solid tumors, non-hodgkin's lymphoma solid tumors and non-Hodgkins lymphoma
Conditions
Interventions
See E6
Sponsors
GlaxoSmithKline
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
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
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1 (dose escalation) Objectives: * To determine the safety, tolerability, and maximally tolerated dose (MTD) of orally-administered GSK3326595 in subjects with solid tumors Part 2 (Dose Expansion) Objectives: * To determine clinical activity of GSK3326595 in disease-specific expansion cohorts Part 3 (Combination with Pembrolizumab) * To determine the safety and tolerability of orally-administered GSK3326595, administered in combination with pembrolizumab, in subjects with solid tumors | — |
Secondary
| Measure | Time frame |
|---|---|
| Part 1 (dose escalation) Objectives: * To determine the recommended Phase 2 dose (RP2D) of orally-administered GSK3326595 * To describe the pharmacokinetics of GSK3326595 after single- and repeat-dose administration * To determine clinical activity of GSK3326595 * To evaluate the preliminary effects of fed versus fasted administration on the pharmacokinetics of GSK3326595 * To evaluate the relative bioavailability of GSK3326595 tablets as compared to capsules Exploratory: * To evaluate the relationship between GSK3326595 exposure and safety/efficacy/PD parameters. * To determine the amount of GSK3326595 excreted in urine * To characterize the pharmacodynamic profile of GSK3326595 in blood * To characterize the metabolic profile of GSK3326595 after single and repeat-dosing (in the PK/PD/metabolite expansion cohort(s) only) * To identify mechanisms of action of GSK3326595 and potential indicators of sensitivity or response to GSK3326595 * To explore the effects of GSK3326595 on tumor metabolism * To explore the effect of host genetic variation on the response to drugs and disease under study as well as related drug classes and diseases Part 2 (Dose Expansion) Objectives: * To further describe the clinical activity of GSK3326595 * To evaluate the safety and tolerability of GSK3326595 in subjects treated at the RP2D * To evaluate the relationship between p53 mutational status and clinical response to GSK3326595 in subjects with NHL * To evaluate the relationship between GSK3326595 exposure and safety/efficacy/PD parameters Exploratory: * To evaluate the relationship between p53 mutational status and clinical response to GSK3326595 in subjects with select solid tumors * To describe the survival and duration of response from (non-ACC tablet cohorts) * To evaluate disease and treatment related symptoms and impact health-related quality of life * To identify mechanism(s) of action of GSK3326595 and potential indicators of sensitivity | — |
Countries
Netherlands
Outcome results
None listed