Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma

NCT02034123 | Terminated Phase 1 Results

• 2 other identifiers: 2008582013-003451-38
• Study Type: interventional
• Target: 29
• Locations: 3 countries
• Sites: 8

Brief Summary

GSK2879552 is a potent, selective, mechanism-based inactivator of Lysine Specific Demethylase 1 (LSD1)/ CoRepressor for Element-1-Silencing Transcription factor (CoREST) activity. This is a phase I, open-label, multi-center, non-randomized, 2-part first time in human (FTIH) study for GSK2879552. Part 1 is a dose escalation phase to determine the recommended phase 2 dose (RP2D) for GSK2879552 based on the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) profiles observed after oral administration of GSK2879552. Any dose level(s) may be expanded up to 12 subjects in order to collect additional data on PK and PD.The safety and PK/PD data will be reviewed prior to the dose decision, and the dose escalation will be guided by the Neuenschwander -continuous reassessment method (N-CRM). Built-in safety constraints are in place to prevent exposing subjects to undue risk of toxicity. Once RP2D is identified, an expansion cohort (Part 2) of up to 30 subjects will be enrolled to further evaluate the clinical activity and tolerability of GSK2879552 in subjects with relapsed/refractory SCLC.

Conditions

Carcinoma, Small Cell

Keywords

First time in humans; Small cell lung carcinoma; Oncology; GSK2879552; LSD1 inhibitor

Outcome Measures

Primary Outcomes (10)

• Part 1: Number of Participants With Serious Adverse Events (SAEs) and Non-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. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, is a congenital anomaly/ birth defect, other situations and is associated with liver injury or impaired liver function. The analysis was performed on All Treated Population which included all participants who received at least one dose of study treatment.

  Median of 7.286 weeks of drug exposure

• Part 1: Number of Participants With Dose Limiting Toxicities (DLT)

  An event was considered a DLT if it occurs within the first 28 days of treatment, and meets one of the following criteria unless it can be clearly established that the event is unrelated to treatment: recurrent Grade 3 anemia after initial transfusion or Grade 3 anemia lasting \> 7 days in participants who are not transfused, Grade 4 neutropenia, Grade 3 neutropenia \> 7 days duration, febrile neutropenia as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, Grade 3 thrombocytopenia requiring dose reduction, Grade 4 thrombocytopenia lasting \> 3 days or of any duration if associated with clinically significant bleeding, drug related Grade 3 or 4 non-hematologic toxicity, drug related Grade 2 toxicity (at any time during treatment) and treatment delay of 14 days or greater due to unresolved drug-related toxicity.

  Median of 7.286 weeks of drug exposure

• Part 1: Number of Participants With Dose Reduction or Delays

  The number of participants who had any dose reduction or delay have been presented. All dose reductions were due to AEs.

  Median of 7.286 weeks of drug exposure

• Part 1: Number of Participants Withdrawn Due to Toxicities

  Participants were monitored from start of the study till the development of toxicity. The data for number of participants withdrawn due to toxicities has been presented.

  Median of 7.286 weeks of drug exposure

• Part 1: Number of Participants With Change in Clinical Chemistry Toxicity Grade From Baseline

  Blood samples were collected for evaluation of clinical chemistry parameters including potassium, aspartate aminotransferase (AST), total bilirubin, creatinine, alanine aminotransferase (ALT), uric acid, glucose, gamma glutamyl transferase (GGT), albumin, sodium, calcium, alkaline phosphatase, and phosphorus, inorganic. Baseline value was defined as the most recent, non-missing value from a central laboratory prior to or on the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The number of participants with any grade increase in clinical chemistry parameters have been presented. The clinical chemistry parameters for which any grade increase worst-case on-therapy value was reported have been only summarized. NA represents data was not available. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

  Baseline and median of 7.286 weeks of drug exposure

• Part 1: Number of Participants With Change in Hematology Toxicity Grade From Baseline

  Blood samples were collected for the analysis of hematology parameters including hemoglobin, lymphocytes, total neutrophils, platelet count and white blood cell (WBC) count. Baseline value was defined as the most recent, non-missing value from a central laboratory prior to or on the first dose of study treatment. Change from Baseline was defined as any visit value minus Baseline value. The number of participants with any grade increase in hematology parameters have been presented. The hematology parameters for which any grade increase worst-case on-therapy value was reported have been only summarized.

  Baseline and median of 7.286 weeks of drug exposure

• Part 1:Number of Participants With Critical Changes in Values of Vital Signs in Response to Drug

  Vital sign measurements includes systolic blood pressure (SBP), diastolic blood pressure (DBP), temperature, respiration rate and heart rate. Vital signs were measured after resting for at least 5 minutes in a semi-supine position. The number of participants with critical changes in values of vital signs in response to drug have been presented.

  Median of 7.286 weeks of drug exposure

• Part 1: Number of Participants With Abnormal Findings for Electrocardiogram (ECG) Parameters

  Single measurements of 12-lead ECGs were obtained in a semi-recumbent or supine position after at least a 5 minutes rest using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. The number of participants with abnormal - not clinically significant and abnormal - clinically significant "worst-case on-therapy" value have been presented.

  Median of 7.286 weeks of drug exposure

• Part 1: Number of Participants With Abnormal Findings Undergoing Physical Examinations

  The complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. A brief physical examination included assessments of the skin, lungs, cardiovascular system, and abdomen (liver and spleen). All abnormal physical examination findings were reported as AEs within the AE specific case report form (CRF) page. Hence, data was not captured separately for this outcome as number of participants with abnormal findings with respect to physical examinations. NA indicates data was not available as all abnormal physical examination findings were reported as AEs.

  Median of 7.286 weeks of drug exposure

• Part 2: Number of Participants Achieving Disease Control Rate at Week 16

  Clinical response was planned to be assessed by the investigator using computer tomography or magnetic resonance imaging scans. Clinical response was defined as disease control rate based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at Week 16. Disease control rate was defined as number of participants achieving complete response (CR), partial response (PR) and stable disease (SD) per RECIST version 1.1. This analysis was planned but not performed for Part 2 as the study was terminated early during Part 1.

  Week 16

Secondary Outcomes (30)

• Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) to Last Time of Quantifiable Concentration (AUC [0-t]) Following Single and Repeat Dose Administration of GSK2879552

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and Day 15

• Part 1: Area Under the Concentration-time Curve From Time Zero (Pre-dose) Extrapolated to Infinite Time (AUC [0-infinity]) Following Single Dose Administration of GSK2879552

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1

• Part 1: Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0-tau]) Following Repeat Dose Administration of GSK2879552

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 15

• Part 1: Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2879552

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and Day 15

• Part 1: Time to Reach Cmax (Tmax) Following Single and Repeat Dose Administration of GSK2879552

  Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1 and Day 15

Study Arms (2)

Dose Escalation Cohort

EXPERIMENTAL

The safety and PK/PD data will be reviewed prior to the dose decision, and the dose escalation will be guided by the Neuenschwander -continuous reassessment method (N-CRM).The dose escalation will complete when RP2D is determined. The RP2D will be the MTD or a lower dose that provides adequate PK exposure and biologic activity with superior tolerability.

Drug: GSK2879552

Dose Expansion Cohort

EXPERIMENTAL

Once the RP2D has been determined, an expansion cohort of up to 30 subjects will be enrolled in order to better characterize the clinical activity and safety profile of the RP2D

Drug: GSK2879552

Interventions

GSK2879552 DRUG

Subjects will receive GSK2879552orally with approximately 200 milliliter (mL) of water.

Dose Escalation Cohort; Dose Expansion Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provided signed written informed consent
• Males and females \>=18 years of age (at the time consent is obtained).
• Histologically or cytologically confirmed diagnosis of small cell lung carcinoma. Subjects must have measurable disease per RECIST 1.1 (for Part 2 only).
• Recurrent or refractory disease after receiving at least one prior standard/approved platinum-containing chemotherapy regimen, or where standard therapy is refused. Part 2 only: Subjects must have recurrent disease after receiving a maximum of two prior chemotherapy regimens including at least one platinum containing regimen.
• Eastern Cooperative Oncology Group (ECOG) performance status of \<= 1. (ECOG performance status of 0 or 1).
• Tumor tissue requirements: Availability of archival tissue, or willingness to undergo fresh biopsy at baseline; Enrollment in PK/PD cohort may be limited to subjects with disease amenable to pre- and post-dose biopsies, and willingness to undergo biopsy.
• All prior treatment-related toxicities must be National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0 \<=Grade 1 at the time of enrollment (except for alopecia)
• Adequate baseline organ function
• 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, as defined in protocol, during the study and for 7 days following the last dose of study treatment.
• Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in protocol from the administration of the first dose of study treatment until 3 months after the last dose of study treatment to allow for clearance of any altered sperm.
• Able to swallow and retain orally administered study treatment and does not have any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.

You may not qualify if:

• Concurrent malignancy other than SCLC. History of other malignancy is allowed as long as there is no evidence of active disease or need for treatment.
• Currently receiving anti-cancer therapy. Exceptions: Zoledronic acid and denosumab to treat bone metastasis are allowed.
• Prior treatment with temozolomide, dacarbazine or procarbazine.
• Prior treatment with poly ADP ribose polymerase (PARP) inhibitors (e.g., olaparib, ABT-888).
• Baseline Montreal Cognitive Assessment (MOCA) score of 22 or lower.
• Received major surgery, radiotherapy, or immunotherapy within 4 weeks of GSK2879552 administration. Chemotherapy regimens with delayed toxicity within the last four weeks (six weeks for prior nitrosourea or mitomycin C). Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity or palliative radiation to a limited area within the last two weeks.
• Administration of an investigational drug within 28 days or 5 half-lives, whichever is shorter preceding the first dose of study treatment(s) in this study.
• French subjects: The French subject has participated in any study using an investigational study treatment(s) during the previous 28 days.
• Subjects with current/a history of bleeding disorder or coagulopathy or who are at particularly high risk for bleeding complications.
• Requiring anticoagulants at therapeutic doses or platelet inhibitor.
• Current use of a prohibited medication or expected to require any of these medications during treatment with the investigational drug
• Evidence of severe or uncontrolled systemic diseases. 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, in the opinion of the investigator
• Known active Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infections. Subjects with laboratory evidence of HBV clearance may be enrolled
• Leptomeningeal metastases or spinal cord compression due to disease.
• Subjects with previously untreated or uncontrolled brain metastases.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (8)

GSK Investigational Site

St Louis, Missouri, 63110, United States

Location

GSK Investigational Site

Columbus, Ohio, 43210, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37203, United States

Location

GSK Investigational Site

Villejuif, 94805, France

Location

GSK Investigational Site

Barcelona, 08035, Spain

Location

GSK Investigational Site

Madrid, 28034, Spain

Location

GSK Investigational Site

Madrid, 28040, Spain

Location

GSK Investigational Site

Málaga, 29010, Spain

Location

Related Publications (1)

• Bauer TM, Besse B, Martinez-Marti A, Trigo JM, Moreno V, Garrido P, Ferron-Brady G, Wu Y, Park J, Collingwood T, Kruger RG, Mohammad HP, Ballas MS, Dhar A, Govindan R. Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory SCLC. J Thorac Oncol. 2019 Oct;14(10):1828-1838. doi: 10.1016/j.jtho.2019.06.021. Epub 2019 Jun 28.

  PMID: 31260835 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Small Cell; Small Cell Lung Carcinoma; Neoplasms

Interventions

GSK2879552

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2013
• First Posted: January 13, 2014
• Study Start: February 4, 2014
• Primary Completion: April 18, 2017
• Study Completion: April 18, 2017
• Last Updated: December 6, 2019
• Results First Posted: January 23, 2019

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (3); FR (1); ES (4)