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Dose Escalation and Expansion Study of GSK3359609 in Subjects With Selected Advanced Solid Tumors (INDUCE-1)

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ClinicalTrials.gov Identifier: NCT02723955
Recruitment Status : Recruiting
First Posted : March 31, 2016
Last Update Posted : October 9, 2019
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
GSK3359609 is an anti-Inducible T cell Co-Stimulator (ICOS) receptor agonist antibody intended for the treatment of cancers of different histology. This is a first-time-in-human (FTIH), open-label, multicenter study designed to investigate the safety, pharmacology, and preliminary antitumor activity in subjects with advanced or recurrent solid tumors with the aim to establish recommended dose(s) of GSK3359609 for further exploration as monotherapy and in combination with pembrolizumab or chemotherapy regimens. The study is comprised of two primary parts, each composed of two phases: Part 1: GSK3359609 monotherapy with Part 1A as dose escalation phase and Part 1B as cohort expansion phase; Part 2: GSK3359609 combination therapy with Part 2A pembrolizumab or GSK3174998 combination dose escalation phase and Part 2B expansion phase with pembrolizumab. Part 2A GSK3359609 combinations with chemotherapy will only consist of safety run-in cohorts. Each part and phase of the study includes a screening period, a treatment period, and a follow-up period. The primary objective of the study is to determine the safety, tolerability, maximum tolerated dose or the maximum administered dose of GSK3359609 alone or in combination.

Condition or disease Intervention/treatment Phase
Neoplasms Drug: GSK3359609 IV infusion Drug: GSK3174998 IV infusion Drug: Pembrolizumab 200 mg IV infusion Drug: Docetaxel 75 milligrams per square meters (mg/m^2) IV infusion Drug: Pemetrexed 500 mg/m^2 plus Carboplatin area under the curve (AUC) 4-6 mg/mL per minute IV infusion Drug: Paclitaxel 200 mg/m^2 plus Carboplatin AUC 4-6 mg/mL per minute IV infusion Drug: Gemcitabine 1250 mg/m^2 plus Carboplatin AUC 4-6 mg/mL per minute IV infusion Drug: Fluorouracil (5-FU) 1000 mg/m^2 plus carboplatin or cisplatin Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 500 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Open Label Study of GSK3359609 Administered Alone and in Combination With Anticancer Agents in Subjects With Selected Advanced Solid Tumors
Actual Study Start Date : June 22, 2016
Estimated Primary Completion Date : December 19, 2022
Estimated Study Completion Date : December 19, 2022

Arm Intervention/treatment
Experimental: Part 1A: Dose escalation GSK3359609
Subjects will receive GSK3359609 as an intravenous (IV) infusion administered once every 3 weeks (Q3W) continuously at a dose level dependent on to which dose level the subject is accrued.
Drug: GSK3359609 IV infusion
GSK3359609 diluted product will be administered as an IV infusion to subjects Q3W.

Experimental: Part 1B: Expansion GSK3359609
Subjects will receive GSK3359609 as an IV infusion administered Q3W continuously at a dose level chosen for further exploration in dose expansion cohorts.
Drug: GSK3359609 IV infusion
GSK3359609 diluted product will be administered as an IV infusion to subjects Q3W.

Experimental: Part 2A: Dose escalation/safety run-in-GSK3359609
Subjects will receive GSK3359609 as an IV infusion administered Q3W continuously in combination with 200 milligram (mg) of pembrolizumab or GSK3174998 as an IV infusion administered once Q3W continuously. Subjects participating in Part 2A chemotherapy combination cohorts will receive GSK3359609 in combination with chemotherapy at doses and schedules based on standard of care practice.
Drug: GSK3359609 IV infusion
GSK3359609 diluted product will be administered as an IV infusion to subjects Q3W.

Drug: GSK3174998 IV infusion
GSK3174998 diluted product will be administered as an IV infusion to subjects Q3W.

Drug: Pembrolizumab 200 mg IV infusion
Pembrolizumab 200 mg will be administered as an IV infusion to subjects Q3W.

Drug: Docetaxel 75 milligrams per square meters (mg/m^2) IV infusion
Docetaxel 75 mg/m^2 diluted product will be administered as an IV infusion to subjects Q3W.

Drug: Pemetrexed 500 mg/m^2 plus Carboplatin area under the curve (AUC) 4-6 mg/mL per minute IV infusion
Pemetrexed 500 mg/m^2 diluted product in combination with Carboplatin AUC 4-6 milligram per milliliter (mg/mL) per minute (diluted product), will be administered as an IV infusion to subjects Q3W.

Drug: Paclitaxel 200 mg/m^2 plus Carboplatin AUC 4-6 mg/mL per minute IV infusion
Paclitaxel 200 mg/m^2 diluted product in combination with Carboplatin AUC 4-6 mg/mL per minute (diluted product), will be administered as an IV infusion to subjects Q3W.

Drug: Gemcitabine 1250 mg/m^2 plus Carboplatin AUC 4-6 mg/mL per minute IV infusion
Gemcitabine 1250 mg/m^2 diluted product in combination with Carboplatin AUC 4-6 mg/mL per minute (diluted product), will be administered as an IV infusion to subjects Q3W.

Drug: Fluorouracil (5-FU) 1000 mg/m^2 plus carboplatin or cisplatin
Carboplatin AUC 4-6 mg/mL per minute or cisplatin at 100 mg/m^2 will be combined with 5-FU at 1000 mg/m^2/day will be administered as an IV infusion to subjects Q3W.

Experimental: Part 2B: Expansion-GSK3359609
Subjects receive GSK3359609 as an IV infusion administered Q3W continuously in combination with 200 mg of pembrolizumab as an IV infusion administered once Q3W continuously.
Drug: GSK3359609 IV infusion
GSK3359609 diluted product will be administered as an IV infusion to subjects Q3W.

Drug: Pembrolizumab 200 mg IV infusion
Pembrolizumab 200 mg will be administered as an IV infusion to subjects Q3W.

Drug: Fluorouracil (5-FU) 1000 mg/m^2 plus carboplatin or cisplatin
Carboplatin AUC 4-6 mg/mL per minute or cisplatin at 100 mg/m^2 will be combined with 5-FU at 1000 mg/m^2/day will be administered as an IV infusion to subjects Q3W.




Primary Outcome Measures :
  1. Part 1: Number of subjects with any adverse event(s) (AE) and serious adverse event(s) (SAE) [ Time Frame: Up to 27 months ]
    AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or associated with liver injury and impaired liver function.

  2. Part 1: Number of subjects with dose limiting toxicity (DLT) [ Time Frame: Up to 28 days ]
    A DLT is defined as an AE that meets at least one of the criteria listed in protocol, according to National Cancer Institute (NCI) common terminology criteria for AE (CTCAE) grade (G) version 4.0, and is considered by the investigator to be clinically relevant and attributed (probably, or possibly) to the study treatment during the first 28 days after the first dose of study treatment.

  3. Part 1: Change from Baseline in systolic and diastolic blood pressure [ Time Frame: Baseline and up to 24 months ]
    Systolic and diastolic blood pressure will be measured in semi-supine position after 5 minutes of rest.

  4. Part 1: Change from Baseline in pulse rate [ Time Frame: Baseline and up to 24 months ]
    Pulse rate will be measured in semi-supine position after 5 minutes of rest.

  5. Part 1: Change from Baseline in body temperature [ Time Frame: Baseline and up to 24 months ]
    Body temperature will be measured in semi-supine position after 5 minutes of rest.

  6. Part 1: Change from Baseline in hemoglobin [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in hemoglobin will be analyzed.

  7. Part 1: Change from Baseline in hematocrit [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in hematocrit will be analyzed.

  8. Part 1: Change from Baseline in red blood cell (RBC) count [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in RBC will be analyzed.

  9. Part 1: Change from Baseline in platelet count [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in platelet count will be analyzed.

  10. Part 1: Change from Baseline in white blood cell (WBC) count [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in WBC count will be analyzed.

  11. Part 1: Change from Baseline in total neutrophils, eosinophils, monocytes, basophils and lymphocytes [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in total neutrophils, eosinophils, monocytes, basophils, and lymphocytes will be analyzed.

  12. Part 1: Change from Baseline in blood urea nitrogen (BUN) [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in BUN will be analyzed.

  13. Part 1: Change from Baseline in creatinine and bilirubin [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in creatinine and bilirubin will be analyzed.

  14. Part 1: Change from Baseline in glucose, calcium, sodium and potassium [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in glucose, calcium, sodium and potassium will be analyzed.

  15. Part 1: Change from Baseline in total protein and albumin [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in total protein and albumin will be analyzed.

  16. Part 1: Change from Baseline in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in AST, ALT and ALP will be analyzed.

  17. Part 1: Number of subjects with any abnormal findings in urine analysis parameters [ Time Frame: Up to 24 months ]
    The following urinalysis parameters will be measured: pH, glucose, protein, blood, ketones by dipstick and specific gravity.

  18. Part 1: Change from Baseline in Troponin I or Troponin T [ Time Frame: Baseline and up to 24 months ]
    Troponin I or Troponin T will be assessed by echocardiogram or multigated acquisition scans (MUGA).

  19. Part 1: Change from Baseline in thyroid stimulating hormone (TSH) [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in TSH will be analyzed.

  20. Part 1: Change from Baseline in triiodothyronine (T3) and thyroxine (T4) [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in T3 and T4 will be analyzed.

  21. Part 1: Number of subjects requiring dose modifications [ Time Frame: Up to 24 months ]
    All dose modifications due to any reason(s) will be recorded.

  22. Part 2: Number of subjects with any AEs and SAEs [ Time Frame: Up to 27 months ]
    AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect or is medically significant or associated with liver injury and impaired liver function.

  23. Part 2: Number of subjects with DLT following administration of GSK3359609 in combination with Pembrolizumab or GSK3174998 [ Time Frame: Up to 28 days ]
    A DLT is defined as an AE that meets at least one of the criteria listed in protocol, according to NCI CTCAE G version 4.0, and is considered by the investigator to be clinically relevant and attributed (probably, or possibly) to the study treatment during the first 28 days after the first dose of study treatment.

  24. Part 2: Change from Baseline in systolic and diastolic blood pressure [ Time Frame: Baseline and up to 24 months ]
    Systolic and diastolic blood pressure will be measured in semi-supine position after 5 minutes of rest.

  25. Part 2: Change from Baseline in pulse rate [ Time Frame: Baseline and up to 24 months ]
    Pulse rate will be measured in semi-supine position after 5 minutes of rest.

  26. Part 2: Change from Baseline in body temperature [ Time Frame: Baseline and up to 24 months ]
    Body temperature will be measured in semi-supine position after 5 minutes of rest.

  27. Part 2: Change from Baseline in hemoglobin [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in haemoglobin will be analyzed.

  28. Part 2: Change from Baseline in hematocrit [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from baseline in hematocrit will be analyzed.

  29. Part 2: Change from Baseline in RBC count [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in RBC will be analyzed.

  30. Part 2: Change from Baseline in platelet count [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in platelet count will be analyzed.

  31. Part 2: Change from Baseline in WBC count [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in WBC count will be analyzed.

  32. Part 2: Change from Baseline in total neutrophils, eosinophils, monocytes, basophils, and lymphocytes [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in total neutrophils, eosinophils, monocytes, basophils, and lymphocytes will be analyzed.

  33. Part 2: Change from Baseline in BUN [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in BUN will be analyzed.

  34. Part 2: Change from Baseline in creatinine and bilirubin [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in creatinine and bilirubin will be analyzed.

  35. Part 2: Change from Baseline in glucose, calcium, sodium and potassium [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in glucose, calcium, sodium and potassium will be analyzed.

  36. Part 2: Change from Baseline in total protein and albumin [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in total protein and albumin will be analyzed.

  37. Part 2: Change from Baseline in AST, ALT and ALP [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in AST, ALT and ALP will be analyzed.

  38. Part 2: Number of subjects with any abnormal findings in urine analysis parameters [ Time Frame: Up to 24 months ]
    The following urinalysis parameters will be measured: pH, glucose, protein, blood, ketones by dipstick and specific gravity.

  39. Part 2: Change from Baseline in Troponin I or Troponin T [ Time Frame: Baseline and up to 24 months ]
    Troponin I or Troponin T will be assessed by echocardiogram or MUGA.

  40. Part 2: Change from Baseline in TSH [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in TSH will be analyzed.

  41. Part 2: Change from Baseline in T3 and T4 [ Time Frame: Baseline and up to 24 months ]
    Blood samples will be collected at indicated time points and change from Baseline in T3 and T4 will be analyzed.

  42. Part 2: Number of subjects requiring dose modifications [ Time Frame: Up to 24 months ]
    All dose modifications due to any reason(s) will be recorded.


Secondary Outcome Measures :
  1. Part 1: Disease control rate (DCR) [ Time Frame: Up to 27 months ]
    DCR is defined as the percentage of subjects with a confirmed complete response (CR) + partial response (PR) at any time, plus stable disease (SD) >=18 weeks.

  2. Part 1: Overall survival (OS) [ Time Frame: up to 4 years ]
    OS is defined as time from the date of first dose of study treatment to the date of death due to any cause.

  3. Part 1: Progression-free survival (PFS) [ Time Frame: Up to 27 months ]
    PFS is defined as time from the date of first dose of study treatment to the date of disease progression according to clinical or radiographic assessment or death due to any cause, whichever occurs earliest.

  4. Part 1: Time to overall response (TTR) [ Time Frame: Up to 27 months ]
    TTR will be summarized for subjects with a confirmed CR or PR and is defined as the time from date of first dose of study treatment to date of first documented confirmed CR or PR.

  5. Part 1: Duration of response (DOR) [ Time Frame: Up to 27 months ]
    DOR will be summarized for subjects with a confirmed CR or PR and is defined as the time from date of initial confirmed response to the date of disease progression or death due to any cause.

  6. Part 1: Overall response rate (ORR) [ Time Frame: Up to 27 months ]
    ORR is defined as the percentage of subjects with a best overall confirmed CR or a PR at any time as per disease-specific criteria.

  7. Part 1: Maximum observed plasma concentration (Cmax) of GSK3359609 [ Time Frame: Day1:predose,end of infusion(EOI),EOI+30 minutes,+1,+2,+4hours, Day2:EOI+24hours, Days3 to 6:EOI+48,+120hours, Day 8 and 15,Day22:pre EOI+4hours,Days29 to 36,Days43 to 106:pre EOI+4hours,Day127:pre dose;Week21 then every12weeks postdose(Up to 27months) ]
    Blood samples will be collected at the indicated time points for evaluation of Cmax.

  8. Part 1: Minimum observed plasma concentration (Cmin) of GSK3359609 [ Time Frame: Day1:predose,EOI,EOI+30 minutes,+1,+2,+4hours, Day2:EOI+24hours, Days3 to 6:EOI+48,+120hours, Day 8 and 15, Day22:pre EOI+4hours,Days29 to 36,Days43 to 106:pre EOI+4hours,Day127:pre dose;Week21 then every12weeks postdose (Up to 27months) ]
    Blood samples will be collected at the indicated time points for evaluation of Cmin.

  9. Part 1: Area under the concentration-time curve over the dosing interval (AUC[0-tau]) of GSK3359609 in plasma [ Time Frame: Day1:predose,EOI,EOI+30 minutes,+1,+2,+4hours, Day2:EOI+24hours, Days3 to 6:EOI+48,+120hours, Day 8 and 15, Day22:pre EOI+4hours,Days29 to 36,Days43 to 106:pre EOI+4hours,Day127:pre dose;Week21 then every12weeks postdose (Up to 27months) ]
    Blood samples will be collected at the indicated time points for evaluation of AUC(0-tau).

  10. Part 1: Number of subjects with positive results in Anti-drug antibody (ADA) test by GSK3359609 dose level [ Time Frame: Up to 27 months ]
    Blood samples will be collected up to 27 months for ADA test.

  11. Part 1: Number of subjects with positive results in GSK3359609 [ Time Frame: Up to 27 months ]
    Blood samples will be collected up to 27 months for immunogenicity.

  12. Part 2: Number of subjects with DLT following administration of GSK3359609 combination with chemotherapies [ Time Frame: Up to 28 days ]
    A DLT is defined as an AE that meets at least one of the criteria listed in protocol, according to NCI CTCAE G version 4.0, and is considered by the investigator to be clinically relevant and attributed (probably, or possibly) to the study treatment during the first 28 days after the first dose of study treatment.

  13. Part 2: Disease control rate (DCR) [ Time Frame: Up to 27 months ]
    DCR is defined as the percentage of subjects with a confirmed CR + PR at any time, plus SD >=18 weeks.

  14. Part 2: Overall survival (OS) [ Time Frame: Up to 4 years ]
    OS is defined as time from the date of first dose of study treatment to the date of death due to any cause.

  15. Part 2: Progression-free survival (PFS) [ Time Frame: Up to 27 months ]
    PFS is defined as time from the date of first dose of study treatment to the date of disease progression according to clinical or radiographic assessment or death due to any cause, whichever occurs earliest.

  16. Part 2: Time to overall response (TTR) [ Time Frame: Up to 27 months ]
    TTR will be summarized for subjects with a confirmed CR or PR and is defined as the time from date of first dose of study treatment to date of first documented confirmed CR or PR.

  17. Part 2: Duration of response (DOR) [ Time Frame: Up to 27 months ]
    DOR will be summarized for subjects with a confirmed CR or PR and is defined as the time from date of initial confirmed response to the date of disease progression or death due to any cause.

  18. Part 2: Overall response rate (ORR) [ Time Frame: Up to 27 months ]
    ORR is defined as the percentage of subjects with a best overall confirmed CR or a PR at any time as per disease-specific criteria.

  19. Part 2: Cmax of GSK3359609 [ Time Frame: Day1:predose,EOI,EOI+30 minutes,+1,+2,+4hours, Day2:EOI+24hours, Days3 to 6:EOI+48,+120hours, Day 8 and 15, Day22:pre EOI+4hours,Days29 to 36,Days43 to 106:pre EOI+4hours,Day127:pre dose;Week21 then every12weeks postdose (Up to 27months) ]
    Blood samples will be collected at the indicated time points for evaluation of Cmax.

  20. Part 2: Cmin of GSK3359609 [ Time Frame: Day1:predose,EOI,EOI+30 minutes,+1,+2,+4hours, Day2:EOI+24hours, Days3 to 6:EOI+48,+120hours, Day 8 and 15, Day22:pre EOI+4hours,Days29 to 36,Days43 to 106:pre EOI+4hours,Day127:pre dose;Week21 then every12weeks postdose (Up to 27months) ]
    Blood samples will be collected at the indicated time points for evaluation of Cmin.

  21. Part 2: AUC(0-tau) of GSK3359609 [ Time Frame: Day1:predose,EOI,EOI+30 minutes,+1,+2,+4hours, Day2:EOI+24hours, Days3 to 6:EOI+48,+120hours, Day 8 and 15, Day22:pre EOI+4hours,Days29 to 36,Days43 to 106:pre EOI+4hours,Day127:pre dose;Week21 then every12weeks postdose (Up to 27months) ]
    Blood samples will be collected at the indicated time points for evaluation of AUC(0-tau).

  22. Part 2: Cmax of GSK3174998 [ Time Frame: Day 1: predose, EOI, EOI+4 hours, EOI+24 hours, Days3 to 6:EOI+48,+120hours, Day 8 and 15, Day22: predose, Day 43:predose, EOI+4hours, Day 64 and 85: predose, EOI+4hours, Day 106: predose,Day127:pre dose;Week21 then every12weeks postdose (Up to 24months) ]
    Blood samples will be collected at the indicated time points for evaluation of Cmax.

  23. Part 2: Cmin of GSK3174998 [ Time Frame: Day 1: predose, EOI, EOI+4 hours, EOI+24 hours, Days3 to 6:EOI+48,+120hours, Day 8 and 15, Day22: predose, Day 43:predose, EOI+4hours, Day 64 and 85: predose, EOI+4hours, Day 106: predose,Day127:pre dose;Week21 then every12weeks postdose (Up to 24months) ]
    Blood samples will be collected at the indicated time points for evaluation of Cmin.

  24. Part 2: AUC(0-tau) of GSK3174998 [ Time Frame: Day 1: predose, EOI, EOI+4 hours, EOI+24 hours, Days3 to 6:EOI+48,+120hours, Day 8 and 15, Day22: predose, Day 43:predose, EOI+4hours, Day 64 and 85: predose, EOI+4hours, Day 106: predose,Day127:pre dose;Week21 then every12weeks postdose (Up to 24months) ]
    Blood samples will be collected at the indicated time points for evaluation of AUC(0-tau).

  25. Part 2: Cmax of Pembrolizumab [ Time Frame: Day 1: pre EOI + 30 minutes, EOI 24 hours, Day 8 and 15, Days 22, 64, and 106: predose, Day 127: predose, and Week 21 then every 12 weeks postdose (Up to 27 months) ]
    Blood samples will be collected at the indicated time points for evaluation of Cmax.

  26. Part 2: Cmin of Pembrolizumab [ Time Frame: Day 1: pre EOI + 30 minutes, EOI 24 hours, Day 8 and 15, Days 22, 64, and 106: predose, Day 127: predose, and Week 21 then every 12 weeks postdose (Up to 27 months) ]
    Blood samples will be collected at the indicated time points for evaluation of Cmin.

  27. Part 2: AUC(0-tau) of Pembrolizumab [ Time Frame: Day 1: pre EOI + 30 minutes, EOI 24 hours, Day 8 and 15, Days 22, 64, and 106: predose, Day 127: predose, and Week 21 then every 12 weeks postdose (Up to 27 months) ]
    Blood samples will be collected at the indicated time points for evaluation of AUC(0-tau).

  28. Part 2: Number of subjects with positive results in ADA test by GSK3359609 in combination with pembrolizumab or GSK3174998 dose level [ Time Frame: Up to 27 months ]
    Blood samples will be collected up to 27 months for ADA test.

  29. Part 2: Number of subjects with positive results in Pembrolizumab [ Time Frame: Up to 27 months ]
    Blood samples will be collected up to 27 months for immunogenicity.

  30. Part 2: Number of subjects with positive results in GSK3174998 [ Time Frame: Up to 27 months ]
    Blood samples will be collected up to 27 months for immunogenicity.

  31. Part 2: Cmax of GSK3359609 combination with chemotherapies [ Time Frame: Day 1: predose, EOI, EOI+1 hour, EOI+2 hours, EOI+4 hours, Days 22, 64, 106, and 127: EOI, EOI+ 2 hours post chemotherapy (Up to 27 months) ]
    Blood samples will be collected at the indicated time points for evaluation of Cmax.

  32. Part 2: Cmin of GSK3359609 combination with chemotherapies [ Time Frame: Day 1: predose, EOI, EOI+1 hour, EOI+2 hours, EOI+4 hours, Days 22, 64, 106, and 127: EOI, EOI+ 2 hours post chemotherapy (Up to 27 months) ]
    Blood samples will be collected at the indicated time points for evaluation of Cmin.

  33. Part 2: Number of subjects with positive results in ADA test by GSK3359609 combination with chemotherapies dose level [ Time Frame: Up to 27 months ]
    Blood samples will be collected up to 27 months for ADA test.



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.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Capable of giving signed, written informed consent.
  • Male or female, age >=18 years (at the time consent is obtained).
  • Histological or cytological documentation of an invasive malignancy that was diagnosed as locally advanced/metastatic or relapsed/refractory and is of one of the following tumor types: bladder/urothelial cancer of the upper and lower urinary tract; cervical; colorectal (includes appendix); esophagus, squamous cell; head and neck; melanoma; malignant pleural mesothelioma (MPM); non-small-cell lung cancer (NSCLC), prostate; Microsatellite Instability-High/deficient mismatch repair (MSI-H/dMMR) tumor (Part 1B and Part 2B) and Human Papilloma Virus (HPV)-positive or Epstein-Barr (EBV)-positive tumor (Part 1B and Part 2B).
  • Disease that has progressed after standard therapy for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate, or if no further standard therapy exists; exceptions are in these tumor types in which pembrolizumab single agent may be a standard: NSCLC, head and neck squamous cell cancer (HNSCC), bladder/urothelial cancer, MSI-H/dMMR cancers and melanoma and cervical cancer. In Part 2B pembrolizumab combination expansion cohorts, prior treatment with anti-Programmed cell death protein 1(PD-1)/ Ligand-1 (L1) may not be required. 1) Subjects must not have received more than 5 prior lines of therapy for advanced disease including both standards of care and investigational therapies. 2) Subjects who received prior PD-1/L1 therapy must have fulfill the following requirements (Part 1B [except PK/PD cohort]/ Part 2B):.a) Have achieved a CR, PR or SD and subsequently had disease progression while still on PD-1/L1 therapy; b) Have received at least 2 doses of an approved PD-1/L1 inhibitor (by any regulatory authority), c) Have demonstrated disease progression as defined by RECIST v1.1 within 18 weeks from the last dose of the PD-1/L1 inhibitor. The initial evidence of disease progression is to be confirmed by a second assessment no less than four weeks from the date of the first documented PD (the confirmatory scan could be the Baseline eligibility scan for this study).
  • Archival tumor tissue obtained at any time from the initial diagnosis to study entry; a fresh tumor biopsy using a procedure that is safe for the subject on a lesion not previously irradiated unless lesion progressed will be required if archival tissue is unavailable.
  • Agree to undergo a pre-treatment and on treatment biopsy and have disease amenable to biopsy required in pharmacokinetic (PK) / pharmacodynamics (PD) dose expansion cohorts.
  • Measurable disease per RECIST version 1.1. Palpable lesions that are not measurable by radiographic or photographic evaluations may not be utilized as the only measurable lesion. Any measurable lesion biopsied at Screening cannot be followed as a target/index lesion unless agreed upon by GlaxoSmithKline (GSK).
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
  • Life expectancy of at least 12 weeks.
  • Adequate organ function.
  • QT interval corrected for heart rate according to Fridericia's formula (QTcF) <450 milliseconds (msec) or QTcF <480 msec for subjects with bundle branch block.
  • A female subject is eligible to participate if she is not pregnant (as confirmed by a negative serum beta-human chorionic gonadotrophin [beta-hCG] test in females of reproductive potential), not lactating or if of reproductive potential agrees to follow one of the options listed in protocol from 30 days prior to the first dose of study medication and until 120 days after the last dose of study treatment.
  • Male subjects with female partners of child bearing potential must agree to use one of the methods of contraception specified in protocol from time of first dose of study treatment until 120 days after the last dose of study treatment.
  • Documented HPV/ EBV-positive tumor as determined by a local laboratory for Part 1B and Part 2B pembrolizumab combination viral-positive expansion cohorts only.
  • Documented MSI-H or dMMR-positive tumor as determined by local laboratory for Part 1B and Part 2B pembrolizumab combination MSI-H/dMMR expansion cohorts only.

Exclusion Criteria

  • Prior treatment with the following therapies: • Anticancer therapy within 30 days or 5 half-lives of the drug, whichever is shorter. At least 14 days must have elapsed between the last dose of prior anticancer agent and the first dose of study drug is administered. • Part 2B (GSK3359609/pembrolizumab combination): prior pembrolizumab washout is not required. • Prior radiation therapy: permissible if at least one non-irradiated measurable lesion is available for assessment according to RECIST version 1.1 or if a solitary measurable lesion was irradiated, objective progression is documented. A wash out of at least two weeks before start of study drug for radiation of any intended use to the extremities for bone metastases and 4 weeks for radiation to the chest, brain, or visceral organs is required. • Investigational therapy within 30 days or 5 half-lives of the investigational product (whichever is shorter). At least 14 days must have elapsed between the last dose of investigational agent and the first dose of study drug is administered.
  • Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
  • Toxicity from previous anticancer treatment.
  • Invasive malignancy or history of invasive malignancy other than disease under study within the last two years except: Any other invasive malignancy for which the subject was definitively treated, has been disease-free for <=2 years and in the opinion of the principal investigator and GSK Medical Monitor will not affect the evaluation of the effects of the study treatment on the currently targeted malignancy, may be included in this clinical trial; and curatively treated non-melanoma skin cancer.
  • Central nervous system (CNS) metastases, with the following exception: • Subjects who have previously-treated CNS metastases, are asymptomatic, and have no requirement for steroids at least 14 days prior to first dose of study drug. Subjects with carcinomatous meningitis or leptomeningeal spread are excluded regardless of clinical stability.
  • Received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor, recombinant erythropoietin) within 14 days prior to the first dose of GSK3359609.
  • Major surgery <=4 weeks before the first dose of study treatment. Subjects must have also fully recovered from any surgery (major or minor) and/or its complications before initiating study treatment.
  • Active autoimmune disease that has required systemic treatment within the last two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). • Note: Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Concurrent medical condition requiring the use of systemic immunosuppressive medications within 7 days before the first dose of study treatment. Physiologic doses of corticosteroids for treatment of endocrinopathies or steroids with minimal systemic absorption, including topical, inhaled, or intranasal corticosteroids may be continued if the subject is on a stable dose.
  • Condition requiring treatment with strong inhibitors/inducers of cytochrome (CYP) p450 3A4 within 7 days prior to first dose of chemotherapy (requirement applies to subjects enrolled to Part 2 chemotherapy combination with docetaxel).
  • Active infection requiring systemic therapy, known human immunodeficiency virus infection, or positive test for hepatitis B active infection or hepatitis C active infection.
  • Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per investigator assessment).
  • Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
  • Receipt of any live vaccine within 4 weeks prior to first dose of study treatment.
  • Recent history of allergen desensitization therapy within 4 weeks of starting study treatment.
  • History of severe hypersensitivity to monoclonal antibodies or to the chemotherapies under investigation including any ingredient used in the formulation.
  • History or evidence of cardiac abnormalities.
  • History of (current and past) idiopathic pulmonary fibrosis, pneumonitis (for past pneumonitis exclusion only if steroids were required for treatment), interstitial lung disease, or organizing pneumonia. Note: post-radiation changes in the lung related to prior radiotherapy and/or asymptomatic radiation-induced pneumonitis not requiring treatment may be permitted if agreed by the investigator and Medical Monitor.
  • Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural effusions.
  • Any serious and/or unstable pre-existing medical, psychiatric disorder, or other condition that could interfere with the subject's safety, obtaining informed consent, or compliance to the study procedures.

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): NCT02723955


Contacts
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Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

  Show 26 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Merck Sharp & Dohme Corp.
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02723955     History of Changes
Other Study ID Numbers: 204691
2016-000148-32 ( EudraCT Number )
First Posted: March 31, 2016    Key Record Dates
Last Update Posted: October 9, 2019
Last Verified: October 2019
Keywords provided by GlaxoSmithKline:
ICOS receptor agonist antibody
Pembrolizumab
KEYNOTE-478
GSK3359609
Cohort expansion
Dose escalation
Additional relevant MeSH terms:
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Gemcitabine
Paclitaxel
Docetaxel
Cisplatin
Carboplatin
Pembrolizumab
Fluorouracil
Pemetrexed
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors