Clinical trial NCT01868022: Study to Evaluate GSK3052230 in Combination With Paclitaxel and Carboplatin, or Docetaxel or as Single Agent in Subjects With Solid Malignancies and Deregulated Fibroblast Growth Factor (FGF) Pathway Signaling
Official title: Multi-arm, Non-randomized, Open-Label Phase IB Study to Evaluate GSK3052230 in Combination With Paclitaxel and Carboplatin, or Docetaxel or as Single Agent in Subjects With Solid Malignancies and Deregulated FGF Pathway Signaling
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Keywords: FGFR1
FP1039
GSK3052230
docetaxel
FGFR
carboplatin
HGS1036
squamous non-small cell lung cancer
paclitaxel
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-06-04
Enrollment: 65
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase IB trial aims to identify anticancer activity of GSK3052230 in subjects with malignancies with abnormal dependence on FGF pathway signaling. Combination doses of GSK3052230 with standard of care chemotherapy in the first and second line or greater setting of metastatic squamous non-small cell lung cancer (NSCLC) and first line malignant pleural mesothelioma subjects will be studied in the 3+3 dose-escalation design. This will be a multi-arm, multicenter, non-randomized, parallel-group, uncontrolled, open-label Phase IB study designed to evaluate the safety, tolerability and preliminary activity of GSK3052230 in combination with paclitaxel + carboplatin (Arm A), in combination with docetaxel (Arm B), or in combination with pemetrexed + cisplatin (Arm C). Approximately 70 subjects will be enrolled in the study (approximately up to 120 may be enrolled).


Eligibility criteria: Inclusion Criteria

* Signed written informed consent
* Histologically or cytologically confirmed diagnosis: Arm A and B- stage IV recurrent metastatic squamous NSCLC with Fibroblast growth factor receptor 1 (FGFR1) gene amplification by central laboratory testing. Arm C- recurrent after local therapy or unresectable MPM with measurable lesions.

For specific arms the following requirements:

Arm A: Subjects who have received no prior therapy for Stage IIIB or Stage IV or recurrent metastatic disease. Note, to avoid any undue delay of initiating systemic chemotherapy for these subjects with newly diagnosed metastatic disease, it is allowed to initiate the first cycle of chemotherapy while eligibility for the study is still being determined, as long as the first dose of GSK3052230 is given no later than Cycle 2 Day 1 of chemotherapy. In addition, subjects with Stage IIIB or Stage IV disease and recurrence after previous NSCLC that has been treated with surgery and adjuvant chemotherapy or a radio- chemotherapy regimen with curative intent are eligible, provided 6 months has passed since this treatment ended.

Arm B: Subjects who have documented tumor progression (based on radiological imaging) or intolerability after receiving at least one prior line of platinum containing combination chemotherapy for Stage IIIB or Stage IV or recurrent metastatic disease. Note: Prior treatment should not include docetaxel but may have included paclitaxel.

Arm C: Subjects who have received no prior systemic therapy for MPM.

- Availability of archival tumor tissue required for assessment of deregulated FGF pathway signalling, but not limited to, FGFR1 amplification or FGF2 or FGFR1 expression. If archival tissue is not available, a fresh biopsy is required. In Arms A and B, subjects will be prospectively screened for FGFR1 gene amplification using a Fluorescence in situ hybridization (FISH) assay for the dose expansion and the MTD/MFD cohorts only. For inclusion in this study, based on the central laboratory testing, FGFR1 gene amplification must meet one of the following criteria: a ratio of FGFR1/CEN 8 of \>=2; or average number of FGFR1 signals per tumor nucleus of \>=6; or the percentage of tumor nuclei containing \>=5 FGFR1 signals is \>=50%.

In Arm C, FGF2 expression by IHC will be evaluated retrospectively in tissue samples by a central laboratory and is not a requirement for study entry.

* Measurable disease per RECIST version 1.1 (Arm A and B) and modified RECIST for Arm C.
* Male or female \>=18 years of age.
* Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception, from 14 days prior to the first dose of study treatment, throughout the study, and for 6 months following the last dose of chemotherapy or 4 weeks after the last dose of GSK3052230, whichever is latest. .
* Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception for at least 2 weeks prior to administration of the first dose of study treatment and for at least 6 months after the last dose of chemotherapy to allow for clearance of any altered sperm.
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 for Arm A and C subjects and 0-2 for Arm B.
* French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category
* Must have adequate organ function as defined by the following baseline values: Absolute neutrophil count \>=1.5 x 10\^9/Liter, Hemoglobin \>=9 gram (g)/decilitre(dL), Platelets \>=100 x 10\^9/L, Partial thromboplastin time (PTT) \<=1.25 x upper limit of normal (ULN), Albumin \>=2.5 g/dL, Serum total bilirubin \<=1.25 times ULN (for Arm B: \<=ULN ), Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) \<=2.5 times ULN (for Arm B: \<=1.5 times ULN), Serum Creatinine \<=1.5 x ULN, Or Measured or Calculated Creatinine Clearance \>=45 mL/min (Arm A or B), \>=65 mL/min (Arm C), Left ventricular ejection fraction \>=50% by ECHO.

Exclusion Criteria

* For Arms A and C: Treatment with any FGFR inhibitor. For Arm B: Treatment with any anti-cancer therapy (for biological anti-cancer therapies see criteria below) during the preceding 4 weeks or within 4 half-lives of the therapy, whichever is longer.
* Receipt of any biological therapy within 6 weeks of the first dose of GSK3052230
* Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (NCI CTCAE version 4.03) Grade 2 or higher from previous anti-cancer therapy, except alopecia.
* Active malignancy other than the cancer under study. Subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.
* Presence of uncontrolled infection
* Prior major surgery or trauma within 28 days before first dose of study drug
* Presence of any non-healing wound, fracture, or ulcer
* Any prohibited medication(s) as described in protocol
* Conditions likely to increase the potential for abdominal perforation or fistula formation, including but not limited to:

Luminal intestinal cancers or bulky abdominal disease. Presence or history of abdominal fistula, gastrointestinal perforation, peptic ulcer disease or intra-abdominal abscess within the six months prior to the first dose of GSK3052230.

Other risk factors for perforation, such as acute diverticulitis, obstruction or previous abdominal or pelvic radiation.

* Symptomatic leptomeningeal or brain metastases or spinal cord compression Note: Subjects previously treated for these conditions are eligible if they meet both of the criteria below: (1) have had stable CNS disease for at least 4 weeks after local therapy as assessed by imaging (contrast enhanced magnetic resonance imaging \[MRI\] or computed tomography \[CT\]) prior to Day 1, and (2) are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 4 weeks prior to Day 1.
* Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study drugs (GSK3052230, docetaxel, paclitaxel, carboplatin, pemetrexed, cisplatin) and or their excipients that contraindicate their participation.
* Known human immunodeficiency virus-positive serology, acquired immunodeficiency syndrome (AIDS), or an AIDS-related illness.
* Prior organ or allogeneic stem cell transplant
* The following cardiac abnormalities:

Corrected QT (QTc) interval \>=480 millisecond. History of acute coronary syndromes (including unstable angina) within the past 24 weeks Coronary angioplasty or stenting within the past 24 weeks. Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.

Abnormal cardiac valve morphology (\>= Grade 2) documented by echocardiogram (subjects with Grade 1 abnormalities \[i.e., mild regurgitation/stenosis\] can be entered on study).

History of known arrhythmias (except sinus arrhythmia and atrial fibrillation that is controlled) within the past 24 weeks.

* Presence or history of hemoptysis (\>1/2 teaspoon of red blood) 2 weeks prior to the first dose of GSK3052230
* Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
* Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator's assessment).
* Pregnant, lactating or actively breast feeding females.
* French subjects: The French subject has participated in any study using an investigational study treatment(s) during the previous 30 days.

Primary outcomes:
measure: Number of Participants With Non-serious Adverse Events (AEs) and Serious AEs (SAEs)
timeFrame: Median of 28.5 weeks
measure: Number of Participants With Severe AEs and SAEs
timeFrame: Median of 28.5 weeks
measure: Number of Participants Withdrew Due to AEs
timeFrame: Median of 28.5 weeks
measure: Number of Participants With Dose Reduction
timeFrame: Median of 28.5 weeks
measure: Number of Participants With Dose Delays
timeFrame: Median of 28.5 weeks
measure: Treatment Duration With GSK3052230
timeFrame: Median of 28.5 weeks
measure: Number of Participants With Dose-Limiting Toxicities (DLT)
timeFrame: Median of 28.5 weeks
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline and up to Median of 28.5 weeks
measure: Change From Baseline in Heart Rate
timeFrame: Baseline and up to Median of 28.5 weeks
measure: Change From Baseline in Temperature
timeFrame: Baseline and up to Median of 28.5 weeks
measure: Number of Participants With Clinically Significant Findings for 12-lead Electrocardiogram (ECG)
timeFrame: Median of 28.5 weeks
measure: Number of Participants With Abnormal Echocardiogram (ECHO) Findings
timeFrame: Median of 28.5 weeks
measure: Number of Participants With Clinical Chemistry Changes From Baseline With Respect to the Normal Range
timeFrame: Median of 28.5 weeks
measure: Number of Participants With the Abnormal Urinalysis Findings
timeFrame: Up to Cycle 16 (each cycle was of 21 days)
measure: Number of Participants With Hematology Change From Baseline With Respect to the Normal Range
timeFrame: Median of 28.5 weeks
measure: Number of Participants With Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD)
timeFrame: Median of 28.5 weeks
measure: Number of Participants With Best Response
timeFrame: Median of 28.5 weeks
measure: Number of Participants With Overall Response Rate (ORR)
timeFrame: Median of 28.5 weeks
Secondary outcomes:
measure: Progression Free Survival (PFS) as Assessed by Investigator
timeFrame: Median of 28.5 weeks
measure: Clearance of GSK3052230
timeFrame: Cycle(C)1 Day (D) 1 Pre-dose, End of infusion, 1 and 2 hours post-dose;C1 D8 Pre-dose,end of infusion; C2 D1 Pre-dose, End of infusion, 1 and 2 hours post-dose;C4 D1 Predose, end of infusion;C6 D1 Pre-dose, end of infusion,C12 D1 Pre-dose, end of infusion
measure: Volume of Distribution of GSK3052230
timeFrame: Cycle(C)1 Day (D) 1 Pre-dose, End of infusion, 1 and 2 hours post-dose;C1 D8 Pre-dose,end of infusion; C2 D1 Pre-dose, End of infusion, 1 and 2 hours post-dose;C4 D1 Predose, end of infusion;C6 D1 Pre-dose, end of infusion,C12 D1 Pre-dose, end of infusion
measure: Number of Participants With Relevant Covariates That Influence Exposure of GSK3052230
timeFrame: Cycle(C)1 Day (D) 1 Pre-dose, End of infusion, 1 and 2 hours post-dose;C1 D8 Pre-dose,end of infusion; C2 D1 Pre-dose, End of infusion, 1 and 2 hours post-dose;C4 D1 Predose, end of infusion;C6 D1 Pre-dose, end of infusion,C12 D1 Pre-dose, end of infusion
measure: Change From Baseline in Forced Vital Capacity (FVC) in of Arm C Participants With Malignant Pleural Mesothelioma (MPM)
timeFrame: Up to 31 cycles (each cycle was of 21 days)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: GSK Investigational Site
state: California
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: Chicago
country: United States
facility: GSK Investigational Site
state: Illinois
city: Peoria
country: United States
facility: GSK Investigational Site
state: Illinois
city: Detroit
country: United States
facility: GSK Investigational Site
state: Michigan
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Chapel Hill
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Charleston
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Leuven
country: Belgium
facility: GSK Investigational Site
city: Koebenhavn Oe
country: Denmark
facility: GSK Investigational Site
city: Amsterdam
country: Netherlands
facility: GSK Investigational Site
city: Arkhangelsk
country: Russian Federation
facility: GSK Investigational Site
city: Ryazan
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: St. Petersburg
country: Russian Federation
facility: GSK Investigational Site
city: Vsevolozhsk
country: Russian Federation
facility: GSK Investigational Site
city: Badajoz
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Málaga
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Leicester
country: United Kingdom
facility: GSK Investigational Site
state: Leicestershire
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Nottingham
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: