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

• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Cancer; Neoplasms	Drug: GSK3326595.	Phase 1

Study Design

Layout table for study information

Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	317 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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
Actual Study Start Date :	August 30, 2016
Estimated Primary Completion Date :	June 15, 2020
Estimated Study Completion Date :	June 15, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: Dose Escalation; In Part 1, subjects will receive GSK3326595 12.5 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.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
Experimental: Part 1: Food effect cohort: GSK3326595 fasted followed by fed; Subjects will receive GSK3326595 in fasted condition in period-1 followed by fed condition in period-2. GSK3326595 dosing will be separated by at least 48 hours wash out period. This cohort will evaluate the effect of high-fat, high-calorie meal on the bioavailability of GSK3326595 at or near the RP2D.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
Experimental: Part 1: Food effect cohort: GSK3326595 fed followed by fasted; Subjects will receive GSK3326595 in fed condition in period-1 followed by fasted condition in period-2. GSK3326595 dosing will be separated by at least 48 hours wash out period. This cohort will evaluate the effect of high-fat, high-calorie meal on the bioavailability of GSK3326595 at or near the RP2D.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
Experimental: Part 2a: Disease-Specific TNBC; This 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.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
Experimental: Part 2b: Disease-Specific MTCC; This 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.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
Experimental: Part 2c: Disease-Specific recurrent GBM; This 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.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
Experimental: Part 2d: Disease-Specific NHL p53 mutant; This 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.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
Experimental: Part 2e: Disease-Specific NHL p53 wildtype; This 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.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
Experimental: Part 2g: Disease-specific ACC; This part 2 expansion cohort will enroll subjects with adenoid cystic carcinoma (ACC). The final dose and regimen for Part 2 will be decided upon completion of dose escalation in Part 1.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
Experimental: Part 2h: Disease specific ER+BC; This part 2 expansion cohort will enroll subjects 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.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.
Experimental: Part 2i: Disease-specific HPV; This part 2 expansion cohort will enroll subjects 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.	Drug: GSK3326595.; The capsules will be of Opaque White for 100 mg and Opaque Light Green for 25 mg. The tablets will be of white to almost white film coated 100 mg tablets with no markings. The capsules and tablets will be administered orally with water (approximately 200 mL) at approximately the same time of day (+/- 4 hours) with no food or antacids for 1 hour before and 2 hours after each dose.

Outcome Measures

Primary Outcome Measures :

1. Part 1: Number of subjects with any adverse events (AEs), serious adverse events (SAEs) [ Time Frame: Up to 2 years ]
   An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. 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.
2. Part 1: Number of subjects withdrawn due to AEs, with dose interruptions and with dose reductions. [ Time Frame: Up to 2 years ]
   Number of subjects withdrawn due to AEs will be evaluated.
3. Part 1: Number of subjects with Dose limiting toxicity (DLT) [ Time Frame: Up to 2 years ]
   An event is considered to be a dose-limiting toxicity (DLT) if the event is attributed (definitely, probably or possibly) to the study treatment during the first 21 days of treatment.
4. Part 1: Number of subjects with clinically significant change in hematology laboratory parameters [ Time Frame: Up to 2 years ]
   Clinical hematology laboratory tests will be performed for abnormal values.
5. Part 1: Number of subjects with clinically significant change in clinical chemistry laboratory parameters [ Time Frame: Up to 2 years ]
   Clinical chemistry laboratory tests will be performed for abnormal values.
6. Part 1: Number of subjects with clinically significant change in urinalysis laboratory parameters [ Time Frame: Up to 2 years ]
   Clinical urinalysis laboratory tests will be performed for abnormal values.
7. Part 1: Number of subjects with clinically significant change in temperature [ Time Frame: Up to 2 years ]
   Temperature measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
8. Part 1: Number of subjects with clinically significant change in systolic and diastolic blood pressure [ Time Frame: Up to 2 years ]
   Systolic and diastolic blood pressure measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
9. Part 1: Number of subjects with clinically significant change in pulse rate [ Time Frame: Up to 2 years ]
   Pulse rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
10. Part 1: Number of subjects with clinically significant change in respiratory rate [ Time Frame: Up to 2 years ]
    Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
11. Part 1: Number of subjects with clinically significant change in physical examinations parameters [ Time Frame: Up to 2 years ]
    A complete and brief physical examination will be carried out to assess the clinically significant change.
12. Part 1: Number of subjects with clinically significant change in organ-specific parameters [ Time Frame: Up to 2 years ]
    Organ-specific evaluations will be done for abnormal values.
13. Part 2: Solid tumor cohorts (non-GBM): Overall response rate (ORR) of subjects [ Time Frame: Up to 2 years ]
    ORR is defined as the percentage of subjects achieving a confirmed complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1
14. Part 2: Non-Hodgkin's lymphoma (NHL) cohort(s): Overall response rate (ORR) of subjects [ Time Frame: Up to 2 years ]
    ORR is defined as the percentage of subjects achieving CR or PR based on Lugano criteria.
15. Part 2: GMB cohort: Progression free survival (PFS) rate of subjects [ Time Frame: Up to 6 months ]
    PFS is defined as the percentage of subjects free from radiographic progression per Response Assessment in Neuro-Oncology (RANO) criteria, or death due to any cause, for six months after starting GSK3326595.

Secondary Outcome Measures :

1. Part 1:Change from Baseline in symmetrical arginine dimethylation (SDMA) as a PD measure [ Time Frame: Baseline and 2 years ]
   Evaluation of change from baseline in SDMA, a pharmacodynamic biomarker of PRMT5 inhibition.
2. Part 1: Maximum observed plasma concentration (Cmax) in plasma following single dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
   Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
3. Part 1: Cmax in plasma following repeat-dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
   Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
4. Part 1: Time to Cmax (tmax) following single dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
   Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
5. Part 1: tmax following repeat-dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
   Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
6. Part 1: Terminal phase half-life (t½) following single dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
   Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
7. Part 1: t½ following repeat-dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
   Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
8. Part 1: Area under the plasma concentration-time curve (AUC) following single dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
   Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
9. Part 1: AUC following repeat-dose administration of GSK3326595 [ Time Frame: Up to 2 years ]
   Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in repeat dose.
10. Part 1: Oral clearance (CL/F) following administration of GSK3326595 [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
11. Part 1: Time invariance (TI) following administration of GSK3326595 [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
12. Part 1: Accumulation ratio (AR) following administration of GSK3326595 [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose.
13. Part 1: Cmax in plasma following single-dose administration of GSK3326595 in fed versus fasted state [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose in fed versus fasted state.
14. Part 1: tmax following repeat-dose administration of GSK3326595 in fed versus fasted state [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose in fed versus fasted state.
15. Part 1: t½ following single-dose administration of GSK3326595 in fed versus fasted state [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose in fed versus fasted state.
16. Part 1: AUC following single -dose administration of GSK3326595 in fed versus fasted state [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose in fed versus fasted state.
17. Part 1: CL/F following single -dose administration of GSK3326595 in fed versus fasted state [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose in fed versus fasted state.
18. Part 1: TI following single -dose administration of GSK3326595 in fed versus fasted state [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose in fed versus fasted state.
19. Part 1: AR following single -dose administration of GSK3326595 in fed versus fasted state [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595 given in single dose in fed versus fasted state.
20. Part 1: Number of subjects with clinical response [ Time Frame: Up to 2 years ]
    Clinical response will be defined as overall response rate (ORR), per standard evaluation criteria. ORR is defined as CR + PR.
21. Part 2: PFS of subjects [ Time Frame: Up to 2 years ]
    PFS defined as time from first dose until radiographic progression per standard criteria, or death due to any cause, whichever is earlier.
22. Part 2: Relationship between p53 mutational status and clinical response in subjects with NHL [ Time Frame: Up to 2 years ]
    Tumor biopsies will be performed to obtain p53 gene data.
23. Part 2: Cmax, dose concentration following administration of GSK3326595 [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595.
24. Part 2: AUC following administration of GSK3326595 [ Time Frame: Up to 2 years ]
    Blood sample will be collected at given time points to study the PK profile of GSK3326595.
25. Part 2: Number of subjects with any AEs and SAEs [ Time Frame: Up to 2 years ]
    An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. 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.
26. Part 2: Number of subjects withdrawn due to AEs, with dose interruptions and with dose reductions [ Time Frame: Up to 2 years ]
    Number of subjects withdrawn due to AEs will be evaluated.
27. Part 2: Number of subjects with clinically significant change in hematology laboratory parameters [ Time Frame: Up to 2 years ]
    Clinical hematology laboratory tests will be performed for abnormal values.
28. Part 2: Number of subjects with clinically significant change in clinical chemistry laboratory parameters [ Time Frame: Up to 2 years ]
    Clinical chemistry laboratory tests will be performed for abnormal values.
29. Part 2: Number of subjects with clinically significant change in urinalysis laboratory parameters [ Time Frame: Up to 2 years ]
    Clinical urine analysis laboratory tests will be performed for abnormal values.
30. Part 2: Number of subjects with clinically significant change in temperature [ Time Frame: Up to 2 years ]
    Temperature measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
31. Part 2: Number of subjects with clinically significant change in systolic and diastolic blood pressure [ Time Frame: Up to 2 years ]
    Systolic and diastolic blood pressure measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
32. Part 2: Number of subjects with clinically significant change in pulse rate [ Time Frame: Up to 2 years ]
    Pulse rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
33. Part 2: Number of subjects with clinically significant change in respiratory rate [ Time Frame: Up to 2 years ]
    Respiratory rate measurements will be performed in a seated or semi-supine position after 5 minutes of rest.
34. Part 2: Change from baseline in SDMA [ Time Frame: Baseline and up to 2 years ]
    PD response assessed by change from baseline in SDMA.
35. Part 2: Number of subjects with clinically significant change in physical examinations [ Time Frame: Up to 2 years ]
    A complete and brief physical examination will be carried out to assess the clinically significant change.
36. Part 2: Number of subjects with clinically significant change in organ-specific parameters [ Time Frame: Up to 2 years ]
    Organ-specific evaluations will be done for abnormal values.
37. Part 2: ORR of subjects present in GBM cohort [ Time Frame: Up to 2 years ]
    ORR is defined as CR + PR.

Eligibility Criteria

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

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, 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); 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). NOTE: Subjects in this cohort must have previously received therapy with a cyclin-dependent kinase (CDK) 4/6 inhibitor or be considered ineligible to receive therapy with these agents; metastatic or non-resectable transitional cell carcinoma of the bladder, ureter, or renal pelvis; recurrent GBM. NOTE: Subjects with prior low-grade glioma with subsequent imaging demonstrating progression to GBM may be enrolled without confirmatory biopsy on a case-by-case basis after discussion with the medical monitor; ACC requiring systemic therapy in the opinion of the treating physician (e.g., for symptomatic disease). NOTE: In order to be eligible for enrollment, subjects must have shown progression via cross-sectional imaging (e.g., CT or MRI) compared to prior scan taken at any time in the past; HPV-positive solid tumor of any primary histology NOTE: (HPV-positive status may be determined locally via any generally accepted test [e.g., HPV DNA OR p16 immunohistochemistry]). A minimum of 10 subjects must be enrolled with cervical cancer.;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.
• Food effect sub-study only: Subjects must consent to additional procedures
• 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 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. This criterion does not apply to subjects with GBM cohort. In Part 1, subjects with GBM may enroll provided that they are on a stable to decreasing dose of corticosteroids for at least 14 days prior to the first dose of GSK3326595. In Part 2, subjects with GBM may enroll irrespective of steroid dose.
• 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 within the last three years. Subjects 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 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.

Contacts and Locations

Contacts

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

Locations

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United States, Florida
GSK Investigational Site	Recruiting
Miami, Florida, United States, 33136
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
GSK Investigational Site	Recruiting
Miami, Florida, United States, 33136
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com
Principal Investigator: Izidore S Lossos
United States, New York
GSK Investigational Site	Recruiting
New York, New York, United States, 10065
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
GSK Investigational Site	Recruiting
New York, New York, United States, 10065
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com
Principal Investigator: Mrinal M. Gounder
United States, Texas
GSK Investigational Site	Not yet recruiting
Dallas, Texas, United States, 75230
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
GSK Investigational Site	Recruiting
Dallas, Texas, United States, 75230
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com
Principal Investigator: James Strauss
GSK Investigational Site	Recruiting
San Antonio, Texas, United States, 78229
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
GSK Investigational Site	Recruiting
San Antonio, Texas, United States, 78229
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com
Principal Investigator: Drew W Rasco
Canada, Ontario
GSK Investigational Site	Recruiting
Toronto, Ontario, Canada, M5G 1X6
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
GSK Investigational Site	Recruiting
Toronto, Ontario, Canada, M5G 1X
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com
Principal Investigator: Lillian Siu
France
GSK Investigational Site	Recruiting
Bordeaux Cedex, France, 33076
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
GSK Investigational Site	Recruiting
Bordeaux Cedex, France, 33076
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com
Principal Investigator: Antoine Italiano
GSK Investigational Site	Recruiting
Lyon Cedex 08, France, 69373
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
GSK Investigational Site	Recruiting
Lyon Cedex 08, France, 69373
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com
Principal Investigator: Philippe Cassier
GSK Investigational Site	Recruiting
Villejuif cedex, France, 94805
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
GSK Investigational Site	Recruiting
Villejuif cedex, France, 94805
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com
Principal Investigator: Sophie Postel-Vinay
Netherlands
GSK Investigational Site	Recruiting
Amsterdam, Netherlands, 1066 CX
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 8990 4466 GSKClinicalSupportHD@gsk.com
GSK Investigational Site	Recruiting
Amsterdam, Netherlands, 1066 C
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com
Principal Investigator: Frans L. Opdam
GSK Investigational Site	Not yet recruiting
Leiden, Netherlands, 2333 Z
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com
GSK Investigational Site	Not yet recruiting
Rotterdam, Netherlands, 3075 E
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Centre 877-379-3718 GSKClinicalSupportHD@gsk.com

Sponsors and Collaborators

GlaxoSmithKline

Investigators

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Study Director:	GSK Clinical Trials	GlaxoSmithKline
Study Director:	GSK Clinical Trials	GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

More Information

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Responsible Party:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT02783300 History of Changes
Other Study ID Numbers:	204653; 2016-000278-39 ( EudraCT Number )
First Posted:	May 26, 2016
Last Update Posted:	December 17, 2018
Last Verified:	December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials:	Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
Time Frame:	IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
Access Criteria:	Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL:	http://clinicalstudydatarequest.com

Keywords provided by GlaxoSmithKline:

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

Additional relevant MeSH terms:

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Lymphoma; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms	Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases