Dose Escalation and Expansion Study of GSK3359609 in Participants With Selected Advanced Solid Tumors (INDUCE-1)

Study Overview
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Brief Summary
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GSK3359609 is an anti-Inducible T cell Co-Stimulator (ICOS) receptor agonist antibody intended for the treatment of cancers of different histology. This is a first-time-in-human (FTIH), open-label, multicenter study designed to investigate the safety, pharmacology, and preliminary antitumor activity in participants with selected, advanced or recurrent solid tumors with the aim to establish recommended dose(s) of GSK3359609 for further exploration as monotherapy and in combination with pembrolizumab or chemotherapy regimens. The study is comprised of two primary parts, each composed of two phases: Part 1: GSK3359609 monotherapy with Part 1A as dose escalation phase and Part 1B as cohort expansion phase; Part 2: GSK3359609 combination therapy with Part 2A pembrolizumab or GSK3174998 or dostarlimab or dostarlimab plus cobolimab or Bintrafusp alfa combination dose escalation phase and Part 2B expansion phase with pembrolizumab. Part 2A GSK3359609 combinations with chemotherapy will only consist of safety run-in cohorts. Each part and phase of the study includes a screening period, a treatment period, and a follow-up period. The primary objective of the study is to determine the safety, tolerability, maximum tolerated dose or the maximum administered dose of GSK3359609 alone or in combination.

Official Title
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A Phase I Open Label Study of GSK3359609 Administered Alone and in Combination With Anticancer Agents in Subjects With Selected Advanced Solid Tumors

Conditions
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Neoplasms

Intervention / Treatment
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* Drug: feladilimab (GSK3359609)
* Drug: GSK3174998
* Drug: Pembrolizumab
* Drug: Docetaxel
* Drug: Pemetrexed
* Drug: Paclitaxel plus Carboplatin
* Drug: Gemcitabine plus Carboplatin
* Drug: Fluorouracil (5-FU) plus carboplatin or cisplatin
* Drug: Dostarlimab
* Drug: Cobolimab
* Drug: Bintrafusp alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Capable of giving signed, written informed consent. Male or female, age >=18 years (at the time consent is obtained). Histological or cytological documentation of an invasive malignancy that was diagnosed as locally advanced/metastatic or relapsed/refractory and is of one of the following tumor types: bladder/urothelial cancer of the upper and lower urinary tract; cervical; colorectal (includes appendix); esophagus, squamous cell; head and neck carcinoma; melanoma; malignant pleural mesothelioma (MPM); non-small-cell lung cancer (NSCLC), prostate; Microsatellite Instability-High/deficient mismatch repair (MSI-H/dMMR) tumor (Part 1B and Part 2B) and Human Papilloma Virus (HPV)-positive or Epstein-Barr (EBV)-positive tumor (Part 1B and Part 2B). Disease that has progressed after standard therapy for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate, or if no further standard therapy exists; exceptions are in these tumor types in which pembrolizumab single agent may be a standard: NSCLC, head and neck squamous cell cancer (HNSCC), bladder/urothelial cancer, MSI-H/dMMR cancers and melanoma and cervical cancer. In Part 2B pembrolizumab combination expansion cohorts, prior treatment with anti-Programmed cell death protein 1(PD-1)/ Ligand-1 (L1) may not be required. 1) Participants must not have received more than 5 prior lines of therapy for advanced disease including both standards of care and investigational therapies. 2) Participants who received prior PD-1/L1 therapy must fulfill the following requirements (Part 1B [except PK/PD cohort]/ Part 2B):a) Have achieved a CR, PR or SD and subsequently had disease progression while still on PD-1/L1 therapy; b) Have received at least 2 doses of an approved PD-1/L1 inhibitor (by any regulatory authority), c) Have demonstrated disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 within 18 weeks from the last dose of the PD-1/L1 inhibitor. The initial evidence of disease progression is to be confirmed by a second assessment no less than four weeks from the date of the first documented Progressive Disease (PD) (the confirmatory scan could be the Baseline eligibility scan for this study). 3) In Part 2A 5-fluorouracil (FU)/platinum combination with GSK3359609 and pembrolizumab cohort, participants must not have received prior systemic therapy administered in the recurrent or metastatic setting (with the exception of systemic therapy given as part of multimodal treatment for locally advanced disease). Archival tumor tissue obtained at any time from the initial diagnosis to study entry; a fresh tumor biopsy using a procedure that is safe for the participant on a lesion not previously irradiated unless lesion progressed will be required if archival tissue is unavailable. Agree to undergo a pre-treatment and on treatment biopsy and have disease amenable to biopsy required in pharmacokinetic (PK) / pharmacodynamics (PD), dose randomized HNSCC, Melanoma dose expansion and Biomarker cohorts.. Measurable disease per RECIST version 1.1. Palpable lesions that are not measurable by radiographic or photographic evaluations may not be utilized as the only measurable lesion. Any measurable lesion biopsied at Screening cannot be followed as a target/index lesion unless agreed upon by GlaxoSmithKline (GSK). Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1. Life expectancy of at least 12 weeks. Adequate organ function. QT interval corrected for heart rate according to Fridericia's formula (QTcF) <450 milliseconds (msec) or QTcF <480 msec for participants with bundle branch block. A female participant is eligible to participate if she is not pregnant (as confirmed by a negative serum beta-human chorionic gonadotrophin [beta-hCG] test in females of reproductive potential), and not lactating or reproductive potential agrees to follow one of the options listed in protocol from 30 days prior to the first dose of study medication and until 120 days after the last dose of study treatment. Male participants with female partners of child bearing potential must agree to use one of the methods of contraception specified in protocol from time of first dose of study treatment until 120 days after the last dose of study treatment. Documented HPV/ EBV-positive tumor as determined by a local laboratory for Part 1B and Part 2B pembrolizumab combination viral-positive expansion cohorts only. Documented MSI-H or dMMR-positive tumor as determined by local laboratory for Part 1B and Part 2B pembrolizumab combination MSI-H/dMMR expansion cohorts only. ICOS expression result using an analytically validated immunohistochemistry (IHC) assay by central laboratory for Part 1B biomarker cohort only. Gene expression (GEX) result using an analytically validated method by central laboratory (Part 1B Biomarker Cohort only). PD-L1 combined positive score (CPS) <1 using the Food and Drug Administration (FDA) approved PD-L1 IHC 22C3 pharmdx assay by central laboratory testing for Part 2B HNSCC PD-L1 CPS <1 Cohort. Documented test result from FDA approved PD-L1 IHC 22C3 pharmDx assay in local laboratory, if available, may be accepted in lieu of the central laboratory test result. Exclusion Criteria Prior treatment with the following therapies: Anticancer therapy within 30 days or 5 half-lives of the drug, whichever is shorter. At least 14 days must have elapsed between the last dose of prior anticancer agent and the first dose of study drug is administered. Part 2B (GSK3359609/pembrolizumab combination): prior pembrolizumab washout is not required. Prior radiation therapy: permissible if at least one 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 two weeks before start of study drug for radiation of any intended use to the extremities for bone metastases and 4 weeks for radiation to the chest, brain, or visceral organs is required. • Investigational therapy within 30 days or 5 half-lives of the investigational product (whichever is shorter). At least 14 days must have elapsed between the last dose of investigational agent and the first dose of study drug is administered. Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation. Toxicity from previous anticancer treatment Invasive malignancy or history of invasive malignancy other than disease under study within the last two years except: Any other invasive malignancy for which the participant was definitively treated, has been disease-free for <=2 years and in the opinion of the principal investigator and GSK Medical Monitor will not affect the evaluation of the effects of the study treatment on the currently targeted malignancy, may be included in this clinical trial; and curatively treated non-melanoma skin cancer. Central nervous system (CNS) metastases, with the following exception: • Participants who have previously-treated CNS metastases, are asymptomatic, and have no requirement for steroids at least 14 days prior to first dose of study drug. Participants with carcinomatous meningitis or leptomeningeal spread are excluded regardless of clinical stability. 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, recombinant erythropoietin) within 14 days prior to the first dose of GSK3359609. Major surgery <=4 weeks before the first dose of study treatment. Participants 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 two 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 7 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 participant is on a stable dose. Condition requiring treatment with strong inhibitors/inducers of cytochrome p (CYP) 450 3A4 within 7 days prior to first dose of chemotherapy (requirement applies to participants enrolled to Part 2 chemotherapy combination with docetaxel). Active infection requiring systemic therapy, known human immunodeficiency virus infection, or positive test for hepatitis B active infection or hepatitis C active infection. 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). Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction that required surgery. Receipt of any live vaccine within 4 weeks prior to first dose of study treatment. Recent history of allergen desensitization therapy within 4 weeks of starting study treatment. History of severe hypersensitivity to monoclonal antibodies or to the chemotherapies under investigation including any ingredient used in the formulation. History or evidence of cardiac abnormalities. History of (current and past) idiopathic pulmonary fibrosis, pneumonitis (for past pneumonitis exclusion only if steroids were required for treatment), 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. 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 participant's safety, obtaining informed consent, or compliance to the study procedures.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1A: Dose escalation feladilimab (GSK3359609)<br>Participants will receive feladilimab (GSK3359609) administered continuously at a dose level dependent on to which dose level the participant is accrued. | Drug: feladilimab (GSK3359609)<br> <br> |
| Experimental: Part 1B: Expansion feladilimab (GSK3359609)<br>Participants will receive feladilimab (GSK3359609) administered continuously at a dose level chosen for further exploration in dose expansion cohorts. | Drug: feladilimab (GSK3359609)<br> <br> |
| Experimental: Part 2A: Dose escalation (feladilimab (GSK3359609)+pembrolizumab)<br>Participants will receive feladilimab (GSK3359609) administered continuously in combination with pembrolizumab. | Drug: feladilimab (GSK3359609)<br> <br> Drug: Pembrolizumab<br> <br> |
| Experimental: Part 2A: Dose escalation (feladilimab (GSK3359609)+GSK3174998)<br>Participants will receive feladilimab (GSK3359609) administered continuously in combination with GSK3174998. | Drug: feladilimab (GSK3359609)<br> <br> Drug: GSK3174998<br> <br> |
| Experimental: Part 2A: Safety run-in (feladilimab (GSK3359609)+chemotherapy)<br>Participants participating in Part 2A chemotherapy combination cohorts will receive feladilimab (GSK3359609) in combination with chemotherapy at doses and schedules based on standard of care practice. | Drug: feladilimab (GSK3359609)<br> <br> Drug: Docetaxel<br> <br> Drug: Pemetrexed<br> <br> Drug: Paclitaxel plus Carboplatin<br> <br> Drug: Gemcitabine plus Carboplatin<br> <br> Drug: Fluorouracil (5-FU) plus carboplatin or cisplatin<br> <br> |
| Experimental: Part 2B: Expansion-feladilimab (GSK3359609)<br>Participants will receive feladilimab (GSK3359609) administered continuously in combination with pembrolizumab. | Drug: feladilimab (GSK3359609)<br> <br> Drug: Pembrolizumab<br> <br> |
| Experimental: Part 2A: Dose escalation (feladilimab (GSK3359609)+ dostarlimab)<br>Participants will receive feladilimab (GSK3359609) administered continuously in combination with dostarlimab. | Drug: feladilimab (GSK3359609)<br> <br> Drug: Dostarlimab<br> <br> |
| Experimental: Part 2A: Dose escalation (feladilimab (GSK3359609)+dostarlimab+cobolimab)<br>Participants will receive feladilimab (GSK3359609) administered continuously in combination with dostarlimab followed by cobolimab. | Drug: feladilimab (GSK3359609)<br> <br> Drug: Dostarlimab<br> <br> Drug: Cobolimab<br> <br> |
| Experimental: Part 2A: Dose escalation (feladilimab (GSK3359609)+bintrafusp alfa)<br>Participants will receive feladilimab (GSK3359609) administered continuously in combination with bintrafusp alfa. | Drug: feladilimab (GSK3359609)<br> <br> Drug: Bintrafusp alfa<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1 and 2: Number of participants with any months adverse event(s) (AE) and serious adverse event(s) (SAE) | AEs and SAEs will be collected. | Up to 27 months | 
| Parts 1 and 2: Number of participants with dose limiting toxicity (DLT) | Number of participants with DLTs will be assessed. | Up to 28 days | 
| Parts 1 and 2: Number of participants with clinically significant changes in laboratory parameters and vital signs | Number of participants with clinically significant changes in laboratory parameters and vital signs will be assessed. | Up to 24 months | 
| Parts 1 and 2: Number of participants requiring dose modifications | All dose modifications due to any reason(s) will be recorded. | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts 1 and 2: Disease control rate (DCR) | DCR is defined as the percentage of participants with a confirmed complete response (CR) + partial response (PR) at any time, plus stable disease (SD) >=18 weeks. | Up to 27 months | 
| Parts 1 and 2: Overall survival (OS) | OS is defined as time from the date of first dose of study treatment to the date of death due to any cause. | Up to 4 years | 
| Parts 1 and 2: Progression-free survival (PFS) | PFS is defined as time from the date of first dose of study treatment to the date of disease progression according to clinical or radiographic assessment or death due to any cause, whichever occurs earliest. | Up to 27 months | 
| Parts 1 and 2: Time to overall response (TTR) | TTR will be summarized for participants with a confirmed CR or PR and is defined as the time from date of first dose of study treatment to date of first documented confirmed CR or PR. | Up to 27 months | 
| Parts 1 and 2: Duration of response (DOR) | DOR will be summarized for participants with a confirmed CR or PR and is defined as the time from date of initial confirmed response to the date of disease progression or death due to any cause. | Up to 27 months | 
| Parts 1 and 2: Overall response rate (ORR) | ORR is defined as the percentage of participants with a best overall confirmed CR or a PR at any time as per disease-specific criteria. | Up to 27 months | 
| Parts 1 and 2: Maximum observed plasma concentration (Cmax) and minimum observed plasma concentration (Cmin) of GSK3359609 | Blood samples will be collected for the concentrations of GSK3359609. | Up to 27 months | 
| Parts 1 and 2: Area under the concentration-time curve over the dosing interval (AUC[0-tau]) of GSK3359609 in plasma | Blood samples will be collected for the concentrations of GSK3359609. | Up to 27 months | 
| Parts 1 and 2: Number of participants with positive results in Anti-drug antibody (ADA) test by GSK3359609 dose level | Blood samples will be collected up to 27 months for ADA test. | Up to 27 months | 
| Part 1 and 2: Number of participants with positive results in GSK3359609 | Blood samples will be collected up to 27 months for immunogenicity. | Up to 27 months | 
| Part 2: Number of participants with DLT following administration of GSK3359609 in combination with chemotherapies | Number of participants with DLTs will be assessed. | Up to 28 days | 
| Part 2: Cmax and Cmin of GSK3174998 | Blood samples will be collected for the concentrations of GSK3174998. | Up to 24 months | 
| Part 2: AUC(0-tau) of GSK3174998 | Blood samples will be collected for the concentrations of GSK3174998. | Up to 24months | 
| Part 2: Cmax and Cmin of Pembrolizumab | Blood samples will be collected for the concentrations of Pembrolizumab. | Up to 27 months | 
| Part 2: AUC(0-tau) of Pembrolizumab | Blood samples will be collected for the concentrations of Pembrolizumab. | Up to 27 months | 
| Part 2: Number of participants with positive results in ADA test by GSK3359609 in combination with pembrolizumab or GSK3174998 dose level | Blood samples will be collected up to 27 months for ADA test. | Up to 27 months | 
| Part 2: Number of participants with positive results in Pembrolizumab | Blood samples will be collected up to 27 months for immunogenicity. | Up to 27 months | 
| Part 2: Number of participants with positive results in GSK3174998 | Blood samples will be collected up to 27 months for immunogenicity. | Up to 27 months | 
| Part 2: Cmax and Cmin of GSK3359609 combination with chemotherapies | Blood samples will be collected for the concentrations of GSK3359606 in combination with chemotherapies. | Up to 27 months | 
| Part 2: Number of participants with positive results in ADA test by GSK3359609 combination with chemotherapies dose level | Blood samples will be collected up to 27 months for ADA test. | Up to 27 months | 
| Part 2: Cmax and Cmin of dostarlimab | Blood samples will be collected for the concentrations of dostarlimab. | Up to 27 months | 
| Part 2: AUC(0-tau) of dostarlimab | Blood samples will be collected for the concentrations of dostarlimab. | Up to 27 months | 
| Part 2: Cmax and Cmin of cobolimab | Blood samples will be collected for the concentrations of cobolimab. | Up to 27 months | 
| Part 2: AUC(0-tau) of cobolimab | Blood samples will be collected for the concentrations of cobolimab. | Up to 27 months | 
| Part 2: Cmax and Cmin of bintrafusp alfa | Blood samples will be collected for the concentrations of bintrafusp alfa. | Up to 27 months | 
| Part 2: AUC(0-tau) of bintrafusp alfa | Blood samples will be collected for the concentrations of bintrafusp alfa. | Up to 27 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ICOS receptor agonist antibody, Pembrolizumab, KEYNOTE-478, GSK3359609, Cohort expansion, Dose escalation, Dostarlimab, Cobolimab, Bintrafusp alfa