| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or Locally Advanced Urothelial Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic or Locally Advanced Urothelial Cancer |
|
| 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 | 10005003 |
| E.1.2 | Term | Bladder cancer |
| 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 (Dose Escalation)
- To characterize the safety and tolerability of erdafitinib in combination with cetrelimab, and to identify the recommended Phase 2 dose(s)
(RP2D) and schedule for erdafitinib
- To characterize the safety and tolerability of erdafitinib in combination with cetrelimab and platinum (cisplatin or carboplatin) chemotherapy, and to identify the recommended Phase 2 dose(s) (RP2D) and schedule for erdafitinib with cetrelimab and platinum (cisplatin or carboplatin) chemotherapy.
Phase 2(Dose Expansion)
- To evaluate the safety and clinical activity of erdafitinib alone and in combination with cetrelimab in cisplatin-ineligible subjects with metastatic or locally advanced urothelial cancer with select FGFR gene alterations and no prior systemic therapy for metastatic disease. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1b (Dose Escalation)
- To characterize the PK of erdafitinib and Cetrelimab
- To assess the immunogenicity of Cetrelimab
- To characterize the PK of erdafitinib in combination with cetrelimab, and platinum (cisplatin or carboplatin) chemotherapy
Phase 2(Dose Expansion)
- To characterize the PK of erdafitinib and cetrelimab
- To assess the immunogenicity of cetrelimab
- To further assess safety at the R2PD of erdafitinib alone and in combination with Cetrelimab
- To further characterize the clinical activity of erdafitinib alone and in combination with Cetrelimab |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1. ≥18 years of age.
2.Criterion modified per Amendment 2
2.1 Histologic demonstration of transitional cell carcinoma of the urothelium. Variant urothelial carcinoma histologies such as glandular or squamous differentiation, or evolution to more aggressive phenotypes such as sarcomatoid or micropapillary change are acceptable.
3. Criterion modified per Amendment 2
3.1 Metastatic or locally advanced urothelial cancer (Stage IV disease per AJCC Staging Guidelines)
4. Criterion modified per Amendment 2
4.1 Criterion modified per Amendment 3
4.2 Phase 1b erdafitinib + cetrelimab cohort and Phase 2: Meet appropriate molecular eligibility criteria. Tumors must have at least one gene fusion or gene mutation.
5. Criterion modified per Amendment 2
5.1 Must have measurable disease by radiological imaging according to the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) at baseline.
6. Criterion modified per Amendment 2
6.1 Criterion modified per Amendment 3
6.2 Prior systemic therapy for metastatic urothelial cancer: Phase 1b erdafitinib + cetrelimab cohort:
–Any number of lines of prior therapy
–Renal function for subjects must have a creatinine clearance (CrCl) >30 mL/min as calculated by Cockcroft-Gault
Phase 1b erdafitinib + cetrelimab + platinum chemotherapy cohort:
–No prior systemic therapy for metastatic disease. Note: Subjects who received neoadjuvant or adjuvant chemotherapy and showed disease progression, within 12 months of the last dose are considered to have received systemic chemotherapy in the metastatic setting
–Renal function for subjects must have a CrCl >50 mL/min as calculated by Cockcroft-Gault
Phase 2:
–No prior systemic therapy for metastatic disease. Note: Subjects who received neoadjuvant or adjuvant chemotherapy and showed disease progression, within 12 months of the last dose are considered to have received systemic chemotherapy in the metastatic setting.
–Cisplatin-ineligible based on:
–ECOG PS 0-1 AND at least one of the following criteria:
–Renal function defined as CrCl ˂60 mL/min as calculated by Cockcroft- Gault (Galsky 2011)
–Grade 2 or higher peripheral neuropathy per NCI-CTCAE version 5.0.
–Grade 2 or higher hearing loss per NCI-CTCAE version 5.0, OR
–ECOG PS 2.
7. Criterion modified per Amendment 2
7.1 Criterion modified per Amendment 3
7.2 ECOG PS Grade as defined below:
Phase 1b erdafitinib + cetrelimab cohort: ECOG 0-2
Phase 1b erdafitinib + cetrelimab + platinum chemotherapy cohort: ECOG 0-1 for cisplatin and ECOG 0-2 for carboplatin.
Phase 2: ECOG 0-2
8. Criterion modified per Amendment 1
8.1 Criterion modified per Amendment 2
8.2 Criterion modified per Amendment 3
8.3 Adequate organ function at Screening
9. Criterion modified per Amendment 2
9.1 Criterion modified per Amendment 1
9.2 Criterion modified per Amendment 3
9.3 Phase 1b erdafitinib + cetrelimab cohort and Phase 2: Before the first dose of study drug:
Women of childbearing potential (defined as: fertile, following menarche and until becoming post-menopausal unless permanently sterile as a result of hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) and fertile men who are sexually active must agree to use a highly effective method of contraception during the study and for 5 months after the last dose of study drug. For men who are sexually active with women of childbearing potential: agree to use a condom with spermicidal foam/gel/film/cream/suppository during the study and for
5 months after the last dose of study drug. Contraception must be consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Women and men must agree not to donate eggs or sperm, respectively, during the study and for 5 months after the last dose of study drug.
Examples of highly effective methods include:
–user-independent methods: implantable progestogen-only hormone contraception associated with inhibition of ovulation; intrauterine device; intrauterine hormone releasing system; vasectomized partner;
–user-dependent methods: combined (estrogen- and progestogen- containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, and transdermal; progestogen-only hormone contraception associated with inhibition of ovulation: oral and injectable.
–Sexual abstinence
10. Women of childbearing potential must have a negative pregnancy test at Screening within ≤7 days of C1D1 using a highly sensitive pregnancy test (serum beta-human chorionic gonadotropin [beta-hCG])
11. Sign an informed consent form indicating that he or she understands the purpose of and procedures required for the study, and is willing and able to participate in the study.
12. Willing and able to adhere to the prohibitions and restrictions
Refer the protocol for all the inclusion criteria
|
|
| E.4 | Principal exclusion criteria |
Any potential subject who meets any of the following criteria will be excluded from participating in the study:
1. Treatment with any other investigational agent or participation in another clinical study with therapeutic intent within 30 days prior to C1D1. For Phase 1b, subjects who have received the following prior antitumor therapy:
- Received nitrosoureas and mitomycin C within 6 weeks.
2.Criterion modified per Amendment 3
2.1 Phase 1b erdafitinib + cetrelimab cohort:
- Chemotherapy within 3 weeks of C1D1.
Phase 1b erdafitinib + cetrelimab + platinum chemotherapy cohort and Phase 2:
-Prior neoadjuvant/adjuvant chemotherapy is allowed if the last dose was given >12 months prior to recurrent disease progression and did not result in drug-related toxicity leading to treatment discontinuation.
3.Criterion modified per Amendment 2
3.1 Criterion modified per Amendment 3
3.2 Prior anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy. Prior neoadjuvant/ adjuvant checkpoint inhibitor therapy is allowed if the last dose was given >12 months prior to recurrent disease progression and did not result in drug-related toxicity leading to treatment discontinuation PD-1 for non-muscle invasive bladder cancer is also allowed.
4. Criterion modified per Amendment 2
4.1 Active malignancies requiring concurrent therapy other than urothelial cancer
5. Symptomatic central nervous system metastases.
6. Prior FGFR inhibitor treatment.
7. Radiation therapy ≤30 days prior to planned C1D1.
8. Criterion modified per Amendment 2
8.1 Criterion modified per Amendment 3
8.2 History of uncontrolled cardiovascular disease including:
a. Unstable angina, myocardial infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known congestive heart failure Class III-V within the preceding 3 months; cerebrovascular accident or transient ischemic attack within the preceding 3 months.
b. Corrected QT interval (QTc) prolongation as confirmed by triplicate assessment at screening (QTc by Fridericia’s formula [QTcF]>480 milliseconds).
c. Pulmonary embolism or other venous thromboembolism within the preceding 2 months.
9. Known to be seropositive for human immunodeficiency virus or acquired immune deficiency syndrome.
10. Any of the following:
- Evidence of serious active viral, bacterial, or uncontrolled systemic fungal infection.
- Active autoimmune disease or a documented history of autoimmune disease that requires systemic steroids or immunosuppressive agents
- Grade 3 or higher toxicity effects from previous treatment with immunotherapy
- Psychiatric conditions (eg, alcohol or drug abuse), dementia, or altered mental status.
- Any other issue that would impair the ability of the subject to receive or tolerate the planned treatment at the investigational site, to understand informed consent or any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject (eg, compromise the well-being) or that could prevent, limit, or confound the protocol-specified assessments.
11. Pulmonary compromise requiring supplemental oxygen use to maintain adequate oxygenation.
12. Active or chronic hepatitis B or hepatitis C disease as determined by hepatitis B surface antigen (HBsAg), hepatitis B core antibody, or hepatitis C antibody (anti- HCV) positivity at screening. If positive, further testing of quantitative levels to rule out active infection is required.
13.Criterion modified per Amendment 3
13.1Phase 1b erdafitinib + cetrelimab and Phase 1b erdafitinib + cetrelimab + platinum chemotherapy cohort: Not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are considered by the investigator as not clinically significant).
Phase 2: Not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are considered by the investigator as not clinically significant such as alopecia, or skin discoloration).
14. Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
15. Criterion modified per Amendment 2
15.1 Allergies, hypersensitivity, or intolerance to protein-based therapies or with a history of any significant drug allergy (such as anaphylaxis, hepatotoxicity, or immune-mediated thrombocytopenia or anemia), or to excipients of erdafitinib or cetrelimab (see the Investigator's Brochures for a list of excipients)
16. Criterion modified per Amendment 2
16.1 Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade
17. Criterion deleted per Amendment 2
18. Criterion modified per Amendment 2
Refer the protocol for all the exclusion criteria.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b (Dose Escalation)
-Frequency and type of dose-limiting toxicity (DLT)
Phase 2 (Dose Expansion)
-Overall response rate (ORR) (partial response [PR] or better) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by investigator assessment
- Incidence of AEs |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Phase 1b (Dose Escalation)
-Concentration and PK parameters of erdafitinib and cetrelimab
-Detection of antibodies to cetrelimab and effects on serum cetrelimab levels
-Concentration and PK parameters of erdafitinib, cetrelimab, and platinum (cisplatin or carboplatin) chemotherapy
Phase 2 (Dose Expansion)
-Plasma erdafitinib and serum cetrelimab concentrations
-Detection of antibodies to cetrelimab and effects on serum cetrelimab levels
-Incidence of AEs, serious adverse events (SAEs) and laboratory values
-Duration of response (DoR)
-Time to response (TTR)
-Progression-free survival (PFS)
-OS
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
Immunogenicity
Biomarker
Exploratory |
|
| 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 |
| Phase 1b (Dose Escalation) and Phase 2 (Dose Expansion) |
|
| 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 | Yes |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 57 |
| 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 |
| Belarus |
| Belgium |
| France |
| Italy |
| Korea, Republic of |
| Russian Federation |
| 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
|
| The end of the study is defined as the last study assessment for the last subject on study or anytime the sponsor terminates the study, whichever comes first. |
|
| 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 | 6 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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