Trial Outcomes & Findings for 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 (NCT NCT01868022)

This was a non-randomized, parallel-group study in participants (par.) with Solid Malignancies and Deregulated Fibroblast growth factor (FGF) Pathway Signaling. Participants administered GSK3052230 in combination with paclitaxel + carboplatin (Arm A) or in combination with docetaxel (Arm B) or in combination with pemetrexed + cisplatin (Arm C).

Total 65 participants were enrolled in 3 Arms. In Arm A 20 participants were enrolled across 3 cohorts, Arm B 9 participants were enrolled across 3 cohorts, Arm C 36 participants were enrolled across 3 cohorts.The study was conducted at 22 centers across 7 countries from 9-Oct-2013 to 24-Oct-2017.

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

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.

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.

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.

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.

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 delay has been reported.

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.

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.

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).

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.

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.

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.

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.

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).

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.

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).

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.

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.

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.

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.

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.

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.

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.

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.