ratio (INR) <1.3 or ≤ institutional ULN
5. Acceptable hematologic function (no red blood cell or platelet transfusions or growth factors are allowed within 4 weeks of the first dose of BT8009):
a) Hemoglobin ≥9 g/dL
b) Absolute neutrophil count (ANC) ≥1500 cells/mm³
c) Platelet count ≥75,000 cells/mm³
6. Negative pregnancy test for women of childbearing potential (WOCBP) (negative serum test at screening and negative urine or serum test within 3 days prior to the first dose of BT8009. Male patients with female partners of childbearing potential and female patients of childbearing potential are required to follow highly effective contraception (oral and hormonal contraceptives allowed) at least as conservative as Clinical Trial Facilitation Group (CTFG) recommendations for less than 1% failure rate during their participation in the study and for 6 months following last dose of study drug. Male patients must also refrain from donating sperm during their participation in the study and for 6 months following last dose of study drug and women must not breastfeed during that time or donate eggs.
7. Availability of archived tumor samples within 12 months prior to the date of the first dose of BT8009 or willingness to provide fresh tumor biopsy during screening.
8. Life expectancy ≥12 weeks after the start of BT8009 treatment according to Investigator's judgment.
Additional Inclusion Criteria for Part A
9. Patients with advanced, histologically confirmed malignant solid tumors as follows: a) urothelial (transitional cell) carcinoma naïve to Nectin-4 directed therapies; or b) having tumor tissue (fresh biopsy or on archived sample less than 12 months old without intervening anti-cancer therapies) testing positive for Nectin-4 expression; or c) solid tumors known to be historically associated with Nectin-4 as follows: pancreatic, TNBC, NSCLC, gastric, esophageal or ovarian.
Exceptions: single-subject accelerated cohorts may enroll patients with advanced solid tumors non-restricted to the above definitions, unless the Safety Review Committee views otherwise. All patients must have disease that recurred after or refractory to previous therapy including appropriate targeted therapies, for example EGFR or ALK therapies for relevant oncogene driver NSCLC patients, and are candidates for a Phase I study due to lack of approved or standard options for treatment.
Additional Inclusion Criteria for Parts B-1 and B-2 Nectin-4 basket monotherapy and combination cohorts
10. Patients with solid tumor metastatic recurrent disease confirmed to express Nectin-4 on fresh biopsy or archived tissue (<12 months old and with no intervening anti-cancer therapies) are eligible and must have exhausted all standard treatment options, including appropriate targeted therapies, must have failed at least one prior line of therapy with evidence of radiographic progression on the most recent line of therapy. Patients must be naïve to Nectin-4 directed therapies. Sponsor may decide not to allow urothelial (transitional cell) patients. If patient’s tumor has been demonstrated to contain a therapeutically targetable somatic or driver mutation, then therapy must have been given based on local standard of care. If platinum therapy is applicable, then therapy must have been given based on local standard guidelines. If prior immunotherapy, the last dose must have been at least 28 days prior to the first dose of BT8009. The Sponsor may decide to require enrollment of specific tumor (sub)types meeting the above definition at any point during the expansion if it is felt necessary to enrich the population for anti-tumor activity.
11. At least 6 patients per cohort must have at least 1 tumor lesion amenable to biopsy and must be willing to undergo a biopsy prior to first dose of BT8009 and following any dose in Cycle 1.
Additional Inclusion Criteria for Part C
12. Patients with solid tumor advanced disease having exhausted all standard of care options are eligible as follows: 1) 6 patients with GFR (by CG or by 24-hour urine) 40-50 mL/min to be enrolled and evaluated first followed by; 2) 6 patients with GFR 30-40 mL/min. Sponsor may opt to specify tumour subtype of Nectin-4 select |
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| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded:
1. Chemotherapy treatments within 14 days prior to first dose of study treatment.
2. Other anticancer treatments within 28 days or 5 half-lives, whichever is shorter. Prior toxicities must have resolved to Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 (except alopecia which must be no greater than Grade 2).
3. Experimental treatments within 4 weeks of first dose of BT8009.
4. Prior treatment with Nectin-4 targeted therapy.
5. Current treatment with strong inhibitors or strong inducers of CYP3A4 or strong inhibitors of P-gp including herbal or food based.
6. Known sensitivity to any of the ingredients of the investigational product or monomethyl auristatin E (MMAE).
7. Weight >100 kg or BSA >2.21 m² (representing human 100 kg equivalent for height of 175 cm).
8. Conditions related to or that may confound monitoring for dry eye, corneal opacities or keratitis); skin conditions related to or that may confound monitoring for rash, life-threatening illness, active uncontrolled infection or organ system dysfunction, or other reasons which in the Investigator opinion could compromise the patient’s safety, or interfere with or compromise the integrity of the study.
9. Clinically relevant troponin elevation
10. Uncontrolled diabetes defined as HbA1c ≥8%
11. Major surgery <4 weeks of first dose of BT8009
12. Receipt of live vaccine <30 days of study treatment
13. Uncontrolled, symptomatic brain metastases
14. Patients with uncontrolled hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg) prior to first dose of BT8009
15. History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation, or is not in the best interest of the patient.
16. HIV or acquired immune deficiency syndrome (AIDS)
17. Patients with a positive hepatitis B surface antigen and/or anti-hepatitis B core antibody. Patients with a negative polymerase chain reaction (PCR) assay are permitted with appropriate antiviral therapy
18. Active hepatitis C infection with positive viral load. Patients who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of ≥12 weeks.
19. History of another malignancy within 3 years before the first dose of BT8009, or any evidence of residual disease from a previously diagnosed malignancy
20. Systemic IV anti-infective treatment, or fever within 14 days prior to first dose of BT8009
21. Suspicion of relevant and recent systemic viral syndrome or need for quarantine/isolation that is not resolved in the opinion of the investigator
22. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures
Additional Exclusion Criteria for Part A-2 and B-2 Nivolumab Combination Cohorts
23. Prior intolerance to immune checkpoint inhibitor
24. Known hypersensitivity to checkpoint inhibitor therapy
25. Prior organ transplant (including allogeneic)
27. Diagnosis of clinically relevant immunodeficiency
28. Active systemic infection requiring therapy
29. More than 10 mg daily prednisone equivalent or other strong immunosuppressant
30. History of autoimmune disease except type I DM well contained on insulin, alopecia or vitiligo
31. History of interstitial lung disease
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measures for Parts A and C will be:
1) The incidence of treatment-emergent adverse events (TEAEs), including laboratory, ECG, and vital sign abnormalities.
2) The incidence of dose-limiting toxicites.
The primary outcome measures for Part B will be:
1) Objective response rate (ORR)
2) Duration of response (DOR)
3) Clinical benefit rate (CR + PR + SD ≥ 6 weeks)
4) Time to tumor progression (TTP)
5) Progression-free survival time (PFS)
6) Rate of PFS at 6 months
7) Rate of Overall Survival (OS) at 12 months
all assessed per RECIST v1.1 criteria
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary outcome measures will be assessed at pre-specified time points throughout the duration of the study (approximately 3 years) |
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| E.5.2 | Secondary end point(s) |
The secondary outcome measures for Parts A and C will be:
1) Objective response rate (ORR)
2) Duration of response (DOR)
3) Clinical benefit rate (CR + PR + SD ≥ 6 weeks)
4) Time to tumor progression (TTP)
5) Progression-free survival time (PFS)
6) Rate of PFS at 6 months
7) Rate of Overall Survival (OS) at 12 months
all assessed per RECIST v1.1 criteria
The primary outcome measures for Part B will be:
1) The incidence of treatment-emergent adverse events (TEAEs), including laboratory, ECG, and vital sign abnormalities.
Secondary endpoints applicable to all parts of the study include:
1) Plasma concentrations of BT8009 with derivations including Cmax, Cmin, AUC, and elimination half-life t(1/2). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary outcome measures will be assessed at pre-specified time points throughout the duration of the study (approximately 3 years) |
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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 | No |
| 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) | 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 | No |
| 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 | 5 |
| 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 | 12 |
| 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 |
| Belgium |
| Canada |
| France |
| Germany |
| Hong Kong |
| Italy |
| Korea, Republic of |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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