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.

Completed

Conditions: solid tumors, non-hodgkin's lymphoma
solid tumors and non-Hodgkins lymphoma

Registration Number: NL-OMON53127

Lead Sponsor: GlaxoSmithKline

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: Not specified

Target Recruitment: 39

Inclusion Criteria

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: His

Exclusion Criteria

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 d

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Part 1 (dose escalation)<br /><br><br /><br>Objectives:<br /><br>* To determine the safety, tolerability, and maximally tolerated dose (MTD) of<br /><br>orally-administered GSK3326595 in subjects with solid tumors<br /><br><br /><br>Part 2 (Dose Expansion)<br /><br><br /><br>Objectives:<br /><br>* To determine clinical activity of GSK3326595 in disease-specific expansion<br /><br>cohorts<br /><br><br /><br>Part 3 (Combination with Pembrolizumab)<br /><br>* To determine the safety and tolerability of orally-administered GSK3326595,<br /><br>administered in combination with pembrolizumab, in subjects with solid tumors</p><br>

Secondary Outcome Measures