| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of progressed or refractory metastatic UCC |
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| E.1.1.1 | Medical condition in easily understood language |
| Treatment of bladder cancer that recurred after treatment with standard therapy |
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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 | 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) |
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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 |
Lead-In Phase
•To determine an acceptable maximum tolerated dose (MTD) of B-701 plus docetaxel in subjects with Stage IV, locally advanced or metastatic UCC who have relapsed after, or are refractory to at least one prior line of chemotherapy.
•To evaluate the safety and efficacy of B-701 in combination with docetaxel and B-701 monotherapy in advanced UCC with FGFR3 genomic aberrations
Randomized Phase:
•To evaluate the efficacy of B-701 plus docetaxel compared with placebo plus docetaxel in the treatment of subjects with Stage IV, locally advanced or metastatic UCC who have relapsed after, or are refractory to at least one prior line of chemotherapy which has not included a taxane, as measured by progression-free survival (PFS). |
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| E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of B-701 plus docetaxel compared with placebo plus docetaxel in the treatment of subjects with UCC as measured by objective response rate (ORR), disease control rate (DCR), duration of objective response (DOR), overall survival (OS), and quality of life (QOL).
•To evaluate the safety and tolerability of B-701 plus docetaxel compared with placebo plus docetaxel in the treatment of subjects with UCC as measured by adverse events (AEs), physical examination, laboratory, and electrocardiogram (ECG) results.
•To study the association between the level of FGFR3 expression, the presence of FGFR3 mutations or fusions, as well as other potential biomarkers (e.g., genetic alterations in other cancer-related genes), in primary tumors or metastases, with efficacy and/or adverse event (AE) outcomes.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Disease Specific Inclusion Criteria:
1. Stage IV, locally advanced or metastatic (T4b, any N; or any T, N2-3) urothelial bladder cancer or transitional cell carcinoma (TCC) arising in another location of the urinary tract, including urethra, ureter, and renal pelvis
2. Histological or cytological diagnosis of UCC. Mixed histologies are permitted as long as TCC is the major component (i.e., > 50% of the pathologic specimen). Pure or predominant squamous cell carcinomas or adenocarcinomas are not permitted
3. Relapsed after or are refractory to at least one prior line of chemotherapy which have not included a taxane (with the exception of Cohort 3 of the Lead-In Phase which will allow the enrollment of subjects with prior treatment with a taxane)
4. Subjects must have received at least one prior chemotherapeutic regimen (at least one cycle each) for advanced or metastatic/recurrent disease, of which at least one regimen included a platinum agent. If a platinum agent is contraindicated for a subject (e.g., due to pre-existing renal impairment such as creatinine clearance < 60 mL/min, myelosuppression, hearing impairment, or history of allergic reaction to platinum-containing compounds), the prior regimen(s) need not have included a platinum agent. Reason for platinum contraindication will be collected in the eCRFs
5. Prior neoadjuvant or adjuvant chemotherapy (without a taxane, except Cohort 3 of the Lead-In Phase which will allow the enrollment of subjects with prior treatment with a taxane) is permitted and will not be counted as first-line chemotherapy, as long as the subject has not progressed within 12 months of the last dose. However, if the patient progressed within 12 months of the last dose of prior neoadjuvant or adjuvant chemotherapy, then this regimen of neoadjuvant or adjuvant chemotherapy will be counted as first-line chemotherapy
6. Measurable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1; see Appendix 3). If possible, sites of measurable disease should not be within a previously irradiated site. However, if all sites of measurable disease have been irradiated, at least one site must have demonstrated growth after irradiation
7. Subjects must be anticipated to have a PFS of at least 4 weeks from the time of randomization (i.e., tumor progression per RECIST v1.1 is not anticipated within the first 4 weeks after randomization)
Cohort 2, Cohort 3, and the Randomized Phase Specific Inclusion Criteria:
1. Tumor shown to have at least one of the following FGFR3 mutations: R248C, S249C, G370/2C, S371/3C, Y373/5C, G380/82R, F384/6L, K650/2X (X=E,T or M) or FGFR3-TACC3 fusion, as shown by tests performed by a CAP or CLIA certified laboratory (or equivalent outside of the US) such as Foundation Medicine, Ashion Analytics, or Paradigm Diagnostics on samples that were obtained at or after the time when the subject was found to have muscle invasive disease or high grade papillary non-muscle invasive disease. In the absence of a pre-existing genetic test results, subjects can submit archival tissue (obtained at or after the time subject was found to have muscle invasive disease) for genetic testing. When such archival tissue is not immediately available, a blood sample may be submitted for initial determination of FGFR3 mutation and/or fusion status. In all cases, subsequent to subject enrollment, previous test results that were not provided by Foundation Medicine will be verified using archival tissue (if not available for the Randomized Phase, a core biopsy may be obtained). When possible, Blood samples will be obtained on Cycle 1 Day 1 to verify results observed in archival tissues or core biopsies.
2. Relapsed after or are refractory to atezolizumab or anotheran immune check point inhibitor (such as atezolizumab, pembrolizumab, nivolumab, avelumab, or durvalumab). This inclusion criterion does not apply if the check point inhibitor is contraindicated. Reason for check point inhibitor contraindication will be collected in the eCRFs. If a check point inhibitor is not an approved or available therapy for UCC, then this inclusion criterion does not apply.
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| E.4 | Principal exclusion criteria |
1. Prior use of any other investigational drug (i.e., monoclonal antibody or experimental therapy) within 2 weeks before Cycle 1, Day 1
2. Palliative radiotherapy within 2 weeks prior to Cycle 1, Day 1
3. Prior anti-cancer therapy (e.g. biologic or other targeted therapy, chemotherapy or hormonal therapy) within 2 weeks prior to Cycle 1, Day 1
a. 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)
b. Clinical AEs, except for alopecia, from any previous treatments must have resolved to ≤ Grade 1
c. Laboratory AEs from any previous treatments must have resolved to ≤ Grade 1 or to within 10% of baseline prior to Cycle 1, Day 1
4. Prior treatment with an inhibitor that is targeted primarily to FGFRs
5. History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
6. Inability to be pre-medicated with a corticosteroid when treated with docetaxel
7. Evidence of significant, uncontrolled concomitant diseases which could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association (NYHA) Class III or IV cardiac disease (see Appendix 2), myocardial infarction within the last 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm)
8. History of major bleeding (requiring a blood transfusion ≥ 2 units) not related to a tumor within the past 12 months
9. History of clinically significant coagulation or platelet disorder in the past 12 months
10. Currently receiving anticoagulation treatment
11. Incomplete healing from wounds from prior surgery; wound is larger than 2 cm in length 28 days prior to randomization
12. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at screening. Any major episode of infection requiring treatment with IV antibiotics or hospitalization must be resolved (including the completion of the course of antibiotics) prior to Cycle 1, Day 1
13. History of other malignancy which could affect compliance with the protocol or interpretation of results
14. Subjects with a history of curatively treated basal or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are allowed
15. Subjects with a malignancy that has been treated with curative intent will also be allowed if the malignancy has been in remission without treatment for ≥ 2 years prior to Cycle 1, Day 1
16.Subjects with localized prostate cancer that has been treated with curative intent will be allowed
17. Presence of positive test results for Hepatitis B (Hepatitis B surface antigen [HBsAg] and/or total Hepatitis B core antibody [anti-HB-c]) or Hepatitis C (Hepatitis C virus [HCV] antibody serology testing)
18. Subjects positive for anti HB-c are eligible only if polymerase chain reaction (PCR) is negative for Hepatitis B viral (HBV) deoxyribonucleic acid (DNA)
19. Known history of human immunodeficiency virus (HIV) seropositive status
20. Primary central nervous system (CNS) malignancy, or CNS metastases
21. Pregnancy (positive pregnancy test), lactation or breastfeeding
22. Weight >110 kg
23. Inability to comply with study and follow up procedures
24. Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the subject at high risk from treatment complications
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint Analysis:
The primary efficacy outcome measure will be PFS, defined as the time from randomization to first occurrence of disease progression (per RECIST v1.1) or death, whichever occurs first. If a subject does not experience progressive disease (PD) or death, PFS will be censored at the day of the last adequate tumor assessment. PFS will be reported by the Investigator at each site and reviewed by the Medical Monitor.
The analysis of the primary efficacy endpoint of PFS will be based on the intent-to-treat (ITT) population. The Kaplan-Meier (KM) curves will be presented for each treatment arm with calculation of median time (months) and its 95% confidence limits.
The hypothesis test of the primary efficacy endpoint will be performed using an overall two-sided significance level of 0.05. The stratified log-rank test with a covariate to control for the stratification factor of liver metastasis (present versus absent) will be performed on the ITT population to test the superiority of Arm A over Arm B.
A sensitivity analysis will also be performed on the Efficacy Evaluable (EE) analysis set (if applicable).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For the lead-In phase , the Objective is to determine the maximum tolerated dose ,which will be evaluated at day 21 of the first cycle of treatment
For the randomized phase: every 6 weeks for the first 6 months and then every 9 weeks until the end of the study treatment
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| E.5.2 | Secondary end point(s) |
To maintain an upper boundary on the overall experiment-wise type I error rate, hypothesis testing of the secondary efficacy endpoints on the ITT population will follow a closed testing procedure. Inferential comparisons between treatment groups for one or more of the following efficacy endpoints, listed in rank order of importance, will be made provided the null hypothesis associated with the final analysis of PFS is rejected at the statistical significance level of two-sided 0.05.
Rank order of efficacy endpoints for analyses:
1. PFS (Primary Endpoint)
2. ORR
3. OS
Inferential testing of the secondary efficacy endpoints will proceed in a sequential step-down manner, provided the null hypothesis associated with the previously tested endpoint is rejected at the pre-defined statistical significance level. Otherwise, no further inferential testing will be conducted.
If formal inferential statistical testing is stopped due to the closed testing procedure, inferential statistics may be employed for the remaining secondary efficacy endpoints.
Definitions of Secondary Endpoints:
• ORR is 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 assessed by the investigator using RECIST 1.1 criteria. Subjects who do not achieve a CR or PR will be counted as a non-responder.
• OS defined as the time from randomization to death from any cause. For subjects who are alive at the time of analysis data cutoff, OS time will be censored at the last date the subject was known to be alive. Survival time for subjects with no post-baseline survival information will be censored on the date of randomization.
• Duration of objective response, defined as the first occurrence of a documented, objective response until the time of relapse or death from any cause. This will be calculated only for subjects who had a confirmed overall response of CR or PR. In the absence of confirmation of death or progressive disease, duration of response will be censored at the last adequate disease assessment date.
• DCR defined as the percentage of subjects who achieve either CR or PR or stable disease (SD), as assessed by the investigator per RECIST v1.1.
• DCR (90), defined as the absence of disease progression and death 90 days from the time of randomization as assessed by the investigator using RECIST v1.1.
• DCR (150), defined as the absence of disease progression and death 150 days from the time of randomization as assessed by the investigator using RECIST v1.1.
• QOL, as assessed by PROMIS GPH Short Survey and will be scored per standard methodology developed for the survey. Results will be compared between treatment groups; changes from baseline will also be calculated. Ad hoc analyses of individual questions relevant to side effects from each treatment may also be performed.
The time-to-event (OS, DOR) variables will be summarized by the method described for PFS except that DOR will be based on responders.
For categorical response variables (i.e., ORR, DCR), the frequency count, percentage, and 95% confidence intervals will be summarized for subjects randomized to the two treatments. The response rates will be compared between the randomized groups via the Cochran-Mantel-Haenszel based on the ITT population.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Every 6 weeks for the first 6 months and then every 9 weeks until the end treatment , and then every 3 months until death or lost of follow up |
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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 | No |
| 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 | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| To determine an acceptable maximum tolerated dose (MTD) of B-701 plus docetaxel |
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| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| As a clarification: Lead In Phase is open the above has been completed for the randomized phase. |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 30 |
| 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 |
| Czech Republic |
| Italy |
| Korea, Republic of |
| Spain |
| Sweden |
| Taiwan |
| Turkey |
| United States |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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