First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors

NCT ID: NCT03681951

Last Updated: 2020-07-31

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-16
• Study Completion Date: 2019-08-13

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.

Conditions

Neoplasms, Pancreatic

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Part 1: Dose Escalation - GSK3145095 monotherapy

In Part 1, advanced or metastatic PDAC will be enrolled. Part 1 will be using escalating doses of GSK3145095 (total daily dose of 100 mg, 200 mg, 400 mg, 800 mg, and 1600 mg) orally as monotherapy for up to 2 years. For each dose level, subjects will receive a single dose of half the total daily dose on Day 1; and as BID (total daily dose divided in two equal doses) starting from Day 2.

Group Type: EXPERIMENTAL

GSK3145095

Intervention Type: DRUG

GSK3145095 will be available as capsule (size 1 containing 5 to 25 mg GSK3145095 and size 0 containing 25 to 75 mg GSK3145095) or tablet (25, 50, 200 mg white to slightly covered round/oval shaped coated) for oral administration in the fasted stated with approximately 200 milliliters (mL) of water.

Part 2: Dose Escalation - GSK3145095 + pembrolizumab

In Part 2, subjects with selected solid tumors, including but not limited to, PDAC, NSCLC, TNBC and/or melanoma will be enrolled. Part 2 will be using GSK3145095 combination escalation to start at least one dose level below the highest dose of GSK3145095 shown to be safe in Part 1, orally BID for up to 2 years along with pembrolizumab 200 mg intravenous (IV) every 3 weeks (Q3W) for up to 2 years.

Group Type: EXPERIMENTAL

GSK3145095

Intervention Type: DRUG

GSK3145095 will be available as capsule (size 1 containing 5 to 25 mg GSK3145095 and size 0 containing 25 to 75 mg GSK3145095) or tablet (25, 50, 200 mg white to slightly covered round/oval shaped coated) for oral administration in the fasted stated with approximately 200 milliliters (mL) of water.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab will be available as solution for infusion (100 milligrams/ 4 milliliter) at a dose of 200 mg via IV infusion for 30 minutes (given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted i.e., infusion time is 25 to 40 minutes).

Part 3: Dose Expansion - GSK3145095 + pembrolizumab

In Part 3, subjects with selected solid tumors will be enrolled. Part 3 will be using GSK3145095 at one or two dose levels shown to be tolerable in Part 2 orally BID for up to 2 years along with pembrolizumab 200 mg IV Q3W for up to 2 years.

Group Type: EXPERIMENTAL

GSK3145095

Intervention Type: DRUG

GSK3145095 will be available as capsule (size 1 containing 5 to 25 mg GSK3145095 and size 0 containing 25 to 75 mg GSK3145095) or tablet (25, 50, 200 mg white to slightly covered round/oval shaped coated) for oral administration in the fasted stated with approximately 200 milliliters (mL) of water.

Pembrolizumab

Intervention Type: DRUG

Pembrolizumab will be available as solution for infusion (100 milligrams/ 4 milliliter) at a dose of 200 mg via IV infusion for 30 minutes (given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted i.e., infusion time is 25 to 40 minutes).

Part 4: Dose Expansion - GSK3145095 + anticancer agent

In Part 4, subjects with selected solid tumors will be enrolled. Part 4 will be using GSK3145095 at one or two dose levels shown to be tolerable in Part 2 orally BID for up to 2 years along with combination of additional anticancer agents.

Group Type: EXPERIMENTAL

GSK3145095

Intervention Type: DRUG

GSK3145095 will be available as capsule (size 1 containing 5 to 25 mg GSK3145095 and size 0 containing 25 to 75 mg GSK3145095) or tablet (25, 50, 200 mg white to slightly covered round/oval shaped coated) for oral administration in the fasted stated with approximately 200 milliliters (mL) of water.

Interventions

GSK3145095

GSK3145095 will be available as capsule (size 1 containing 5 to 25 mg GSK3145095 and size 0 containing 25 to 75 mg GSK3145095) or tablet (25, 50, 200 mg white to slightly covered round/oval shaped coated) for oral administration in the fasted stated with approximately 200 milliliters (mL) of water.

Intervention Type: DRUG

Pembrolizumab

Pembrolizumab will be available as solution for infusion (100 milligrams/ 4 milliliter) at a dose of 200 mg via IV infusion for 30 minutes (given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted i.e., infusion time is 25 to 40 minutes).

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Parexel

INDUSTRY

Sponsor Role: collaborator

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Indianapolis, Indiana, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

Philadelphia, Pennsylvania, United States

GSK Investigational Site

Houston, Texas, United States

Countries

United States

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

205013

Identifier Type: -

Identifier Source: org_study_id