A Study of TSR-022 in Participants With Advanced Solid Tumors (AMBER)

Last updated: March 14, 2024
Sponsor: GlaxoSmithKline
Overall Status: Active - Recruiting

Phase

1

Condition

Neoplasms

Treatment

TSR-022

TSR-042

Pemetrexed

Clinical Study ID

NCT06322693
213348
2023-507564-39
  • Ages > 18
  • All Genders

Study Summary

This is a first-in-human study evaluating the anti-T cell immunoglobulin and mucin containing protein-3 (TIM-3) antibody TSR-022. The study will be conducted in 2 parts with Part 1 consisting of dose escalation and Part 2 dose expansion. Part 1 will determine the recommended Phase 2 dose (RP2D) of TSR-022 and Part 2 will evaluate the antitumor activity of TSR-022 in combination with TSR-042 or docetaxel and as monotherapy.

Eligibility Criteria

Inclusion

Inclusion Criteria

  • Participant is at least 18 years of age.
  • Female participants of childbearing potential must have a negative serum or urinepregnancy test within 72 hours prior to the date of the first dose of study medicationor be of non-childbearing potential.
  • Participant has an ECOG performance status of less than or equal to (<=)1.
  • Participant has adequate organ function. Inclusion Criteria for Participants in Part 1 and Part 2 Cohorts A, B, and C:
  • Participant with advanced or metastatic solid tumor who meets the requirements for thepart of the study/cohort he/she will participate in, as follows:
  • Part 2: Histologically proven advanced (unresectable) or metastatic solid tumor thatis measurable by computed tomography (CT) or magnetic resonance imaging (MRI) perRECIST version 1.1 criteria Inclusion Criteria for Participants in Part 2 Cohort D
  • Participants with advanced or metastatic non-small cell lung carcinoma (NSCLC) that ismeasurable by CT or MRI per RECIST version 1.1 criteria and meet the followingcriteria:
  • NSCLC histology includes squamous or non-squamous cell carcinoma.
  • Participants have received no more than 2 prior lines of therapy, which must include aplatinum-based chemotherapy (for example [e.g.], cisplatin, carboplatin) and an anti-programmed death-ligand 1 (PD-L1) antibody.
  • Participants must have documented radiographic progression by RECIST version 1.1criteria on prior anti-programmed cell death protein (PD-1) or anti-PD-L1 therapy.
  • Biopsies -All participants enrolled must undergo a biopsy prior to study entry, andthe biopsy tissue must be submitted to the central laboratory for all participants inorder to determine T-cell immunoglobulin and mucin-domain containing-3 (TIM-3)expression level prior to first dose. If a participant has had a biopsy prior toentering the 35-day screening period and within approximately 12 weeks of studytreatment, that biopsy may be accepted as the Baseline fresh biopsy. Inclusion Criteria for Participants in Part 2 Cohort E
  • Participant is greater than or equal to (>=)18 years old, is able to understand thestudy procedures, and agrees to participate in the study by providing written informedconsent which includes compliance with the requirements and restrictions listed in theInformed consent form (ICF) and protocol.
  • Participant has histologically or cytologically proven advanced or metastatic NSCLC,and only squamous or non-squamous cell carcinoma.
  • Participant has received no more than 2 prior lines of therapy for advanced ormetastatic disease, which must only include a platinum-based (eg, cisplatin,carboplatin) doublet chemotherapy regimen and an anti-PD-1 or anti-PD-L1 antibody (noother biologic agents alone or in combination; novel combinations are not allowed).Participants previously treated with targeted therapies, including angiogenesisinhibitors (eg, bevacizumab, ramucirumab, lenvatinib), are not eligible.
  • Participant has measurable disease, that is, presenting with at least 1 measurablelesion per RECIST v1.1 as determined by the local site Investigator/radiologyassessment. Target lesions situated in a previously irradiated area are consideredmeasurable if disease progression has been demonstrated in such lesions and if thereare other target lesions. If there is only 1 target lesion that was previouslyirradiated, the participant is not eligible.
  • Participant has documented radiological disease progression on prior platinum-basedchemotherapy and on prior anti-PD-1 or anti-PD-L1 therapy according to RECIST v1.1.
  • Participant agrees to submit an archival formalin fixed paraffin embedded (FFPE) tumortissue specimen that was collected on or after diagnosis of metastatic disease fromlocation(s) not irradiated prior to biopsy. Both tissue block and freshly cut slidesare acceptable. If archival tissue is not available, the participant must undergobiopsy prior to study entry.
  • Participant has an ECOG performance status score of 0 or 1.
  • Participant has a life expectancy of at least 3 months and is anticipated to be ableto complete 4 cycles of docetaxel treatment.
  • Participant has adequate organ function as defined in the protocol
  • Contraceptive use by male and female participants should be consistent with localregulations regarding the methods of contraception for those participating in clinicalstudies. Inclusion Criteria for Participants in Part 2 Cohort F
  • Histologically confirmed locally advanced or metastatic and/or unresectableHepatocellcular Carcinoma (HCC) a Barcelona Clinic Liver Cancer Stage B or C bCirrhosis grade of Child-Pugh Class A
  • No prior systemic therapy for HCC
  • Documented HBV testing at screening, including hepatitis B surface antigen (HBsAg),hepatitis B surface antibody (HBsAB) and hepatitis B core antibody (HBcAb).Participants with a positive HBsAg will require negative hepatitis B virus (HBV) DNAtesting at screening. a Participants with chronic HBV infection (HBsAg +) are required to be receiving effectiveantiviral therapy (i.e., with Tenofovir or Entecavir) for at least 14 days with willingnessto continue for the length of the study and have HBV deoxyribonucleic acid (DNA) less than 100 International Units Per Milliliter (IU/mL) within 28 days prior to initiation of studytreatment. b Participants with a negative (HBsAg) and positive HBcAb result are eligible only if HBVDNA is negative (Past HBV participants).
  • Documented hepatitis C virus (HCV) antibody testing conducted at screening. If HCVantibody is positive, then hepatitis C virus ribonucleic acid (HCV ribonucleic acid (RNA) must be negative. Participants with recently treated HCV prior to study startmust be greater than (>)12 weeks from final HCV treatment.
  • Must have measurable disease, defined as at least one tumor lesion that can beaccurately measured according to RECIST v1.1
  • Participant agrees to submit an archival FFPE tumor tissue specimen that was collectedon or after diagnosis of metastatic disease from location(s) not irradiated prior tobiopsy. Both tissue block and freshly cut slides are acceptable. If archival tissue isnot available, the participant must undergo biopsy prior to study entry. a. Participants are also encouraged, but not required, to have a fresh tumor tissuebiopsy of a primary or metastatic tumor prior to dosing (samples will be used toenable biomarker analysis).
  • International normalized ratio (INR) or prothrombin time (PT) <= 2× upper limit ofnormal (ULN) unless participant is receiving anticoagulant therapy as long as PT orpartial thromboplastin (PTT) is within therapeutic range of intended use ofanticoagulants. Activated partial thromboplastin time (aPTT) <=2×ULN unlessparticipant is receiving anticoagulant therapy as long as PT or PTT is withintherapeutic range of intended use of anticoagulants
  • Negative human immunodeficiency virus (HIV) test at screening
  • The Investigator is responsible for review of medical history, menstrual history, andrecent sexual activity to decrease the risk for inclusion of a woman with an earlyundetected pregnancy.

Exclusion

Exclusion criteria:

  • History of Grade greater than or equal to (>=)3 immune-related AE with priorimmunotherapy, with the exception of non-clinically significant lab abnormalities.
  • Participant has known uncontrolled central nervous system (CNS) metastases and/orcarcinomatous meningitis.
  • Participant has a known additional malignancy that progressed or required activetreatment within the last 2 years. Participants with a prior or concurrent malignancywhose natural history or treatment does not have the potential to interfere with thesafety or efficacy assessment of the investigational regimen may be included onlyafter discussion with the Medical Monitor.
  • Participant is considered a poor medical risk due to a serious, uncontrolled medicaldisorder, non-malignant systemic disease or active infection requiring systemictherapy.
  • Participant is pregnant or breastfeeding or expecting to conceive children within theprojected duration of the study, starting with the Screening Visit through 150 daysafter the last dose of study treatment.
  • Participant has a diagnosis of immunodeficiency or is receiving systemic steroidtherapy or any other form of immunosuppressive therapy within 7 days prior to thefirst dose of study treatment. Exclusion Criteria for Participants in Part 2 Cohort D
  • A participant with negative (as determined by Central Testing Lab) or unevaluableTIM-3 expression from tissue obtained prior to study entry will not be eligible forthe study.
  • Participant has received prior therapy as defined below:
  • Prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent that resulted inpermanent discontinuation due to an AE.
  • Prior treatment with an anti-lymphocyte activation gene (LAG)-3 or anti-TIM-3.
  • Radiologic or clinical progression <= 8 weeks after initiation of prior anti-PD-1 oranti-PD-L1 antibody.
  • Participants with known epidermal growth factor receptor (EGFR) mutation, anaplasticlymphoma kinase (ALK) translocation, or receptor tyrosine kinase (ROS1) mutation.
  • Participant has received a vaccine other than a vaccine against severe acuterespiratory syndrome (SARS)-coronavirus 2 (CoV-2) infection ("Coronavirus Disease 2019" [COVID-19]) within 7 days of planned start of study therapy. The use of allCOVID-19 vaccines is allowed, with the exception of COVID-19 vaccines using therecombinant adenoviral vector platform within 30 days of planned start of studytherapy. If a COVID-19 vaccine using this platform is to be administered within 30days of planned start of study therapy, this must first be discussed with and approvedby the Sponsor's Medical Monitor. Exclusion Criteria for Participants in Part 2 Cohort E
  • Participant has been previously treated with an anti PD 1, anti PD L1, or anti PD L2agent that resulted in permanent discontinuation due to an AE
  • Participant has been previously treated with an anti TIM-3 or anti cytotoxic Tlymphocyte-associated protein 4 (CTLA 4) agent or docetaxel.
  • Participant has a documented sensitizing EGFR, ALK, or ROS-1 mutation. Participantswhose tumors have not been tested for these driver mutations and therefore who haveunknown driver mutation status are not eligible. Participants with squamous histologydo not need to be tested for these driver mutations.
  • Participant had radiological or clinical disease progression (that is [ie,] worseningperformance status, clinical symptoms, and laboratory data) <=8 weeks after initiationof prior anti PD 1 or anti-PD-L1 antibody. The clinical disease progression shouldhave been confirmed by a subsequent radiological scan.
  • Participant has received radiation to the lung that is >30 Gray (Gy) within 6 monthsprior to the first dose of study treatment.
  • Participant has completed palliative radiotherapy within 7 days prior to the firstdose of study treatment.
  • Participant has an additional malignancy or a history of prior malignancy, with theexception of adequately treated basal or squamous skin cancer, cervical carcinoma insitu, or bladder carcinoma in situ without evidence of disease, or had a malignancytreated with curative intent and with no evidence of disease recurrence for 5 yearssince the initiation of that therapy.
  • Participant has known new or progressive brain metastases and/or leptomeningealmetastases. Participants who have received prior therapy for their brain metastasesand have radiologically stable central nervous system disease may participate,provided they are neurologically stable for at least 4 weeks before study entry andare off corticosteroids within 3 days prior to the first dose of study treatment.
  • Participant has tested positive for the following at Screening or within 3 monthsbefore the first dose of study treatment:
  • Presence of hepatitis B surface antigen.
  • Presence of hepatitis C antibody in the absence of an Ribonucleic acid (RNA) test forhepatitis C virus.
  • Participant has known human immunodeficiency virus (HIV) (positive for HIV 1 or HIV 2antibodies).
  • Participant has active autoimmune disease that required systemic treatment in the past 2 years, is immunocompromised in the opinion of the Investigator, or is receivingsystemic immunosuppressive treatment. Replacement therapy (eg, thyroxine, insulin, orphysiologic corticosteroid replacement therapy of prednisone, or equivalent, foradrenal or pituitary insufficiency) is not considered a form of systemic treatment.
  • Participant has received systemic steroid therapy within 3 days prior to the firstdose of the study treatment or is receiving any other form of immunosuppressivemedication. Replacement therapy is not considered a form of systemic therapy. Use ofinhaled corticosteroids, local steroid injection, or steroid eye drops is allowed.
  • Participant has current interstitial lung disease, current pneumonitis, or a historyof pneumonitis that required the use of glucocorticoids to assist with management.Lymphangitic spread of the NSCLC is not exclusionary.
  • Participant does not meet requirements per local prescribing guidelines for receivingtreatment with docetaxel, including severe hypersensitivity reactions to drugsformulated with polysorbate 80.
  • Participant has received prior anticancer therapy (chemotherapy, targeted therapies,radiotherapy, or immunotherapy) within 21 days, or less than 5 times the half life ofthe most recent therapy prior to study Day 1, whichever is shorter. Exclusion Criteria for Participants in Part 2 Cohort F
  • Known fibrolamellar HCC, sarcomatoid HCC or mixed cholangiocarcinoma and HCC
  • Participant must not have had major surgery <= 3 weeks prior to initiating protocoltherapy and participant must have recovered from any surgical effects
  • Participants must not have received investigational therapy <= 4 weeks, or within atime interval less than at least 5 half-lives of the investigational agent, whicheveris shorter, prior to initiating protocol therapy.
  • Active or untreated central nervous system (CNS) and leptomeningeal metastases
  • Prior therapy with any medication targeting PD-1, PD-L1, or TIM-3
  • Participant must not have a known hypersensitivity to TSR-042 and TSR-022 componentsor excipients.
  • Participants with active malignancy (other than HCC) or a prior malignancy within thepast 2 years are excluded. Participants with completely resected cutaneous melanoma (early stage), basal cell carcinoma, cutaneous squamous cell carcinoma, cervicalcarcinoma in-situ, breast carcinoma in-situ, and localized prostate cancer areeligible.
  • Participant must not have serious, uncontrolled medical disorder, or nonmalignantsystemic disease as determined by the treating physician. Examples include, but arenot limited to uncontrolled ventricular arrhythmia, uncontrolled major seizuredisorder, unstable spinal cord compression, or superior vena cava syndrome.
  • Has a history or evidence of cardiac abnormalities within the 6 months prior toenrollment, including:
  1. Serious, uncontrolled cardiac arrhythmia or clinically significant ECGabnormalities including second-degree (Type II) or third-degree atrioventricular (AV) block.
  2. Cardiomyopathy, myocarditis, myocardial infarction, acute coronary syndromes (including angina pectoris), coronary angioplasty, stenting, or bypass grafting.
  3. Congestive heart failure [New York Heart Association (NYHA) Class III or IV]
  4. Symptomatic pericarditis
  • Known history of Human Immunodeficiency Virus (HIV) infection
  • Active tuberculosis infection or other microbial infection or any active systemicinfection requiring parenteral antibiotic therapy. All prior infections must haveresolved following optimal therapy.
  • Participant has an active autoimmune disease that has required systemic treatment inthe past 2 years (. i.e., with use of disease-modifying agents, corticosteroids, orimmunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,etc.) is not considered a form of systemic treatment.
  • History of idiopathic pulmonary fibrosis, interstitial lung disease, bronchial asthma,organizing pneumonia, bronchiolitis obliterans, drug-induced pneumonitis, oridiopathic pneumonitis
  • History of organ transplantation including allogeneic bone marrow transplantation
  • Participant has a diagnosis of immunodeficiency or has been receiving systemic steroidtherapy or any other form of immunosuppressive therapy within 7 days prior toinitiating protocol therapy.
  • Participant has received a live vaccine within 7 days of initiating protocol therapy.
  • Psychiatric illness/social situations that would limit compliance with studyrequirements
  • Pregnant, lactating, breastfeeding, or intending to become pregnant during the studyand for 150 days after the study

Study Design

Total Participants: 475
Treatment Group(s): 8
Primary Treatment: TSR-022
Phase: 1
Study Start date:
July 08, 2016
Estimated Completion Date:
February 19, 2027

Connect with a study center

  • GSK Investigational Site

    Daegu, 41931
    Korea, Republic of

    Active - Recruiting

  • GSK Investigational Site

    Seongnam-si, Gyeonggi-do, 13620
    Korea, Republic of

    Active - Recruiting

  • GSK Investigational Site

    Seoul, 7061
    Korea, Republic of

    Active - Recruiting

  • GSK Investigational Site

    Palma de Mallorca, Islas Baleares 07120
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Barcelona, 8028
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Girona, 17007
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Jerez de la Frontera, 11407
    Spain

    Active - Recruiting

  • GSK Investigational Site

    L'Hospitalet De Llobregat, 08908
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Las Palmas De Gran Canaria, 35016
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Madrid, 28046
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Majadahonda (Madrid), 28222
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Málaga, 29010
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Pamplona, 31008
    Spain

    Completed

  • GSK Investigational Site

    Santander, 39008
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Sevilla, 41013
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Valencia, 46010
    Spain

    Active - Recruiting

  • GSK Investigational Site

    Goodyear, Arizona 85338
    United States

    Completed

  • GSK Investigational Site

    Scottsdale, Arizona 85258
    United States

    Completed

  • GSK Investigational Site

    Tucson, Arizona 85711
    United States

    Completed

  • GSK Investigational Site

    Encinitas, California 92024
    United States

    Active - Recruiting

  • GSK Investigational Site

    Fountain Valley, California 92708
    United States

    Active - Recruiting

  • GSK Investigational Site

    Los Angeles, California 90024
    United States

    Active - Recruiting

  • GSK Investigational Site

    San Marcos, California 92069
    United States

    Active - Recruiting

  • GSK Investigational Site

    Whittier, California 90606
    United States

    Active - Recruiting

  • GSK Investigational Site

    Aurora, Colorado 80045
    United States

    Active - Recruiting

  • GSK Investigational Site

    Denver, Colorado 80218
    United States

    Completed

  • GSK Investigational Site

    New Haven, Connecticut 06511
    United States

    Active - Recruiting

  • GSK Investigational Site

    Washington, District of Columbia 20007
    United States

    Active - Recruiting

  • GSK Investigational Site

    Jacksonville, Florida 32224
    United States

    Completed

  • GSK Investigational Site

    Miami Beach, Florida 33140
    United States

    Completed

  • GSK Investigational Site

    Sarasota, Florida 34232
    United States

    Active - Recruiting

  • GSK Investigational Site

    Tampa, Florida 33612
    United States

    Active - Recruiting

  • GSK Investigational Site

    Atlanta, Georgia 30322
    United States

    Completed

  • GSK Investigational Site

    Augusta, Georgia 30912
    United States

    Completed

  • GSK Investigational Site

    Arlington Heights, Illinois 60005
    United States

    Active - Recruiting

  • GSK Investigational Site

    Chicago, Illinois 60637
    United States

    Active - Recruiting

  • GSK Investigational Site

    Niles, Illinois 60714
    United States

    Active - Recruiting

  • GSK Investigational Site

    Iowa City, Iowa 52242-1009
    United States

    Active - Recruiting

  • GSK Investigational Site

    Wichita, Kansas 67214
    United States

    Completed

  • GSK Investigational Site

    Louisville, Kentucky 40202
    United States

    Completed

  • GSK Investigational Site

    Pikeville, Kentucky 41501
    United States

    Active - Recruiting

  • GSK Investigational Site

    Rockville, Maryland 20850
    United States

    Active - Recruiting

  • GSK Investigational Site

    Boston, Massachusetts 02114
    United States

    Active - Recruiting

  • GSK Investigational Site

    Detroit, Michigan 48202
    United States

    Completed

  • GSK Investigational Site

    Rochester, Minnesota 55905
    United States

    Completed

  • GSK Investigational Site

    Hackensack, New Jersey 07601
    United States

    Completed

  • GSK Investigational Site

    Bronx, New York 10461
    United States

    Active - Recruiting

  • GSK Investigational Site

    New York, New York 10016
    United States

    Active - Recruiting

  • GSK Investigational Site

    Cincinnati, Ohio 45242
    United States

    Completed

  • GSK Investigational Site

    Cleveland, Ohio 44106
    United States

    Active - Recruiting

  • GSK Investigational Site

    Toledo, Ohio 43623
    United States

    Active - Recruiting

  • GSK Investigational Site

    Eugene, Oregon 97401
    United States

    Active - Recruiting

  • GSK Investigational Site

    Portland, Oregon 97213-2982
    United States

    Completed

  • GSK Investigational Site

    Bethlehem, Pennsylvania 18015
    United States

    Completed

  • GSK Investigational Site

    Pittsburgh, Pennsylvania 15213-2584
    United States

    Active - Recruiting

  • GSK Investigational Site

    Charleston, South Carolina 29425
    United States

    Active - Recruiting

  • GSK Investigational Site

    Greenville, South Carolina 29605
    United States

    Completed

  • GSK Investigational Site

    Nashville, Tennessee 37203
    United States

    Active - Recruiting

  • GSK Investigational Site

    Austin, Texas 78705
    United States

    Completed

  • GSK Investigational Site

    Dallas, Texas 75246
    United States

    Active - Recruiting

  • GSK Investigational Site

    Fort Worth, Texas 76104
    United States

    Completed

  • GSK Investigational Site

    Houston, Texas 77030
    United States

    Active - Recruiting

  • GSK Investigational Site

    Longview, Texas 75601
    United States

    Active - Recruiting

  • GSK Investigational Site

    McAllen, Texas 78503-1298
    United States

    Active - Recruiting

  • GSK Investigational Site

    San Antonio, Texas 78229
    United States

    Completed

  • GSK Investigational Site

    Temple, Texas 76508
    United States

    Completed

  • GSK Investigational Site

    Tyler, Texas 75702
    United States

    Active - Recruiting

  • GSK Investigational Site

    Weslaco, Texas 78596
    United States

    Active - Recruiting

  • GSK Investigational Site

    Fairfax, Virginia 8613
    United States

    Active - Recruiting

  • GSK Investigational Site

    Kennewick, Washington 99336
    United States

    Active - Recruiting

  • GSK Investigational Site

    Puyallup, Washington 98373
    United States

    Active - Recruiting

  • GSK Investigational Site

    Tacoma, Washington 98405
    United States

    Active - Recruiting

  • GSK Investigational Site

    Madison, Wisconsin 53792
    United States

    Completed

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