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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2015 by Janssen Research & Development, LLC
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT01703481
First received: March 22, 2012
Last updated: July 20, 2015
Last verified: July 2015
  Purpose

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.


Condition Intervention Phase
Tumor or Lymphoma
Drug: JNJ-42756493: Part 1
Drug: JNJ-42756493: Part 2
Drug: JNJ-42756493: Part 3
Drug: JNJ-42756493: Part 4
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Janssen Research & Development, LLC:

Primary Outcome Measures:
  • Part 1: Maximum Tolerated Dose (MTD) of JNJ-42756493 [ Time Frame: Up to Part 1 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to Part 4 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    The Cmax is the maximum observed plasma concentration.

  • Minimum Observed Plasma Concentration (Cmin) of JNJ-42756493 [ Time Frame: Up to Part 4 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    The Cmin is the minimum observed plasma concentration.

  • Time to Reach Maximum Observed Plasma Concentration (Tmax) of JNJ-42756493 [ Time Frame: Up to Part 4 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    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) [ Time Frame: Up to Part 4 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to Part 4 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to Part 4 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to Part 4 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to Part 4Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to Part 4 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    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) [ Time Frame: Up to Part 4 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to Part 4 Day 84 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Up to Part 4 Day 84 (Cycle 4, Day 21) ] [ Designated as safety issue: Yes ]
    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.


Estimated Enrollment: 260
Study Start Date: June 2012
Estimated Study Completion Date: August 2016
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1
Dose Escalation, Part 1: Participants will be enrolled in sequential cohorts to determine recommended Phase 2 doses (RP2D).
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).
Experimental: Part 2
Dose Confirmation, Part 2: Tumor biopsy cohorts will confirm RP2D.
Drug: 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).
Experimental: Part 3, Cohort A
First dose expansion, Part 3: Participants with squamous non-small cell lung cancer.
Drug: 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.
Experimental: Part 3, Cohort B
First dose expansion, Part 3: Participants with small cell lung cancer.
Drug: 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.
Experimental: Part 3, Cohort C
First dose expansion, Part 3: Participants with breast cancer.
Drug: 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.
Experimental: Part 3, Cohort D
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).
Drug: 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.
Experimental: Part 4, Cohort E
Second dose expansion, Part 4: Participants with non-small cell lung cancer.
Drug: 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.
Experimental: Part 4, Cohort F
Second dose expansion, Part 4: Participants with solid tumors (consisting of one of the following: breast, urothelial, GBM).
Drug: 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.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01703481

Contacts
Contact: Use link at the bottom of the page to see if you qualify for an enrolling site (see list). If you still have questions: JNJ.CT@sylogent.com

  Show 42 Study Locations
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
  More Information

Additional Information:
No publications provided

Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT01703481     History of Changes
Other Study ID Numbers: CR100845, 42756493EDI1001, 2012-000697-34
Study First Received: March 22, 2012
Last Updated: July 20, 2015
Health Authority: United States: Food and Drug Administration
Spain: Spanish Agency of Medicines
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Janssen Research & Development, LLC:
Tumor
Fibroblast Growth Factor Receptor (FGFR)
Non-Small Cell Lung Cancer (NSCLC)
Small Cell Lung Cancer (SCLC)
JNJ-42756493

Additional relevant MeSH terms:
Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on September 01, 2015