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GSK3174998 Alone or With Pembrolizumab in Subjects With Advanced Solid Tumors (ENGAGE-1)

This study is currently recruiting participants.
Verified January 2017 by GlaxoSmithKline
Sponsor:
ClinicalTrials.gov Identifier:
NCT02528357
First Posted: August 19, 2015
Last Update Posted: January 18, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose

This is a first time in human (FTIH), open-label, non-randomized, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary clinical activity of GSK3174998 administered intravenously to subjects with selected advanced or recurrent solid tumors.

This dose-escalation study will assess the safety, activity of GSK3174998 as monotherapy (Part 1), in combination with pembrolizumab (Part 2), and potentially in combination with additional therapies.

The study will be conducted in 2 parts, each part consisting of a dose-escalation phase followed by a cohort expansion phase. Part 1 will evaluate GSK3174998 monotherapy, while Part 2 will evaluate GSK3174998 in combination with pembrolizumab.

GSK3174998 will first be evaluated as monotherapy in escalating doses. Once a dose of GSK3174998 has been identified that is both tolerable and demonstrates pharmacodynamic activity, enrollment of Part 2 may begin. In Part 2, escalating doses of GSK3174998 will be evaluated with fixed doses of pembrolizumab.

The study will enroll up to approximately 264 subjects with different tumor types (approximately 144 subjects in Parts 1A and 2A [dose escalation]; approximately 120 subjects in Parts 1B and 2B [cohort expansion]). The maximum duration of treatment with GSK3174998 plus or minus pembrolizumab will be 2 years or 35 cycles, whichever comes first. The follow-up period for safety assessments will be a minimum of 3 months from the date of the last dose. The post-treatment follow-up period includes disease assessments every 12 weeks.


Condition Intervention Phase
Cancer Drug: GSK3174998 Drug: Pembrolizumab Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Open-Label Study of GSK3174998 Administered Alone and in Combination With Anticancer Agents Including Pembrolizumab in Subjects With Selected Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Part 1 and 2: Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to Day 820 ]
    AEs will be collected from the start of study treatment until 30 days after the last dose of study treatment. SAEs and AEs of Special Interest (AESI) will be collected from the start of study treatment until 90 days after the last dose of study treatment

  • Part 1A and 2A: Dose limiting toxicities (DLT) [ Time Frame: From the start of medication up to 28 days ]
    An AE is considered to be a DLT if it is considered by the investigator to be clinically relevant and attributed (definitely, probably, or possibly) to the study treatment during the first 4 weeks (i.e., 28 days) of treatment and meets at least one of the pre-defined toxicity criteria.

  • Part 1 and 2: Number of withdrawals due to AEs [ Time Frame: Up to Day 820 ]
  • Part 1 and 2: Number of dose reductions or delays [ Time Frame: Up to 2 years ]
  • Part 1 and 2: Change in composite of clinical laboratory assessments as a measure of safety, including hematology, clinical chemistry, thyroid functions and urinalysis parameters [ Time Frame: Up to Day 820 ]
    Clinical laboratory assessments will include assessments of hematology, clinical chemistry, thyroid functions and urinalysis parameters

  • Part 1 and 2: Change in composite of vital signs as a measure of safety, including temperature, systolic and diastolic blood pressure, and pulse rate [ Time Frame: Up to Day 820 ]
    Vital sign measurements will be performed in semi-supine position after 5 minutes rest and will include temperature, systolic and diastolic blood pressure, and pulse rate

  • Part 1 and 2: Changes in electrocardiogram (ECG) as a measure of safety [ Time Frame: Up to Day 820 ]
    12-lead ECGs will be obtained at each planned ECG assessment during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF) intervals


Secondary Outcome Measures:
  • Part 1 and 2: Objective response rate (ORR) [ Time Frame: 5 years ]
    ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1

  • Part 1 and 2: Disease Control Rate (DCR) [ Time Frame: 5 years ]
    The ratio of subjects with CR+ PR + stable disease (SD) at >=week 12 after start of treatment

  • Part 1 and 2: Time to response [ Time Frame: 5 years ]
    Time to response is defined as the time from the start of treatment until the first documented evidence of CR or PR

  • Part 1 and 2: Overall survival (OS) [ Time Frame: 5 years ]
    OS is defined as the interval from first dose of study treatment to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact

  • Part 1 and 2: Duration of Response (DoR) [ Time Frame: 5 years ]
    Duration of response is defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause among subjects who achieve an overall response (i.e., unconfirmed or confirmed CR or PR).

  • Part 1 and 2: Progression Free Survival (PFS) [ Time Frame: 5 years ]
    PFS is defined as time from the date of first dose to the date of disease progression according to clinical or radiological assessment or death due to any causes, whichever occurs earliest.

  • Part 1 and 2: Number and percentage of subjects who develop detectable antidrug antibodies (ADA) against GSK3174998 [ Time Frame: Up to Day 820 ]
    Subjects will be monitored for anti-GSK3174998 antibodies throughout the study

  • Part 2 only: Number and percentage of subjects who develop detectable ADA against Pembrolizumab [ Time Frame: Up to Day 820 ]
    Subjects will be monitored for anti- pembrolizumab antibodies throughout the study

  • Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameters - tmax, terminal phase half life [ Time Frame: Up to 12 weeks post treatment ]
    If data permits, the following parameters will be determined: time to Cmax (tmax), apparent terminal phase half-life (t½) (single dose)

  • Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameter - AUC [ Time Frame: Up to 12 weeks post treatment ]
    If data permits, the following parameters will be determined: area under the plasma concentration-time curve (AUC(0-t), AUC(0-tau) (repeat dosing) and/or AUC(0-infinity) (single dose)

  • Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameter - terminal phase rate constant [ Time Frame: Up to 12 weeks post treatment ]
    If data permits, the following parameters will be determined: apparent terminal phase elimination rate constant (single dose)

  • Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameter - clearance [ Time Frame: Up to 12 weeks post treatment ]
    If data permits, the following parameters will be determined: systemic clearance of parent drug (CL)

  • Part 1 and 2: GSK3174998 and Part 2: Pembrolizumab PK parameters - Cmax and Cmin [ Time Frame: Up to 12 weeks post treatment ]
    If data permits, the following parameters will be determined: maximum concentration (Cmax), minimum concentration (Cmin)


Estimated Enrollment: 264
Study Start Date: September 2015
Estimated Study Completion Date: January 2020
Estimated Primary Completion Date: January 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Part 1A: GSK3174998 Monotherapy- Dose escalation
Subjects will receive GSK3174998 intravenously (IV) (dose range 0.003 to 10.0 milligram per kilogram [mg/kg]) every 3 weeks (Q3W) for up to 2 years or 35 cycles, whichever comes first.
Drug: GSK3174998
Lyophilized powder 40 mg reconstituted to get a dose range of 0.003 to <=10 mg/kg to be given as IV infusion for 30 minutes (min), Q3W
Experimental: Part 1B: GSK3174998 Monotherapy- Cohort expansion
Subjects will receive GSK3174998 IV (at one dose level shown to be tolerable in dose escalation part 1A) Q3W for up to 2 years or 35 cycles, whichever comes first.
Drug: GSK3174998
Lyophilized powder 40 mg reconstituted to get a dose range of 0.003 to <=10 mg/kg to be given as IV infusion for 30 minutes (min), Q3W
Experimental: Part 2A: GSK3174998+ pembrolizumab - Dose escalation
Subjects will receive GSK3174998 IV (dose range 0.003 to 10.0 mg/kg) Q3W for up to 2 years or 35 cycles, whichever comes first + Pembrolizumab 200 mg IV Q3W for up to 2 years or 35 cycles, whichever comes first.
Drug: GSK3174998
Lyophilized powder 40 mg reconstituted to get a dose range of 0.003 to <=10 mg/kg to be given as IV infusion for 30 minutes (min), Q3W
Drug: Pembrolizumab
Pembrolizumab as 100 mg/4 mL solution (dose: 200 mg) to be given as IV infusion for 30 min, Q3W
Experimental: Part 2B: GSK3174998+ pembrolizumab - Cohort expansion
Subjects will receive GSK3174998 IV (at one dose level shown to be tolerable in dose escalation of part 2A) Q3W for up to 2 years or 35 cycles, whichever comes first + Pembrolizumab 200 mg IV Q3W for 2 years or 35 cycles, whichever comes first.
Drug: GSK3174998
Lyophilized powder 40 mg reconstituted to get a dose range of 0.003 to <=10 mg/kg to be given as IV infusion for 30 minutes (min), Q3W
Drug: Pembrolizumab
Pembrolizumab as 100 mg/4 mL solution (dose: 200 mg) to be given as IV infusion for 30 min, Q3W

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Provide signed, written informed consent.
  • Male and female subjects, age >=18 years (at the time consent is obtained).
  • Histological documentation of locally advanced, recurrent or metastatic solid malignancy that has progressed after standard therapy appropriate for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate. Subjects should not have received more than 5 prior lines of therapy for advanced disease including both standards of care and investigational therapies. Subjects whose cancers harbor molecular alterations for which targeted therapy is standard of care should have received health authority approved appropriate targeted therapy for their tumor types before enrollment.
  • Subjects with the following solid tumors are eligible for screening: Non-small cell lung cancer (NSCLC), Squamous cell carcinoma of the head and neck (SCCHN), Renal cell carcinoma (RCC), melanoma, bladder, Triple-negative breast cancer (TNBC), and Colorectal carcinoma displaying microsatellite instability (MSI CRC).
  • A biopsy of the tumor tissue obtained at anytime from the initial diagnosis to study entry. Although a fresh biopsy obtained during screening is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a fresh biopsy. For Part 1B and Part 2B, any archival tumor specimen must have been obtained within 3 months of starting study drug.
  • Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Palpable lesions that are not measurable by radiologic or photographic evaluations may not be utilized as the only measurable lesion.
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
  • Life expectancy of at least 12 weeks.
  • Adequate organ function as defined by System Laboratory Values; Hematologic (Absolute neutrophil count [ANC] >=1.5x10^9/ liter [L], Lymphocyte count >1,000/cubic millimeter [mm^3], Hemoglobin >=9 grams/deciliter [g/dL], Platelets >=100x10^9/L), Hepatic (Total bilirubin <=1.5x upper limit of normal [ULN] [For subjects with Gilbert's Syndrome, only if direct bilirubin <=35%, <=3.0xULN], alanine aminotransferase [ALT] <=1.5xULN); Renal (Serum Creatinine <=1.5xULN OR Calculated creatinine clearance [CrCl >50 mL/min) and Endocrine (Thyroid stimulating hormone [TSH] within normal limits. If TSH is not within normal limits at baseline, the subject may still be eligible if total T3 or free T3 and free T4 are within the normal limits.
  • QT duration corrected for heart rate by Fridericia's formula (QTcF) <450 msec or <480 milliseconds (msec) for subjects with bundle branch block.

Female subjects and male subjects with female partners of child bearing potential must comply with adequate contraception requirements from the time of first dose of study medication until 120 days after the last dose of study medication.

Exclusion Criteria:

  • Prior treatment with the following agents (from last dose of prior treatment to first dose of GSK3174998): Tumor necrosis factor receptor (TNFR) agonists, including OX40, CD27, CD137 (4-1BB), CD357 (GITR): at any time; Checkpoint inhibitors, including PD-1, PD-L1, and anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) inhibitors: within 4 weeks.
  • Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
  • Active residual toxicity from prior therapies.
  • Secondary malignancy.
  • Brain metastases.
  • Active autoimmune disease that has required systemic treatment within the last 2 years.
  • Active infection, known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen or hepatitis C.
  • Current active liver or biliary disease.
  • Acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction within the past 6 months.
  • Severe hypersensitivity to other monoclonal antibodies (mAbs).
  • Recent (within 6 months) history of second degree (Type II) or third degree atrioventricular (AV) block cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting, or bypass grafting; Class II, III, or IV heart failure, or symptomatic pericarditis.
  • Current or history of idiopathic pulmonary fibrosis, interstitial lung disease, or organizing pneumonia.
  • History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
  • Uncontrolled symptomatic ascites or pleural effusions within 6 months.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02528357


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

Locations
United States, Massachusetts
GSK Investigational Site Recruiting
Boston, Massachusetts, United States, 02215
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, New York
GSK Investigational Site Not yet recruiting
New York, New York, United States, 10016
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   
GSK Investigational Site Not yet recruiting
New York, New York, United States, 10065
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   
United States, Texas
GSK Investigational Site Not yet recruiting
Houston, Texas, United States, 77030
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   
Netherlands
GSK Investigational Site Recruiting
Amsterdam, Netherlands, 1066 CX
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
Merck Sharp & Dohme Corp.
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02528357     History of Changes
Other Study ID Numbers: 201212
First Submitted: August 17, 2015
First Posted: August 19, 2015
Last Update Posted: January 18, 2017
Last Verified: January 2017

Keywords provided by GlaxoSmithKline:
mAb
GSK3174998
anticancer agent
checkpoint
OX40
Pembrolizumab
MK-3475-167
solid tumor
immunotherapy
KEYNOTE-167
monoclonal antibody
antitumor

Additional relevant MeSH terms:
Pembrolizumab
Antineoplastic Agents