Clinical trial NCT03681951: First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors
Official title: A Phase I/II, Open-Label Study to Investigate the Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics of GSK3145095 Administered Alone and in Combination With Anticancer Agents Including Pembrolizumab in Adult Participants With Selected Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Neoplasms, Pancreatic
Keywords: Anticancer Agents
FTIH
Pembrolizumab
Rip1K
GSK3145095
Dose Escalation
Immunotherapy resistance
Dose Expansion
RECIST 1.1
Advanced solid tumors
Innate immunity
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2018-09-24
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Part 1 dose escalation will administer escalating doses of GSK3145095 as monotherapy only. Part 2 will combine escalating doses of GSK3145095 with 200 mg pembrolizumab. Dose escalation of GSK3145095 will begin at least one level below the highest dose shown to have an acceptable toxicity profile in at least 3 subjects in Part 1. Part 3 will enroll subjects treated with one or more dose levels of GSK3145095 in combination with 200 mg pembrolizumab. Part 4 will investigate the combination of additional anticancer agents with one or more doses of GSK3145095 identified as safe in Part 1.
Primary purpose: TREATMENT

Brief summary: In an unbiased CRISPR screen, RIPK1 was identified as a top gene contributing to immunotherapy resistance. In addition, RIPK1 has been reported to drive pancreatic oncogenesis. In murine models, inhibition of RIPK1 kinase activity in the pancreatic tumor microenvironment leads to the replacement of tumor-permissive myeloid infiltrates with innate cells that promote an effective antitumor response by adaptive cells. The investigators hypothesize that inhibition of RIPK1 in human pancreatic cancer subjects will modulate the immune infiltrate to sensitize tumors to checkpoint blockade.

Detailed description: Study 205013 is a Phase 1 FTIH study of GSK3145095 alone and in combination with other anticancer agents including pembrolizumab in subjects with pancreatic ductal adenocarcinoma (PDAC) and other selected tumors. The study includes up to 4 parts: Part 1 dose escalation will be conducted in approximately 30 adult subjects with advanced or metastatic PDAC using escalating doses of GSK3145095 as monotherapy only. Part 2 will combine escalating doses of GSK3145095 with 200 milligram (mg) pembrolizumab. Dose escalation of GSK3145095 will begin at least one level below the highest dose shown to have an acceptable toxicity profile in at least 3 subjects in Part 1. Part 2 may be conducted in a broader population of selected solid tumors using a combination of escalating doses of GSK3145095 and 200 mg pembrolizumab. Part 3 will enroll subjects treated with one or more dose levels of GSK3145095 in combination with 200 mg pembrolizumab. Part 4 will investigate the combination of additional anticancer agents with one or more doses of GSK3145095 identified as safe in Part 1. Up to approximately 220 subjects will be treated in the study. Parts 1 and 2 will each treat up to approximately 30 subjects. Parts 3 and 4 will treat up to approximately 160 subjects (up to 80 subjects in each Part). The total duration of the study is expected to last up to 2 years.

Eligibility criteria: Inclusion Criteria:

* Subjects must provide signed, written informed consent.
* Male and female subjects, age \>=18 years (at the time consent is obtained). a) Male subjects are eligible to participate if they agree to the following during the study treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment: Refrain from donating sperm, be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use contraception/barrier: male condom and female partner to use an additional highly effective contraceptive method with a failure rate of \<1 percent per year. b) female subjects are eligible to participate if they are not either pregnant or breastfeeding, and at least one of the following conditions applies: is not a woman of childbearing potential (WOCBP), is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1 percent per year), with low user dependency during the study treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. Therefore, a barrier method is also required for subjects using a hormonal option (including hormonal intrauterine device \[IUD\], oral contraceptive pills/ patch/ vaginal inserts, and hormonal implants) and both highly effective methods of contraception should be utilized during the treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment.If a highly effective non-hormonal method is used, then only one method of contraception is required (by a female participant or partner of a male participant; in either situation the male partner must still use a male condom in addition) during the treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) as required by local regulations) within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the subject must be excluded from participation if the serum pregnancy result is positive. If the subject hasn't been on an acceptable method of contraception for at least 2 weeks prior to start of therapy, pregnancy testing must be done weekly for the first month of treatment. Additional requirements for pregnancy testing during and after study treatment. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
* Histological documentation of locally advanced, recurrent or PDAC (Part 1), non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), or melanoma (Part 2) that has progressed after standard therapy appropriate for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate. Subjects should have received at least one, but not more than 2 prior lines of therapy for advanced disease including both standards of care and investigational therapies. Subjects whose cancers harbor molecular alterations for which targeted therapy is standard of care should have received health authority-approved appropriate targeted therapy for their tumor types before enrollment.
* All subjects in Parts 1 and 2 must consent to provide a fresh biopsy during screening of a primary tumor lesion or from other metastases (e.g. liver, lung, etc.), and a second biopsy after approximately 5 weeks of treatment.
* Measurable disease per RECIST version 1.1. Palpable lesions that are not measurable by radiologic or photographic evaluations may not be utilized as the only measurable lesion. Subjects are encouraged to provide a pre-Baseline scan (within 24 weeks before the Baseline scan) to support exploratory investigation of tumor growth kinetics.
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1.
* Life expectancy of at least 12 weeks.
* Adequate organ function.
* QT duration corrected for heart rate by Fridericia's formula (QTcF) \<450 milliseconds (or QTcF \<480 milliseconds for subjects with bundle branch block).

Exclusion Criteria:

* Prior treatment with the following agents: Agents affecting tumor associated macrophage function or number, including but not limited to inhibitors of Receptor-interacting protein 1 (RIP1), Receptor-interacting protein 3 (RIP3), Colony stimulating factor 1 receptor (CSFR-1), C-C chemokine receptor type 2 (CCR2), and Cluster of differentiation 40 (CD40). Other anticancer therapy, including chemotherapy, targeted therapy, and biological therapy, within 14 days or 5 half-lives (from last dose of prior treatment to first dose of GSK3145095), whichever is shorter. Prior radiation therapy is permissible if at least one non-irradiated measurable lesion is available for assessment via RECIST version 1.1. No washout after palliative radiation is required. Investigational therapy within 14 days or 5 half-lives (from last dose of prior treatment to first dose of GSK3145095), whichever is shorter.
* Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
* Toxicity from previous treatment: Subjects whose toxicity related to prior treatment has not resolved to \<=Grade 1 (except alopecia, hearing loss, Grade \<=2 neuropathy or endocrinopathy managed with replacement therapy) are not eligible.
* Malignancy other than disease under study, except as noted: Subject with any other malignancy from which the subject has been disease-free for more than 2 years and, in the opinion of the principal investigators and GlaxoSmithKline (GSK) Medical Monitor, will not affect the evaluation of the effects of this clinical trial treatment on currently targeted malignancy, can be included in this clinical trial.
* Major surgery \<=4 weeks before the first dose of study treatment. Subjects must have also fully recovered from any surgery (major or minor) and/or its complications before initiating study treatment.
* Active autoimmune disease that has required systemic treatment within the last 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Concurrent medical condition requiring the use of systemic immunosuppressive medications within 28 days before the first dose of study treatment. 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 subject is on a stable dose.
* Active infection (including active herpes zoster infection), known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen or hepatitis C.
* Current active liver or biliary disease (except for Gilbert's syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per investigator assessment).
* Known current drug or alcohol abuse.
* Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
* Receipt of any live vaccine within 4 weeks before starting study treatment.
* Recent history of allergen desensitization therapy within 4 weeks before starting study treatment (applies to subjects enrolled in Parts 2 and 3 only).
* History or evidence of cardiovascular risk including any of the following: recent (within the past 6 months) history of serious uncontrolled cardiac arrhythmia or clinically significant electrocardiogram (ECG) abnormalities including second degree (Type II) or third degree atrioventricular block. Documented cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within the past 6 months before beginning screening. Documented congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association functional classification system. Recent (within the past 6 months) history of symptomatic pericarditis.
* Current or history of idiopathic pulmonary fibrosis, interstitial lung disease, or organizing pneumonia.
* History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
* Recent history (within 14 days) of ascites or pleural effusions requiring drainage.
* Any serious and/or unstable pre-existing medical, psychiatric disorder, or other condition that could interfere with the subjects safety, obtaining informed consent, or compliance to the study procedures.
* Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved with this trial, unless prospective Institutional Review Board (IRB) approval (by chair or designee) is given allowing exception to this criterion for a specific subject.

Primary outcomes:
measure: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1
timeFrame: Up to Day 95
measure: Number of Participants With Non-serious AEs and SAEs-Part 2
timeFrame: Up to 2 years and 90 days
measure: Number of Participants With AEs by Severity Grades-Part 1
timeFrame: Up to Day 95
measure: Number of Participants With AEs by Severity Grades-Part 2
timeFrame: Up to 2 years and 90 days
measure: Number of Participants With Dose-limiting Toxicities (DLTs)-Part 1
timeFrame: Up to Day 28
measure: Number of Participants With DLTs-Part 2
timeFrame: Up to 28 days
measure: Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) Based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria-Part 3
timeFrame: Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 2 years 90 days)
measure: Percentage of Participants Achieving Complete Response or Partial Response Based on RECIST 1.1 Criteria-Part 4
timeFrame: Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 2 years and 90 days)
Secondary outcomes:
measure: Best Overall Response (BOR) Rate-Part 1
timeFrame: Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 95 days)
measure: Best Overall Response (BOR) Rate-Part 2
timeFrame: Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 2 years and 90 days)
measure: Progression-free Survival (PFS)-Part 3
timeFrame: Until disease progression or death whichever is earlier (maximum follow-up up to 2 years and 90 days)
measure: Progression-Free Survival (PFS) -Part 4
timeFrame: Until disease progression or death whichever is earlier (maximum follow-up up to 2 years and 90 days)
measure: Overall Survival -Part 3
timeFrame: Until death (maximum follow-up up to 2 years and 90 days)
measure: Overall Survival -Part 4
timeFrame: Until death (maximum follow-up up to 2 years and 90 days)
measure: Number of Participants With Non-serious AEs and SAEs-Part 3
timeFrame: Up to 2 years and 90 days
measure: Number of Participants With Non-serious AEs and SAEs-Part 4
timeFrame: Up to 2 years and 90 days
measure: Number of Participants With AEs by Severity Grades-Part 3
timeFrame: Up to 2 years and 90 days
measure: Number of Participants With AEs by Severity Grades-Part 4
timeFrame: Up to 2 years and 90 days
measure: Area Under the Plasma Drug Concentration Versus Time Curve (AUC[0-t]) Following Single Dose of GSK3145095 on Day 1-Part 1
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: AUC (0-t) Following Single Dose of GSK3145095 on Day 1-Part 2
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Area Under the Concentration-time Curve Over the Dosing Interval (AUC [0-tau]) Following Single Dose of GSK3145095 on Day 1-Part 1
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: AUC (0-tau) Following Single Dose of GSK3145095 on Day 1-Part 2
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Maximum Observed Plasma Drug Concentration (Cmax) Following Single Dose of GSK3145095 on Day 1-Part 1
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Cmax Following Single Dose of GSK3145095 on Day 1-Part 2
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Minimum Observed Plasma Drug Concentration (Cmin) Following Single Dose of GSK3145095 on Day 1-Part 1
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Cmin Following Single Dose of GSK3145095 on Day 1-Part 2
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Time to Maximum Observed Plasma Drug Concentration (Tmax) Following Single Dose of GSK3145095 on Day 1-Part 1
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Tmax Following Single Dose of GSK3145095 on Day 1-Part 2
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Clearance (CL/F) Following Single Dose of GSK3145095 on Day 1-Part 1
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: CL/F Following Single Dose of GSK3145095 on Day 1-Part 2
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Volume of Distribution (Vz/F) Following Single Dose of GSK3145095 on Day 1-Part 1
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Vz/F Following Single Dose of GSK3145095 on Day 1-Part 2
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Terminal Half-life (t1/2) Following Single Dose of GSK3145095 on Day 1-Part 1
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: T1/2 Following Single Dose of GSK3145095 on Day 1-Part 2
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: AUC (0-t) Following Repeat Dose of GSK3145095 on Day 15-Part 1
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: AUC (0-t) Following Repeat Dose of GSK3145095 on Day 15-Part 2
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: AUC (0-tau) Following Repeat Dose of GSK3145095 on Day 15-Part 1
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: AUC (0-tau) Following Repeat Dose of GSK3145095 on Day 15-Part 2
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Cmax Following Repeat Dose of GSK3145095 on Day 15-Part 1
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Cmax Following Repeat Dose of GSK3145095 on Day 15-Part 2
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Cmin Following Repeat Dose of GSK3145095 on Day 15-Part 1
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Cmin Following Repeat Dose of GSK3145095 on Day 15-Part 2
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Tmax Following Repeat Dose of GSK3145095 on Day 15-Part 1
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Tmax Following Repeat Dose of GSK3145095 on Day 15-Part 2
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: CL/F Following Repeat Dose of GSK3145095 on Day 15-Part 1
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: CL/F Following Repeat Dose of GSK3145095 on Day 15-Part 2
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Vz/F Following Repeat Dose of GSK3145095 on Day 15-Part 1
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Vz/F Following Repeat Dose of GSK3145095 on Day 15-Part 2
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: T1/2 Following Repeat Dose of GSK3145095 on Day 15-Part 1
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: T1/2 Following Repeat Dose of GSK3145095 on Day 15-Part 2
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Dose Proportionality of GSK3145095 for Dose Levels 100 mg (50 mg BID) to 1600 mg (800 mg BID) Using AUC (0-t) Following Single Dose-Part 1
timeFrame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Dose Proportionality of GSK3145095 for Dose Levels 100 mg (50 mg BID) to 1600 mg (800 mg) BID Using Cmax Following Single Dose-Part 1
timeFrame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Dose Proportionality of GSK3145095 for Dose Levels 100 mg (50 mg BID) to 1600 mg (800 mg BID) Using AUC (0-tau) Following Repeat Dose-Part 1
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Dose Proportionality of GSK3145095 for Dose Levels 100 mg (50 mg BID) to 1600 mg (800 mg BID) Using Cmax Following Repeat Dose-Part 1
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Dose Proportionality of GSK3145095 Using AUC (0-t) Following Single Dose-Part 2
timeFrame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Dose Proportionality of GSK3145095 Using Cmax Following Single Dose-Part 2
timeFrame: Day 1: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Dose Proportionality of GSK3145095 Using AUC (0-tau) Following Repeat Dose-Part 2
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8,10, and 24 hours post dose
measure: Dose Proportionality Using Cmax Following Repeat Dose of GSK3145095-Part 2
timeFrame: Day 15: Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post dose
measure: Accumulation Ratio Following Repeat Dose of GSK3145095 on Day 15-Part 1
timeFrame: Day 1: Pre-dose,0.5,1,1.5,2,3,4,6,8, 10, and 24 hour post-dose, Days 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10,24 hour post dose
measure: Accumulation Ratio Following Repeat Dose of GSK3145095 on Day 15-Part 2
timeFrame: Day 1: Pre-dose,0.5,1,1.5,2,3,4,6,8, 10, and 24 hour post-dose, Days 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10,24 hour post dose
measure: Time Invariance of GSK3145095-Part 1
timeFrame: Day 1: Pre-dose,0.5,1,1.5,2,3,4,6,8,10, and 24 hour post-dose, Days 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10,24 hour post dose
measure: Time Invariance of GSK3145095-Part 2
timeFrame: Day 1: Pre-dose,0.5,1,1.5,2,3,4,6,8, 10, and 24 hour post-dose, Days 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10, and 24 hour post dose
measure: Plasma Concentration of Pembrolizumab -Part 2
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: Cmax of Pembrolizumab-Part 2
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: AUC (0-tau) of Pembrolizumab-Part 2
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: Cmin of Pembrolizumab-Part 2
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: AUC (0-t) Following Single Dose of GSK3145095 on Day 1-Part 3
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Cmax Following Single Dose of GSK3145095 on Day 1-Part 3
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Tmax Following Single Dose of GSK3145095 on Day 1-Part 3
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: T1/2 Following Single Dose of GSK3145095 on Day 1-Part 3
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: AUC (0-t) Following Repeat Dose of GSK3145095 on Day 15-Part 3
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose
measure: Cmax Following Repeat Dose of GSK3145095 on Day 15-Part 3
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose
measure: Tmax Following Repeat Dose of GSK3145095 on Day 15-Part 3
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose
measure: T1/2 Following Repeat Dose of GSK3145095 on Day 15-Part 3
timeFrame: Day 15:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hours post-dose
measure: AUC (0-t) Following Single Dose of Pembrolizumab-Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hour after end of infusion
measure: AUC (0-tau) Following Single Dose of Pembrolizumab -Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hour after end of infusion
measure: Cmax Following Single Dose of Pembrolizumab -Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hour after end of infusion
measure: Tmax Following Single Dose of Pembrolizumab -Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hour after end of infusion
measure: T1/2 Following Single Dose of Pembrolizumab -Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hour after end of infusion
measure: AUC (0-t) Following Repeat Dose of Pembrolizumab -Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: AUC (0-tau) Following Repeat Dose of Pembrolizumab -Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: Cmax Following Repeat Dose of Pembrolizumab -Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: Tmax Following Repeat Dose of Pembrolizumab -Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: T1/2 Following Repeat Dose of Pembrolizumab -Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: Dose Proportionality of GSK3145095 Using AUC (0-t) Following Single Dose-Part 3
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Dose Proportionality of GSK3145095 Using Cmax Following Single Dose-Part 3
timeFrame: Day 1:Pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 hours post-dose
measure: Dose Proportionality of GSK3145095 Using AUC (0-tau) Following Repeat Dose of GSK3145095-Part 3
timeFrame: Day 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10,24 hour post morning dose; Day 15: 0.5,1,2,3,6,8 hour post evening dose
measure: Dose Proportionality of GSK3145095 Using Cmax Following Repeat Dose-Part 3
timeFrame: Day 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10,24 hour post morning dose; Day 15: 0.5,1,2,3,6,8 hour post evening dose
measure: Accumulation Ratio Following Repeat Dose of GSK3145095-Part 3
timeFrame: Days 1: Pre-dose,0.5,1,1.5,2,3,4,6,8,10,24 hour post-dose; Day 15: Pre-dose,0.5,1,1.5,2,3,4,6,8,10,24 hour post morning dose; Day 15: 0.5,1,2,3,6,8 hour post evening dose
measure: Time Invariance Following Repeat Dose of GSK3145095-Part 3
timeFrame: Days 1: Pre - dose ,0.5,1,1.5,2,3,4,6,8,10,24 hour; Day 15: Pre - dose ,0.5,1,1.5,2,3,4,6,8,10,24 hour post morning dose ; Day 15:0.5,1,2,3,6,8 hour post evening dose
measure: Dose Proportionality for Pembrolizumab Using AUC (0-t) Following Single Dose-Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hour after end of infusion
measure: Dose Proportionality for Pembrolizumab Using Cmax Following Single Dose-Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hour after end of infusion
measure: Dose Proportionality for Pembrolizumab Using AUC (0-tau) Following Repeat Dose-Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: Dose Proportionality for Pembrolizumab Using Cmax Following Repeat Dose-Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Days 8,15 (anytime during visit); Days 22,43,64 and every 21 days thereafter (pre-dose), for up to 2 years
measure: Accumulation Ratio Following Repeat Dose of Pembrolizumab-Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Day 15 (anytime during visit)
measure: Time Invariance Following Repeat Dose of Pembrolizumab-Part 3
timeFrame: Day 1: pre-dose, 0.5 hour (within 30 minutes after end of infusion), 24 hours after end of infusion; Day 15 (anytime during visit)
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: