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, pharmacodynamics, and clinical activity 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. each cycle will consist of 21 days for daily continuous
dosing cohorts or 28 days for intermittent dosing cohorts.

The study consists of 4 parts.
Part 1 is the Dose-escalation Phase, which will be guided by pharmacokinetics, pharmacodynamics and
safety. Part 1 is designed to determine the RP2D based on the safety, pharmacokinetic, and
pharmacodynamic data of JnJ-42756493.
Part 2 is the Dose Confirmation Phase. Part 2 consists of pre- and post-treatment tumor biopsy cohorts
to confirm the RP2D based on the pharmacodynamic effect of JnJ-42756493 on FGFR signaling pathway
in tumor.
Part 3 is the first Dose-expansion Phase, which was initially designed to evaluate biomarker incidence
rates and preliminary clinical activity at the first RP2D of 9.0 mg daily. it consists of 4 expansion cohorts,
which includes 3 disease-specific expansion cohorts, squamous nSCLC, SCLC, breast cancer, and a solid
tumor cohort.
Part 4 is the second Dose expansion Phase, which is designed to evaluate biomarker incidence rates
(using revised biomarker inclusion criteria) and preliminary clinical activity at the second RP2D of 10 mg
intermittent dosing schedule (with pharmacodynamic-based option to escalate to 12 mg).
The study will end with the last assessment of the last subject. The study will take approximately
60 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 and for which standard curative treatment is no
longer effective
- 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 amplifications, 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 amplifications, 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 (squamous and non-squamous).
- Cohort F: advanced or refractory solid malignancy (consisting of one of the
following: Breast, Urothelial, GBM, Ovarian, Head & Neck, Esophageal,
Gastric, and Cholangiocarcinoma)
- 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 use a condom with spermicide 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, true sexual abstinence, and surgical
sterilization (eg, confirmed successful vasectomy or tubal ligation).True sexual abstinence is an
acceptable method of contraception and is defined as refraining from heterosexual
intercourse during the entire period of the study, including up to 3 months for
females and 5 months for males after the last dose of study drug is given. Periodic
abstinence (calendar, symptothermal, postovulation methods) is not considered an
acceptable contraceptive method.
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.