| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or Metastatic Urothelial Carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of bladder cancer that recurred or progressed after treatment with standard or approved therapy |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10005005 |
| E.1.2 | Term | Bladder cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Phase 1b
Primary Objective:
1. To establish the initial safety and determine a recommended Phase 2 dose (RP2D) of B-701 in combination with pembrolizumab
Phase 2 Primary Objective:
1.To evaluate the safety and tolerability of B-701 plus pembrolizumab in subjects with urothelial cell carcinoma (UCC).
2.To evaluate the efficacy of B-701 in combination with pembrolizumab in the treatment of subjects with UCC as measured by objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) |
|
| E.2.2 | Secondary objectives of the trial |
1.To evaluate the change in expression of markers associated with tumor subtype, immune cell infiltrate, and immune response when B-701 is administered alone during the 14-day lead-in period
2.To evaluate the efficacy of B-701 in combination with pembrolizumab in the treatment of subjects with UCC as measured by duration of objective response (DOR), progression free survival (PFS), and disease control rate (DCR), and overall survival (OS) by RECIST 1.1
3. To describe the impact of FGFR3 status at enrollment [wildtype (WT), mutation and/or fusion (MF)] on the safety and efficacy of B-701 alone and in combination with pembrolizumab in subjects with advanced UCC
4. To evaluate the change in patient reported outcome (PRO) quality of life measurements over time by the European Organization for Research and Treatment Quality of Life Questionnaire (EORTC QLQ- C30) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have locally advanced (on TNM staging: T4b and any N, or any T and N2-3) or metastatic transitional cell carcinoma of the urothelium, including the urinary bladder, urethra, ureter, and/or renal pelvis. The diagnosis must be histologically or cytologically confirmed.
2. Have progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy OR are not eligible for
cisplatin-containing chemotherapy defined as meeting any one of the criteria as specified in the protocol.
3.Have available archival tumor or be willing to undergo diagnostic biopsy at screening. Sample must be of suitable quality and quantity to satisfy group assignment and biomarker endpoints (as described in the Sample Collection & Processing Manual).
4. Have measurable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).
5. Male and female subjects, age ≥ 18 years.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS)
≤ 1 (see Appendix 1).
7. Willingness to avoid pregnancy or fathering children based on the criteria as described in study protocol.
8.Ability to understand and sign informed consent form:
(ICF) and comply with all study procedures
9. Have adequate hematologic and end organ function defined by the following laboratory results obtained within 2 weeks prior to the first dose of study treatment:
a) Absolute neutrophil count ≥ 1,500/µL.
b) Platelet count ≥ 100,000/µL.
c) Hemoglobin ≥ 9.0 g/dL without transfusion.
d) Albumin ≥ 2.5 g/dL.
e) Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 × upper limit of normal (ULN), with the following exceptions:
- Subjects with documented bone metastases: ALP ≤ 5 × ULN.
- Creatinine clearance ≥ 30 mL/min on the basis of the Cockroft Gault glomerular filtration rate estimation: ((140-age)×(weight in kg)×(0.85 if female) )/(72×(serum creatinine in mg/dL))
f) Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) must be ≤ 1.5 × ULN. |
|
| E.4 | Principal exclusion criteria |
1. Participants with a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on the Screening chest CT scan.
2. Prior therapy with an anti-programmed cell death 1 (PD-1) or anti-PDLigand 1 agent, or with an agent directed to another co-inhibitory T-cell receptor or FGFR inhibitor.
3. Patients with autoimmune disease or medical conditions that required systemic corticosteroids (> 10 mg/day prednisone or its equivalent) or other immunosuppressive medications or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of study treatment. Note: Replacement therapy (e.g. physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
4. Prior anti-cancer therapy (e.g. biologic or other targeted therapy, chemotherapy or hormonal therapy) within 14 days prior to the first dose of study medication.
A washout of less than 14 days may be allowed after discussion with the Medical Monitor, provided that the subject has recovered from any clinically relevant toxicity (Exception: participants with neuropathy of Grade 1 will be allowed study entry).
5. Acute clinical AEs, except for alopecia, from any previous treatments must have resolved to ≤ Grade 1 or chronic defined as present for more than 6 months without worsening and not greater than Grade 2.
6. Laboratory AEs from any previous treatments must have resolved to ≤ Grade 1 or to within 10% of baseline prior to the first dose of study treatment.
7. Participants who are receiving or have received any other investigational drugs or devices within in the 2 weeks prior to the first dose of study medications.
8. Participants with a diagnosis of immunodeficiency.
9. Primary central nervous system (CNS) malignancy or CNS metastases.
10. Participants with a history of allergic reactions attributed to monoclonal antibody therapy (or recombinant antibody-related fusion proteins).
11. History of major bleeding (requiring a blood transfusion ≥ 2 units) not related to a tumor within the past 12 months.
12. History of clinically significant coagulation or platelet disorder in the past 12 months.
13. Participants receiving anticoagulation treatment.
14. Participants who have not recovered adequately from the toxicity and/or complications from the interventions prior to starting therapy.
15. Incomplete healing from wounds from prior surgery (wounds larger than 2 cm in length) within 28 days prior to first dose of study treatment.
16. Participants with an active uncontrolled infection requiring systemic therapy (e.g., IV antibiotics or antifunagal therapy). Note: The use of oral anti-infectious agents for prophylaxis or treatment
of resolving infections is not considered exclusionary under this rule.
17. Participants who have received a live vaccine within 30 days of planned start of study therapy.
Note: Seasonal influenza vaccines with inactivated flu vaccines are allowed; however, live attenuated vaccines such as intranasal influenza vaccines (e.g., Flu Mist®) are not allowed.
18. Participants with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements.
19. Participants with a history of other malignancy which could affect compliance with the protocol or interpretation of results. Individuals with a history of curatively treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix, and definitively treated prostate cancer discovered incidentally at surgery are allowed. Participants with other malignancies that have been treated with curative intent will also be allowed if the malignancy has been in remission without treatment for ≥ 2 years prior to Cycle 0 Day 1.
20. Pregnant and breast-feeding women are excluded from this study because the risks with B-701 and pembrolizumab are unknown. Because there is an unknown but potential risk for AEs in nursing infant(s) secondary to treatment of the mother with B-701 and pembrolizumab, breastfeeding should be discontinued.
21. Presence of positive test results for Hepatitis B (Hepatitis B surface antigen [HBsAg] and/or total Hepatitis B core antibody [anti-HB-c]), Hepatitis C (Hepatitis C virus [HCV] antibody serology testing), human immunodeficiency virus (HIV1/2 antibody +), and /or evidence of active tuberculosis (history and/or radiology findings) Note: Subjects positive anti anti-hepatitis core antibody are eligible only
if confirmatory polymerase chain reaction (PCR) is negative for evidence of Hepatitis B virus (within the institutional cut off value) and for study purposes the reported positive antibody testing will be considered to be a false positive test result. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Endpoint Phase 1b:
• Day dose-limiting toxicity (DLT) within the 35-day observation period.
Endpoints Phase 2, Primary Endpoints:
• Safety and tolerability measurements of AEs, physical examination findings, laboratory test results, and vital signs over time.
• ORR defined as the percentage of subjects who have baseline measurable disease and who achieve a best response of either complete response (CR) or partial response (PR) (as defined by RECIST 1.1) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• DLT for 35 days from the first dose of monotherapy and combination therapy
• One biopsy within 7 days prior of to Day 1 of Cycle 0.
• The second biopsy within 3 days of Cycle 1 Day 1 infusion of B-701 plus pembrolizumab.
Note: If the subject has undergone a diagnostic tumor biopsy procedure within 56 days of enrolling in the study, and the biopsy has adequate material, this sample may be used in place of the first biomarker tumor biopsy sample and can also serve as the archival tissue if there is adequate material to support all endpoints)
• From screening through End of Treatment/ET Visit |
|
| E.5.2 | Secondary end point(s) |
• Biomarker Endpoint
For subjects who receive Cycle 0: Determine the change following B-701 14-day lead-in period on the immune infiltration of tumors in subjects with UCC by evaluating the expression of markers associated with tumor sub type, immune cell infiltrates and cytokine expression and describe the impact of FGFR3 status at enrollment (wild-type (WT) or mutant fusion MF)) on the safety and efficacy of B-701 alone and in combination with pembrolizumab in subjects with advanced UCC.
• Efficacy Endpoints - assessed by the investigator using RECIST v1.1 criteria (for progression)
- DOR defined as the time from first occurrence of a documented, objective response until the time of relapse or death from any cause.
- DCR defined as the percentage of subjects who achieve either Investigator response (CR) or partial response (PR) or stable disease (SD).
• DCR (90), defined as the absence of disease progression and death 90 days from the time of first study drug administration.
• DCR (180), defined as the absence of disease progression and death 180 days from the time of first study drug administration.
PFS defined as the time from a first study treatment dose to first occurrence of disease progression (per RECIST v1.1) or death from any cause, whichever occurs first.
- OS defined as the time from first study drug administration to death from any cause.
• Patient Reported Outcomes
Assess the change over time in subject reported quality of life as measured by the European Organization for Research and Treatment Quality of Life Questionnaire (EORTC QLQ-C30) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From screening through Survival, End of Study Telephone Contact |
|
| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 |
| Denmark |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Serbia |
| Spain |
| Sweden |
| Turkey |
| Ukraine |
| United States |
|
| 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
|
The end of the study (i.e., the last visit) will occur due to Sponsor decision or when the last subject experiences disease progression, dies, or is discontinued from study treatment due to withdrawal of
consent of investigator discretion.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 20 |
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