Neoplasms
Conditions
Keywords
TSR-022, Nivolumab, Advanced solid tumors, Metastatic solid tumors, Immunotherapy, Colorectal cancer, Non-small cell lung cancer, Melanoma, TSR-033, TSR-042, Hepatocellular carcinoma cancer, Docetaxel
Brief 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.
Interventions
DRUGTSR-022
TSR-022 will be administered.
DRUGNivolumab
Nivolumab will be administered.
DRUGTSR-042
TSR-042 will be administered.
DRUGTSR-033
TSR-033 will be administered.
DRUGDocetaxel
Docetaxel will be administered.
DRUGPemetrexed
Pemetrexed will be administered.
DRUGCisplatin
Cisplatin will be administered.
DRUGCarboplatin
Carboplatin will be administered.
Sponsors
Tesaro, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
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Intervention model description
This is a multi-center, open-label, first-in-human Phase 1 study.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant is at least 18 years of age. * Female participants of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the date of the first dose of study medication or 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 the part of the study/cohort he/she will participate in, as follows: * Part 2: Histologically proven advanced (unresectable) or metastatic solid tumor that is measurable by computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 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 is measurable by CT or MRI per RECIST version 1.1 criteria and meet the following criteria: * NSCLC histology includes squamous or non-squamous cell carcinoma. * Participants have received no more than 2 prior lines of therapy, which must include a platinum-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 1.1 criteria 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, and the biopsy tissue must be submitted to the central laboratory for all participants in order 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 to entering the 35-day screening period and within approximately 12 weeks of study treatment, 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 the study procedures, and agrees to participate in the study by providing written informed consent which includes compliance with the requirements and restrictions listed in the Informed 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 or metastatic disease, which must only include a platinum-based (eg, cisplatin, carboplatin) doublet chemotherapy regimen and an anti-PD-1 or anti-PD-L1 antibody (no other biologic agents alone or in combination; novel combinations are not allowed). Participants previously treated with targeted therapies, including angiogenesis inhibitors (eg, bevacizumab, ramucirumab, lenvatinib), are not eligible. * Participant has measurable disease, that is, presenting with at least 1 measurable lesion per RECIST v1.1 as determined by the local site Investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if disease progression has been demonstrated in such lesions and if there are other target lesions. If there is only 1 target lesion that was previously irradiated, the participant is not eligible. * Participant has documented radiological disease progression on prior platinum-based chemotherapy 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) tumor tissue specimen that was collected on or after diagnosis of metastatic disease from location(s) not irradiated prior to biopsy. Both tissue block and freshly cut slides are acceptable. If archival tissue is not available, the participant must undergo biopsy 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 able to 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 local regulations regarding the methods of contraception for those participating in clinical studies. Inclusion Criteria for Participants in Part 2 Cohort F * Histologically confirmed locally advanced or metastatic and/or unresectable Hepatocellcular Carcinoma (HCC) * Barcelona Clinic Liver Cancer Stage B or C * Cirrhosis 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) DNA testing at screening. * Participants with chronic HBV infection (HBsAg +) are required to be receiving effective antiviral therapy (i.e., with Tenofovir or Entecavir) for at least 14 days with willingness to 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 study treatment. * Participants with chronic HBV infection (HBsAg+) require documented Hepatitis D virus (HDV) antibody testing conducted at screening. If HDV antibody is positive, then HDV ribonucleic acid (RNA) must be negative to participate. * Participants with a negative HBsAg and positive HBcAb result are eligible only if HBV DNA is negative (Past HBV participants). * Documented hepatitis C virus (HCV) antibody testing conducted at screening. If HCV antibody is positive, then HCV RNA must be negative. Participants with recently treated HCV prior to study start must be greater than (\>)12 weeks from final HCV treatment. * Must have measurable disease, defined as at least one tumor lesion that can be accurately measured according to RECIST v1.1 * Participant agrees to submit an archival FFPE tumor tissue specimen that was collected on or after diagnosis of metastatic disease from location(s) not irradiated prior to biopsy. Both tissue block and freshly cut slides are acceptable. If archival tissue is not available, the participant must undergo biopsy prior to study entry. • Participants are also encouraged, but not required, to have a fresh tumor tissue biopsy of a primary or metastatic tumor prior to dosing (samples will be used to enable biomarker analysis). * International normalized ratio (INR) or prothrombin time (PT) \<= 2× upper limit of normal (ULN) unless participant is receiving anticoagulant therapy as long as PT or partial thromboplastin (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) \<=2×ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic 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, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Exclusion criteria
* History of Grade greater than or equal to (\>=)3 immune-related AE with prior immunotherapy, with the exception of non-clinically significant lab abnormalities. * Participant has known uncontrolled central nervous system (CNS) metastases and/or carcinomatous meningitis. * Participant has a known additional malignancy that progressed or required active treatment within the last 2 years. Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the Medical Monitor. * Participant is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active infection requiring systemic therapy. * Participant is pregnant or breastfeeding or expecting to conceive children within the projected duration of the study, starting with the Screening Visit through 150 days after the last dose of study treatment. * Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1 (a): Number of participants achieving dose limiting toxicity (DLTs) | Up to 28 days |
| Part 1 (b,c,d): Number of participants achieving dose limiting toxicity (DLTs) | Up to 42 days |
| Part 1 (f,g,h): Number of participants achieving dose limiting toxicity (DLTs) | Up to 21 days |
| Part 1: Number of participants with adverse events (AEs), serious adverse events (SAEs), AEs leading to discontinuation, treatment emergent adverse events (TEAEs), TEAEs leading to death and immune-related adverse events (irAEs) | Up to 2 years |
| Part 1: Number of participants with clinically significant changes in laboratory parameters, vital signs, electrocardiogram (ECG) findings, Eastern Cooperative Oncology Group (ECOG) status, physical examination and use of concomitant medications | Up to 2 years |
| Part 1 (e) and Part 2: Overall Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 | Up to 2 years |
Secondary
| Measure | Time frame |
|---|---|
| Part 1 (a, b, c, d, f, g, h): ORR by RECIST v 1.1 | Up to 2 years |
| Part 2 (A, B, C, D): ORR by Immune related RECIST (irRECIST) | Up to 2 years |
| Part 2: Duration of response (DOR) by RECIST v 1.1 | Up to 2 years |
| Part 2 (A, B, C, D): DOR by irRECIST | Up to 2 years |
| Parts 1 and 2: Disease control rate (DCR) by RECIST v 1.1 | Up to 2 years |
| Part 2 (A, B, C, D): DCR by irRECIST | Up to 2 years |
| Part 2: Progression-free survival (PFS) by RECIST v 1.1 | Up to 2 years |
| Part 2 (A, B, C, D): PFS by irRECIST | Up to 2 years |
| Parts 1 and 2 (A, B, C, D, E, F): Serum concentration of TSR-022 | Up to 2 years |
| Part 1d: Serum concentration of TSR-033 | Up to 2 years |
| Part 1 (c, d, e, f, g, h): Serum concentration of TSR-042 | Up to 2 years |
| Part 2 (A, B, C, D, F): Serum concentration of TSR-042 | Up to 2 years |
| Part 2: Overall survival (OS) | Up to 2 years |
| Part 1a: Minimum plasma concentration (Cmin) of TSR-022 as monotherapy | Up to 2 years |
| Part 1b: Cmin of TSR-022 in combination with nivolumab | Up to 2 years |
| Part 1c: Cmin of TSR-022 in combination with TSR-042 | Up to 2 years |
| Part 1d: Cmin of TSR-022 in combination with TSR-042 and TSR-033 | Up to 2 years |
| Part 2F: Cmin of TSR-022 in combination with TSR-042 | Up to 2 years |
| Part 1a: Area under the concentration × time curve from time 0 to infinity AUC (0-inf) of TSR-022 as monotherapy | Up to 2 years |
| Part 1b: AUC (0-inf) of TSR-022 in combination with nivolumab | Up to 2 years |
| Part 1c: AUC (0-inf) of TSR-022 in combination with TSR-042 | Up to 2 years |
| Part 1d: AUC (0-inf) of TSR-022 in combination with TSR-042 and TSR-033 | Up to 2 years |
| Part 2F: AUC (0-inf) of TSR-022 in combination with TSR-042 | Up to 2 years |
| Part 1a: Area under the concentration time curve from time 0 to last assessment (AUC 0-last) of TSR-022 as monotherapy | Up to 2 years |
| Part 1b: AUC (0-last) of TSR-022 in combination with nivolumab | Up to 2 years |
| Part 1c: AUC (0-last) of TSR-022 in combination with TSR-042 | Up to 2 years |
| Part 1d: AUC (0-last) of TSR-022 in combination with TSR-042 and TSR-033 | Up to 2 years |
| Part 2F: AUC (0-last) of TSR-022 in combination with TSR-042 | Up to 2 years |
| Part 1a: Terminal half life (t 1/2) of TSR-022 as monotherapy | Up to 2 years |
| Part 1b: t1/2 of TSR-022 and in combination with nivolumab | Up to 2 years |
| Part 1c: t1/2 of TSR-022 in combination with TSR-042 | Up to 2 years |
| Part 1d: t1/2 of TSR-022 in combination with TSR-042 and TSR-033 | Up to 2 years |
| Part 2F: t1/2 of TSR-022 in combination with TSR-042 | Up to 2 years |
| Part 1a: Area under the concentration × time curve during the dosing interval (AUCtau) of TSR-022 as monotherapy | Up to 2 years |
| Part 1b: AUCtau of TSR-022 and in combination with nivolumab | Up to 2 years |
| Part 1c: AUCtau of TSR-022 in combination with TSR-042 | Up to 2 years |
| Part 1d: Number of participants with ADA to TSR-033 | Up to 2 years |
| Part 2F: Number of participants with AEs, SAEs, AEs leading to discontinuation, TEAEs, TEAEs leading to death | Up to 2 years |
| Part 1d: AUCtau of TSR-022 in combination with TSR-042 and TSR-033 | Up to 2 years |
| Part 2F: Percent change from Baseline in Alpha-fetoprotein (AFP) | Baseline, and up to 2 years |
| Part 2F: AUCtau of TSR-022 in combination with TSR-042 | Up to 2 years |
| Part 1: Number of participants with anti-drug antibodies (ADAs) to TSR-022 | Up to 2 years |
| Part 2 (A, B, C, D, E, F): Number of participants with ADA to anti-TSR-022 | Up to 2 years |
| Part 1 (c, d, e, f, g, h): Number of participants with ADA to TSR-042 | Up to 2 years |
| Part 2 (A, B, C, D, F): Number of Participants with ADA to TSR-042 | Up to 2 years |
Countries
South Korea, Spain, United States
Outcome results
None listed