Clinical trial NCT01703481: A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-42756493 in Adult Participants With Advanced or Refractory Solid Tumors or Lymphoma
Official title: A Phase 1 Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-42756493, a Pan-Fibroblast Growth Factor Receptor (FGFR) Tyrosine Kinase Inhibitor, in Subjects With Advanced or Refractory Solid Tumors or Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Tumor or Lymphoma
Keywords: Tumor
Fibroblast Growth Factor Receptor (FGFR)
Non-Small Cell Lung Cancer (NSCLC)
Small Cell Lung Cancer (SCLC)
JNJ-42756493
Lead sponsor: Janssen Research & Development, LLC
Sponsor class: INDUSTRY
First posted: 2012-10-10
Enrollment: 188
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, pharmacokinetics (study of what the body does to a drug), and pharmacodynamics (study of what a drug does to the body) of JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, in adult participants with advanced or refractory solid tumors or lymphoma.

Detailed description: This is a first-in-human, non-randomized (individuals will not be assigned by chance to study treatments), open-label (individuals will know the identity of study treatments), multicenter (more than 1 hospital work on a study), Phase 1 study. The study consists of 4 parts. Part 1 is the dose-escalation phase, which will be guided by pharmacokinetics, pharmacodynamics and safety. In part 1, safe and biologically active Phase 2 doses (recommended Phase 2 doses \[RP2D\]) for JNJ-42756493 will be primarily assessed. Participants will be enrolled in sequential cohorts (first cohort will receive the starting dose and subsequent cohorts will receive increased doses of JNJ-42756493). Part 2 is the Dose Confirmation Phase, which consists of a pre and post treatment tumor biopsy cohorts to confirm the RP2D based on the pharmacodynamic effect of JNJ-42756493 on fibroblast growth factor receptor (FGFR) signaling pathway in tumor. Part 3 is the first Dose Expansion Phase, which is designed to evaluate inclusion biomarkers and preliminary clinical activity at the first RP2D. It consists of 4 expansion cohorts, 1 each for squamous cell lung cancer, small cell lung cancer, breast cancer, other solid tumors (Cohorts A, B, C, and D). Part 4 is the second Dose Expansion Phase, which is designed to evaluate inclusion biomarkers and preliminary clinical activity at the second RP2D. Biomarker eligibility has also been refined based on emerging data. It consists of 2 expansion cohorts, Cohort E for non-small cell lung cancer and Cohort F for select solid tumors including breast, urothelial, GBM, ovarian, head \& neck, esophageal, gastric, and cholangiocarcinoma (Cohorts E and F). Enrollment of some cohorts may be discontinued due to lack of enrollment or for futility. The study is estimated to take approximately 48 months to complete. Participants' safety will be monitored throughout the study.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed: solid malignancy or lymphoma that is metastatic or unresectable, and for which standard curative treatment is no longer effective (Part 1); any type of advanced or refractory solid malignancy (excluding lymphoma) that is metastatic or unresectable and for which standard curative treatment is no longer effective (Part 2); advanced or refractory squamous non-small cell lung cancer (Cohort A, Part 3), advanced or refractory small cell lung cancer (Cohort B, Part 3), advanced or refractory breast cancer (Cohort C, Part 3), any type of advanced or refractory solid malignancy (excluding lymphoma) (\[consisting of one of the following: gastric, head and neck, lung adenocarcinoma, urothelial, glioblastoma multiforme (GBM), ovarian or prostate\]) (Cohort D, Part 3), advanced or refractory non small cell lung cancer(Cohort E, Part 4), any type of advanced or refractory solid malignancy (consisting of one of the following: Breast, Urothelial, GBM, Ovarian, Head \& Neck, Esophageal, Gastric, and Cholangiocarcinoma) (Cohort F, Part 4)
* Eastern Cooperative Oncology Group performance status score 0 or 1
* Adequate bone marrow, liver, and renal function within the 14 days prior to Day 1 of Cycle 1 of study drug up until pre-dose of Cycle 1
* Magnesium within 0.85 to 1.25 \* institutional normal limits, Sodium greater than or equal to 130 milli equivalent per liter, Potassium within institutional normal limits (within 14 days prior to Day 1 of Cycle 1 up until pre-dose of Cycle 1)

Exclusion Criteria:

* Chemotherapy, targeted therapies, radiotherapy, immunotherapy, or treatment with an investigational anticancer agent within 2 weeks or at least 5 half-lives of the drug, whichever is longer and up to a maximum of 4 weeks (in the case of nitrosoureas and mitomycin C within 6 weeks) before the first administration of study drug. Localized radiation therapy and ongoing luteinizing hormone-releasing hormone (LHRH) agonists, bisphosphonates and denosumab, are permitted
* Participants with GBM can be enrolled 2 weeks after last treatment
* History or current condition of uncontrolled cardiovascular disease
* Participants with persistent phosphate greater than upper limit of normal during screening (within 14 days prior to Day 1 of Cycle 1 up until pre-dose of Cycle 1) and despite medical management of phosphate levels
* Participants taking medications known to have a significant risk of causing QTc prolongation and Torsades de Pointes
* Left ventricular ejection fraction (LVEF) less than 50 percent as assessed by echocardiography (or multi-gated acquisition) performed at screening
* Any medical condition that requires intact wound healing capacity and is expected to endanger participant safety if wound healing capacity would be severely reduced during administration of the investigational agent
* Participants not recovered from reversible toxicity of prior anticancer therapy (except toxicities which are not clinically significant such as alopecia, skin discoloration, or Grade 1 neuropathy)

Primary outcomes:
measure: Part 1: Maximum Tolerated Dose (MTD) of JNJ-42756493
timeFrame: Up to Part 1 Day 84 (Cycle 4, Day 21)
Secondary outcomes:
measure: Maximum Observed Plasma Concentration (Cmax) of JNJ-42756493
timeFrame: Up to Part 4 Day 84 (Cycle 4, Day 21)
measure: Minimum Observed Plasma Concentration (Cmin) of JNJ-42756493
timeFrame: Up to Part 4 Day 84 (Cycle 4, Day 21)
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-42756493
timeFrame: Up to Part 4 Day 84 (Cycle 4, Day 21)
measure: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)
timeFrame: Up to Part 4 Day 84 (Cycle 4, Day 21)
measure: Elimination Half Life of JNJ-42756493
timeFrame: Up to Part 4 Day 84 (Cycle 4, Day 21)
measure: Apparent Volume of Distribution at Steady-State (Vss) of JNJ-42756493
timeFrame: Up to Part 4 Day 84 (Cycle 4, Day 21)
measure: Total Clearance of JNJ-42756493
timeFrame: Up to Part 4 Day 84 (Cycle 4, Day 21)
measure: Accumulation Index (AI) of JNJ-42756493
timeFrame: Up to Part 4Day 84 (Cycle 4, Day 21)
measure: Number of Participants With Objective Tumor Response
timeFrame: Up to Part 4 Day 84 (Cycle 4, Day 21)
measure: Progression Free Survival (PFS)
timeFrame: Up to Part 4 Day 84 (Cycle 4, Day 21)
measure: Duration of Objective Response
timeFrame: Up to Part 4 Day 84
measure: Number of Participants With an Adverse Event
timeFrame: Up to Part 4 Day 84 (Cycle 4, Day 21)
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Tucson
country: United States
state: Arizona
city: La Jolla
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Sacramento
country: United States
state: California
city: Santa Monica
country: United States
state: California
city: Denver
country: United States
state: Colorado
city: Tampa
country: United States
state: Florida
city: Augusta
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Goshen
country: United States
state: Indiana
city: Boston
country: United States
state: Massachusetts
city: Detroit
country: United States
state: Michigan
city: Saint Louis
country: United States
state: Missouri
city: New Brunswick
country: United States
state: New Jersey
city: Albuquerque
country: United States
state: New Mexico
city: Charlotte
country: United States
state: North Carolina
city: Durham
country: United States
state: North Carolina
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Tyler
country: United States
state: Texas
city: Fairfax
country: United States
state: Virginia
city: Bordeaux
country: France
city: Caen Cedex 05
country: France
city: Dijon
country: France
city: Lyon
country: France
city: Marseille
country: France
city: Saint Herblain Cedex
country: France
city: Villejuif
country: France
city: Badalona
country: Spain
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Málaga
country: Spain
city: Pamplona
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
Study officials:
affiliation: Janssen Research & Development, LLC
name: Janssen Research & Development, LLC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Tabernero J, Bahleda R, Dienstmann R, Infante JR, Mita A, Italiano A, Calvo E, Moreno V, Adamo B, Gazzah A, Zhong B, Platero SJ, Smit JW, Stuyckens K, Chatterjee-Kishore M, Rodon J, Peddareddigari V, Luo FR, Soria JC. Phase I Dose-Escalation Study of JNJ-42756493, an Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients With Advanced Solid Tumors. J Clin Oncol. 2015 Oct 20;33(30):3401-8. doi: 10.1200/JCO.2014.60.7341. Epub 2015 Aug 31.
citation: Valade E, Dosne AG, Xie H, Kleiman R, Li LY, Perez-Ruixo JJ, Ouellet D. Assessment of the effect of erdafitinib on cardiac safety: analysis of ECGs and exposure-QTc in patients with advanced or refractory solid tumors. Cancer Chemother Pharmacol. 2019 Sep;84(3):621-633. doi: 10.1007/s00280-019-03896-1. Epub 2019 Jul 6.
citation: Bahleda R, Italiano A, Hierro C, Mita A, Cervantes A, Chan N, Awad M, Calvo E, Moreno V, Govindan R, Spira A, Gonzalez M, Zhong B, Santiago-Walker A, Poggesi I, Parekh T, Xie H, Infante J, Tabernero J. Multicenter Phase I Study of Erdafitinib (JNJ-42756493), Oral Pan-Fibroblast Growth Factor Receptor Inhibitor, in Patients with Advanced or Refractory Solid Tumors. Clin Cancer Res. 2019 Aug 15;25(16):4888-4897. doi: 10.1158/1078-0432.CCR-18-3334. Epub 2019 May 14.