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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
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).
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).
Participants will receive JNJ-42756493 at first RP2D of 9 mg daily in Part 3 orally once daily on a 21 days cycle.
Unnamed facility
Birmingham, Alabama, United States
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.
Time frame: Up to Part 1 Day 84 (Cycle 4, Day 21)
Maximum Observed Plasma Concentration (Cmax) of JNJ-42756493
The Cmax is the maximum observed plasma concentration.
Time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
Minimum Observed Plasma Concentration (Cmin) of JNJ-42756493
The Cmin is the minimum observed plasma concentration.
Time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
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.
Time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
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.
Time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
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).
Time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
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Masking
NONE
Enrollment
188
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.
Unnamed facility
Tucson, Arizona, United States
Unnamed facility
La Jolla, California, United States
Unnamed facility
Los Angeles, California, United States
Unnamed facility
Sacramento, California, United States
Unnamed facility
Santa Monica, California, United States
Unnamed facility
Denver, Colorado, United States
Unnamed facility
Tampa, Florida, United States
Unnamed facility
Augusta, Georgia, United States
Unnamed facility
Chicago, Illinois, United States
...and 27 more locations
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.
Time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
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.
Time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
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).
Time frame: Up to Part 4Day 84 (Cycle 4, Day 21)
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.
Time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
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.
Time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)
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.
Time frame: Up to Part 4 Day 84
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.
Time frame: Up to Part 4 Day 84 (Cycle 4, Day 21)