Primary: to characterize the safety and tolerability of GSK3052230 in combination with chemotherapy regimens, to determine the MTD and to assess overall response rate in patients with stage IV or recurrent squamous NSCLC with FGFR1 gene…
ID
Source
Brief title
Condition
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Adverse events, MTD, overall survival.
Secondary outcome
PFS, population PK, Pulmonary Function Test parameters.
Background summary
Preclinically, the fibroblast growth factor (FGF) pathway plays many roles in
the development of cancer, including regulation of cell growth and
differentiation, regulation of angiogenesis and participation in tumor-stroma
interactions. FGFs can stimulate the proliferation of tumor cells and tumor
cell lines. Blockade of FGF signaling can prevent tumor cell growth. FGF
signaling is mediated by a family of transmembrane receptor tyrosine kinases
encoded by four distinct genes producing FGF
receptor subtypes termed FGFR1-4. FGFR1 is the best characterized of the 4
FGFRs.
GSK3052230 blocks the FGF pathway and may have anti-tumor activity either by
inhibiting tumor cell proliferation and/or by inhibition of tumor associated
angiogenesis. GSK3052230 has been studied in a Phase 1, open-label,
dose-escalation study. No MTD has been established. The 20 mg/kg once weekly
dosing schedule was determined to be safe and was declared the *maximum
feasible dose*.
Increased expression of FGFRs, FGFR1 gene amplification, or production of FGFs
correlates with poor prognosis in a variety of tumor types including NSCLC. A
focal amplification of the FGFR1 gene has been detected in approximately 20% of
subjects with squamous NSCLC.
Malignant mesothelioma remains a deadly disease with few effective therapies.
The median overall survival ranges from 9-17 months regardless of disease
stage. The first-line standard of care remains cisplatin and pemetrexed. There
remains no widely approved regimen for recurrent mesothelioma. The poor PFS and
OS data underscore the need for more effective therapies in recurrent
mesothelioma.
This Phase I study is primarily designed to characterize the safety and
tolerability of GSK3052230 in combination with chemotherapy regimens, to
determine the MTD and to assess overall response rate in patients with stage IV
or recurrent squamous NSCLC with FGFR1 gene amplification and recurrent or
unresectable mesothelioma.
New information on18-02-2016:
The enrollment in2 study arms (arms A and B) has been closed. Subjects still on
treatment in these arms will continue as planned. The enrollmant for arm C
(mesothelioma) will continue as planned. This decision has been taken after
review of the available study data sofar.
The decision is not based on safety issues.
Arm A (NSCLC, chemotherapy: paclitaxel + carboplatin (standard)): The
preliminary efficacy data in therapy naive subjects with NSCLC indicate a
similar treatment effect of chemotherapy with and without GSK3052230. The
estimated PFS in this arm is approx. 5* months (versus 4-6 months). 18 subjects
have been included in this arm.
In addition the introduction of new immuno-oncological compounds sets new
standards in terms of efficacy. The available data from arm A do not seem to
compare favourably with these standards.
Arm B (NSCLC, chemotherapy: docetaxel (standard)): The inclusion in arm B is
very slow (9 subjects sofar). Dince the last dose escalation cohort t (20
mg/kg) has been completed, it has been decided to close this arm as well..
Study objective
Primary: to characterize the safety and tolerability of GSK3052230 in
combination with chemotherapy regimens, to determine the MTD and to assess
overall response rate in patients with stage IV or recurrent squamous NSCLC
with FGFR1 gene amplification and recurrent or unresectable mesothelioma.
Secondary: PFS, population PK, improvement in Pulmonary Function Tests.
Study design
3-arm, multicenter, non-randomized, parallel-group, uncontrolled, open-label
Phase IB study. Dose escalation (see protocol page 33).
Arm A: NSCLC, chemotherapy: paclitaxel + carboplatin (arm closed 18-02-16).
Arm B: NSCLC, chemotherapy: docetaxel (arm closed 18-02-16).
Arm C: mesothelioma, chemotherapy: pemetrexed + cisplatin.
GSK3052230 will be administered as a 30-minute intravenous (i.v.) infusion once
a week (Day 1, Day 8, Day 15) of each 21-day cycle. Chemotherapy will be
administered i.v. on Day 1 of each 21-day cycle. Paclitaxel/carboplatin will be
limited to 4 to 6 cycles. Docetaxel and pemetrexed/cisplatin until disease
progression.
Approx.70 (range 38-120) patients.
Intervention
Treatment with GSK3052230.
Study burden and risks
Risk: Adverse events of study medication combined with chemotherapy.
Burden: Visits cycle 1 4x, cycle 2 and thereafter 3x, final visit approx. 30
days after last administration of study medication.
I.v. infusion with GSK3052230 every week.
Chemotherapy conform standard.
Pre-screening for NSCLC patients for FGFR1 mutation (archived tumor material,
if necessary fresh tumor tissue). Mandatory.
Research tumor tissue in patients with a mesothelioma (archived tumor material,
if necessary fresh tumor tissue). Mandatory.
Physical examination 1x/cycle.
Eye examination every 4th cycle.
Blood tests: During First 6 weeks 65-100 ml per visit and thereafter approx. 45
ml per visit. During screening and final visit approx. 15 ml.
Pregnancy test: start and end of study.
Urine tests every 4th cycle.
ECG: cycle 1 2x, thereafter every 4th cycle.
Tumor measurements conform standard.
Pulmonary function test every odd cycle.
Questionnaire on symptoms every cycle.
Optional: pharmacogenetic blood test (6 ml once).
Huis ter Heideweg 62
Zeist 3705 LZ
NL
Huis ter Heideweg 62
Zeist 3705 LZ
NL
Listed location countries
Age
Inclusion criteria
• Histologically or cytologically confirmed diagnosis:
Arms A and B: Stage IV or recurrent metastatic squamous NSCLC with FGFR1 gene amplification.
Arm A: No prior therapy for Stage IV or recurrent metastatic disease.
Arm B: Documented tumor progression or intolerability after receiving only one prior line of platinum containing combination chemotherapy for Stage IV or recurrent metastatic disease.
Arm C: recurrent after local therapy or unresectable mesothelioma with measurable lesions. No prior systemic therapy for mesothelioma.
See protocol page 28 for further details..
• Availability of archival tumor tissue or fresh biopsy is required.
Arms A and B, Prospective screening for FGFR1 gene amplification.
• Measurable disease.
• Male or female at least18 years.
• Women of childbearing potential must agree to use effective contraception. See protocol page 29 for details.
• Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception. See protocol page 29 for details.
• ECOG Performance Status of 0-1 for Arm A and 0-2 for Arms B and C.
Exclusion criteria
• For Arms A, B, C: Treatment with any FGFR inhibitor.
For Arm B: Treatment with any anti-cancer therapy during the preceding 4 weeks or within 4 half-lives of the therapy.
• Any biological therapy within 6 weeks of the first dose of GSK3052230.
• Uncontrolled infection, major surgery or trauma within 28 days, any non-healing wound, fracture, or ulcer.
• Any prohibited medication(s) as described on protocol page 78-79.
• Conditions likely to increase the potential for abdominal perforation or fistula formation. See protocol page 30 for details.
• Symptomatic leptomeningeal or brain metastases or spinal cord compression. See protocol page 30 for details.
• Hemoptysis (>* teaspoon of red blood) 2 weeks prior to the first dose of GSK3052230.
• Pregnant, lactating females.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| Other | clinicaltrials.gov, NCT01868022 |
| EudraCT | EUCTR2013-000354-21-NL |
| CCMO | NL48044.031.14 |