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

Trial Status: Active

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

Inclusion Criteria

  • Males and females >=18 years of age (at the time consent is obtained). For NHL cohort only, participants must be <=75 years of age at the time consent is obtained.
  • Capable of giving signed informed consent.
  • Able to swallow and retain orally-administered medication.
  • Eastern cooperative oncology group (ECOG) performance status of 0 to 2.
  • Diagnosis of one of the following:
  • Part 1: Histologically- or cytological-confirmed diagnosis of non-resectable or metastatic solid malignancy that has progressed on prior therapy (radiographic documentation of progression is adequate for study participation).
  • Part 2: Histologically- or cytologically-confirmed diagnosis of metastatic or non-resectable disease that has progressed on prior therapy (ACC tablet cohort does not require prior therapy for enrollment i.e. must be systemic therapy naive; for all tumors, (radiographic documentation of progression is adequate for study participation):
  • TNBC (estrogen receptor negative [ER-]/ progesterone receptor [PR-]/Human Epidermal Growth Factor Receptor 2 negative [Her2-], as defined by local laboratory standards);
  • ER+BC (estrogen receptor positive [ER+] or progesterone receptor positive [PR+], Her2-, as defined by local laboratory standards);
  • metastatic or non-resectable transitional cell carcinoma of the bladder, ureter, or renal pelvis;
  • recurrent GBM;
  • ACC requiring systemic therapy. In order to be eligible for enrolment, ACC participants must: have shown progression by local evaluation of scans, as per RECIST 1.1, within the 13 months prior to enrolment and have measurable disease, as confirmed by independent central review of baseline scans prior to first dose.
  • HPV-positive solid tumor of any primary histology.
  • NHL that is not one of the following subtypes, as determined by local laboratory testing: Burkitt's lymphoma or other high-grade lymphoma and double- or triple-hit large B-cell lymphoma.
  • NSCLC, of any histologic sub-type; with local mutational analysis demonstrating wild-type status of TP53 (i.e., p53 wild-type NSCLC).
  • Part 3: Histologically- or cytologically-confirmed diagnosis of metastatic or nonresectable NSCLC (of any histologic sub-type), metastatic transitional cell carcinoma of the urinary system (mTCC), squamous cell carcinoma of the head and neck (HNSCC), or melanoma that failed to respond to prior treatment with Programmed Cell Death-Protein 1 (PD-1) or Programmed Death-Ligand 1 (PD-L1) targeted therapy.
  • Prior therapy: ACC tablet cohort: participants must be systemic therapy-naïve. Prior surgery and/or radiation is permitted. NHL cohort: participants may have received up to 4 prior lines of systemic therapy for disease. Tumors with actionable mutations (e.g., BRAF V600E gene mutation in melanoma; Epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements in NSCLC) must have received prior therapy with targeted agents prior to enrollment. Apart from ACC tablet cohort, participants must have received at least one line of prior systemic therapy (or have a disease for which no approved therapy exists), and have no standard-of-care therapy that would be expected achieve a durable clinical response, or refuse standard therapy, or are not candidates for standard therapy.
  • Evaluable disease: During Part 1, evaluable disease is required; measurable disease per RECIST v1.1 is recommended but not required and Participants enrolled in Part 2 and Part 3 must demonstrate measurable disease per the disease-specific criteria.
  • PK/PD/biomarker/metabolite expansion cohort(s) only: Participants must consent to pre- and post-dose tumor biopsies and additional sample collection procedures.
  • Food effect and relative bioavailability sub-study only: Participants must consent to additional procedures.
  • Part 3 only: Participants must consent to additional procedures (including paired biopsies).
  • All prior treatment-related toxicities must be National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 =<Grade 1 (except alopecia [permissible at any Grade] and peripheral neuropathy [which must be =<Grade 2]) at the time of treatment allocation.
  • Adequate organ function as per Hematologic, Hepatic and Renal Laboratory Values.
  • Reproductive criteria:
  • A male participant with female partner of child bearing potential must agree to use one of the methods of contraception for the duration specified in protocol.
  • A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum human chorionic gonadotrophin [hCG] test), not nursing, and at least one of the following conditions apply: Reproductive potential: participants must agree to follow one of the options and the duration specified in protocol;
  • Non-reproductive potential defined as
  • i) Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion, Hysterectomy, Documented Bilateral Oophorectomy;
  • ii) Postmenopausal defined as 12 months of spontaneous amenorrhea with an appropriate clinical profile or females over 60 years of age. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment.

Exclusion Criteria

  • Malignancy attributed to prior solid organ transplant.
  • Leptomeningeal disease, spinal cord compression, or brain metastases that require immediate central nervous system (CNS)-specific treatment in the opinion of the Investigator (e.g., for symptomatic disease).
  • Recent prior therapy, defined as
  • 1. Any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, whichever is longer, prior to the first dose of GSK3326595. Any nitrosoureas or mitomycin C within 42 days prior to the first dose of GSK3326595. Prior therapy with biologic agents (including monoclonal antibodies) is permitted so long as 28 days have elapsed since therapy and all therapy-related AEs have resolved to =<Grade 1, note that participants with immunotherapy-related endocrinopathies, currently managed with replacement therapy, will be allowed on study.
  • 2. Any radiotherapy within 14 days or major surgery within 28 days prior to the first dose of GSK3326595. For participants in the GBM cohort, participants must have completed radiation therapy at least 28 days prior to the first dose of GSK3326595.
  • 3. Anti-androgen therapies for prostate cancer, such as bicalutamide, must be stopped 4 weeks prior to enrollment. Second-line hormone therapies such as enzalutamide or abiraterone should be stopped 2 weeks prior to enrolment. Participants with prostate cancer should remain on luteinizing hormone releasing hormone (LHRH) agonists or antagonists. Participants with prostate cancer may also remain on low-dose prednisone or prednisolone (up to 10 mg/day) and still be eligible for this study.
  • Part 3 only: History of any of the following: Recent history (within the past 2 years) of autoimmune disease or syndrome that required systemic treatment; a diagnosis of immunodeficiency or administration of systemic steroids (>=10 mg oral prednisone or equivalent) or other immunosuppressive agents within 7 days prior to randomization; Receipt of any live vaccine within 30 days prior randomization; Prior allogeneic/autologous bone marrow or solid organ transplantation; Current pneumonitis or history of non-infectious pneumonitis that required steroids or other immunosuppressive agents; Recent history of allergen desensitization therapy within 4 weeks of randomization; History of severe hypersensitivity to monoclonal antibodies.
  • History of a second malignancy, excluding non-melanoma skin cell cancer within the last three years. Participants with second malignancies that were indolent, in situ or definitively treated may be enrolled even if less than three years have elapsed since treatment. Consult the GSK Medical Monitor if second malignancies meet the requirements specified above.
  • Current use of a prohibited medication or planned use of any forbidden medications during treatment with GSK3326595.
  • Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes). Any serious and/or unstable pre-existing medical (aside from malignancy), psychiatric disorder, or other conditions that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator.
  • Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
  • History of known human immunodeficiency virus (HIV) infection or positive HIV test result at screening.
  • Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. Participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C Ribonucleic acid (RNA) polymerase chain reaction (PCR) is obtained.
  • Any of the following cardiac abnormalities: 1. Recent history (within 6 months of first dose of study drug) of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting. 2. Presence of a cardiac pacemaker, 3. Baseline QTcF >=450 millisecond, 4. Uncontrolled arrhythmias. Participants with rate-controlled atrial fibrillation for >1 month prior to first dose of study drugs may be eligible. 5. Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.


University of Miami Miller School of Medicine-Sylvester Cancer Center
Status: ACTIVE

New York

New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE

Trial Phase Phase I

Trial Type Treatment

Lead Organization

  • Primary ID 204653
  • Secondary IDs NCI-2017-02201, 2016-000278-39
  • ID NCT02783300