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

Primary Purpose

Tumor or Lymphoma

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

JNJ-42756493: Part 1

JNJ-42756493: Part 2

JNJ-42756493: Part 3

JNJ-42756493: Part 4

About this trial

This is an interventional treatment trial for Tumor or Lymphoma focused on measuring Tumor, Fibroblast Growth Factor Receptor (FGFR), Non-Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), JNJ-42756493

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Experimental

Arm Label

Part 1

Part 2

Part 3, Cohort A

Part 3, Cohort B

Part 3, Cohort C

Part 3, Cohort D

Part 4, Cohort E

Part 4, Cohort F

Arm Description

Dose Escalation, Part 1: Participants will be enrolled in sequential cohorts to determine recommended Phase 2 doses (RP2D).

Dose Confirmation, Part 2: Tumor biopsy cohorts will confirm RP2D.

First dose expansion, Part 3: Participants with squamous non-small cell lung cancer.

First dose expansion, Part 3: Participants with small cell lung cancer.

First dose expansion, Part 3: Participants with breast cancer.

First dose expansion, Part 3: Participants with solid tumors (consisting of one of the following: gastric, head and neck, lung adenocarcinoma, urothelial, glioblastoma multiforme [GBM], ovarian or prostate).

Second dose expansion, Part 4: Participants with non-small cell lung cancer.

Second dose expansion, Part 4: Participants with solid tumors (consisting of one of the following: breast, urothelial, GBM).

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Maximum Observed Plasma Concentration (Cmax) of JNJ-42756493

The Cmax is the maximum observed plasma concentration.

Minimum Observed Plasma Concentration (Cmin) of JNJ-42756493

The Cmin is the minimum observed plasma concentration.

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.

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.

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).

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.

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.

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).

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.

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.

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.

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.

Full Information

NCT ID

NCT01703481

First Posted

March 22, 2012

Last Updated

May 24, 2019

Sponsor

Janssen Research & Development, LLC

1. Study Identification

Unique Protocol Identification Number

NCT01703481

Brief Title

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

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Completed

Study Start Date

June 15, 2012 (Actual)

Primary Completion Date

July 5, 2017 (Actual)

Study Completion Date

July 5, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Janssen Research & Development, LLC

4. Oversight

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Tumor or Lymphoma

Keywords

Tumor, Fibroblast Growth Factor Receptor (FGFR), Non-Small Cell Lung Cancer (NSCLC), Small Cell Lung Cancer (SCLC), JNJ-42756493

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

188 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1

Arm Type

Experimental

Arm Description

Dose Escalation, Part 1: Participants will be enrolled in sequential cohorts to determine recommended Phase 2 doses (RP2D).

Arm Title

Part 2

Arm Type

Experimental

Arm Description

Dose Confirmation, Part 2: Tumor biopsy cohorts will confirm RP2D.

Arm Title

Part 3, Cohort A

Arm Type

Experimental

Arm Description

First dose expansion, Part 3: Participants with squamous non-small cell lung cancer.

Arm Title

Part 3, Cohort B

Arm Type

Experimental

Arm Description

First dose expansion, Part 3: Participants with small cell lung cancer.

Arm Title

Part 3, Cohort C

Arm Type

Experimental

Arm Description

First dose expansion, Part 3: Participants with breast cancer.

Arm Title

Part 3, Cohort D

Arm Type

Experimental

Arm Description

Arm Title

Part 4, Cohort E

Arm Type

Experimental

Arm Description

Second dose expansion, Part 4: Participants with non-small cell lung cancer.

Arm Title

Part 4, Cohort F

Arm Type

Experimental

Arm Description

Second dose expansion, Part 4: Participants with solid tumors (consisting of one of the following: breast, urothelial, GBM).

Intervention Type

Drug

Intervention Name(s)

JNJ-42756493: Part 1

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

JNJ-42756493: Part 2

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

JNJ-42756493: Part 3

Intervention Description

Participants will receive JNJ-42756493 at first RP2D of 9 mg daily in Part 3 orally once daily on a 21 days cycle.

Intervention Type

Drug

Intervention Name(s)

JNJ-42756493: Part 4

Intervention Description

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.

Primary Outcome Measure Information:

Title

Part 1: Maximum Tolerated Dose (MTD) of JNJ-42756493

Description

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)

Secondary Outcome Measure Information:

Title

Maximum Observed Plasma Concentration (Cmax) of JNJ-42756493

Description

The Cmax is the maximum observed plasma concentration.

Time Frame

Up to Part 4 Day 84 (Cycle 4, Day 21)

Title

Minimum Observed Plasma Concentration (Cmin) of JNJ-42756493

Description

The Cmin is the minimum observed plasma concentration.

Time Frame

Up to Part 4 Day 84 (Cycle 4, Day 21)

Title

Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-42756493

Description

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)

Title

Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau)

Description

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)

Title

Elimination Half Life of JNJ-42756493

Description

Time Frame

Up to Part 4 Day 84 (Cycle 4, Day 21)

Title

Apparent Volume of Distribution at Steady-State (Vss) of JNJ-42756493

Description

Time Frame

Up to Part 4 Day 84 (Cycle 4, Day 21)

Title

Total Clearance of JNJ-42756493

Description

Time Frame

Up to Part 4 Day 84 (Cycle 4, Day 21)

Title

Accumulation Index (AI) of JNJ-42756493

Description

Time Frame

Up to Part 4Day 84 (Cycle 4, Day 21)

Title

Number of Participants With Objective Tumor Response

Description

Time Frame

Up to Part 4 Day 84 (Cycle 4, Day 21)

Title

Progression Free Survival (PFS)

Description

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)

Title

Duration of Objective Response

Description

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

Title

Number of Participants With an Adverse Event

Description

Time Frame

Up to Part 4 Day 84 (Cycle 4, Day 21)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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)

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Janssen Research & Development, LLC Clinical Trial

Organizational Affiliation

Janssen Research & Development, LLC

Official's Role

Study Director

Facility Information:

City

Birmingham

State/Province

Alabama

Country

United States

City

Tucson

State/Province

Arizona

Country

United States

City

La Jolla

State/Province

California

Country

United States

City

Los Angeles

State/Province

California

Country

United States

City

Sacramento

State/Province

California

Country

United States

City

Santa Monica

State/Province

California

Country

United States

City

Denver

State/Province

Colorado

Country

United States

City

Tampa

State/Province

Florida

Country

United States

City

Augusta

State/Province

Georgia

Country

United States

City

Chicago

State/Province

Illinois

Country

United States

City

Goshen

State/Province

Indiana

Country

United States

City

Boston

State/Province

Massachusetts

Country

United States

City

Detroit

State/Province

Michigan

Country

United States

City

Saint Louis

State/Province

Missouri

Country

United States

City

New Brunswick

State/Province

New Jersey

Country

United States

City

Albuquerque

State/Province

New Mexico

Country

United States

City

Charlotte

State/Province

North Carolina

Country

United States

City

Durham

State/Province

North Carolina

Country

United States

City

Nashville

State/Province

Tennessee

Country

United States

City

Dallas

State/Province

Texas

Country

United States

City

Houston

State/Province

Texas

Country

United States

City

Tyler

State/Province

Texas

Country

United States

City

Fairfax

State/Province

Virginia

Country

United States

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

12. IPD Sharing Statement

Citations:

PubMed Identifier

26324363

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.

Results Reference

result

PubMed Identifier

31280362

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.

Results Reference

derived

PubMed Identifier

31088831

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.

Results Reference

derived

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

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