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.
