A study to evaluate the safety, the distribution and elimination of the compound in the body, and the effectiveness of Erdafitinib by itself, in combination with JNJ-63723283 (Cetrelimab) or in combination with JNJ63723283 (Cetrelimab) and chemotherapy, in patients with metastatic or Locally Advanced urothelial cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Janssen Cilag International

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

24 Sep 2018 → ongoing

Decision date (initial)

2024-03-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Janssen Research & Development L.L.C

External identifiers

EU CT number

2023-510295-31-00

EudraCT number

2017-001980-19

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Pharmacodynamic, Safety, Dose response, Pharmacokinetic

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.

Conditions and MedDRA coding

Metastatic or Locally Advanced Urothelial Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. 1. >/= 18 years
2. 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. 3.Criterion modified per Ament. 2 3.1Metastatic or locally advanced urothelial cancer (Stage IV disease per AJCC Staging Guidelines).
4. 4.Criterion modified per Ament. 2 4.1Criterion modified per Ament. 3 4.2Phase 1b erdafitinib + cetrelimab cohort and Phase 2: Meet appropriate molecular eligibility criteria. Tumors must have at least one gene fusion or gene mutation.
5. 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. 6.Criterion modified per Amendment 2 6.1Criterion modified per Amendment 3 6.2Prior 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≥30 mL/min to receive carboplatin and ≥60 mL/min to receive cisplatin 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: o ECOG PS 0-1 AND at least one of the following criteria: - Renal function defined as CrCl≤60 mL/min as calculated by CockcroftGault (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. 7. Criterion modified per Ament. 2 7.1 Criterion modified per Ament. 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. 8.Criterion modified per Ament. 1 8.1Criterion modified per Ament. 2 8.2Criterion modified per Ament. 3 8.3Adequate organ function at Screening
9. 9.Criterion modified per Ament. 2 9.1Criterion modified per Ament 1 9.2Criterion modified per Ament 3 9.3Phase 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 hormonereleasing system; vasectomized partner; user-dependent methods: combined (estrogen- and progestogencontaining) 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. 10.Women of childbearing potential must have a negative pregnancy test at screening within ≤7 days of C1D1 (first dose of study drug) using a highly sensitive pregnancy test (serum beta-human chorionic gonadotropin [beta-hCG].

Exclusion criteria 20

1. 1.Treatment with any other investigational agent or participation in another clinical study with therapeut icintent 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. 2.Criterion modified Amend. 3 2.1Phase 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 >12m prior to recurrent disease progression and did not result in drug-related toxicity leading to treatment discontinuation.
3. 3 Criterion modified Amend. 2 3.1Criterion modified Amned. 3 3.2Prior 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 >12ms 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. 4.Criterion modified Amend.2 4.1Active malignancies requiring concurrent therapy other than urothelial cancer.
5. 5.Symptomatic central nervous system metastases.
6. 6.Prior FGFR inhibitor treatment.
7. 7.Radiation therapy ≤30 days prior to planned C1D1.
8. 8.Criterion modified Amend.2 8.1Criterion modified Amend.3 8.2History of uncontrolled cardiovascular disease including: – 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 3m.
9. 9.Known to be seropositive for human immunodeficiency virus or acquired immune deficiency syndrome.
10. 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 or that could prevent, limit, or confound the protocol-specified assessments.
11. 11.Pulmonary compromise requiring supplemental oxygen use to maintain adequate oxygenation.
12. 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. 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. 14.Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, known gastric ulcers, or unhealed incisions.
15. 15.Criterion modified Amend.2 15.1Allergies, 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.
16. 16.Criterion modified Amend.2 16.1Current central serous retinopathy (CSR) or retinal pigment epithelial detachment (RPED) of any Grade.
17. 17.Criterion deleted Amend. 2
18. 18. Criterion modified Amend.2 18.1 Use of immunosuppressant agents, including, but not limited to: its equivalent, methotrexate, cyclosporine, azathioprine, and tumor necrosis factor α (TNF-α) blockers, within 2 weeks before the planned first dose of study drug.
19. 19. Vaccinated with a live attenuated vaccine within 28 days prior to the first dose of study drug and for 3 months after receiving the last dose of study drug. Annual inactivated influenza vaccine is permitted.
20. 20. Criterion modified Amend. 3

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase 1b (Dose Escalation) - Frequency and type of dose-limiting toxicity (DLT).
2. 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.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Janssen Cilag International

Sponsor organisation

Janssen Cilag International

Address

Turnhoutseweg 30

City

Beerse

Postcode

2340

Country

Belgium

Scientific contact point

Organisation

Janssen Cilag International

Contact name

CTIS Point of Contact

Public contact point

Organisation

Janssen Cilag International

Contact name

CTIS Point of Contact

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications