Clinical trial NCT02034123: Investigation of GSK2879552 in Subjects With Relapsed/Refractory Small Cell Lung Carcinoma
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Carcinoma, Small Cell
Keywords: First time in humans
Small cell lung carcinoma
Oncology
GSK2879552
LSD1 inhibitor
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2014-01-13
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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.
* 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.
* 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.

Primary outcomes:
measure: Part 1: Number of Participants With Serious Adverse Events (SAEs) and Non-SAEs
timeFrame: Median of 7.286 weeks of drug exposure
measure: Part 1: Number of Participants With Dose Limiting Toxicities (DLT)
timeFrame: Median of 7.286 weeks of drug exposure
measure: Part 1: Number of Participants With Dose Reduction or Delays
timeFrame: Median of 7.286 weeks of drug exposure
measure: Part 1: Number of Participants Withdrawn Due to Toxicities
timeFrame: Median of 7.286 weeks of drug exposure
measure: Part 1: Number of Participants With Change in Clinical Chemistry Toxicity Grade From Baseline
timeFrame: Baseline and median of 7.286 weeks of drug exposure
measure: Part 1: Number of Participants With Change in Hematology Toxicity Grade From Baseline
timeFrame: Baseline and median of 7.286 weeks of drug exposure
measure: Part 1:Number of Participants With Critical Changes in Values of Vital Signs in Response to Drug
timeFrame: Median of 7.286 weeks of drug exposure
measure: Part 1: Number of Participants With Abnormal Findings for Electrocardiogram (ECG) Parameters
timeFrame: Median of 7.286 weeks of drug exposure
measure: Part 1: Number of Participants With Abnormal Findings Undergoing Physical Examinations
timeFrame: Median of 7.286 weeks of drug exposure
measure: Part 2: Number of Participants Achieving Disease Control Rate at Week 16
timeFrame: Week 16
Secondary outcomes:
measure: 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
timeFrame: 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
measure: 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
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 1
measure: Part 1: Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0-tau]) Following Repeat Dose Administration of GSK2879552
timeFrame: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Day 15
measure: Part 1: Maximum Observed Plasma Concentration (Cmax) Following Single and Repeat Dose Administration of GSK2879552
timeFrame: 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
measure: Part 1: Time to Reach Cmax (Tmax) Following Single and Repeat Dose Administration of GSK2879552
timeFrame: 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
measure: Part 1: Apparent Terminal Phase Elimination Rate Constant (Lambda z) Following Single and Repeat Dose Administration of GSK2879552
timeFrame: 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
measure: Part 1: Apparent Terminal Phase Half-life (T1/2) Following Single and Repeat Dose Administration of GSK2879552
timeFrame: 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
measure: Part 1: Accumulation Ratio Following Administration of GSK2879552
timeFrame: 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
measure: Part 1: Time Invariance Ratio Following Administration of GSK2879552
timeFrame: 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
measure: Part 1: Number of Participants Achieving Disease Control Rate at Week 16
timeFrame: Week 16
measure: Part 1 :Median Effective Dose (ED50) of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and Dose
timeFrame: Baseline and median of 7.286 weeks of drug exposure
measure: Part 1: ED50 of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and Cmax
timeFrame: Baseline and median of 7.286 weeks of drug exposure
measure: Part 1: ED50 of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and AUC (0 to Infinity)
timeFrame: Baseline and median of 7.286 weeks of drug exposure
measure: Part 2: Number of Participants With SAEs and Non-SAEs
timeFrame: Up to 2 years
measure: Part 2: Number of Participants With DLTs
timeFrame: Up to 2 years
measure: Part 2: Number of Participants With Dose Reduction or Delays
timeFrame: Up to 2 years
measure: Part 2: Number of Participants Withdrawn Due to Toxicities
timeFrame: Up to 2 years
measure: Part 2: Number of Participants With Change in Clinical Chemistry Toxicity Grade From Baseline
timeFrame: Baseline and up to 2 years
measure: Part 2: Number of Participants With Change in Hematology Toxicity Grade From Baseline
timeFrame: Baseline and up to 2 years
measure: Part 2:Number of Participants With Critical Changes in Values of Vital Signs in Response to Drug
timeFrame: Up to 2 years
measure: Part 2: Number of Participants With Abnormal Findings for ECG Parameters
timeFrame: Up to 2 years
measure: Part 2: Number of Participants With Abnormal Findings Undergoing Physical Examinations
timeFrame: Up to 2 years
measure: Part 2: Clearance Following Administration of GSK2879552
timeFrame: Pre-dose, 0.5, and 3 hours post-dose on Day 1; Pre-dose on Day 8; Pre-dose, 0.5 to 1 hour, and 4 to 6 hours on Day 15; Pre-dose at Day 22 and up to every 4 weeks until Week 48
measure: Part 2: Volume of Distribution Following Administration of GSK2879552
timeFrame: Pre-dose, 0.5, and 3 hours post-dose on Day 1; Pre-dose on Day 8; Pre-dose, 0.5 to 1 hour, and 4 to 6 hours on Day 15; Pre-dose at Day 22 and up to every 4 weeks until Week 48
measure: Part 2: ED50 of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and Dose
timeFrame: Baseline and up to 2 years
measure: Part 2: ED50 of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and Cmax
timeFrame: Baseline and up to 2 years
measure: Part 2: ED50 of GSK2879552 With Respect to Platelet Nadir as Percent Change From Baseline and AUC (0 to Infinity)
timeFrame: Baseline and Up to 2 years
measure: Part 2: Duration of Response
timeFrame: Up to 2 years
measure: Part 2: Progression Free Survival (PFS)
timeFrame: Up to 2 years
measure: Part 2: Percentage of Participants Achieving CR and PR
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Villejuif cedex
country: France
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Málaga
country: Spain
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.