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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

Study to Evaluate <span class="go-doc-concept go-doc-intervention">GSK3052230</span> in Combination With <span class="go-doc-concept go-doc-intervention">Paclitaxel</span> and <span class="go-doc-concept go-doc-intervention">Carboplatin</span>, or <span class="go-doc-concept go-doc-intervention">Docetaxel</span> or as Single Agent in Subjects With Solid Malignancies and Deregulated Fibroblast Growth Factor (FGF) Pathway Signaling

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

    NCT ID: NCT01868022

    ORG ID: 117360

    Trial Conditions

    Cancer

    Trial Interventions

    Drug Synonyms Arms
    GSK3052230 Arm A: GSK3052230 + paclitaxel/carboplatin, Arm C: GSK3052230 + pemetrexed and cisplatin, Arm B: GSK3052230 + docetaxel
    paclitaxel Arm A: GSK3052230 + paclitaxel/carboplatin
    carboplatin Arm A: GSK3052230 + paclitaxel/carboplatin
    docetaxel Arm B: GSK3052230 + docetaxel
    pemetrexed Arm C: GSK3052230 + pemetrexed and cisplatin
    cisplatin Arm C: GSK3052230 + pemetrexed and cisplatin

    Trial 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).

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Arm A: GSK3052230 + paclitaxel/carboplatin Experimental Subject 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 + docetaxel Experimental Subject 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 cisplatin Experimental Subject 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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Rate and severity of adverse events (AEs) as a measure of safety and tolerability

    Number of Participants withdrawn due to AEs as measure of safety and tolerability

    Dose interruptions and reduction as a measure of safety and tolerability

    Treatment duration as a measure of safety and tolerability

    Dose limiting toxicity (DLT) as a measure of safety and tolerability

    Change from baseline in vital sign as a measure of safety and tolerability

    Change from baseline in 12-lead electrocardiogram (ECG) as a measure of safety and tolerability

    Change from baseline in Echocardiogram (ECHO) as measure of safety and tolerability

    Change from baseline in laboratory test as measure of safety and tolerability

    Maximum tolerated dose (MTD) or maximum feasible dose (MFD) of GSK3052230 in arm A and B

    Best response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

    Overall response rate (ORR) per RECIST 1.1 or modified RECIST

    Change from baseline in physical examination parameters

    Secondary Outcome Measures

    Progression-free survival (PFS) by investigator assessment per RECIST 1.1 or modified RECIST

    GSK3052230 population pharmacokinetic (PK) profile

    Change from baseline in Forced Vital Capacity (FVC) in subjects with MPM

    Trial Keywords

    GSK3052230

    carboplatin

    squamous non-small cell lung cancer

    FGFR1

    docetaxel

    FP1039

    paclitaxel

    FGFR

    HGS1036