First Time in Humans (FTIH) Study of GSK3368715 in Participants With Solid Tumors and Diffuse Large B-cell Lymphoma (DLBCL)

NCT03666988 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 2076752018-001629-20
• Study Type: interventional
• Target: 31
• Locations: 4 countries
• Sites: 9

Brief Summary

Arginine methylation mediated by protein arginine methyl-transferases (PRMTs) is an important post-translational modification of proteins involved in a diverse range of cellular processes. Misregulation and overexpression of PRMT1 (a type I PRMT) has been associated with a number of solid and hematopoietic cancers. GSK3368715 leads to inhibition of tumor cell growth across tumor types with cytotoxic response observed in lymphoma, acute myeloid leukemia (AML) and a subset of solid tumor cell lines. This study will assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), food effect and preliminary clinical activity of GSK33368715 in participants with relapsed/refractory DLBCL and selected solid tumors with frequent methyl-thioadenosine phosphorylase (MTAP)-deficiency. The study will consist of two parts. In Part 1 (Dose Escalation) escalating doses of GSK3368715 will be evaluated and recommended phase 2 dose (RP2D) will be established in participants with selected solid relapsed/refractory tumors. Once a RP2D is identified, a food effect sub-study will be initiated to determine the effect of a high-fat, high calorie meal on the bioavailability of GSK3368715. In Part 2 (Dose Expansion), this RP2D will be further investigated in two expansion cohorts; participants with DLBCL (Expansion Cohort 2A) and relapsed/refractory solid tumors including pancreatic, bladder, and non-small cell lung cancer (NSCLC)(Expansion Cohort 2B). The study includes a screening period, an intervention period and follow up.

Conditions

Neoplasms

Keywords

Dose-escalation; First time in humans; Solid tumors; GSK3368715; Diffuse Large B-Cell Lymphoma

Outcome Measures

Primary Outcomes (4)

• Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)

  A DLT is considered by the investigator to be clinically relevant,attributed event during the first 21days of intervention meeting the following criteria:Non-hematologic toxicity:Aspartate Aminotransferase(AST)/Alanine Aminotransferase(ALT) Grade 3/4,ALT\>=5 times Upper limit of Normal(ULN),ALT\>=3times ULN(\>=4 weeks),ALT\>=3 times ULN plus(+)bilirubin\>=2 times ULN,ALT \>= 3 times ULN+liver symptoms or International Normalization Ratio(INR)\>1.5.Nausea:Grade 3;Vomiting or diarrhea:Grade3/4(\>3days);Fatigue:Grade 3(\>5days).Hypertension:Uncontrolled Grade 3/4.Electrocardiogram(ECG)-change:\>20 milliseconds(msec) QRS extension.Lab abnormality:uncontrolled Grade3(\>3days)/Grade4.Hematologic toxicity:Neutropenia:uncontrolled Grade3(\>3days)/febrile neutropenia/Grade 4.Thrombocytopenia:uncontrolled Grade 3(\>3days)/Grade 3(clinically significant Hemorrhage)/Grade 4.Venous thromboembolism (VTE):Grade2 needing systemic anticoagulation/Grade\>=3 during the first 8 weeks or if sooner,study discontinuation

  Up to 21 days

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

  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. Any untoward event resulting in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.

  Up to 28 months

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

  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 are presented.

  Up to 28 months

• Part 2: Percentage of Participants Achieving Objective Response Rate (ORR)

  ORR is defined as the percentage of participants with a confirmed complete response (CR) or a partial response (PR). Participants with solid tumor were planned to be assessed per Response Criteria for Solid Tumors (RECIST) 1.1 and DLBCL participants were planned to be assessed per Lugano Criteria. This analysis was planned but not performed for Part 2 as the study was terminated during Part 1.

  Up to 48 months

Secondary Outcomes (25)

• Part 1: Percentage of Participants Achieving Best Overall Response Rate

  Up to 28 months

• Part 1: Maximum Observed Plasma Concentration (Cmax) Following Administration of GSK3368715

  Pre-dose, 15, 30 minutes, 1, 1.5, 2 ,3 ,4 ,6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose,30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15

• Part 1: Time to Reach Cmax (Tmax) Following Administration of GSK3368715

  Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose,30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15

• Part 1: Area Under the Concentration Time Curve From Time Zero to Last Time of Quantifiable Concentration (AUC [0-t]) Following Administration of GSK3368715

  Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1; Pre-dose,30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Day 15

• Part 1: AUC From Time Zero Extrapolated to Infinite Time (AUC [0-infinity]) Following Administration of GSK3368715

  Pre-dose, 15, 30 minutes, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72 hours post-dose on Day 1

Study Arms (5)

Part 1: GSK3368715 dose escalation

EXPERIMENTAL

Eligible participants with solid relapsed/refractory tumors will receive escalating doses of GSK3368715 at a starting dose of 50 mg, administered orally once daily.

Drug: GSK3368715

Part 1: GSK3368715 PK/PD/Metabolite/Biomarker

EXPERIMENTAL

Additional participants in Part 1, treated at or close to the expected the maximum tolerated dose (MTD)/RP2D, will be evaluated for metabolic and biomarker profiling. Participants may be enrolled into this cohort(s) even after MTD/RP2D has been identified and Part 2 has been initiated.

Drug: GSK3368715

Part 1: GSK3368715 Food effect

EXPERIMENTAL

Eligible participants will receive single dose of GSK3368715 at starting dose of 50 mg tablet orally in fasted state followed by fed state in Period 1 and Fed followed by fasted state in Period 2.

Drug: GSK3368715

Part 2:GSK3368715 dose expansion - DLBCL participants

EXPERIMENTAL

Eligible participants with relapsed/refractory DLBCL will receive RP2D of GSK3368715 established during Part 1, administered orally once daily.

Drug: GSK3368715

Part 2:GSK3368715 dose expansion-solid tumor participants

EXPERIMENTAL

Eligible participants with relapsed/refractory solid tumors (pancreas cancer, NSCLC, and bladder cancer) will receive RP2D of GSK3368715 established during Part 1, administered orally once daily.

Drug: GSK3368715

Interventions

GSK3368715 DRUG

GSK3368715 will be available with dosing strengths of 25 mg, 100 mg and 250 mg to be administered once daily as an oral capsule.

Part 1: GSK3368715 PK/PD/Metabolite/Biomarker; Part 1: GSK3368715 dose escalation; Part 2:GSK3368715 dose expansion - DLBCL participants; Part 2:GSK3368715 dose expansion-solid tumor participants

Eligibility Criteria

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

You may qualify if:

• Participant must be \>=18 to years of age inclusive, at the time of signing the informed consent.
• Diagnosis of one of the following; Part 1 (Dose Escalation and food effect): Histologically- or cytological-confirmed diagnosis of solid tumor malignancy that is metastatic or non-resectable; have received all standard treatment options or are no longer eligible for additional standard treatment options. Evaluable disease that may be measured directly by the size of the tumor or can be evaluated by other methods. Availability of a biopsy of the tumor tissue obtained at any time from the initial diagnosis to study entry. Although a fresh biopsy, which is obtained during screening, is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a fresh biopsy. For participants in the PK/PD cohort, a fresh biopsy and consent for one on treatment biopsy are required for enrollment. Part 2 (Dose Expansion): Cohort 2A \& 2B: The availability of archival tumor tissue, or willingness to undergo a fresh biopsy to determine MTAP status (any archival tumor specimen must have been obtained within 6 months prior to starting study drug unless approved by the study Medical Monitor). Local MTAP or Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) results are acceptable for enrollment, but must be confirmed through central laboratory testing. Cohort 2A: Histologically- or cytological-confirmed diagnosis of DLBCL; relapse or refractory disease after at least 1 but not more than 4 lines of prior therapy; at least 1 measurable site of disease according to the Lugano Classification. The site of disease must be greater than 1.5 centimeter (cm) in the long axis regardless of short axis measurement or greater than 1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions. Cohort 2B: Pancreatic Cancer: Histologically or cytologically confirmed adenocarcinoma of the pancreas; unresectable, locally advanced (Stage III), or metastatic (Stage IV) disease; relapsed or refractory disease after at least 1 prior line of approved, systemic therapy; at least 1 measurable tumor lesion per RECIST 1.1. NSCLC: histologically or cytologically confirmed NSCLC; stage IV disease; tested for presence of echinoderm microtubule-associated protein-like 4- anaplastic lymphoma kinase (EML4-ALK) rearrangement; received at least 2 prior lines of approved, systemic therapy, of which 1 therapy has to be a platinum containing regimen or failed a first-line platinum-containing regimen in combination with an anti- progressive disease (PD1) monocloncal antibody and refused a second-line regimen despite being informed about the different therapeutic options and their specific clinical benefit by the investigator; the content of this informed consent discussion including the therapeutic options reviewed by the investigator need to be documented and the participant needs to sign a specific consent form; at least 1 measurable tumor lesion per RECIST 1.1. Transitional cell carcinoma of the Urothelium: histologically or cytologically confirmed transitional cell carcinoma (TCC) of the urothelium (urinary bladder, urethra, ureter or renal pelvis) including mixed pathology with predominantly (that is \[i.e.\], \> 50 percent of the histopathology sample) TCC with the exception of neuroendocrine or small cell carcinoma; unresectable, locally advanced (T4b) or metastatic (lymph node or visceral) disease; relapsed or refractory disease after at least 1 prior line of approved systemic therapy; at least 1 measurable tumor lesion per RECIST 1.1.
• Adequate organ function as defined by: Absolute neutrophil count (ANC) with a laboratory value of \>=1.5 times 10\^9 per liter (L); Hemoglobin with a laboratory value of \>=9 grams per deciliter (g/dL) for solid malignancy and \>=8 g/dL for Non-Hodgkin's lymphoma; Platelets with a laboratory value of \>=100 times 10\^9/ L; prothrombin time/ International Normalization Ratio (PT/INR) and partial thromboplastin time (PTT) with a laboratory value of \<=1.5 times upper limit of normal (ULN), unless participant is receiving systemic anticoagulation (Hematologic); Albumin with a laboratory value of \>=2 g/dL, total bilirubin with a laboratory value of \<=1.5 times ULN, alanine aminotransferase (ALT) with a laboratory value of \<=2.5 times ULN (Part 1 and 2) or \<5 times ULN (Part 2 only) is acceptable for participants with documented liver metastases/tumor infiltration (Hepatic); calculated creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation or measured from 24 h urine with a laboratory value of \>= 50 milliliters per min (mL/min) (Renal); Ejection fraction with a laboratory value of \>=Lower limit of normal (LLN) by echocardiogram (minimum of 50 percent)/ multigated (radionuclide) angiogram (MUGA), Electrocardiogram (ECG): corrected QT (QTc) interval using Fridericia's formula (QTcF) with a laboratory value of \<450 milliseconds (msec) (Cardiac).
• Eastern cooperative oncology group (ECOG) performance status of 0 or 1.
• Able to swallow and retain orally-administered medication.
• Capable of giving signed informed consent.

You may not qualify if:

• History of malignancy other than the disease under study. Participants who have been disease-free for 5 years, or participants with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Participants with second malignancies that are indolent or definitively treated may be enrolled even if less than 5 years have elapsed since treatment.
• Primary central nervous system (CNS) tumors, Glioblastoma multiforme (GBM), symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. Participants previously treated for these conditions that have had stable CNS disease (verified with consecutive imaging studies) for \>1 months, are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to study Day 1 are permitted. Stability of brain metastases must be confirmed with imaging. Participants treated with gamma knife therapy can be enrolled 2 weeks post-procedure as long as there are no post-procedure complications/they are stable.
• Any severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes, or active infection).
• Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the Investigator.
• Any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach and/or bowels.
• History of known human immunodeficiency virus (HIV) infection or positive HIV test result at screening.
• Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening to first dose of study intervention.
• Any of the following cardiac abnormalities: Uncontrolled high blood pressure; any history of coronary artery disease, including acute coronary syndromes, myocardial infarction, unstable angina, and history of coronary angioplasty, or stenting; presence of a cardiac pacemaker or implanted defibrillator; atrioventricular (AV)-block (asymptomatic 2nd degree Type II or 3rd degree and any degree AV block if related to heart disease or if symptomatic), right bundle branch block (RBBB), left bundle branch block (LBBB), and any fasicular hemiblocks; A QRS interval at Screening or Baseline \>110 msec; participants with any symptomatic or sustained arrhythmias (past or present), including but not limited to: Atrial fibrillation, Atrial flutter, Ventricular tachycardia, Ventricular fibrillation, Supraventricular tachycardia; Current or past congestive heart failure; Evidence of a left ventricular ejection fraction below the institutional lower limit of normal on Screening echocardiogram; Evidence of significant structural heart disease on echocardiography at Screening (including any valvular disease greater than "mild" in severity); Cardiac troponin \> upper limit of the reference range at Screening.
• Treatment with any local or systemic anti-neoplastic therapy or investigational anticancer agent within 14 days or 4 half-lives, whichever is longer, up to a maximum wash-out period of 28 days prior to initiation of study drug administration. Anti-androgen therapies for prostate cancer, such as bicalutamide, must be stopped 28 days prior to first dose of GSK3368715. Second-line hormone therapies such as enzalutamide or abiraterone should be stopped 14 days prior to enrolment. Participants with prostate cancer may remain on luteinizing hormone-releasing hormone (LHRH) agonists or antagonists and/or low-dose prednisone or prednisolone (up to 10 milligrams per day \[mg/day\]). Nitrosureas and mitomycin C must be stopped within 42 days prior to first dose of GSK3368715.
• Allogeneic hematopoietic stem-cell transplantation.
• Toxicities from previous anti-cancer therapies have not resolved to Baseline or National Cancer Institute (NCI) CTCAE V5.0. \<=Grade 1 (except fatigue and alopecia \[permissible at any grade\] and peripheral neuropathy \[which must be \<= Grade 2\]) at the time of starting study intervention.
• Major surgery (i.e. requiring general anesthesia) within 3 weeks before screening, or not fully recovered from major surgery, or major surgery planned during study participation. Planned surgical procedures to be conducted under local anesthesia are allowed.
• Prior organ transplantation.
• Concurrent anti-coagulation therapy. Treatment with low-molecular heparin is allowed.
• Current use of a prohibited medication or planned use of any forbidden medications during intervention with GSK3368715.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (9)

GSK Investigational Site

Los Angeles, California, 90033, United States

Location

GSK Investigational Site

Newport Beach, California, 92663, United States

Location

GSK Investigational Site

Philadelphia, Pennsylvania, 19104-4206, United States

Location

GSK Investigational Site

Houston, Texas, 77030, United States

Location

GSK Investigational Site

Salt Lake City, Utah, 84112, United States

Location

GSK Investigational Site

Melbourne, Victoria, 3000, Australia

Location

GSK Investigational Site

Toronto, Ontario, M5G 1X5, Canada

Location

GSK Investigational Site

Barcelona, 08035, Spain

Location

GSK Investigational Site

Madrid, 28050, Spain

Location

Related Publications (1)

• El-Khoueiry AB, Clarke J, Neff T, Crossman T, Ratia N, Rathi C, Noto P, Tarkar A, Garrido-Laguna I, Calvo E, Rodon J, Tran B, O'Dwyer PJ, Cuker A, Abdul Razak AR. Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors. Br J Cancer. 2023 Aug;129(2):309-317. doi: 10.1038/s41416-023-02276-0. Epub 2023 May 26.

  PMID: 37237172 DERIVED

MeSH Terms

Conditions

Neoplasms; Lymphoma, Large B-Cell, Diffuse

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune 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 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: This will be an open-label study. Hence, masking will not be performed.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Eligible participants will receive sequential doses of GSK3368715, administered orally once daily in Part 1 of the study and in Part 2, participants will receive RP2D determined in Part 1.

Study Record Dates

• First Submitted: September 10, 2018
• First Posted: September 12, 2018
• Study Start: October 22, 2018
• Primary Completion: March 4, 2021
• Study Completion: March 4, 2021
• Last Updated: May 20, 2022
• Results First Posted: May 20, 2022

Record last verified: 2022-02

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

AU (1); CA (1); ES (2); US (5)