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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 subjects with advanced or recurrent solid tumors, as well as clinical activity in subjects with a subset of solid tumors and non-Hodgkin's lymphoma. This is an open-label, repeat-dose, multicenter, 2-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 subjects with relapsed and/or refractory solid tumors. It is estimated that up to 66 subjects will be enrolled into the dose escalation cohort of the study, including up to 42 subjects to identify the MTD and approximately 12 subjects in the PK/PD/metabolite/biomarker expansion cohort(s) and approximately 12 subjects in the food effect sub-study. Disease-specific expansion cohorts (Part 2) are planned to further explore clinical activity of GSK3326595 in subjects with selected solid tumors and non-Hodgkin's lymphomas. It is estimated that up to 251 subjects will be enrolled in the disease-specific expansion cohorts of the study. The duration of study will depend on recruitment rates and the timing of subjects' duration on study (withdrawal rates due to toxicity or progression), with an approximate duration of 2 years.

Related Conditions:
  • Bladder Urothelial Carcinoma
  • Breast Carcinoma
  • Glioblastoma
  • Infiltrating Renal Pelvis and Ureter Urothelial Carcinoma
  • Malignant Solid Tumor
  • Non-Hodgkin Lymphoma
  • Renal Pelvis Urothelial Carcinoma
  • Ureter Urothelial 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 Subjects With Solid Tumors and Non-Hodgkin's Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 204653
  • NCT ID: NCT02783300

Trial Conditions

  • Cancer

Trial Interventions

DrugSynonymsArms
GSK3326595 CapsulesPart 2a: Disease-Specific TNBC

Trial 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 subjects with advanced or recurrent solid tumors, as well as clinical activity in subjects with a subset of solid tumors and non-Hodgkin's lymphoma. This is an open-label, repeat-dose, multicenter, 2-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. This Part will be conducted in adult subjects with relapsed and/or refractory solid tumors. It is estimated that up to 42 subjects will be enrolled into the dose escalation cohort of the study, including up to 30 subjects to identify the MTD and approximately 12 subjects in the PK/PD/metabolite/biomarker expansion cohort(s).

Disease-specific expansion cohorts (Part 2) are planned to further explore clinical activity of GSK3326595 in subjects with selected solid tumors and non-Hodgkin's lymphomas. It is estimated that up to 138 subjects will be enrolled in the disease-specific expansion cohorts of the study.

The duration of study will depend on recruitment rates and the timing of subjects' duration on study (withdrawal rates due to toxicity or progression), with an approximate duration of 2 years.

Detailed Description

Trial Arms

NameTypeDescriptionInterventions
Part 1: Dose EscalationExperimentalIn Part 1, subjects will receive GSK3326595 12.5 mg once daily and escalate until the maximum tolerated dose (MTD) is reached. Projected dose levels are 12.5 mg, 25 mg, 50 mg, 100 mg, 200 mg, and 400 mg. Twice daily (BID) dosing may also be explored if the safety, PK, and PD data suggest that a sufficient therapeutic exposure cannot be achieved using the initial schedule. Dose adjustments may involve either an increase or a decrease in the planned dose as well as a repeat of the previous.
  • GSK3326595 Capsules
Part 2a: Disease-Specific TNBCExperimentalThis part 2 expansion cohort will enroll subjects with TNBC. The final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • GSK3326595 Capsules
Part 2b: Disease-Specific MTCCExperimentalThis part 2 expansion cohort will enroll subjects with metastatic transitional cell carcinoma (MTCC) of the bladder. The final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • GSK3326595 Capsules
Part 2c: Disease-Specific recurrent GBMExperimentalThis part 2 expansion cohort will enroll subjects with recurrent GBM. The final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.
  • GSK3326595 Capsules
Part 2d: Disease-Specific NHL p53 mutantExperimentalThis part 2 expansion cohort will enroll subjects 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 Capsules
Part 2e: Disease-Specific NHL p53 wildExperimentalThis part 2 expansion cohort will enroll subjects 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 Capsules

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 or 1

- 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, subjects 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 [ER]-/ progesterone receptor [PR]-/Human Epidermal Growth Factor Receptor 2 [Her2]-, as defined by local laboratory standards); metastatic or non-resectable transitional cell carcinoma of the bladder, ureter, or renal pelvis; recurrent GBM; or non-Hodgkin's lymphoma. At the time of enrollment, subjects 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.

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

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

- All prior treatment-related toxicities must be National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v4 =< 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 subject 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 subject 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: subject 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

- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Subjects previously treated for these conditions that have had stable central nervous system (CNS) disease (verified with consecutive imaging studies) for >1 month , are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to study Day 1 are permitted. Stability of brain metastases must be confirmed with imaging. Subject treated with gamma knife therapy can be enrolled 2 weeks post-procedure as long as there are no post-procedure complications/they are stable. In addition, subjects treated or currently taking enzyme-inducing anticonvulsant (EIAC) are allowed on study. This criterion does not apply to subjects in the Part 2 GBM cohort

- 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, 2. Any radiotherapy within 14 days or major surgery within 28 days prior to the first dose of GSK3326595. For subjects in the GBM cohort, subjects 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. Subjects with prostate cancer should remain on luteinizing hormone releasing hormone (LHRH) agonists or antagonists. Subjects 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.

- History of a second malignancy, excluding non-melanoma skin cell cancer, unless that malignancy was treated definitively and has not recurred for at least three years.

- 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 subject'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. Subjects 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. Subjects 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:Both
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Number of subjects with any adverse events (AEs) and serious adverse events (SAEs)
Time Frame:Up to 2 years
Safety Issue:No
Description:AEs and SAEs will be collected from the start of study treatment until 30 days after the last dose of study treatment

Secondary Outcome Measures

Measure:Part 1: Composite of PD data
Time Frame:Baseline and 2 years
Safety Issue:No
Description:Evaluation of change from baseline in symmetrical arginine dimethylation (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:No
Description:
Measure:Part 1: Cmax in plasma following repeat-dose administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 1: Time to Cmax (tmax) following single dose administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 1: tmax following repeat-dose administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 1: Terminal phase half-life (t½) following single dose administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 1: t½ following repeat-dose administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 1: Area under the plasma concentration-time curve (AUC) following single dose administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 1: AUC following repeat-dose administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 1: Oral clearance (CL/F) following administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 1: Time invariance (TI) following administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 1: Accumulation ratio (AR) following administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Progression Free Survival (PFS) to describe the duration of response to GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:PFS defined as time from first dose until radiographic progression as measured by standard measures and defined by standard criteria
Measure:Part 2: Relationship between p53 mutational status and clinical response in subjects with NHL
Time Frame:Up to 2 years
Safety Issue:No
Description:Tumor biopsies will be performed to obtain p53 gene data.
Measure:Part 2: Cmax, dose concentration following administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 2: AUC following administration of GSK3326595
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Number of subjects with any AEs and SAEs
Time Frame:Up to 2 years
Safety Issue:No
Description:AEs and SAEs will be collected from the start of study treatment until 30 days after the last dose of study treatment
Measure:Part 2: Number of subjects withdrawn due to AEs, with dose interruptions and with dose reductions
Time Frame:Up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Dose limiting toxicity (DLT)
Time Frame:Up to 2 years
Safety Issue:No
Description:An event is considered to be a dose-limiting toxicity (DLT) if the event meets at least one of the pre-defined toxicity criteria and is attributed as related to the study treatment during the first 21 days of treatment.
Measure:Part 2: Changes from Baseline in hematology laboratory parameters
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Changes from Baseline in clinical chemistry laboratory parameters
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Changes from Baseline in urinalysis laboratory parameters
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Changes from Baseline in temperature
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Changes from Baseline in systolic and diastolic blood pressure
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Changes from Baseline in pulse rate
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Changes from Baseline in respiratory rate
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Changes from Baseline in performance status assessment based on the Eastern Cooperative Oncology Group (ECOG) scale
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:Eastern Cooperative Oncology Group (ECOG) scale rating from 0 to 5.
Measure:Part 2: Changes from Baseline in ECG parameters
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Changes from Baseline in Echocardiogram (ECHO) parameters
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Changes from Baseline in Troponin
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Number of pregnancies reported during study period
Time Frame:Up to 2 years
Safety Issue:No
Description:Details of all pregnancies in female subjects and female partners of male subjects will be collected.
Measure:Part 1: Disease control rate (DCR) based on RECIST 1.1 criteria
Time Frame:Up to 2 years
Safety Issue:No
Description:DCR is defined as complete response ([CR)] + partial response ([PR)] + stable disease ([SD]).
Measure:Part 1: Overall Response Rate (ORR), based on RECIST 1.1 criteria
Time Frame:Up to 2 years
Safety Issue:No
Description:ORR is defined as CR + PR.
Measure:Part 2: Change from baseline in SDMA
Time Frame:Up to 2 years
Safety Issue:No
Description:Pharmacodynamic response assessed by change from baseline in symmetrical arginine dimethylation (SDMA).
Measure:Part 2: Changes from Baseline in physical examinations
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:
Measure:Part 2: Changes from Baseline in organ-specific parameters
Time Frame:Baseline and up to 2 years
Safety Issue:No
Description:

Trial Keywords

  • GSK3326595
  • glioblastoma multiforme (GBM)
  • Solid tumor
  • Non-Hodgkin's lymphoma (NHL)
  • breast cancer
  • bladder cancer
  • dose escalation