Study of a Combination of GSK1795091 and Immunotherapies in Subjects With Advanced Solid Tumors

GlaxoSmithKline (GSK)

Status and phase: Completed; Phase 1

Conditions: Neoplasms

Treatments: Drug: GSK3359609; Drug: GSK1795091; Drug: Pembrolizumab; Drug: GSK3174998

Study type: Interventional

Funder types: Industry

Identifiers

NCT03447314

204686

2017-003545-23 (EudraCT Number)

Details and patient eligibility

About

GSK1795091 is being developed for administration in combination with other immune system modulators for the treatment of cancers. The study will be conducted in two parts. In Part 1, dose escalation will be performed to identify combination dose levels comprising GSK1795091 with either 24 milligrams (mg) GSK3174998 (Part 1a), 80 mg GSK3359609 (Part 1b), or 200 mg pembrolizumab (Part 1c). One dose level of GSK3174998, GSK3359609, or pembrolizumab with up to 5 dose levels of GSK1795091 are planned for evaluation. In Part 2 (dose-expansion), subjects will receive a single dose level of GSK1795091 as identified based on data from Part 1, in combination with either GSK3174998, GSK3359609, or pembrolizumab.

Enrollment: 54 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Subject must be >=18 years of at the time of signing the informed consent.
• Histological documentation of advanced solid tumor.
• Archival tumor tissue obtained at any time 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. Subjects enrolled in a PK/Pharmacodynamic Cohort must provide a fresh biopsy of a tumor lesion not previously irradiated during the screening period and must agree to provide at least one additional on-treatment biopsy.
• Disease that has progressed after standard therapies or for which standard therapy is otherwise unsuitable (example, intolerance).
• Measurable disease, that is, presenting with at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST version 1.1).
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
• Life expectancy of at least 12 weeks.
• Adequate organ function.
• 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.
• Male or female subjects will be included. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the following conditions applies: a) Not a woman of childbearing potential (WOCBP) OR b). A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions specified.

Additional Inclusion criteria for Subjects in Part 2a (GSK3174998 expansion) and Part 2b (GSK3359609 expansion):

• Histological or cytological documentation of squamous cell carcinoma of the head and neck (SCCHN) (oral cavity, oropharynx, hypopharynx, or larynx) that is recurrent, locally advanced, or metastatic and is not amenable to curative treatment options, surgery or definitive chemoradiation therapy.
• Received, ineligible for, or otherwise unsuitable for platinum-based therapy and anti-Programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) therapy
• Received no more than 3 prior lines of systemic therapy for metastatic disease.

Additional Inclusion Criteria for Subjects in Part 2c (pembrolizumab expansion):

• Histological or cytological documentation of SCCHN (oral cavity, oropharynx, hypopharynx, or larynx) that is recurrent, locally advanced, or metastatic and is not amenable to curative treatment options, surgery or definitive chemoradiation therapy.
• Received no more than 2 prior lines of systemic therapy for metastatic disease.

Exclusion criteria

• Malignancy other than disease under study with the exception of those from which the subject has been disease-free for more than 2 years and not expected to affect the safety of the subject or the endpoints of the trial.
• Symptomatic central nervous system (CNS) metastases or asymptomatic CNS metastases that have required steroids within 2 weeks prior to first dose of study treatment.
• Active autoimmune disease that has required systemic disease modifying or immunosuppressive treatment within the last 2 years. Replacement therapy (example, thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted.
• Concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study treatment.
• Known human immunodeficiency virus infection.
• Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
• Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study treatment.
• Positive Hepatitis C test result at screening or within 3 months prior to first dose of study treatment.
• QT interval corrected for heart rate according to Fridericia's formula (QTcF) >450 milliseconds (msec) or QTcF >480 msec for subjects with bundle branch block
• Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
• Recent history of allergen desensitization therapy within 4 weeks of starting study treatment.
• History of severe hypersensitivity to monoclonal antibodies (mAbs).
• History or evidence of cardiovascular (CV) risk including any of the following: a) 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. b) Cardiomyopathy, myocardial infarction, acute coronary syndromes (including unstable angina pectoris), coronary angioplasty, stenting, or bypass grafting within the past 6 months before enrollment. c) Congestive heart failure (Class II, III, or IV) as defined by the New York Heart Association (NYHA) functional classification system. d) Recent (within the past 6 months) history of symptomatic pericarditis.
• History of idiopathic pulmonary fibrosis, pneumonitis, interstitial lung disease, or organizing pneumonia, or evidence of active, non-infectious pneumonitis.
• Recent history (within 6 months) of uncontrolled symptomatic ascites or pleural effusions.
• 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.
• Is or has an immediate family member (example, 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.
• Prior treatment with the following agents: a) OX40, inducible T-cell co-stimulator (ICOS) agonist at any time. b) Prior systemic or intratumoral therapy with TLR agonist. c) Anticancer therapy or investigational therapy within 30 days or 5 half-lives of the drug, whichever is shorter. d) Prior radiation therapy: permissible if at least 1 non-irradiated measurable lesion is available for assessment according to RECIST version 1.1 or if a solitary measurable lesion was irradiated, objective progression is documented. A wash out of at least 14 days before start of study treatment for radiation of any intended use to the extremities for bone metastases and 28 days for radiation to the chest, brain, or visceral organs is required.
• Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation.
• Toxicity from previous treatment including: a) Toxicity Grade >=3 related to prior immunotherapy and that lead to study treatment discontinuation. b) Toxicity related to prior treatment has not resolved to Grade <=1 (except alopecia, or endocrinopathy managed with replacement therapy).
• 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, and recombinant erythropoietin) within 2 weeks before the first dose of study treatment.
• 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.
• Known drug or alcohol abuse.
• Receipt of any live vaccine within 4 weeks.

Additional Exclusion Criteria for Subjects in Part 2c

• Received prior anti-PD-1/PD-L1 therapy.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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54 participants in 18 patient groups

Part 1a: 50ng GSK1795091 + 24mg GSK3174998

Experimental group

Description:

Participants will be administered GSK1795091 50 nanogram (ng) intravenously (IV) on Days 1 and 8 followed by once weekly administration of GSK1795091 50 ng IV in combination with GSK3174998 24 milligram (mg) administered at 3-week intervals (Q3W) via the IV route until Week 12. From Week 12 onwards, GSK1795091 50 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval.

Treatment:

Drug: GSK1795091

Drug: GSK3174998

Part 1a: 100ng GSK1795091 + 24mg GSK3174998

Experimental group

Description:

Participants will be administered GSK1795091 100 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 100 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 100 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval.

Treatment:

Drug: GSK1795091

Drug: GSK3174998

Part 1a: 150ng GSK1795091 + 24mg GSK3174998

Experimental group

Description:

Participants will be administered GSK1795091 150 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 150 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 150 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval.

Treatment:

Drug: GSK1795091

Drug: GSK3174998

Part 1a: 200ng GSK1795091 + 24mg GSK3174998

Experimental group

Description:

Participants will be administered GSK1795091 200 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 200 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 200 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval.

Treatment:

Drug: GSK1795091

Drug: GSK3174998

Part 1a: 250ng GSK1795091 + 24mg GSK3174998

Experimental group

Description:

Participants will be administered GSK1795091 250 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 250 ng IV in combination with GSK3174998 24 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 250 ng IV will be administered in combination with GSK3174998 24 mg at Q3W interval.

Treatment:

Drug: GSK1795091

Drug: GSK3174998

Part 1b: 50ng GSK1795091 + 80mg GSK3359609

Experimental group

Description:

Participants will be administered GSK1795091 50 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 50 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 50 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval.

Treatment:

Drug: GSK1795091

Drug: GSK3359609

Part 1b: 100ng GSK1795091 + 80mg GSK3359609

Experimental group

Description:

Participants will be administered GSK1795091 100 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 100 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 100 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval.

Treatment:

Drug: Pembrolizumab

Drug: GSK1795091

Drug: GSK3359609

Part 1b: 150ng GSK1795091 + 80mg GSK3359609

Experimental group

Description:

Participants will be administered GSK1795091 150 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 150 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 150 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval.

Treatment:

Drug: GSK1795091

Drug: GSK3359609

Part 1b: 200ng GSK1795091 + 80mg GSK3359609

Experimental group

Description:

Participants will be administered GSK1795091 200 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 200 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 200 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval.

Treatment:

Drug: GSK1795091

Drug: GSK3359609

Part 1b: 250ng GSK1795091 + 80mg GSK3359609

Experimental group

Description:

Participants will be administered GSK1795091 250 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 250 ng IV in combination with GSK3359609 80 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 250 ng IV will be administered in combination with GSK3359609 80 mg at Q3W interval.

Treatment:

Drug: GSK1795091

Drug: GSK3359609

Part 1c: 50ng GSK1795091 + 200mg Pembrolizumab

Experimental group

Description:

Participants will be administered GSK1795091 50 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 50 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 50 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval.

Treatment:

Drug: Pembrolizumab

Drug: GSK1795091

Part 1c: 100ng GSK1795091 + 200mg Pembrolizumab

Experimental group

Description:

Participants will be administered GSK1795091 100 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 100 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 100 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval.

Treatment:

Drug: Pembrolizumab

Drug: GSK1795091

Part 1c: 150ng GSK1795091 + 200mg Pembrolizumab

Experimental group

Description:

Participants will be administered GSK1795091 150 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 150 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 150 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval.

Treatment:

Drug: Pembrolizumab

Drug: GSK1795091

Part 1c: 200ng GSK1795091 + 200mg Pembrolizumab

Experimental group

Description:

Participants will be administered GSK1795091 200 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 200 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 200 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval.

Treatment:

Drug: Pembrolizumab

Drug: GSK1795091

Part 1c: 250ng GSK1795091 + 200mg Pembrolizumab

Experimental group

Description:

Participants will be administered GSK1795091 250 ng IV on Days 1 and 8 followed by once weekly administration of GSK1795091 250 ng IV in combination with pembrolizumab 200 mg administered at Q3W via the IV route until Week 12. From Week 12 onwards, GSK1795091 250 ng IV will be administered in combination with pembrolizumab 200 mg at Q3W interval.

Treatment:

Drug: Pembrolizumab

Drug: GSK1795091

Part 2a: GSK1795091 + 24 mg GSK3174998

Experimental group

Description:

Participants will be administered GSK1795091 at a dose identified in Part 1 along with GSK3174998 24 mg.

Treatment:

Drug: GSK1795091

Drug: GSK3174998

Part 2b: GSK1795091 + 80 mg GSK3359609

Experimental group

Description:

Participants will be administered GSK1795091 at a dose identified in Part 1 along with GSK3359609 80 mg.

Treatment:

Drug: GSK1795091

Drug: GSK3359609

Part 2c: GSK1795091 + 200 mg Pembrolizumab

Experimental group

Description:

Participants will be administered GSK1795091 at a dose identified in Part 1 along with pembrolizumab 200 mg.

Treatment:

Drug: Pembrolizumab

Drug: GSK1795091