A Phase I, Open-Label Study of GSK3174998 Administered Alone and in Combination with Anticancer Agents including Pembrolizumab in Subjects with Selected Advanced Solid Tumors
There are 2 parts to this study. The goal of Part 1 of this clinical research study is to find the highest tolerable dose of GSK3174998 that can be given to patients with advanced solid tumors. The goal of Part 2 is learn about the effectiveness of combining the dose of GSK3174998 found in Part 1 with pembrolizumab. The safety of these drugs will be studied in both parts. This is the first study using GSK3174998 in humans.
Disease Group: Breast,Gastrointestinal,Genitourinary,Lung,Melanoma
Treatment Agent: GSK3174998,Pembrolizumab
Treatment Location: Both at MDACC & and Other Sites
Sponsor: GlaxoSmithKline (GSK)
Part 1: Primary Objective To evaluate the safety and tolerability and identify the MTD (Maximum tolerated dose) or the MAD (Maximum administered dose) of GSK3174998 administered intravenously to subjects with selected advanced or recurrent solid tumors. Secondary Objectives To evaluate the antitumor activity of GSK3174998 in subjects with selected advanced or recurrent solid tumors. To characterize the PK of GSK3174998 monotherapy. To evaluate the pharmacodynamic activity of GSK3174998 monotherapy. To determine the immunogenicity of GSK3174998. Exploratory Objectives To explore the relationship between antitumor activity, PK parameters, and pharmacodynamic activity and other patient characteristics. To explore the association between treatment with GSK3174998 and changes in genomic DNA, gene expression (RNA and protein), measures of immune function in tissue and blood and antitumor activity. To explore the immune response biomarkers in tumor tissue and their association with the antitumor activity GSK3174998. Pharmacogenetics (PGx): To evaluate the association of genetic variations in the host DNA and response to therapy. Part 2: Combination GSK3174998 plus pembrolizumab Primary Objective To evaluate the safety and tolerability and identify the MTDa or MAD of GSK3174998 administered intravenously in combination with IV pembrolizumab to subjects with selected advanced or recurrent solid tumors. Secondary Objectives To evaluate the antitumor activity of GSK3174998 in combination with pembrolizumab in subjects with selected advanced or recurrent solid tumors. To characterize the PK of GSK3174498 and pembrolizumab when administered in combination. To determine the immunogenicity of GSK3174998 and pembrolizumab when administered in combination. Exploratory Objectives To explore the relationship between antitumor activity, PK parameters, and pharmacodynamic response after treatment with GSK3174998 in combination with pembrolizumab. To explore the immune response biomarkers in tumor tissue and their association with the antitumor activity with GSK3174998 in combination with pembrolizumab. PGx: To evaluate the association of genetic variations in the host DNA and response to therapy Exploratory objectives include evaluation of pharmacodynamic activity in the blood and tumor microenvironment.
IRB Review and Approval Date: 08/26/2016
Recruitment Status: Open
Projected Accrual: 264
1) Provide signed, written informed consent.
2) Male and female subjects, age >/=18 years (at the time consent is obtained).
3) Histological documentation of locally advanced, recurrent or metastatic solid malignancy 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 not have received more than 5 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.
4) Subjects with the following solid tumors are eligible for screening: Non-small cell lung cancer (NSCLC), Squamous cell carcinoma of the head and neck (SCCHN), Renal cell carcinoma (RCC), melanoma, bladder, Triple-negative breast cancer (TNBC), and colorectal carcinoma displaying microsatellite instability (MSI CRC).
5) A biopsy of the tumor tissue obtained at anytime from the initial diagnosis to study entry. Although a fresh biopsy obtained during screening is preferred, archival tumor specimen is acceptable if it is not feasible to obtain a fresh biopsy. For Part 1B and Part 2B, any archival tumor specimen must have been obtained within 3 months of starting study drug. Note: Subjects enrolled in Part 1A or Part 2A Pharmacodynamic Cohorts must provide a fresh biopsy of a tumour lesion not previously irradiated during the screening period and must agree to provide at least one additional on-treatment biopsy.
6) 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.
7) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
8) Life expectancy of at least 12 weeks.
9) Adequate organ function: ANC: >/= 1.5x109/L ;Lymphocyte count >1,000/mm3; Hemoglobin: >/= 9 g/dL; Platelets: >/=100x109/L; Hepatic: Total bilirubin- For subjects with Gilbert’s Syndrome (only if direct bilirubin </= 35%): </=1.5xULN </=, 3.0xULN ALT: </= 1.5xULN Renal: Serum Creatinine OR Calculated CrCla: </= 1.5xULN > 50 mL/min; Endocrine: TSHb: WNL
10) QT duration corrected for heart rate by Fridericia’s formula (QTcF) <450 msec or QTcF <480 msec for subjects with bundle branch block. The QTcF is the QT interval corrected for heart rate according to Fridericia’s formula, machine-read or manually over-read.
11) In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
12) Female subject: is eligible to participate if she is not pregnant (as confirmed by a negative serum beta-human chorionic gonadotrophin (hCG) test), not lactating, and at least one of the following conditions applies: a. Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation, Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion , Hysterectomy, Documented Bilateral Oophorectomy, Postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) and estradiol levels consistent with menopause.
13) Continued from Inclusion Criteria #12: Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. b. Reproductive potential and agrees to follow one of the options listed in the GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP). requirements from 30 days prior to the first dose of study medication and until 120 days after the last dose of study medication and completion of the follow-up visit.
14) Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until 120 days after the last dose of study medication. a. Vasectomy with documentation of azoospermia. b. Male condom plus partner use of one of the contraceptive options below: Contraceptive subdermal implant with a <1% rate of failure per year, as stated in the product label. Intrauterine device or intrauterine system with a <1% rate of failure per year, as stated in the product label. Oral Contraceptive, either combined or progestogen alone. Injectable progestogen Contraceptive vaginal ring Percutaneous contraceptive patches.
1) Prior treatment with the following agents (from last dose of prior
treatment to first dose of GSK3174998): TNFR agonists, including OX40,
CD27, CD137 (4-1BB), CD357 (GITR): at any time. NOTE: Subjects treated
in Part 1/monotherapy with GSK3174998 may be enrolled into Part
2/combination with pembrolizumab upon disease progression and upon
discussion and approval from the GSK Medical Monitor. Checkpoint
inhibitors, including PD-1, PD-L1, and CTLA-4 inhibitors: within 4
weeks. Other anticancer therapy, including chemotherapy, targeted
therapy, and biological therapy: within 4 weeks or 5 half lives of the
drug, whichever is shorter. Prior radiation therapy is permissible if at
least one unirradiated measurable lesion is available for assessment via
RECIST version 1.1. A wash out of at least two weeks before start of
study drug for palliative radiation to the extremities for osseous bone
metastases and 4 weeks for radiation to the chest, brain, or visceral
organs is required.
2) Continued from Exclusion Criteria #1: Investigational therapy: if the subject has participated in a clinical trial and has received an investigational product: within 30 days or 5 half-lives of the investigational product (whichever is shorter). At least 14 days must have passed between the last dose of prior investigational agent and the first dose of study drug. Note: if the agent is a TNFR agonist or a checkpoint inhibitor, the above exclusions take precedence.
3) Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
4) Toxicity from previous treatment: Subjects with >/= Grade 3 toxicity related to prior immunotherapy leading to study treatment discontinuation are not eligible. 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.
5) Malignancy other than disease under study, except as noted below: 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 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.
6) Central nervous system (CNS) metastases, with the following exception: Subjects who have previously-treated CNS metastases, are asymptomatic, and have had no requirement for steroids for 2 weeks prior to first dose of study drug. Note: Subjects with carcinomatous meningitis are excluded regardless of clinical stability.
7) Has received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including granulocyte colony stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GMCSF], recombinant erythropoietin) within 2 weeks before the first dose of study drug.
8) 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.
9) 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.
10) 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.
11) Active infection , known human immunodeficiency virus infection, or positive test for hepatitis B surface antigen or hepatitis C.
12) Current active liver or biliary disease (with the exception of Gilbert’s syndrome or asymptomatic gallstones, liver metastases, or otherwise stable chronic liver disease per investigator assessment). NOTE: Stable chronic liver disease should generally be defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
13) Known, current drug or alcohol abuse.
14) Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction
15) Receipt of any live vaccine within 4 weeks.
16) Recent history of allergen desensitization therapy within 4 weeks of starting study treatment.
17) History of severe hypersensitivity to other mAbs.
18) 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 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 enrollment. 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.
19) Current or history of idiopathic pulmonary fibrosis, interstitial lung disease, or organizing pneumonia. Note: post-radiation changes in the lung related to prior radiotherapy and/or asymptomatic radiation-induced pneumonitis not requiring treatment may be permitted if agreed by the investigator and Medical Monitor.
20) History of (non-infectious) pneumonitis that required steroids or current pneumonitis.
21) Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural effusions.
22) Any serious and/or unstable pre-existing medical, psychiatric disorder, or other condition that could interfere with the subject’s safety, obtaining informed consent, or compliance to the study procedures.
23) 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 IRB approval (by chair or designee) is given allowing exception to this criterion for a specific subject.
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