A Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of JNJ-42756493 in Adult Participants With Advanced or Refractory Solid Tumors or Lymphoma

Tumor or Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01703481
• Other study ID #: CR100845
• Secondary ID: 42756493EDI10012
• Status: Completed
• Phase: Phase 1
• Start date: June 15, 2012
• Est. completion date: July 5, 2017

Study information

• Verified date: April 2019
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 188
• Est. completion date: July 5, 2017
• Est. primary completion date: July 5, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Lymphoma
• Tumor or Lymphoma

Intervention

Drug:
• JNJ-42756493: Part 1
Participants will receive 0.5 mg (starting dose) capsule of JNJ-42756493 orally (by mouth) once daily on Day 1 of Cycle 1. Dose of the study medication will be escalated sequentially till the dose limiting toxicity is achieved to determine the recommended part 2 doses (RP2D).
• JNJ-42756493: Part 2
Participants will receive JNJ-42756493 at the RP2D or below RP2D (maximum tolerated dose from Part 1) orally once daily on a 21 days cycle to confirm RP2D (in Part 2).
• JNJ-42756493: Part 3
Participants will receive JNJ-42756493 at first RP2D of 9 mg daily in Part 3 orally once daily on a 21 days cycle.
• JNJ-42756493: Part 4
Participants will receive JNJ-42756493 second RP2D of 10 mg intermittent dosing in Part 4 (with option to increase to 12 mg intermittent dosing based on phosphate level), orally on an intermittent schedule of daily for 7 days followed by 7 days off with a 28-day cycle.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  France,  Spain, 

References & Publications (1)

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- — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Maximum Tolerated Dose (MTD) of JNJ-42756493	The maximum tolerated dose as determined in Part 1 of the study will be used as the recommended dose for Part 2, 3 and Part 4.	Up to Part 1 Day 84 (Cycle 4, Day 21)
Secondary	Maximum Observed Plasma Concentration (Cmax) of JNJ-42756493	The Cmax is the maximum observed plasma concentration.	Up to Part 4 Day 84 (Cycle 4, Day 21)
Secondary	Minimum Observed Plasma Concentration (Cmin) of JNJ-42756493	The Cmin is the minimum observed plasma concentration.	Up to Part 4 Day 84 (Cycle 4, Day 21)
Secondary	Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-42756493	The Tmax is defined as actual sampling time to reach maximum observed analyte concentration.	Up to Part 4 Day 84 (Cycle 4, Day 21)
Secondary	Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)	The AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval (24 hour). It is used to characterize drug absorption.	Up to Part 4 Day 84 (Cycle 4, Day 21)
Secondary	Elimination Half Life of JNJ-42756493	The elimination half-life (t1/2) is the time measured for the plasma concentration to decrease by 1 half to its original concentration. It is associated with the terminal slope of the semi logarithmic drug concentration-time curve, and is calculated as 0.693/lambda(z).	Up to Part 4 Day 84 (Cycle 4, Day 21)
Secondary	Apparent Volume of Distribution at Steady-State (Vss) of JNJ-42756493	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state, which is estimated by (D/AUC[0-infinity])*(AUMC[0-infinity])/AUC[0-infinity]) where D is the dose of study drug, AUMC(0-infinity) is the area under the first moment curve extrapolated to infinity and AUC(0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time.	Up to Part 4 Day 84 (Cycle 4, Day 21)
Secondary	Total Clearance of JNJ-42756493	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Total clearance of drug is calculated as dose divided by AUCtau at steady-state.	Up to Part 4 Day 84 (Cycle 4, Day 21)
Secondary	Accumulation Index (AI) of JNJ-42756493	Accumulation index is calculated by Cmax on Day 1 of Cycle 2/Cmax on Day 1 of Cycle 1 and/or AUCtau on Day 1 of Cycle 2/AUCtau on Day 1 of Cycle 1, where tau is the length of the dosing interval (24 hour).	Up to Part 4Day 84 (Cycle 4, Day 21)
Secondary	Number of Participants With Objective Tumor Response	Objective response based on assessment of confirmed Complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST). CR defined as disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of the diameters of the target lesions taking as reference the Baseline sum diameters. Confirmed responses are those that persist on repeat imaging study for at least 4 weeks after initial documentation of response.	Up to Part 4 Day 84 (Cycle 4, Day 21)
Secondary	Progression Free Survival (PFS)	Progression free survival is the time period from start of study medication till the disease progression or death, whichever occurs first.	Up to Part 4 Day 84 (Cycle 4, Day 21)
Secondary	Duration of Objective Response	Duration of objective response is time interval from the first date that criteria for complete response or partial response are met to the first date of progression of disease.	Up to Part 4 Day 84
Secondary	Number of Participants With an Adverse Event	An adverse event is any untoward medical event that occurs in a participant administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product.	Up to Part 4 Day 84 (Cycle 4, Day 21)