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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

NCT01868022

Description:

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).

Related Conditions:
  • Non-Small Cell Lung Carcinoma
  • Squamous Cell Lung Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 117360
  • SECONDARY ID: 2013-000354-21
  • NCT ID: NCT01868022

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
GSK3052230Arm A: GSK3052230 + paclitaxel/carboplatin
paclitaxelArm A: GSK3052230 + paclitaxel/carboplatin
carboplatinArm A: GSK3052230 + paclitaxel/carboplatin
docetaxelArm B: GSK3052230 + docetaxel
pemetrexedArm C: GSK3052230 + pemetrexed and cisplatin
cisplatinArm C: GSK3052230 + pemetrexed and cisplatin

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
Arm A: GSK3052230 + paclitaxel/carboplatinExperimentalSubject will receive GSK3052230 as 30-minute intravenous (i.v.) infusion once a week (Day 1, Day 8, Day 15) of each 21-day cycle + paclitaxel (constant infusion for 3 hrs) and carboplatin (constant infusion for 30 to 60 minutes) iv on Day 1 of each 21-day cycle. The number of cycles of paclitaxel/carboplatin will be limited to 4 to 6 cycles.
  • GSK3052230
  • paclitaxel
  • carboplatin
Arm B: GSK3052230 + docetaxelExperimentalSubject will receive GSK3052230 as 30-minute intravenous (i.v.) infusion once a week (Day 1, Day 8, Day 15) of each 21-day cycle + docetaxel as 1 hour iv infusion on Day 1 of each 21-day cycle. Subjects may continue to receive docetaxel until disease progression or as long as they are considered to derive benefit from treatment.
  • GSK3052230
  • docetaxel
Arm C: GSK3052230 + pemetrexed and cisplatinExperimentalSubject will receive GSK3052230 as 30 minute iv infusion once a week (Day 1, Day 8, Day 15) of each 21 day cycle + pemetrexed iv infusion over 10 minutes on Day 1 of each 21 day cycle followed 30 minutes later by iv Cisplatin infused over 2 hours
  • GSK3052230
  • pemetrexed
  • cisplatin

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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Participants With Non-serious Adverse Events (AEs) and Serious AEs (SAEs)
Time Frame:Median of 28.5 weeks
Safety Issue:
Description:An AE is any untoward medical occurrence in a clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, protocol-specific events including drug-induced liver injury with hyperbilirubinaemia, any new primary cancers, cardiac toxicity including Left Ventricular Ejection Fraction (LVEF) changes or treatment emergent cardiac valve toxicity and treatment emergent acute anterior uveitis were categorized as SAE. Participants having non-serious AE or SAE were included in the analysis. The All Treated Subjects Population comprised of all participants who received at least one dose of study treatment.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS) as Assessed by Investigator
Time Frame:Median of 28.5 weeks
Safety Issue:
Description:PFS is defined as the interval between first dose of GSK3052230 and the earliest date of disease progression or death due to any cause by investigator assessment per RECIST 1.1 (for Arm A and B participants) or modified RECIST (for Arm C participants). For participants who do not progress or die, PFS was censored at the time of last radiological scan. Participants who discontinued study with no post-treatment tumor assessment were censored at date of first dose of study drug. Mean and 95 percent CI has been reported. NA indicates that data were not available as only 1 participant had event, other two censored therefore there is no confidence interval.
Measure:Clearance of GSK3052230
Time Frame: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
Safety Issue:
Description:Serial blood sample were collected at an indicated time points. A nonlinear mixed effects model was used to determine clearances. The Pharmacokinetic Population (PK) consisted of all participants in the All Treated Subject Population for whom a blood sample for pharmacokinetics was obtained and analyzed. Plasma GSK3052230 concentration-time data were to be combined with data from other studies to be analyzed using a population PK approach. However, other studies with GSK3052230 were not performed and thus no population PK analyses were done.
Measure:Volume of Distribution of GSK3052230
Time Frame: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
Safety Issue:
Description:Serial blood sample were collected at an indicated time points. A nonlinear mixed effects model was used to determine volume distribution. Plasma GSK3052230 concentration-time data were to be combined with data from other studies to be analyzed using a population PK approach. However, other studies with GSK3052230 were not performed and thus no population PK analyses were done.
Measure:Number of Participants With Relevant Covariates That Influence Exposure of GSK3052230
Time Frame: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
Safety Issue:
Description:Relevant covariates included parameters like age, weight and disease related covariates. Plasma GSK3052230 concentration-time data were to be combined with data from other studies to be analyzed using a population PK approach. However, other studies with GSK3052230 were not performed and thus no population PK analyses were done.
Measure:Change From Baseline in Forced Vital Capacity (FVC) in of Arm C Participants With Malignant Pleural Mesothelioma (MPM)
Time Frame:Up to 31 cycles (each cycle was of 21 days)
Safety Issue:
Description:FVC is the total amount of air exhaled during the Forced Expiratory Volume test. Baseline is defined as the most recent, non-missing value prior to or on the first study GSK3052230 treatment dose date. Change from Baseline is calculated as visit value minus Baseline value. Assessment of FVC was done on Day 1 of every odd cycle for Arm C participants with MPM. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates that data were not available as standard deviation could not be calculated for a single participant.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • FGFR1
  • FP1039
  • GSK3052230
  • docetaxel
  • FGFR
  • carboplatin
  • HGS1036
  • squamous non-small cell lung cancer
  • paclitaxel

Last Updated

August 19, 2019