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 | Crick

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Number of Participants With Non-serious Adverse Events (AEs) and Serious AEs (SAEs)

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.

Time frame: Median of 28.5 weeks

Number of Participants With Severe AEs and SAEs

The severity of AEs were graded utilizing National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.3. Grade 1 represents mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 represents moderate; minimal, local or noninvasive intervention indicated. Grade 3 represents severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 represents life-threatening consequences; urgent intervention indicated. Grade 5 represents death related to AE.

Time frame: Median of 28.5 weeks

Number of Participants Withdrew Due to AEs

An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. The AEs leading to permanent discontinuation from the study has been reported.

Time frame: Median of 28.5 weeks

Number of Participants With Dose Reduction

Dose reduction and delays were done due to toxicity, or in the interest of participant's safety per investigator discretion. Requirement for more than 2 dose reductions resulted in permanent discontinuation of chemotherapy. Participants with dose reduction has been reported.

Time frame: Median of 28.5 weeks

Number of Participants With Dose Delays

Time frame: Median of 28.5 weeks

Treatment Duration With GSK3052230

The number of participants administered study treatment were summarized according to the duration of therapy. The extent of treatment exposure is calculated as the number of cycles administered. The duration of exposure to study treatment is calculated from first day to last day of treatment plus 1 day. Median and full range (minimum and maximum) has been reported.

Time frame: Median of 28.5 weeks

Number of Participants With Dose-Limiting Toxicities (DLT)

DLT is defined as toxicities due to GSK3052230 or due to the combination of GSK3052230 with chemotherapy within Cycle 1 (first 21 days of period on study) that are unlikely to be due to another cause, such as the known effects of cytotoxics chemotherapy alone, disease progression, or accident, and protocol-specified criteria. Clinically significant toxicities that persist or occur beyond Cycle 1 that the investigator and GlaxoSmithKline (GSK) medical monitor consider dose-limiting may also be designated a DLT for the purpose of establishing Maximum tolerated dose (MTD). Number of participants with DLTs has been reported.

Time frame: Median of 28.5 weeks

Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

Blood pressure was measured in a semi-supine position after 5 minutes of rest. Blood pressure was measured before start of first chemotherapy infusion and within 20 minutes before start of GSK3052230 infusion on Day 1 of every cycle and Baseline. 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. The worst-case post-Baseline values has been presented. NA indicates that data were not available as standard deviation could not be calculated for a single participant. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame: Baseline and up to Median of 28.5 weeks

Change From Baseline in Heart Rate

Heart rate was measured in a semi-supine position after 5 minutes of rest. Heart rate was measured before start of first chemotherapy infusion and within 20 minutes before start of GSK3052230 infusion on Day 1 of every cycle and Baseline. 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. The worst-case post-Baseline values has been presented.

Time frame: Baseline and up to Median of 28.5 weeks

Change From Baseline in Temperature

Temperature was measured in a semi-supine position after 5 minutes of rest. Temperature was measured before start of first chemotherapy infusion and within 20 minutes before start of GSK3052230 infusion on Day 1 of every cycle and Baseline. 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. The worst-case post-Baseline values has been presented.

Time frame: Baseline and up to Median of 28.5 weeks

Number of Participants With Clinically Significant Findings for 12-lead Electrocardiogram (ECG)

A single 12-lead ECG was performed at the specified timepoints during the study where the participant was instructed to be in semi-recumbent position for 5 minutes before obtaining the ECG. An ECG machine that automatically calculated the heart rate and measures like the PR, QRS, QT, and corrected QT intervals. Number of participants with worst-case post-Baseline abnormal clinically significant findings and abnormal not clinically significant findings in ECG results has been reported.

Time frame: Median of 28.5 weeks

Number of Participants With Abnormal Echocardiogram (ECHO) Findings

Echocardiography scans were obtained at given time points using an echocardiogram and the findings for left ventricular ejection fraction (LVEF) were obtained. LVEF values at end of treatment (EOT) were recorded as no change or any increase and any decrease values. Only those participants available at the specified time points were analyzed.

Time frame: Median of 28.5 weeks

Number of Participants With Clinical Chemistry Changes From Baseline With Respect to the Normal Range

Clinical chemistry parameters included potassium, sodium, chloride (Cl), total carbon dioxide (CO2), total and ionized calcium, magnesium, phosphate, albumin, glucose (fasting), Blood urea nitrogen (BUN), creatinine (Cr), uric acid, creatinine clearance, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT), alkaline phosphatase, Total bilirubin (T. Bil), and Direct bilirubin (D. Bil), total T3 and T4, free T4, amylase, lipase, prothrombin time, partial thromboplastin time, international normalized ratio, and fibrinogen. 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. Clinical chemistry parameters with change from Baseline with respect to normal range only has been presented. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame: Median of 28.5 weeks

Number of Participants With the Abnormal Urinalysis Findings

Urinalysis parameters included urine protein, urine glucose, urine ketones and occult blood were assessed. Dipstick test was performed for routine urinalysis. Abnormal values such as trace, 1+, 2+, 3+, 4+, \>1000, \>=1000, and \>10 have been reported.

Time frame: Up to Cycle 16 (each cycle was of 21 days)

Number of Participants With Hematology Change From Baseline With Respect to the Normal Range

Hematology parameters included platelet Count, red blood cell (RBC) Count, hemoglobin, absolute white blood cell (WBC) Count, absolute neutrophils (Neu), absolute lymphocytes (Lym), absolute monocytes (Mono), absolute eosinophils (Eos), absolute basophils (Baso). 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. Hematology parameters with worst-case change from Baseline with respect to normal range only has been presented. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles).

Time frame: Median of 28.5 weeks

Number of Participants With Maximum Tolerated Dose (MTD) or Maximum Feasible Dose (MFD)

The MTD is defined as the highest dose level tested at which \< 33 percent of participants experience a DLT. In cases when MTD is not reached dose was described as the MFD.

Time frame: Median of 28.5 weeks

Number of Participants With Best Response

Best response defined as complete response (CR:disappearance of all target. Any pathological lymph nodes \< 10 millimeter \[mm\] in the short axis) or partial response (PR at least a 30 percent decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters), stable disease (SD neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) or progressive disease (PR at least a 20 percent increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the treatment started. In addition, the sum must have an absolute increase from nadir of 5 mm) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or modified RECIST. Best response as per RECIST version 1.1 for Arm A and B participants has been reported. Best response according to RECIST version 1.1 or modified RECIST for Arm C participants has been reported.

Time frame: Median of 28.5 weeks

Number of Participants With Overall Response Rate (ORR)

Overall Response Rate (ORR) is defined as the percentage of participants achieving a confirmed Complete response (CR) or Partial response (PR) from the start of treatment until disease progression as per RECIST version 1.1 or modified RECIST for participants in Arm C. This was determined based on Investigator assessments of response. 95% confidence intervals (CI) are calculated based on the unconditional exact method. ORR as per RECIST vesrion 1.1 for Arm A and B has been reported. ORR as per RECIST version 1.1 and modified RECIST version 1.1 for Arm C has been reported. The study population used for decision-making at the interim analyses during the dose expansion cohorts of the study arms is termed as the All Evaluable Participants Population. NA indicates 0 participants met ORR criteria therefore no dispersion.

Time frame: Median of 28.5 weeks

Secondary Outcomes

Progression Free Survival (PFS) as Assessed by Investigator

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.

Time frame: Median of 28.5 weeks

Clearance of GSK3052230

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.

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

Volume of Distribution of GSK3052230

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.

Number of Participants With Relevant Covariates That Influence Exposure of GSK3052230

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

Overview

Conditions

Interventions

Eligibility

Locations (29)

Outcomes

Primary Outcomes

Secondary Outcomes