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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT02034123
First received: December 5, 2013
Last updated: August 14, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Lung Cancer, Small Cell
Drug: GSK2879552
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Open-label, Dose Escalation Study to Investigate The Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK2879552 Given Orally in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Adverse Events (AEs), serious AEs (SAEs), dose limiting toxicities (DLTs), dose reductions or delays, withdrawals due to toxicities as a measure of safety and tolerability- Part 1 Dose Escalation [ Time Frame: From the day of first dose and at each study visit. Subjects will be followed until disease progression, withdrawal of consent, or AE, with an expected average of 12 weeks of duration in the study ] [ Designated as safety issue: No ]
  • Changes in safety parameters: , laboratory values, vital signs, electrocardiograms (ECGs), and physical examinations as a measure of safety and tolerability- Part 1 Dose Escalation [ Time Frame: From the day of first dose and at each study visit. Subjects will be followed until disease progression, withdrawal of consent, or unacceptable toxicity with an expected average of 12 weeks of duration in the study ] [ Designated as safety issue: No ]
    Vital sign assessment will include systolic and diastolic blood pressure, temperature, respiration rate and heart rate. Laboratory values will include hematology and clinical chemistry

  • Objective response rate (ORR) - Part 2 Expansion [ Time Frame: Screening and every 8 weeks thereafter. Subjects will be followed until disease progression, withdrawal of consent, or unacceptable toxicity with an expected average of 12 weeks of duration in the study ] [ Designated as safety issue: No ]
    ORR is defined as percentage of subjects achieving complete response (CR) and partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1


Secondary Outcome Measures:
  • GSK2879552 pharmacokinetics following single-(Day 1) and repeat-dose (Day 15) - Part 1 Dose Escalation [ Time Frame: Day 1 and Day 15 ] [ Designated as safety issue: No ]
    The PK parameters will include Area under the time-concentration curve (AUC), Maximum concentration (Cmax), time of occurrence of Cmax (tmax), terminal phase and/or effective half-life (t½), accumulation ratio, and time invariance. At Days 1 and 15, blood samples for PK assessment will be collected from pre-dose through 24 hrs post dose.

  • Objective response rate - Part 1 Dose Escalation [ Time Frame: Screening and every 8 weeks thereafter. Subjects will be followed until disease progression, withdrawal of consent, or unacceptable toxicity with an expected average of 12 weeks of duration in the study ] [ Designated as safety issue: No ]
    ORR is defined as percentage of subjects achieving CR and PR per RECIST 1.1

  • GSK2879552 exposure markers (e.g. dose, Cmax, Cmin or AUC [0-tau]), Pro Gastrin Releasing Peptide (ProGRP), and platelet levels in blood - Part 1 Dose Escalation [ Time Frame: Days 1, 2, 4, 8, 11, 15, 16, 18, 22, weeks 4, 5, 6, 7 and then every 4 weeks thereafter. Subjects will be followed until disease progression, withdrawal of consent, or AE, with an expected average of 12 weeks of duration in the study ] [ Designated as safety issue: No ]
  • AEs, SAEs, dose limiting toxicities, dose reductions or delays, withdrawals due to toxicities as a measure of safety and tolerability - Part 2 Expansion [ Time Frame: From the day of first dose and at each study visit. Subjects will be followed until disease progression, withdrawal of consent, or AE, with an expected average of 12 weeks of duration in the study ] [ Designated as safety issue: No ]
  • Changes in safety parameters: , laboratory values, vital signs, ECGs and physical examinations as a measure of safety and tolerability - Part 2 Expansion [ Time Frame: From the day of first dose and at each study visit. Subjects will be followed until disease progression, withdrawal of consent, or AE, with an expected average of 12 weeks of duration in the study ] [ Designated as safety issue: No ]
    Vital sign assessment will include systolic and diastolic blood pressure, temperature, respiration rate and heart rate. Laboratory values will include haematology and clinical chemistry

  • Population PK parameters for GSK2879552 - Part 2 Expansion [ Time Frame: Day 1 and Day 15 ] [ Designated as safety issue: No ]
    The PK parameters will include clearance (CL/F) and volume of distribution (V/F), and relevant covariates which may influence exposure (e.g., age, weight, or disease associated covariates). At Days 1 and 15, blood samples for PK analysis will be collected from pre-dose through 3 hrs post dose or through 4-6 hours post dose.

  • GSK2879552 exposure markers (e.g. dose, Cmax, Cmin or AUC [0-tau]), Pro Gastrin Releasing Peptide (ProGRP), and platelet levels in blood - Part 2 Expansion [ Time Frame: Days 1, 8, 15, 22 and 4 weeks thereafter. Subjects will be followed until disease progression, withdrawal of consent, or AE, with an expected average of 12 weeks of duration in the study ] [ Designated as safety issue: No ]
  • Duration of response and progression free survival (PFS)- Part 2 Expansion [ Time Frame: From day of first dose until the last contact. Subjects will be followed until disease progression, withdrawal of consent, or AE, with an expected average of 12 weeks of duration in the study ] [ Designated as safety issue: No ]

Estimated Enrollment: 80
Study Start Date: February 2014
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dose Escalation Cohort
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
Subjects will receive GSK2879552orally with approximately 200 milliliter (mL) of water.
Experimental: Dose Expansion Cohort
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
Subjects will receive GSK2879552orally with approximately 200 milliliter (mL) of water.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.
  • 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.

Exclusion Criteria:

  • 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.
  • 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.
  • Cardiac abnormalities
  • Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2879552 or LSD1 inhibitors that contraindicates their participation.
  • Lactating female
  • Consumption of Seville oranges, grapefruit, grapefruit hybrids, grapefruit juice, pommelos, or exotic citrus fruits, from 1 day prior to the first dose of study treatment(s) until the last dose of study drug.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02034123

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Locations
United States, Missouri
GSK Investigational Site Recruiting
St. Louis, Missouri, United States, 63021
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Ohio
GSK Investigational Site Recruiting
Columbus, Ohio, United States, 43210
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
United States, Tennessee
GSK Investigational Site Recruiting
Nashville, Tennessee, United States, 37203
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
France
GSK Investigational Site Recruiting
Villejuif cedex, France, 94805
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02034123     History of Changes
Other Study ID Numbers: 200858
Study First Received: December 5, 2013
Last Updated: August 14, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
First time in humans
Small cell lung carcinoma
Oncology
GSK2879552
LSD1 inhibitor

Additional relevant MeSH terms:
Carcinoma
Lung Neoplasms
Small Cell Lung Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms

ClinicalTrials.gov processed this record on August 20, 2014