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,
participants 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 negative [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);
- 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 subjects
must: be treatment-naïve or may have received no more than two prior lines of systemic
therapy for locally advanced/metastatic disease (systemic therapy administered in the
context of localized disease, e.g., adjuvant therapy, does not count towards the
two-line maximum). A minimum of 25% of subjects must be enrolled as treatment-naïve;
AND have shown progression within the 13 months prior to enrolment, via
cross-sectional imaging (e.g., Computed tomography (CT) or Magnetic resonance imaging
[MRI]); AND have measurable disease, as confirmed by independent central review of
baseline scans;
- HPV-positive solid tumor of any primary histology.
- non-Hodgkin's lymphoma.
- NSCLC, of any histologic sub-type; with local mutational analysis demonstrating
wild-type status of TP53 (i.e., p53 wild-type NSCLC).
- At the time of enrollment, participants 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.
3. 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 PD-1 or PD-L1
targeted therapy.
- Evaluable disease: 1. During Part 1, evaluable disease is required; measurable disease
per RECIST v1.1 is recommended but not required, 2. 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, Renal and Cardiac Laboratory
Values
- Reproductive criteria: 1. 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. 2. 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 milligram (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 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. 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.
