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

NCT03681951 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: 205013
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 6

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.

Conditions

Neoplasms, Pancreatic

Keywords

Anticancer Agents; FTIH; Pembrolizumab; Rip1K; GSK3145095; Dose Escalation; Immunotherapy resistance; Dose Expansion; RECIST 1.1; Advanced solid tumors; Innate immunity

Outcome Measures

Primary Outcomes (8)

• Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose which results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or other situations.

  Up to Day 95

• Number of Participants With Non-serious AEs and SAEs-Part 2

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. SAE is defined as any untoward medical occurrence that, at any dose which results in death, is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect or other situations.

  Up to 2 years and 90 days

• Number of Participants With AEs by Severity Grades-Part 1

  All adverse events were analyzed using National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. Graded from Grade 1: mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL), Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: death related AE. Higher grade indicates more severe condition. Number of participants with maximum severity grades were presented.

  Up to Day 95

• Number of Participants With AEs by Severity Grades-Part 2

  All adverse events were to be analyzed using NCI-CTCAE Version 5.0. Graded from Grade 1: mild asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL, Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4: Life-threatening consequences; urgent intervention indicated, Grade 5: death related AE. Higher grade indicates more severe condition.

  Up to 2 years and 90 days

• Number of Participants With Dose-limiting Toxicities (DLTs)-Part 1

  All toxicities were graded using NCI-CTCAE version 5.0. An AE was considered a DLT if it occurred during the first 28 days of treatment, was considered by the investigator to be clinically relevant, and met one of the following DLT criteria: hematologic toxicity: Grade 4 neutropenia, febrile neutropenia, Grade 4 anemia, Grade 3 thrombocytopenia, Grade 3 thrombocytopenia with bleeding; Grade 3 or greater non-hematologic toxicity, any Grade 2 ocular toxicity requiring systemic steroids.

  Up to Day 28

• Number of Participants With DLTs-Part 2

  All toxicities were graded using NCI-CTCAE version 5.0. An AE was considered a DLT if it occurred during the first 28 days of treatment, was considered by the investigator to be clinically relevant, and met one of the following DLT criteria: hematologic toxicity: Grade 4 neutropenia, febrile neutropenia, Grade 4 anemia, Grade 3 thrombocytopenia, Grade 3 thrombocytopenia with bleeding; Grade 3 or greater non-hematologic toxicity, any Grade 2 ocular toxicity requiring systemic steroids.

  Up to 28 days

• 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

  A participant's disease status and determination of disease progression at post Baseline visits was to be evaluated by the local investigator's assessments by RECIST version 1.1. The overall response rate (ORR)-CR and PR was to be determined by the investigator assessment of the participants computed tomography (CT) or magnetic resonance imaging (MRI) using RECIST version 1.1 criteria for target lesions. ORR is defined as the percentage of participants with a best overall confirmed CR or PR at any time as per disease-specific criteria. PR is when there is at least 30 percent decrease in sum of the longest diameter of the target lesions. Complete Response is when there is disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 millimeters (mm).

  Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 2 years 90 days)

• Percentage of Participants Achieving Complete Response or Partial Response Based on RECIST 1.1 Criteria-Part 4

  A participant's disease status and determination of disease progression at post Baseline visits was to be evaluated by the local investigator's assessments by RECIST version 1.1. The overall response rate (complete response and partial response) was to be determined by the investigator assessment of the participants CT or MRI using RECIST version 1.1 criteria for target lesions. ORR is defined as the percentage of participants with a best overall confirmed CR or PR at any time as per disease-specific criteria. Partial Response is when there is at least 30 percent decrease in sum of the longest diameter of the target lesions. Complete Response is when there is disappearance of all non-nodal target lesions, with the short axes of any target lymph nodes reduced to \<10 mm.

  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 (88)

• Best Overall Response (BOR) Rate-Part 1

  Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 95 days)

• Best Overall Response (BOR) Rate-Part 2

  Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 2 years and 90 days)

• Progression-free Survival (PFS)-Part 3

  Until disease progression or death whichever is earlier (maximum follow-up up to 2 years and 90 days)

• Progression-Free Survival (PFS) -Part 4

  Until disease progression or death whichever is earlier (maximum follow-up up to 2 years and 90 days)

• Overall Survival -Part 3

  Until death (maximum follow-up up to 2 years and 90 days)

Study Arms (4)

Part 1: Dose Escalation - GSK3145095 monotherapy

EXPERIMENTAL

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.

Drug: GSK3145095

Part 2: Dose Escalation - GSK3145095 + pembrolizumab

EXPERIMENTAL

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.

Drug: GSK3145095; Drug: Pembrolizumab

Part 3: Dose Expansion - GSK3145095 + pembrolizumab

EXPERIMENTAL

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.

Drug: GSK3145095; Drug: Pembrolizumab

Part 4: Dose Expansion - GSK3145095 + anticancer agent

EXPERIMENTAL

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.

Drug: GSK3145095

Interventions

GSK3145095 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 1: Dose Escalation - GSK3145095 monotherapy; Part 2: Dose Escalation - GSK3145095 + pembrolizumab; Part 3: Dose Expansion - GSK3145095 + pembrolizumab; Part 4: Dose Expansion - GSK3145095 + anticancer agent

Pembrolizumab 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 2: Dose Escalation - GSK3145095 + pembrolizumab; Part 3: Dose Expansion - GSK3145095 + pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects must provide signed, written informed consent.
• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead
• Parexel: collaborator

Study Sites (6)

GSK Investigational Site

Indianapolis, Indiana, 46202, United States

Location

GSK Investigational Site

New York, New York, 10016, United States

Location

GSK Investigational Site

New York, New York, 10032, United States

Location

GSK Investigational Site

New York, New York, 10065, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19111, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

pembrolizumab

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 10, 2018
• First Posted: September 24, 2018
• Study Start: November 16, 2018
• Primary Completion: August 13, 2019
• Study Completion: August 13, 2019
• Last Updated: July 31, 2020
• Results First Posted: July 31, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints of the study.
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

US (6)