Clinical Trials /

Dose Escalation Study of GSK3326595 in Subjects With Solid Tumors and Non-Hodgkin's Lymphoma

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 non-Hodgkin's lymphoma. 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 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 70 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 16 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 non-Hodgkin's lymphomas. 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, approximately30 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 2 years.

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

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Dose Escalation Study of GSK3326595 in Subjects With Solid Tumors and Non-Hodgkin's Lymphoma
  • Official Title: A Phase I, Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK3326595 in Participants 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 1: 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 non-Hodgkin's lymphoma. 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 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 70 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 16 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 non-Hodgkin's lymphomas. 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, approximately30 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 2 years.

Trial Arms

NameTypeDescriptionInterventions
Part 1: Dose EscalationExperimentalIn Part 1, participants will receive GSK3326595 12.5 milligram (mg) once daily 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, A cohort of participants will be enrolled into a food effect and relative bioavailability sub-study.
  • GSK3326595
Part 2a: Disease-Specific TNBCExperimentalThis part 2 expansion cohort will enroll participants with triple-negative breast cancer (TNBC). The final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • GSK3326595
Part 2b: Disease-Specific MTCCExperimentalThis part 2 expansion cohort will enroll participants with metastatic transitional cell carcinoma (MTCC) of the urinary system. The final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • GSK3326595
Part 2c: Disease-Specific recurrent GBMExperimentalThis part 2 expansion cohort will enroll participants with recurrent GBM. The final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • GSK3326595
Part 2d: Disease-Specific NHL p53 mutantExperimentalThis part 2 expansion cohort will enroll participants with NHL p53 mutant gene. The final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • GSK3326595
Part 2e: Disease-Specific NHL p53 wildtypeExperimentalThis part 2 expansion cohort will enroll participants with NHL p53 wild-type gene. The final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • 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 final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • GSK3326595
Part 2g: Disease-specific ACC (GSK3326595 tablet)ExperimentalThis part 2 expansion cohort will enroll participants with ACC and will receive GSK3326595 tablets. The final dose and regimen for Part 2 will be decided upon completion of dose escalation of Part 1.
  • 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 final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • 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 final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • GSK3326595
Part 2j: Disease specific NSCLC p53 wild-typeExperimentalThis part 2 expansion cohort will enroll participants with non small-cell lung cancer (NSCLC) and will receive GSK3326595. The final dose and regimen for Part 2 will be decided upon completion of dose escalation of Part 1.
  • GSK3326595
Part 3: Dose Determination at 100 mgExperimentalAll participants will receive pembrolizumab at the approved dose (200 mg intravenous (IV) every 3 weeks), in combination with GSK3326595 dosed orally at 100 mg once daily (QD).
  • GSK3326595
  • Pembrolizumab
Part 3: Dose Determination at 200 mgExperimentalAll participants 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 mgExperimentalAll participants 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

Eligibility Criteria

        Inclusion Criteria:

          -  Males and females >=18 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: 1. Part 1: Histologically- or cytological-confirmed
             diagnosis of non-resectable or metastatic solid malignancy. At the time of enrollment,
             participants either: have progressed on prior therapy (radiographic documentation of
             progression is adequate for study participation) AND have no standard-of-care therapy
             that would be expected to achieve a durable clinical response, OR refuse standard
             therapy, OR are not candidates for standard therapy, OR have a disease for which no
             generally-accepted standard-of-care exists. 2. Part 2: Histologically- or
             cytologically-confirmed diagnosis of metastatic or non-resectable:

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

          -  ER+BC (estrogen receptor positive [ER+] or progesterone receptor positive [PR+], human
             epidermal growth factor receptor 2 negative (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 subjects
             must: be treatment-naïve or may have received no more than two prior lines of systemic
             therapy for locally advanced/metastatic disease (systemic therapy administered in the
             context of localized disease, e.g., adjuvant therapy, does not count towards the
             two-line maximum). A minimum of 25% of subjects must be enrolled as treatment-naïve;
             AND have shown progression within the 13 months prior to enrolment, via
             cross-sectional imaging (e.g., Computed tomography (CT) or Magnetic resonance imaging
             [MRI]); AND have measurable disease, as confirmed by independent central review of
             baseline scans;

          -  HPV-positive solid tumor of any primary histology.

          -  non-Hodgkin's lymphoma.

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

          -  At the time of enrollment, participants either: have progressed on prior therapy
             (radiographic documentation of progression is adequate for study participation) 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.

             3. 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 PD-1 or PD-L1
             targeted therapy.

          -  Evaluable disease: 1. During Part 1, evaluable disease is required; measurable disease
             per RECIST v1.1 is recommended but not required, 2. 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, Renal and Cardiac Laboratory
             Values

          -  Reproductive criteria: 1. 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. 2. 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 milligram (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 RNA polymerase chain reaction
             (PCR) is obtained.

          -  Any of the following cardiac abnormalities: 1. History of acute coronary syndromes
             (including myocardial infarction and unstable angina), coronary angioplasty, or
             stenting within the past 6 months prior to first dose of study drug. 2. Presence of a
             cardiac pacemaker, 3. Baseline Corrected QT (Fridericia's formula) interval (QTcF)
             >=450 millisecond (msec), 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 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 2 years
Safety Issue:
Description:Evaluation of change from baseline in SDMA, a pharmacodynamic biomarker of PRMT5 inhibition.
Measure:Part 2:Change from Baseline in symmetrical arginine dimethylation (SDMA) as a PD measure
Time Frame:Baseline and 2 years
Safety Issue:
Description:Evaluation of change from baseline in SDMA, a pharmacodynamic biomarker of PRMT5 inhibition.
Measure:Part 3:Change from Baseline in symmetrical arginine dimethylation (SDMA) as a PD measure
Time Frame:Baseline and 2 years
Safety Issue:
Description:Evaluation of change from baseline in SDMA, a pharmacodynamic biomarker of PRMT5 inhibition.
Measure:Part 1: Maximum observed plasma concentration (Cmax) in plasma following single dose administration of GSK3326595
Time Frame:Up to 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 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 extrapolated from time zero to infinity (AUC[0-inf]) following single dose administration of GSK3326595
Time Frame:Up to 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 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 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 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 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 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 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 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 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: Oral clearance (CL/F) following repeat dose administration of GSK3326595
Time Frame:Up to 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 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 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 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: Time invariance (TI) following repeat dose administration of GSK3326595
Time Frame:Up to 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 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 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 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 extrapolated from time zero to infinity (AUC[0-inf]) following single dose administration of GSK3326595
Time Frame:Up to 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 from time zero to the last quantifiable concentration after dosing (AUC[0-t]) following single-dose administration of GSK3326595
Time Frame:Up to 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 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 over the dosing interval tau (AUC[0-tau]) following single dose administration of GSK3326595
Time Frame:Up to 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 2 years
Safety Issue:
Description:ORR is defined as the percentage of participants achieving a confirmed complete response (CR) or partial response (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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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:Baseline and up to 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: Number of participants with any AEs
Time Frame:Up to 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 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 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 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 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 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 2 years
Safety Issue:
Description:ORR is defined as CR + PR.
Measure:Part 2: Cmax, dose concentration following administration of GSK3326595
Time Frame:Up to 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 2 years
Safety Issue:
Description:DOR is defined as time from first evidence of response (CR or PR per 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 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: Change from Baseline in Hemoglobin (Hb) (Grams per Liter)
Time Frame:Baseline and up to 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 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 Mean Corpuscle Hemoglobin (MCH) (Picograms)
Time Frame:Baseline and up to 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 Mean Corpuscle Volume (MCV) (Femtoliters)
Time Frame:Baseline and up to 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 (Trillion cells per liter)
Time Frame:Baseline and up to 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 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 Blood urea nitrogen (BUN), Creatinine, Glucose (fasting), Sodium, Potassium, Calcium, Total and direct bilirubin (Micromoles per liter)
Time Frame:Baseline and up to 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 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 (grams per day)
Time Frame:Baseline and up to 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 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 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 potential of hydrogen (pH)
Time Frame:Baseline and up to 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 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 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 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 Pulse rate (Beats per minute)
Time Frame:Baseline and up to 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 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 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 Electrocardiogram (ECG) Parameters: PR Interval, QRS Interval, QT Interval, Corrected QT interval using the Fridericia formula (QTcF) (Milliseconds)
Time Frame:Baseline and up to 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 systolic blood pressure (SBP) and diastolic blood pressure (DBP) (Millimeter of mercury)
Time Frame:Baseline and up to 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 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 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
  • Glioblastoma multiforme (GBM)
  • Solid tumor
  • Non-Hodgkin's lymphoma (NHL)
  • Breast cancer
  • Urinary tract cancer
  • Dose escalation

Last Updated

December 11, 2019