Clinical Trials /

Dose Escalation Study of GSK3326595 in Participants With Solid Tumors and Non-Hodgkin's Lymphoma (NHL)

NCT02783300

Description:

The study drug, GSK3326595, is an inhibitor of protein arginine methyltransferase 5 (PRMT5) that potently inhibits tumor growth in vitro and in vivo in animal models. This first time in human (FTIH), open-label, dose escalation study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of GSK3326595 in participants with advanced or recurrent solid tumors, as well as clinical activity in participants with a subset of solid tumors and NHL. This is an open-label, repeat-dose, multicenter, three-part study to establish the maximally tolerated dose (MTD)/ recommended phase 2 dose (RP2D) based on safety and tolerability and preliminary clinical efficacy of orally-administered GSK3326595. Part 1 is a dose-escalation phase to identify the MTD/RP2D based on the safety, PK, and PD profiles observed after oral administration of GSK3326595 and to preliminarily identify whether or not there is an effect of fed versus fasted state and of tablet versus capsule formulation on the PK of GSK3326595. This Part will be conducted in adult participants with relapsed and/or refractory solid tumors. It is estimated that up to 66 participants will be enrolled into the dose escalation cohort of the study, including up to 42 participants to identify the MTD and approximately 12 participants in the PK/PD/metabolite/biomarker expansion cohort(s) and approximately 12 participants in the food effect and relative bioavailability sub-study. Disease-specific expansion cohorts (Part 2) are planned to further explore clinical activity of GSK3326595 in participants with selected solid tumors and NHL. It is estimated that up to 316 participants will be enrolled in Part 2. Part 3 will be a dose determination study to evaluate the safety, PK/PD profile, and clinical activity of orally-administered GSK3326595 in combination with intravenous pembrolizumab. Overall, approximately 30 participants will be enrolled in Part 3. The duration of study will depend on recruitment rates and the timing of participant's duration on study (withdrawal rates due to toxicity or progression), with an approximate duration of 6 years.

Related Conditions:
  • Adenoid Cystic Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Solid Tumor
  • Melanoma
  • Non-Hodgkin Lymphoma
  • Non-Small Cell Lung Carcinoma
  • Transitional Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Dose Escalation Study of GSK3326595 in Participants With Solid Tumors and Non-Hodgkin's Lymphoma (NHL)
  • Official Title: A Phase I, Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK3326595 in Subjects With Solid Tumors and Non-Hodgkin's Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 204653
  • SECONDARY ID: 2016-000278-39
  • NCT ID: NCT02783300

Conditions

  • Neoplasms

Interventions

DrugSynonymsArms
GSK3326595Part 1a: Dose Escalation
PembrolizumabPart 3: Dose Determination at 100 mg

Purpose

The study drug, GSK3326595, is an inhibitor of protein arginine methyltransferase 5 (PRMT5) that potently inhibits tumor growth in vitro and in vivo in animal models. This first time in human (FTIH), open-label, dose escalation study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of GSK3326595 in participants with advanced or recurrent solid tumors, as well as clinical activity in participants with a subset of solid tumors and NHL. This is an open-label, repeat-dose, multicenter, three-part study to establish the maximally tolerated dose (MTD)/ recommended phase 2 dose (RP2D) based on safety and tolerability and preliminary clinical efficacy of orally-administered GSK3326595. Part 1 is a dose-escalation phase to identify the MTD/RP2D based on the safety, PK, and PD profiles observed after oral administration of GSK3326595 and to preliminarily identify whether or not there is an effect of fed versus fasted state and of tablet versus capsule formulation on the PK of GSK3326595. This Part will be conducted in adult participants with relapsed and/or refractory solid tumors. It is estimated that up to 66 participants will be enrolled into the dose escalation cohort of the study, including up to 42 participants to identify the MTD and approximately 12 participants in the PK/PD/metabolite/biomarker expansion cohort(s) and approximately 12 participants in the food effect and relative bioavailability sub-study. Disease-specific expansion cohorts (Part 2) are planned to further explore clinical activity of GSK3326595 in participants with selected solid tumors and NHL. It is estimated that up to 316 participants will be enrolled in Part 2. Part 3 will be a dose determination study to evaluate the safety, PK/PD profile, and clinical activity of orally-administered GSK3326595 in combination with intravenous pembrolizumab. Overall, approximately 30 participants will be enrolled in Part 3. The duration of study will depend on recruitment rates and the timing of participant's duration on study (withdrawal rates due to toxicity or progression), with an approximate duration of 6 years.

Trial Arms

NameTypeDescriptionInterventions
Part 1a: Dose EscalationExperimentalIn Part 1, participants will receive GSK3326595 12.5 milligram (mg) once daily (QD) and escalate until the maximum tolerated dose (MTD) is reached. Projected daily dose levels are 12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg. BID dosing may divide this total daily dose into two equal doses, administered twice daily. Additional doses (either lower than 12.5 mg, higher than 1200 mg, or intermediate doses between those listed above) and schedules may be explored based on emerging safety, PK and PD data. Further enrollment to this cohort is closed.
  • GSK3326595
Part 2a: Disease-Specific TNBCExperimentalThis part 2 expansion cohort will enroll participants with triple-negative breast cancer (TNBC). The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
  • GSK3326595
Part 2b: Disease-Specific MTCCExperimentalThis part 2 expansion cohort will enroll participants with metastatic transitional cell carcinoma (MTCC) of the urinary system. The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
  • GSK3326595
Part 2c: Disease-Specific recurrent GBMExperimentalThis part 2 expansion cohort will enroll participants with recurrent glioblastoma multiforme (GBM). The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
  • GSK3326595
Part 2d: Disease-Specific NHL p53 mutantExperimentalThis part 2 expansion cohort will enroll participants with NHL p53 mutant gene. The dose of GSK3326595 was started at 400 mg QD but going forward participants will receive 300 mg QD.
  • GSK3326595
Part 2e: Disease-Specific NHL p53 wildtypeExperimentalThis part 2 expansion cohort will enroll participants with NHL p53 wild-type gene. The dose of GSK3326595 was started at 400 mg QD but going forward participants will receive 300 mg QD.
  • GSK3326595
Part 2f: Disease-specific ACC (GSK3326595 capsule)ExperimentalThis part 2 expansion cohort will enroll participants with adenoid cystic carcinoma (ACC) and will receive GSK3326595 capsules. The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
  • GSK3326595
Part 2g: Disease-specific ACC (GSK3326595 tablet)ExperimentalThis part 2 expansion cohort will enroll participants with ACC who have not received any systemic therapy for locally advanced or metastatic disease and will receive GSK3326595 tablets. The dose of GSK3326595 will be 300 mg QD.
  • GSK3326595
Part 2h: Disease specific ER+BCExperimentalThis part 2 expansion cohort will enroll participants with hormone receptor-positive adenocarcinoma of the breast (ER+BC). The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
  • GSK3326595
Part 2i: Disease-specific HPVExperimentalThis part 2 expansion cohort will enroll participants with human papillomavirus (HPV) positive solid tumors of any histology (including cervical cancer and squamous cell carcinoma of the head and neck [HNSCC]). The dose of GSK3326595 will be 400 mg QD. Further enrollment to this cohort is closed.
  • GSK3326595
Part 2j: Disease specific p53 wild-type NSCLCExperimentalThis part 2 expansion cohort will enroll participants with P53 wild-type non small-cell lung cancer (NSCLC) and will receive GSK3326595. The dose of GSK3326595 will be 300 mg QD.
  • GSK3326595
Part 3: Dose Determination at 100 mgExperimentalThe participants with NSCLC, melanoma, mTCC, or HNSCC will receive pembrolizumab at the approved dose (200 mg intravenous [IV] every 3 weeks), in combination with GSK3326595 dosed orally at 100 mg QD.
  • GSK3326595
  • Pembrolizumab
Part 3: Dose Determination at 200 mgExperimentalThe participants with NSCLC, melanoma, mTCC, or HNSCC will receive pembrolizumab at the approved dose (200 mg IV every 3 weeks), in combination with GSK3326595 dosed orally at 200 mg QD.
  • GSK3326595
  • Pembrolizumab
Part 3: Dose Determination at 300 mgExperimentalThe participants with NSCLC, melanoma, mTCC, or HNSCC will receive pembrolizumab at the approved dose (200 mg IV every 3 weeks), in combination with GSK3326595 dosed orally at 300 mg QD.
  • GSK3326595
  • Pembrolizumab
Part 1b: Food Effect and Relative BioavailabilityExperimentalPart 1 will include a sub-study that will be an open-label, randomized, single dose, three period, cross over study to investigate the effect of a high-fat, high-calorie meal on the bioavailability of GSK3326595, and compare two formulations of GSK3326595 (capsule versus tablet). The dose of GSK3326595 will be 300 mg QD.
  • GSK3326595

Eligibility Criteria

        Inclusion Criteria:

          -  Males and females >=18 years of age (at the time consent is obtained). For NHL cohort
             only, participants must be <=75 years of age at the time consent is obtained.

          -  Capable of giving signed informed consent.

          -  Able to swallow and retain orally-administered medication.

          -  Eastern cooperative oncology group (ECOG) performance status of 0 to 2.

          -  Diagnosis of one of the following:

          -  Part 1: Histologically- or cytological-confirmed diagnosis of non-resectable or
             metastatic solid malignancy that has progressed on prior therapy (radiographic
             documentation of progression is adequate for study participation).

          -  Part 2: Histologically- or cytologically-confirmed diagnosis of metastatic or
             non-resectable disease that has progressed on prior therapy (ACC tablet cohort does
             not require prior therapy for enrollment i.e. must be systemic therapy naive; for all
             tumors, (radiographic documentation of progression is adequate for study
             participation):

          -  TNBC (estrogen receptor negative [ER-]/ progesterone receptor [PR-]/Human Epidermal
             Growth Factor Receptor 2 negative [Her2-], as defined by local laboratory standards);

          -  ER+BC (estrogen receptor positive [ER+] or progesterone receptor positive [PR+],
             Her2-, as defined by local laboratory standards);

          -  metastatic or non-resectable transitional cell carcinoma of the bladder, ureter, or
             renal pelvis;

          -  recurrent GBM;

          -  ACC requiring systemic therapy. In order to be eligible for enrolment, ACC
             participants must: have shown progression by local evaluation of scans, as per RECIST
             1.1, within the 13 months prior to enrolment and have measurable disease, as confirmed
             by independent central review of baseline scans prior to first dose.

          -  HPV-positive solid tumor of any primary histology.

          -  NHL that is not one of the following subtypes, as determined by local laboratory
             testing: Burkitt's lymphoma or other high-grade lymphoma and double- or triple-hit
             large B-cell lymphoma.

          -  NSCLC, of any histologic sub-type; with local mutational analysis demonstrating
             wild-type status of TP53 (i.e., p53 wild-type NSCLC).

          -  Part 3: Histologically- or cytologically-confirmed diagnosis of metastatic or
             nonresectable NSCLC (of any histologic sub-type), metastatic transitional cell
             carcinoma of the urinary system (mTCC), squamous cell carcinoma of the head and neck
             (HNSCC), or melanoma that failed to respond to prior treatment with Programmed Cell
             Death-Protein 1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) targeted therapy.

          -  Prior therapy: ACC tablet cohort: participants must be systemic therapy-naïve. Prior
             surgery and/or radiation is permitted. NHL cohort: participants may have received up
             to 4 prior lines of systemic therapy for disease. Tumors with actionable mutations
             (e.g., BRAF V600E gene mutation in melanoma; Epidermal growth factor receptor (EGFR)
             mutations or anaplastic lymphoma kinase (ALK) rearrangements in NSCLC) must have
             received prior therapy with targeted agents prior to enrollment. Apart from ACC tablet
             cohort, participants must have received at least one line of prior systemic therapy
             (or have a disease for which no approved therapy exists), and have no standard-of-care
             therapy that would be expected achieve a durable clinical response, or refuse standard
             therapy, or are not candidates for standard therapy.

          -  Evaluable disease: During Part 1, evaluable disease is required; measurable disease
             per RECIST v1.1 is recommended but not required and Participants enrolled in Part 2
             and Part 3 must demonstrate measurable disease per the disease-specific criteria.

          -  PK/PD/biomarker/metabolite expansion cohort(s) only: Participants must consent to pre-
             and post-dose tumor biopsies and additional sample collection procedures.

          -  Food effect and relative bioavailability sub-study only: Participants must consent to
             additional procedures.

          -  Part 3 only: Participants must consent to additional procedures (including paired
             biopsies).

          -  All prior treatment-related toxicities must be National Cancer Institute Common
             Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 =<Grade 1 (except
             alopecia [permissible at any Grade] and peripheral neuropathy [which must be =<Grade
             2]) at the time of treatment allocation.

          -  Adequate organ function as per Hematologic, Hepatic and Renal Laboratory Values.

          -  Reproductive criteria:

          -  A male participant with female partner of child bearing potential must agree to use
             one of the methods of contraception for the duration specified in protocol.

          -  A female participant is eligible to participate if she is not pregnant (as confirmed
             by a negative serum human chorionic gonadotrophin [hCG] test), not nursing, and at
             least one of the following conditions apply: Reproductive potential: participants must
             agree to follow one of the options and the duration specified in protocol;

          -  Non-reproductive potential defined as

          -  i) Pre-menopausal females with one of the following: Documented tubal ligation,
             Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of
             bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy;

          -  ii) Postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate
             clinical profile or females over 60 years of age. Females on hormone replacement
             therapy (HRT) and whose menopausal status is in doubt will be required to use one of
             the highly effective contraception methods if they wish to continue their HRT during
             the study. Otherwise, they must discontinue HRT to allow confirmation of
             post-menopausal status prior to study enrollment.

        Exclusion Criteria:

          -  Malignancy attributed to prior solid organ transplant.

          -  Leptomeningeal disease, spinal cord compression, or brain metastases that require
             immediate central nervous system (CNS)-specific treatment in the opinion of the
             Investigator (e.g., for symptomatic disease).

          -  Recent prior therapy, defined as

          -  1. Any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, whichever is
             longer, prior to the first dose of GSK3326595. Any nitrosoureas or mitomycin C within
             42 days prior to the first dose of GSK3326595. Prior therapy with biologic agents
             (including monoclonal antibodies) is permitted so long as 28 days have elapsed since
             therapy and all therapy-related AEs have resolved to =<Grade 1, note that participants
             with immunotherapy-related endocrinopathies, currently managed with replacement
             therapy, will be allowed on study.

          -  2. Any radiotherapy within 14 days or major surgery within 28 days prior to the first
             dose of GSK3326595. For participants in the GBM cohort, participants must have
             completed radiation therapy at least 28 days prior to the first dose of GSK3326595.

          -  3. Anti-androgen therapies for prostate cancer, such as bicalutamide, must be stopped
             4 weeks prior to enrollment. Second-line hormone therapies such as enzalutamide or
             abiraterone should be stopped 2 weeks prior to enrolment. Participants with prostate
             cancer should remain on luteinizing hormone releasing hormone (LHRH) agonists or
             antagonists. Participants with prostate cancer may also remain on low-dose prednisone
             or prednisolone (up to 10 mg/day) and still be eligible for this study.

          -  Part 3 only: History of any of the following: Recent history (within the past 2 years)
             of autoimmune disease or syndrome that required systemic treatment; a diagnosis of
             immunodeficiency or administration of systemic steroids (>=10 mg oral prednisone or
             equivalent) or other immunosuppressive agents within 7 days prior to randomization;
             Receipt of any live vaccine within 30 days prior randomization; Prior
             allogeneic/autologous bone marrow or solid organ transplantation; Current pneumonitis
             or history of non-infectious pneumonitis that required steroids or other
             immunosuppressive agents; Recent history of allergen desensitization therapy within 4
             weeks of randomization; History of severe hypersensitivity to monoclonal antibodies.

          -  History of a second malignancy, excluding non-melanoma skin cell cancer within the
             last three years. Participants with second malignancies that were indolent, in situ or
             definitively treated may be enrolled even if less than three years have elapsed since
             treatment. Consult the GSK Medical Monitor if second malignancies meet the
             requirements specified above.

          -  Current use of a prohibited medication or planned use of any forbidden medications
             during treatment with GSK3326595.

          -  Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
             respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding
             episodes). Any serious and/or unstable pre-existing medical (aside from malignancy),
             psychiatric disorder, or other conditions that could interfere with participant's
             safety, obtaining informed consent or compliance to the study procedures, in the
             opinion of the Investigator.

          -  Any clinically significant gastrointestinal (GI) abnormalities that may alter
             absorption such as malabsorption syndrome or major resection of the stomach and/or
             bowels.

          -  History of known human immunodeficiency virus (HIV) infection or positive HIV test
             result at screening.

          -  Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test
             result at screening or within 3 months prior to first dose of study treatment.
             Participants with positive Hepatitis C antibody due to prior resolved disease can be
             enrolled only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) polymerase
             chain reaction (PCR) is obtained.

          -  Any of the following cardiac abnormalities: 1. Recent history (within 6 months of
             first dose of study drug) of acute coronary syndromes (including myocardial infarction
             and unstable angina), coronary angioplasty, or stenting. 2. Presence of a cardiac
             pacemaker, 3. Baseline QTcF >=450 millisecond, 4. Uncontrolled arrhythmias.
             Participants with rate-controlled atrial fibrillation for >1 month prior to first dose
             of study drugs may be eligible. 5. Class II, III or IV heart failure as defined by the
             New York Heart Association (NYHA) functional classification system.

          -  History of sensitivity to any of the study medications, or components thereof or a
             history of drug or other allergy that, in the opinion of the investigator or Medical
             Monitor, contraindicates their participation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Number of participants with any adverse events (AEs)
Time Frame:Up to approximately 2 years
Safety Issue:
Description:An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.

Secondary Outcome Measures

Measure:Part 1:Change from Baseline in symmetrical arginine dimethylation (SDMA) as a PD measure
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.
Measure:Part 2:Change from Baseline in SDMA as a PD measure
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.
Measure:Part 3:Change from Baseline in SDMA as a PD measure
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Evaluation of change from baseline in SDMA, a PD biomarker of PRMT5 inhibition.
Measure:Part 1: Maximum observed plasma concentration (Cmax) in plasma following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.
Measure:Part 1: Cmax in plasma following repeat-dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 1: Area under the plasma concentration-time curve (AUC) extrapolated from time zero to infinity (AUC[0-inf]) following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 1: AUC (0-inf) following repeat dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 1: AUC from time zero to the last quantifiable concentration after dosing (AUC[0-t]) following single-dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.
Measure:Part 1: AUC(0-t) following repeat-dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 1: AUC over the dosing interval tau (AUC[0-tau]) following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 1: AUC(0-tau) following repeat dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 1: Terminal phase half-life (t½) following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 1: t½ following repeat-dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 1: Oral clearance (CL/F) following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 1: CL/F following repeat dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 1: Accumulation ratio (AR) following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 1: AR following repeat dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 1: Time invariance (TI) following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 1: TI following repeat dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 1: Time to Cmax (tmax) following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 1: tmax following repeat-dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 1: ORR of participants
Time Frame:Up to approximately 2 years
Safety Issue:
Description:ORR is defined as the percentage of participants achieving a confirmed CR or PR based on RECIST 1.1 criteria
Measure:Part 3: AUC(0-inf) following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 3: AUC(0-t) following single-dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 3: AUC(0-t) following repeat-dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 3: AUC(0-tau) following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 3: AUC(0-tau) following repeat dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 3: AUC[0-inf] following repeat dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 3: tmax following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 3: tmax following repeat-dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 3: t½ following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 3: t½ following repeat-dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 3: CL/F following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 3: CL/F following repeat dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 3: AR following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 3: AR following repeat dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 3: Cmax in plasma following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 3: Cmax in plasma following repeat-dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 3: TI following single dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
Measure:Part 3: TI following repeat dose administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
Measure:Part 3: ORR of participants
Time Frame:Up to approximately 2 years
Safety Issue:
Description:ORR is defined as the percentage of participants achieving a confirmed CR or PR based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and based on independent central review (ICR) in ACC cohort administered with tablet formulation.
Measure:Part 1: Cmax following single-dose administration of GSK3326595 tablets in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose.
Measure:Part 1: Tmax following single-dose administration of GSK3326595 tablets in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: t½ following single-dose administration of GSK3326595 tablets in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: AUC (0-t) following single-dose administration of GSK3326595 tablets in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: AUC (0-inf) following single-dose administration of GSK3326595 tablets in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: AUC (0-tau) following single-dose administration of GSK3326595 tablets in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: CL/F following single-dose administration of GSK3326595 tablets in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: TI following single-dose administration of GSK3326595 tablets in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: AR following single-dose administration of GSK3326595 tablets in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: Cmax following single-dose administration of GSK3326595 tablets in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: Tmax following single-dose administration of GSK3326595 tablets in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: t½ following single-dose administration of GSK3326595 tablets in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 2: Relationship between p53 mutational status and ORR in participants with NHL
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Tumor biopsies will be performed to obtain p53 gene data.
Measure:Part 1: AUC (0-t) following single-dose administration of GSK3326595 tablets in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: AUC (0-inf) following single-dose administration of GSK3326595 tablets in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: AUC (0-tau) following single-dose administration of GSK3326595 tablets in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: CL/F following single-dose administration of GSK3326595 tablets in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: AR following single-dose administration of GSK3326595 tablets in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: TI following single-dose administration of GSK3326595 tablets in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: Cmax following single-dose administration of GSK3326595 capsules in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: Tmax following single-dose administration of GSK3326595 capsules in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: AUC (0-inf) following single-dose administration of GSK3326595 capsules in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: AUC (0-t) following single-dose administration of GSK3326595 capsules in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: AUC (0-tau) following single-dose administration of GSK3326595 capsules in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: CL/F following single-dose administration of GSK3326595 capsules in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: TI following single-dose administration of GSK3326595 capsules in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: AR following single-dose administration of GSK3326595 capsules in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: t½ following single-dose administration of GSK3326595 capsules in fasted condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fasted condition.
Measure:Part 1: Cmax following single-dose administration of GSK3326595 capsules in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: Tmax following single-dose administration of GSK3326595 capsules in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: AUC (0-inf) following single-dose administration of GSK3326595 capsules in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: AUC (0-t) following single-dose administration of GSK3326595 capsules in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: AUC (0-tau) following single-dose administration of GSK3326595 capsules in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: CL/F following single-dose administration of GSK3326595 capsules in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: TI following single-dose administration of GSK3326595 capsules in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: AR following single-dose administration of GSK3326595 capsules in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 1: t½ following single-dose administration of GSK3326595 capsules in fed condition
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595 given as a single dose in fed condition.
Measure:Part 2: Number of participants with any AEs
Time Frame:Up to approximately 2 years
Safety Issue:
Description:An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.
Measure:Part 2: Number of participants with SAEs
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment will be categorized as SAE.
Measure:Part 2: Number of participants withdrawn due to AEs
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Number of participants withdrawn due to AEs will be evaluated.
Measure:Part 2: Number of participants with dose interruptions and with dose reductions
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Number of participants with dose interruptions and with dose reductions will be analyzed.
Measure:Part 2: PFS of participants
Time Frame:Up to approximately 2 years
Safety Issue:
Description:PFS defined as time from first dose until radiographic progression per standard criteria, or death due to any cause, whichever is earlier.
Measure:Part 2: AUC following administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595.
Measure:Part 2: ORR of participants present in GBM cohort
Time Frame:Up to approximately 2 years
Safety Issue:
Description:ORR is defined as CR + PR based on Response Assessment in Neuro-Oncology (RANO) Working Group criteria.
Measure:Part 2: Cmax, dose concentration following administration of GSK3326595
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Blood sample will be collected at given time points to study the PK profile of GSK3326595.
Measure:Part 2: Duration of Response (DOR) for ACC cohort
Time Frame:Up to approximately 2 years
Safety Issue:
Description:DOR is defined as time from first evidence of response (CR or PR per Immune Response Evaluation Criteria in Solid Tumors [iRECIST 1.1]) to earlier date of disease progression or death due to any cause.
Measure:Part 2: ORR of participants for ACC cohort
Time Frame:Up to approximately 2 years
Safety Issue:
Description:ORR is defined as the percentage of participants achieving a confirmed CR or PR based on RECIST 1.1 criteria.
Measure:Part 2: Overall survival (OS) of participants for ACC cohort
Time Frame:Up to approximately 2 years
Safety Issue:
Description:OS is defined as time from first dose until death from any cause in ACC participants who are systemic-treatment naïve.
Measure:Part 2: Change from Baseline in Hb (Grams per Liter)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure:Part 2: Change from Baseline in Hematocrit (Proportion of red blood cells in blood)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure:Part 2: Change from Baseline in MCH (Picograms)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure:Part 2: Change from Baseline in MCV (Femtoliters)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of hematology parameter.
Measure:Part 2: Change from Baseline in hematology parameter: RBC Count and Reticulocytes (Trillion cells per liter)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of hematology parameters.
Measure:Part 2: Change from Baseline in Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils, platelet count (Giga cells per Liter)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of hematology parameters.
Measure:Part 2: Change from Baseline in BUN, Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure:Part 2: Change from Baseline in AST, ALT, Alkaline phosphatase (International units per Liter)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure:Part 2: Change from Baseline in total protein and albumin (grams per day)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure:Part 2: Change from Baseline in Serum Lipase, Serum Amylase (Units per liter)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Blood samples will be collected at indicated time points for analysis of chemistry parameters.
Measure:Part 2: Change from Baseline in temperature (Degrees Celsius)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Change from Baseline temperature will be assessed in a seated or semi-supine position with a completely automated device.
Measure:Part 2: Change from Baseline in Urinalysis Parameter: Specific Gravity (Ratio)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Urine samples will be collected at indicated time points for the assessment of specific gravity.
Measure:Part 2: Change from Baseline in Urinalysis Parameters- Urine pH
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Urine samples will be collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0).
Measure:Part 2: Change from Baseline in urinalysis parameter: Glucose (Millimole per liter)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Urine samples will be collected at indicated time points for the assessment of urinary glucose.
Measure:Part 2: Change from Baseline in urinalysis parameter: Ketones (Millimoles per liter)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Urine samples will be collected at indicated time points for the assessment of urinary ketones.
Measure:Part 2: Change from Baseline in urinalysis parameter: Occult blood (10^9 cells per liter)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Urine samples will be collected at indicated time points for the assessment of urinary occult blood.
Measure:Part 2: Change from Baseline in urinalysis parameter: Protein
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Urine samples will be collected at indicated time points for the assessment of urinary protein.
Measure:Part 2: Change from Baseline in Pulse rate (Beats per minute)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Change from Baseline pulse rate will be assessed in a semi-supine position.
Measure:Part 2: Number of participants with clinically significant change in respiratory rate
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
Measure:Part 2: Number of participants with clinically significant change in temperature
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Temperature measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
Measure:Part 2: Change from Baseline in ECG Parameters: PR Interval, QRS Interval, QT Interval, QTcF (Milliseconds)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:12-lead ECGs will be obtained using an ECG machine that automatically calculates and measures PR, QRS, QT, and QTcF intervals. Twelve lead ECG will be measured in a supine or semi supine position after 10 minutes rest.
Measure:Part 2: Change from Baseline in SBP and DBP (Millimeter of mercury)
Time Frame:Baseline and up to approximately 2 years
Safety Issue:
Description:Change from Baseline in SBP and DBP will be assessed in a semi-supine position with a completely automated device.
Measure:Part 2: Number of participants with abnormality in physical examinations
Time Frame:Up to approximately 2 years
Safety Issue:
Description:A complete physical examination will include, assessments of the head, eyes, ears, nose, throat, Skin, thyroid, Cardiovascular, Respiratory, Gastrointestinal, Neurological systems, lymph nodes and extremities. Brief physical examination will include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen.
Measure:Part 2: Number of participants with clinically significant change in organ-specific parameters
Time Frame:Up to approximately 2 years
Safety Issue:
Description:Organ-specific evaluations will be done for abnormal values.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • GSK3326595
  • Solid tumor
  • Non-Hodgkin's lymphoma (NHL)
  • Urinary tract cancer
  • Dose escalation
  • Adenoid cystic carcinoma (ACC)
  • Non small-cell lung cancer (NSCLC)
  • Squamous cell carcinoma of the head and neck (HNSCC)
  • Melanoma

Last Updated

May 22, 2020