MC# 18-02 - 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
Disease Type(s): Solid Tumor, Adenoid Cystic Carcinoma, Lymphoma, Glioblastoma, Breast, Bladder
Drug Classification(s): Targeted Therapy, Small Molecule
Molecular Target(s): PRMT5
Mechanism of Action
GSK3326595 is an inhibitor of protein arginine methyltransferase 5 (PRMT5) that potently inhibits tumor growth in vitro and in vivo in animal models.
In this study, the sponsor and investigators want to learn:
- How much GSK3326595 can be given with an acceptable level of side effects
- The effects of GSK3326595
- How much GSK3326595 is absorbed into the blood and how fast it is removed
- If research tests can be used in the future to predict who will benefit from GSK3326595
- 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 (defined study protocol) of 0 to 2
- Diagnosis of one of the following:
- Histologically- or cytologically-confirmed diagnosis of metastatic or non- resectable:
- TNBC (ER-/PR-/Her2-, as defined by local laboratory standards)
- ER+/Her2- or PR+/Her2- breast cancer, as defined by local laboratory standards
- 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
- Transitional cell carcinoma of the bladder, ureter, or renal pelvis
- Recurrent GBM
- ACC requiring systemic therapy in the opinion of the treating physician (e.g., for symptomatic disease)
- 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
- 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
- Subjects enrolled must demonstrate measurable disease per the disease- specific criteria described in study protocol.
- All prior treatment-related toxicities must be 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.
- Subjects with treatment-related toxicities that are unlikely to resolve in the opinion of the treating physician may be enrolled on a case-by-case basis after discussion with the medical monitor
- Adequate organ function, as per Hematologic, Hepatic, Renal and Cardiac Laboratory Values
- Reproductive criteria:
- 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 the protocol.
- 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 applies:
- Reproductive potential: subject must agree to follow one of the options and the duration specified in study protocol.
- Non-reproductive potential defined as:
- Pre-menopausal females with one of the following:
- Documented tubal ligation
- Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion
- Documented Bilateral Oophorectomy
- 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.
- Pre-menopausal females with one of the following:
- Malignancy attributed to prior solid organ transplant.
- Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. NOTE: Subjects previously treated for these conditions that have had stable central nervous system (CNS) disease (verified with consecutive imaging studies) for >1months, 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. Subjects with GBM may enroll irrespective of steroid dose.
- Recent prior therapy, defined as follows:
- 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, with the exception of those listed in study protocol.
- 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.
- 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 enrollment. 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 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. The GSK Medical Monitor will be consulted 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.NOTE: 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:
- 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.
- Presence of a cardiac pacemaker
- Baseline Corrected QT (Fridericia’s formula) interval (QTcF) ≥450 msec
- Uncontrolled arrhythmias. Subjects with rate-controlled atrial fibrillation for > 1 month prior to first dose of study drugs may be eligible.
- 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.
- Dallas, TX - Mary Crowley Cancer Research - Medical City