| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nectin-4 Expressing Advanced Malignancies. |
|
| 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. |
|
| 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 |
|
| 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 and renal cohorts (Parts A-1, A-2, Part C) are:
• To assess safety and tolerability of BT8009 in patients with advanced solid tumor malignancies associated with Nectin-4 expression as a monotherapy (Part A-1) or in combination with nivolumab (Part A-2) or in patients with advanced solid tumor malignancies having renal insufficiency (Part C).
• To define the maximum tolerated dose (MTD) of BT8009, if observed, and determine a recommended Phase II dose (RP2D) as a monotherapy and in combination with nivolumab (Parts A-1 and A-2).
The primary objective of the expansion cohort (Parts B-1 and B-2) is:
• To assess the clinical activity of BT8009 in patients with solid tumor indications associated with Nectin-4 expression as a monotherapy (Part B-1) and in combination with nivolumab (Part B-2) using RECIST 1.1.
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives of Parts A-1 and A-2 and renal cohorts (Part C) are:
1. Assess signals of anti-tumor activity in pts. with advanced solid tumor malignancies associated with Nectin-4 as a monotherapy (Part A-1) and in combination with nivolumab (Part A-2) or in pts. with advanced solid tumor malignancies having renal insufficiency (Part C).
2. Determine PK parameters of BT8009 and MMAE in pts. with advanced solid tumor malignancies associated with Nectin-4 as a monotherapy and in combination with nivolumab (Part A-2) or in patients with advanced solid tumor malignancies having renal insufficiency (Part C).
3. Determine incidence of anti-drug antibody (ADA) development.
Secondary objectives of the expansion cohorts (Parts B-1 and B-2) are: 1) assess safety and tolerability of BT8009 in patients with solid tumors as monotherapy (Part B-1) and in combination with nivolumab (Part B-2); 2) Determine PK parameters of BT8009 and MMAE; 3) determine incidence of ADA development
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet the following criteria in order to be included in the research study:
1. Written informed consent, according to local guidelines, signed and dated by the patient or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analyses.
2. At least 18 years-of-age at the time of signature of the informed consent form.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
4. Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
5. Acceptable organ function, as evidenced by the following laboratory data:
a. Renal function, as follows: 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
6. 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
7. 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).
8. Availability of archived tumor samples or willingness to provide fresh tumor biopsy during screening.
9. Life expectancy ≥12 weeks after the start of BT8009 treatment according to the Investigator’s judgment.
10. Must be willing and able to comply with the protocol, the scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures.
11. Must have exhausted all standard treatment options, including appropriate targeted therapies, for example, EGFR or ALK therapies for relevant oncogene driver NSCLC patients.
Additional Inclusion Criteria – Part A Only
12. Patients with the following advanced, histologically confirmed malignant solid tumors that recurred after or have been refractory to previous therapy: a) urothelial (transitional cell) carcinoma (fresh biopsy or an archived sample must be submitted); or b) having pancreatic, breast, non-small-cell lung cancer (NSCLC), gastric, esophageal, head and neck, or ovarian tumor tissue (fresh biopsy or an archived sample) testing positive for Nectin-4 expression.
Exceptions: single-subject accelerated cohorts may enroll patients with advanced solid tumors not-restricted to the above definitions, unless the SRC views otherwise. The Sponsor may require a) or b) at any time during the enrollment; eligibility will be confirmed by the Medical Monitor. The Sponsor and/or SRC may decide to require enrollment of specific tumor (sub)types at any point during the escalation to enrich the evaluation of biomarkers, safety, anti-tumor activity, or PK.
Additional Inclusion Criteria – Part B-1 and B-2 Nectin-4 basket monotherapy and combination cohorts
13. Patients with solid tumor metastatic recurrent disease confirmed as Nectin-4 positive on fresh biopsy or archived tissue must have failed at least one prior line of therapy with evidence of radiographic progression on the most recent line of therapy. If patient’s tumor has been demonstrated to contain a therapeutically targetable somatic or driver mutation, therapy must be given with appropriate locally-approved therapy, then therapy must have been given based on local standard standards of care. If platinum therapy is applicable, then FDA-approved or appropriate locally-approved 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 and/or SRC may decide to require or limit enrollment of specific tumor (sub)types meeting the above definition at any point during the expansion to enrich the population for anti-tumor activity.
14. 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 – Part C renal insufficiency cohort
15. Patients with solid tumor advanced disease are eligible as follows: 1) 6 patients with a GFR (by CG or by 24-hour urine) 40-50 mL/min (or equivalent units) to be enrolled and evaluated first followed by; 2) 6 patients with a GFR 30-40 mL/min (or equivalent units). Sponsor may opt to specify tumor (sub)type or Nectin-4 selected.
|
|
| E.4 | Principal exclusion criteria |
1. Chemotherapy treatment ≤14 days prior to first dose, other anticancer treatments, treatment ≤28 days or 5 terminal half-lives, whichever is shorter. Prior toxicities must have resolved to Grade 1 per CTCAE v 5.0 (except alopecia, which must be no greater than Grade 2)
2. Experimental treatments ≤4 weeks of first dose
3. Prior treatment with Nectin-4 targeted therapy
4. Current treatment with strong inhibitors or strong inducers of CYP3A4 or strong inhibitors of P-gp, including herbal or food-based.
5. Known sensitivity to any of the ingredients in the product
6. BSA >2.21 m2.
7. Significant medical condition, including but not limited to eye (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 including but not limited to autoimmune conditions such as eczema or psoriasis), 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, including consideration of GI, skin and pulmonary co-morbidities and including review of screening chest CT to ensure no clinically significant co-morbidities. Prior ≤ Grade 2 thyroid endocrinopathy is allowed, if appropriately controlled with thyroid hormone and stable for at least 2 months on therapy.
8. Clinically relevant troponin elevation (considering local reference standards)
9. Uncontrolled diabetes (HbA1c ≥8%)
10. Major surgery (excluding placement of vascular access) ≤4 weeks of first dose and recovered adequately prior to starting
11. Receipt of live/attenuated vaccine ≤30 days
12. Uncontrolled, symptomatic brain metastases (must have stable neurologic status following local therapy for >4 weeks without steroids or on stable or decreasing dose of ≤10 mg daily prednisone or equiv. at start of treatment and must be without neurologic dysfunction that would confound the evaluation of neurologic/other AEs).
13. Patients with uncontrolled hypertension (systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg)
14. Any condition, therapy or lab abnormality that might confound results of study, interfere with patient’s participation, or is not in the best interest of the patient in the opinion of the PI, including but not limited to: history of a cerebral vascular event (stroke or TIA), unstable angina, myocardial infarction, CHF or symptoms of NYHA Class III-IV documented ≤6 months prior to first dose or: a) mean resting corrected QT interval (QTcF) >470 msec, b) any factors that increase the 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, or c) any clinically important abnormalities in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third-degree heart block.
15. Known HIV or AIDS
16. 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.
17. Active hepatitis C infection with positive viral load if hepatitis C virus (HCV) 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.
18. History of another malignancy ≤3 years before the first dose, 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).
19. Systemic IV anti-infective treatment, or fever not attributable to underlying malignancy ≤14 days prior to first dose
20. Suspicion of relevant and recent systemic viral syndrome or need for quarantine/isolation that is not resolved in the opinion of the Investigator.
21. 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
22. Prior intolerance to immune checkpoint inhibitor
23. Known hypersensitivity to checkpoint inhibitor therapy
24. Prior organ transplant (including allogeneic)
25. Diagnosis of clinically relevant immunodeficiency
26. Active systemic infection requiring therapy
27. More than 10 mg/day prednisone equiv. or other strong immunosuppressant
28. Autoimmune disease except type I DM well controlled on insulin, alopecia or vitiligo
29. Interstitial lung disease |
|
| 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
|
|
| 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). |
|
| 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 secondary 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).
2) Measurement of ADA
|
|
| 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) |
|
| 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 | 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 | 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 | 2 |
| 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 |
|
| 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 | 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 |
Print
