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 ID
STU 072013-039

Cancer Related
Yes

Healthy Volunteers
No

Study Sites

  • Zale Lipshy University Hospital

Contact
Laurin Priddy
214/648-1688
LAURIN.LOUDAT@UTSouthwestern.edu

Principal Investigator
Joan Schiller

Summary

This study is a first-in-human, open-label, multicenter, 4-part, Phase 1 study to evaluate the
safety, pharmacokinetics, and pharmacodynamics of JnJ-42756493 administered orally to
subjects [GreaterThanorequalTo]18 years of age with advanced or refractory solid malignancies or lymphoma who are
not candidates for approved or available therapies. all subjects must be considered evaluable by
the treatment physician. each cycle will consist of 21 days of daily continuous dosing or 28 days
of intermittent dosing schedule.

The study consists of 4 parts.
Part 1 is designed to determine the RP2D based on the safety, pharmacokinetic, and
pharmacodynamic data of JnJ-42756493.
Part 2 will consist of a pre and post treatment tumor biopsy cohort to evaluate the
pharmacodynamic effect of JnJ-42756493 in tumor and to confirm FGFR pathway inhibition, to
further expand the information on the safety, and pharmacokinetics/pharmacodynamics.
Part 3 is the first Dose-expansion Phase, which was initially designed to evaluate inclusion
biomarkers and preliminary clinical activity at the first RP2D of 9.0 mg daily. it consists of
4 expansion cohorts, (including 3 disease-specific and 1 mixed-disease type): squamous nSCLC
cohort, SCLC cohort, breast cancer cohort, and solid tumor cohort.
Part 4 is the second Dose expansion Phase, which is designed to evaluate clinical activity at the
second RP2D of 10 mg intermittent dosing schedule.
The end of study is defined as the last study assessment for the last treated subject. The study is
estimated to take approximately 48 months to complete.

Participant Eligibility

1. Be 18 years of age, or older.
2. Histologically or cytologically confirmed:
Part 1
Any type of advanced or refractory solid malignancy or lymphoma that is metastatic or
unresectable, and for which standard curative treatment is no longer effective.
Part 2

* Any type of advanced or refractory solid malignancy (excluding lymphoma) that
is metastatic or unresectable

* Subjects must meet the following molecular eligibility criteria (diagnosed at a
local or at a central laboratory): tumors that are KRAS wild type in combination
with any of the following: FGFR, FGFR activating mutations, FGFR
translocations, or other molecular aberrations leading to activation of the FGFR
pathway).

* Subjects must be amenable to pre- and post-treatment biopsies.
Part 3
- Subjects must meet the following molecular eligibility criteria (diagnosed at a
local or at a central laboratory): tumors that are KRAS wild type in combination
with any of the following: FGFR activating mutations, FGFR translocations, or
other molecular aberrations leading to activation of the FGFR pathway).
- Cohort A: advanced or refractory squamous NSCLC.
- Cohort B: advanced or refractory SCLC.
- Cohort C: advanced or refractory breast cancer.
- Cohort D: advanced or refractory solid malignancy (consisting of one of the
following: gastric, head& neck, lung adenocarcinoma, urothelial, glioblastoma
multiforme (GBM), ovarian or prostate).
- There are no restrictions regarding number of prior lines of therapies but should
have received and progressed after at least 1 line of standard anti-cancer therapy.
Part 4

* Part 4 subjects must meet the following molecular eligibility criteria (diagnosed
at a local or at a central laboratory): tumors with FGFR activating mutations or
FGFR translocations).
- Cohort E: advanced or refractory NSCLC.
- Cohort F: advanced or refractory solid malignancy of (consisting of one of the
following: Breast, Urothelial, GBM)
- There are no restrictions regarding number of prior lines of therapies but should
have received and progressed after at least 1 line of standard anti-cancer therapy.

3. For Part 3 and 4, the presence of measurable disease according to the Response
Evaluation Criteria in Solid Tumors (RECIST) Criteria, and documented disease
progression as defined by RECIST (Version 1.1) at baseline. GBM may be assessed
using Revised Assessment in Neuro-Oncology (RANO) criteria.
4. Eastern Cooperative Oncology Group (ECOG) performance status score 0 or 1
(Attachment 1).
5.1 Adequate bone marrow, liver, and renal function within the 14 days prior to Day 1
of Cycle 1 up until pre-dose of Cycle 1, as described below:
- Bone marrow function (without the support of cytokines and/or erythropoietin in
preceding 2 weeks):
Absolute neutrophil count (ANC) >1500/mm3
Platelet count >75,000/mm3
Hemoglobin >8.5 g/dL (without transfusion or demonstrate stability (i.e no
significant decline in Hb) for 2 weeks after transfusion)
- Liver function:
Total bilirubin <=1.5 x institutional upper limit of normal (ULN).
Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) <=2.5 x
institutional ULN in the absence of liver metastasis, or <=5.0 x institutional ULN.
Renal function
Serum creatinine <= 1.5 mg/dl or calculated creatinine clearance (Attachment 2) >=50 mL/min/1.73 m2.
6. Magnesium within 0.85 to 1.25x institutional normal limits Sodium >=130 mEq/L.
Potassium within institutional normal limits. (within 14 days prior to Day 1 of
Cycle 1 up until pre-dose of Cycle 1).
7. Female subjects (if of child bearing potential) and male subjects (with a partner of
child bearing potential) must use medically acceptable methods of birth control before
study entry, for the duration of the study, and for at least 3 months after the last intake of
study drug. Male subjects must accept the use of condoms when sexually active during
the study. Medically acceptable methods of contraception that may be used by the
subject and/or his/her partner include oral contraceptives, contraceptive injections,
contraceptive patch, intrauterine device, double-barrier method, and surgical
sterilization (eg, confirmed successful vasectomy or tubal ligation).
8. Negative pregnancy test (urinary or serum beta human chorionic gonadotropin [[BETA]-hCG])
at Screening for women of child bearing potential who are sexually active.
9. Sign an informed consent document indicating that they understand the purpose of and
procedures required for the study and are willing to participate in the study.