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.

A subject will be eligible for inclusion in this study only if all of the
following criteria apply:
1. Males and females *18 years of age (at the time consent is obtained)
NOTE: For NHL cohort ONLY, subjects must be *75 years of age at the time
consent is obtained
2. Capable of giving signed informed consent
3. Able to swallow and retain orally-administered medication
4. Eastern cooperative oncology group (ECOG) performance status (defined in
Appendix 3) of 0 to 2
5. Diagnosis of one of the following:
a. 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)
b. Part 2: Histologically- or cytologically-confirmed diagnosis of metastatic
or non-resectable disease that has progressed on or after prior therapy (ACC
tablet cohort does not require prior therapy for enrollment; for all tumors,
radiographic documentation of progression is adequate for study participation):
* TNBC [estrogen receptor negative (ER-), progesterone receptor negative (PR-)
and 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+), 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 order to be eligible for enrolment, ACC
subjects must:
o have shown progression by local evaluation of scans, as per RECIST 1.1,
within the 13 months prior to enrolment, AND
o have measurable disease, as confirmed by independent central review of
baseline scans prior to first dose.
* 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;
* non-Hodgkin*s lymphoma that is NOT one of the following subtypes, as
determined by local laboratory testing:
o Burkitt*s lymphoma or other high-grade lymphoma
o Double- or triple-hit large B-cell lymphoma
NOTE: Any questions regarding eligibility of subtypes should be directed to the
medical monitor
* OR NSCLC, of any histologic sub-type; with local mutational analysis
demonstrating wild-type status of TP53 (i.e., p53 wild-type NSCLC)
NOTE: Subjects in the cohort must have previously received treatment with an
anti-PD1 and/or PD-L1 therapy or be considered ineligible to receive therapy
with these agents
NOTE: Subjects whose tumors harbor actionable mutations (e.g., EGFR mutations
or ALK rearrangements) must have received prior therapy with targeted agents
prior to enrollment.
c. Part 3: Histologically- or cytologically-confirmed diagnosis of metastatic
or non-resectable NSCLC (of any histologic sub-type), mTCC, HNSCC, or melanoma
that failed to respond to prior treatment with PD-1 or PD-L1 targeted therapy
and recurrent/metastatic cervical squamous cell carcinoma that have progressed
on or after PD-1 or PD-L1 directed therapy or are PD-1/PD-L1 treatment naïve.
NOTE: NSCLC, mTCC, HNSCC or Melanoma Subjects must have had SD (with subsequent
documented progression as per iRECIST) or PD as best response to prior PD-1 or
PD L1 targeted therapy to be eligible for enrollment.
6. Prior therapy
* ACC tablet cohort: subjects must be systemic therapy-naïve. Prior surgery
and/or radiation is permitted
* NHL cohort: subjects may have received up to 4 prior lines of systemic
therapy for disease
* Tumors with actionable mutations (e.g., BRAF V600E in melanoma; EGFR
mutations or ALK rearrangements in NSCLC) must have received prior therapy with
targeted agents prior to enrollment
* Apart from ACC tablet cohort, subjects 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 to achieve
a durable clinical response, OR refuse standard therapy, OR are not candidates
for standard therapy.
7. Evaluable disease
a. During Part 1, evaluable disease is required; measurable disease per RECIST
v1.1 is recommended but not required
b. Subjects enrolled in Part 2 and Part 3 must demonstrate measurable disease
per the disease-specific criteria described in Appendix 4.
8. PK/PD/biomarker/metabolite expansion cohort(s) only (Section 4.2.5):
Subjects must consent to pre- and post-dose tumor biopsies and additional
sample collection procedures as specified in the Time and Events Table (Section
8.1).
9. Food effect and relative bioavailability sub-study only (Section 4.2.6):
Subjects must consent to additional procedures as specified in the Time and
Events Table (Table 13).
10. Part 3 only: Subjects must consent to additional procedures (including
paired biopsies) as specified in the Time and Events Table (Table 15)
11. 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.
NOTE: 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
12. Adequate organ function, as defined in Table 7.
13. Reproductive criteria:
a. A male subject with female partner of child bearing potential must agree to
use one of the methods of contraception specified in Section 7.3.2 for the
duration specified in that section.
b. 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 Section 7.3.1.
* 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
Hysterectomy
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.

A subject will not be eligible for inclusion in this study if any of the
following criteria apply:
1. Malignancy attributed to prior solid organ transplant
2. Leptomeningeal disease, spinal cord compression, or brain metastases that
require immediate CNS-specific treatment in the opinion of the Investigator
(e.g., for symptomatic disease).
NOTE: Subjects who require local therapy for CNS metastases may be considered
for eligibility once local therapy is completed and acute treatment-related
toxicities have resolved
NOTE: Subjects with untreated lesions should be followed with intracranial
imaging (e.g., MRI) at each disease assessment, as detailed in Section 8.1.
NOTE: This criterion does not apply to subjects with GBM. 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.
3. 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 Section 4.2.4.2. Note that
subjects with immunotherapy-related endocrinopathies, currently managed with
replacement therapy, will be allowed on study.
* 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.
4. 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
Note: Replacement therapies which include hormone replacement (e.g., thyroid
hormone) or physiological doses of corticosteroids for treatment of
endocrinopathies (e.g., adrenal insufficiency) are not considered systemic
treatments.
* 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
Note: Physiologic doses of corticosteroids for treatment of endocrinopathies or
steroids with minimal systemic absorption, including topical, inhaled, or
intranasal corticosteroids may be continued if the participant is on a stable
dose. Steroids as premedication for hypersensitivity reactions (e.g., computed
tomography [CT] scan premedication) are permitted.
* 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
Note: post-radiation changes in the lung related to prior radiotherapy and/or
asymptomatic radiation-induced pneumonitis not requiring treatment (Grade 1)
may be permitted if agreed upon by the investigator and Medical Monitor.
* Recent history of allergen desensitization therapy within 4 weeks of
randomization
* History of severe hypersensitivity to monoclonal antibodies
5. 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
there are questions whether second malignancies meet the requirements specified
above.
6. Current use of a prohibited medication or planned use of any forbidden
medications during treatment with GSK3326595 (see Section 7.1.2 for the list of
medications).
7. 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.
8. Any clinically significant gastrointestinal (GI) abnormalities that may
alter absorption such as malabsorption syndrome or major resection of the
stomach and/or bowels.
9. History of known human immunodeficiency virus (HIV) infection or positive
HIV test result at screening. NOTE: HIV * Patients may be eligible if they
fullfill all of the requirements below: Have started on antiviral therapy for
at least 4 weeks prior to start of study drug treatment, Not be taking HIV
related therapy (antivirals, antibiotics) that is on the prohibited list per
protocol, Have a CD4 count *350 cells/uL, Have a HIV viral load <400 copies/ml.
10. Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C
antibody test result at screening.
NOTE: Subjects with chronic hepatitis B virus (HBV) infection, who meet the
criteria for anti HBV therapy may be eligible if subject is on a supportive
antiviral therapy prior to initiation of cancer therapy.
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. Also Hep B - Patients may be eligible if they
have both: completed curative therapy, have a HCV viral load limit.
11. Any of the following cardiac abnormalities:
* 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
* 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.
12. 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.
13. History of optic nerve neuropathy or neuritis.