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Study of Niraparib, TSR-022, Bevacizumab, and Platinum-Based Doublet Chemotherapy in Combination With TSR-042

Study Purpose

Part A: To test the safety and tolerability of combination therapy with Niraparib and TSR-042 and to establish a safe dose that will be used in a Phase 2 study. Part B: To test the safety and tolerability of combination therapy with Carboplatin-Paclitaxel and TSR-042 and to establish a safe dose that will be used in a Phase 2 study. Part C: To test the safety and tolerability of combination therapy with Niraparib, TSR-042 and Bevacizumab and to establish a safe dose that will be used in a Phase 2 study. Part D: To test the safety and tolerability of combination therapy with Carboplatin-Paclitaxel, TSR-042 and Bevacizumab and to establish a safe dose that will be used in a Phase 2 study. Part E: To test the safety and tolerability of combination therapy with Carboplatin-Pemetrexed and TSR-042 and to establish a safe dose that will be used in a Phase 2 study. Part F: To test the safety and tolerability of combination therapy with Carboplatin-Pemetrexed, TSR-022 and TSR-042 and to establish a safe dose that will be used in a Phase 2 study. Part G: To test the safety and tolerability of combination therapy with Carboplatin-nab-Paclitaxel, TSR-042 and to establish a safe dose that will be used in a Phase 2 study. Part H: To test the safety and tolerability of combination therapy with Carboplatin-nab-Paclitaxel, TSR-022 and TSR-042 and to establish a safe dose that will be used in a Phase 2 study. Part I: To test the safety and tolerability of combination therapy with Carboplatin-Paclitaxel, TSR-022 and TSR-042 and to establish a safe dose that will be used in a Phase 2 study.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

 No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

 Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion Criteria

Inclusion Criteria:

  • - Patient has histologically or cytologically proven advanced (unresectable) or metastatic cancer as outlined below according to study part and disease type: - Part A: Patients with previously treated advanced or metastatic cancer.
Patient may have received no more than 4 lines of treatment for advanced or metastatic cancer. Hormonal treatment will not be considered a prior line of treatment.
  • - Part B: Patients with advanced or metastatic cancer for which treatment with carboplatin-paclitaxel is considered appropriate therapy.
Patient may have received no more than 1 prior line of chemotherapy in the metastatic setting. Hormonal treatment will not be considered a prior line of treatment.
  • - Part C: Patients with previously treated advanced or metastatic cancer.
Patient may have received no more than 4 lines of treatment for advanced or metastatic cancer. Hormonal treatment will not be considered a prior line of treatment.
  • - Part D: Patients in whom carboplatin-paclitaxel and bevacizumab is considered appropriate therapy.
Patient may have received no more than 1 prior line of chemotherapy in the metastatic setting. Hormonal treatment will not be considered a prior line of treatment.
  • - Part E and F: Patients who have not received prior systemic therapy, including targeted therapy and biologic agents, for their advanced or metastatic (Stage ≥ IIIB or IV) Non-Squamous NSCLC.
Patients who have received neoadjuvant or adjuvant therapy are eligible as long as development of advanced or metastatic disease occurred at least 12 months after completion of neoadjuvant or adjuvant therapy.
  • - Part G, H, and I: Patients who have not received prior systemic therapy, including targeted therapy and biologic agents, for their advanced or metastatic (Stage ≥ IIIB or IV) NSCLC.
Patients who have received neoadjuvant or adjuvant therapy are eligible as long as development of advanced or metastatic disease occurred at least 12 months after completion of neoadjuvant or adjuvant therapy.
  • - Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  • - Patient has adequate organ function.
  • - Female patient has a negative serum pregnancy test within 72 hours prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 180 days after the last dose of study treatment, or is of non-childbearing potential.
  • - Male patient agrees to use an adequate method of contraception and not donate sperm starting with the first dose of study treatment through 90 days after the last dose of study treatment.
Note: Abstinence is acceptable if this is the established and preferred contraception for the patient.
  • - Patient has measurable lesions by RECIST v1.1.
For Part A and C, in addition to the general inclusion criteria, patients must also meet the following additional criterion to be considered eligible to participate in this study:
  • - Patient is able to take oral medications.
  • - For patients to be eligible for any parts of the study using niraparib 300 mg as a starting dose, a screening actual body weight ≥ 77 kg and screening platelet count ≥ 150,000 u/L is necessary.

Exclusion Criteria:

(Patients will not be eligible for the study entry if any of the following criteria are met)
  • - Patient has known active central nervous system metastases, carcinomatous meningitis, or both.
  • - Patient has a known additional malignancy that progressed or required active treatment within the last 2 years.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer.
  • - Patient is considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active infection that requires systemic therapy.
  • - Patient has a condition (such as transfusion-dependent anemia or thrombocytopenia), therapy, or laboratory abnormality that might confound the study results or interfere with the patient's participation.
  • - Patient is pregnant or expecting to conceive children within the projected duration of the study, starting with the screening visit through 180 days after the last dose of study treatment.
Note: No data are available regarding the presence of niraparib or its metabolites in human milk, or on its effects on the breastfed infant or milk production. Because of the potential for serious adverse reactions in breastfed infants from niraparib, female patients should not breastfeed during treatment with niraparib and for 1 month after receiving the final dose.
  • - Patient has a known history of human immunodeficiency virus (type 1 or 2 antibodies).
  • - Patient has known active hepatitis B or hepatitis C.
  • - Patient has an active autoimmune disease that has required systemic treatment in the past 2 years.
  • - Patient has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
  • - Patient has undergone prior treatment with a known PARP inhibitor.
  • - Known history or current diagnosis of MDS or AML.
  • - Patient has a known hypersensitivity to TSR-042 components or excipients.
For Parts B, D, E, F, G, H, and I, patients will not be eligible for study entry if any of the following additional exclusion criterion are met: • Patient has a known hypersensitivity to any of the following relevant study treatments: carboplatin, paclitaxel, pemetrexed, nab-paclitaxel, or TSR-022 components or excipients. For Parts C and D only, patients will not be eligible for study entry if the following additional exclusion criterion is met:
  • - Patient has clinically significant cardiovascular disease (e.g., significant cardiac conduction abnormalities, uncontrolled hypertension, myocardial infarction, cardiac arrhythmia or unstable angina, New York Heart Association Grade 2 or greater congestive heart failure, serious cardiac arrhythmia requiring medication, Grade 2 or greater peripheral vascular disease, and history of cerebrovascular accident [CVA]) within 6 months of enrollment.
  • - Patient has a history of bowel obstruction, including subocclusive disease, related to the underlying disease and history of abdominal fistula, gastrointestinal perforation, or intra abdominal abscesses.
Evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction.
  • - Patient has proteinuria as demonstrated by urine protein: creatinine ratio ≥1.0 at screening or urine dipstick for proteinuria ≥2 (patients discovered to have ≥2 proteinuria on dipstick at baseline should undergo 24-hour urine collection and must demonstrate <2 g of protein in 24 hours to be eligible).
  • - Patient is at increased bleeding risk due to concurrent conditions (e.g., major injuries or surgery within the past 28 days prior to start of study treatment, history of hemorrhagic stroke, transient ischemic attack, subarachnoid hemorrhage, or clinically significant hemorrhage within the past 3 months).
  • - Patient has a known hypersensitivity to bevacizumab components or excipients.
For Parts E and F only, patients will not be eligible for study entry if any of the following additional exclusion criteria are met:
  • - Patient is unable to interrupt aspirin or other nonsteroidal ant-inflammatory drugs, other than an aspirin dose ≤ 1.3 g per day, for a 5-day period (8-day period for long -acting agents, such as piroxicam.
  • - Patient is unable or unwilling to take folic acid, vitamin B12 supplement.
  • - Patient has symptomatic ascites or pleural effusion.
A patient who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible. For Parts G, H, and I only, patients will not be eligible for study entry if any of the following additional exclusion criteria are met: • Patient has pre-existing peripheral neuropathy that is Grade ≥ 2 by Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria. For Parts E, F, G, H and I only, patients will not be eligible for study entry if any of the following additional exclusion criteria are met: • Patient has interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

 NCT03307785
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

 Phase 1
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

 Tesaro, Inc.
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

 GSK Clinical Trials
Principal Investigator Affiliation GlaxoSmithKline
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

 Industry
Overall Status Active, not recruiting
Countries United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

 Neoplasms, Metastatic Cancer, Advanced Cancer, Solid Tumor, Non Small Cell Lung Cancer Metastatic, Non Small Cell Lung Cancer Stage IIIB, Non Small Cell Lung Cancer
Arms & Interventions

Arms

Experimental: Part A: TSR-042 and niraparib 200 mg QD

Patients will receive TSR-042 500 milligram (mg), intravenous (IV) infusion on Day 1 of every cycle (every 3 weeks [Q3W]) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (every 6 weeks [Q6W]) beginning on Day 1 of Cycle 5 along with niraparib 200 mg, once daily (QD), orally on Days 1 to 21 repeated Q3W.

Experimental: Part A: TSR-042 and niraparib 300 mg QD

Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (Q6W) beginning on Day 1 of Cycle 5 along with niraparib 300 mg, QD, orally on Days 1 to 21 repeated Q3W.

Experimental: Part B: TSR-042 and carboplatin-paclitaxel

Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (Q6W) beginning on Day 1 of Cycle 5 along with carboplatin, IV infusion on Day 1 Q3W and paclitaxel 175 milligram per square meter (mg/m^2), IV infusion on Day 1 Q3W administered for 4 to 6 cycles.

Experimental: Part C: TSR-042, niraparib 200 mg QD and bevacizumab

Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (Q6W) beginning on Day 1 of Cycle 5 along with niraparib 200 mg administered orally on Days 1 to 21 repeated Q3W and bevacizumab 15 mg/kilogram (kg), IV infusion on Day 1 of every 21-day cycle Q3W for up to 15 months.

Experimental: Part C: TSR-042, niraparib 300 mg QD and bevacizumab

Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (Q6W) beginning on Day 1 of Cycle 5 along with niraparib 300 mg administered orally on Days 1 to 21 repeated Q3W and bevacizumab 15 mg/kg, IV infusion on Day 1 of every 21-day cycle Q3W for up to 15 months.

Experimental: Part D: TSR-042, carboplatin-paclitaxel and bevacizumab

Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) for 4 cycles (each cycle is 21 days); followed by TSR-042 1000 mg, IV infusion on Day 1 of every other cycle (Q6W) beginning on Day 1 of Cycle 5 along with carboplatin, IV infusion on Day 1 Q3W and paclitaxel 175 mg/m^2, IV infusion on Day 1 Q3W administered for 4 to 6 cycles; and bevacizumab 15 mg/kg, IV infusion on Day 1 of every 21-day cycle Q3W for up to 15 months.

Experimental: Part E: TSR-042 and carboplatin-pemetrexed

Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) along with carboplatin, IV infusion on Day 1 Q3W and pemetrexed 500 mg/m^2, IV infusion on Day 1 Q3W (with vitamin supplementation) administered for 6 cycles (each cycle is 21 days).

Experimental: Part F: TSR-042, TSR-022, and carboplatin-pemetrexed

Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W); and TSR-022 900 mg, IV infusion on Day 1 Q3W along with carboplatin, IV infusion on Day 1 Q3W administered for 5 cycles (each cycle is 21 days); and pemetrexed 500 mg/m^2, IV infusion on Day 1 Q3W (with vitamin supplementation).

Experimental: Part G: TSR-042 and carboplatin-nab-paclitaxel

Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W) along with carboplatin, IV infusion on Day 1 Q3W for 4 to 6 cycles (each cycle is 21 days) and nab-paclitaxel 100 mg/m^2, IV infusion on Days 1, 8 and 15 (every week [Q1W]) of every 3 week cycle for 4 to 6 cycles.

Experimental: Part H: TSR-042, TSR-022, and carboplatin-nab-paclitaxel

Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W); followed by TSR-022 900 mg, IV infusion on Day 1 Q3W along with carboplatin, IV infusion on Day 1 Q3W for 4 to 6 cycles (each cycle is 21 days) and nab-paclitaxel 100 mg/m^2, IV infusion on Days 1, 8 and 15 (Q1W) of every 3 week cycle for 4 to 6 cycles.

Experimental: Part I: TSR-042, TSR-022, and carboplatin-paclitaxel

Patients will receive TSR-042 500 mg, IV infusion on Day 1 of every cycle (Q3W); followed by TSR-022 900 mg, IV infusion on Day 1 Q3W along with carboplatin, IV infusion on Day 1 Q3W and paclitaxel 175 mg/m^2, IV infusion on Day 1 Q3W for 4 to 6 cycles (each cycle is 21 days).

Interventions

Drug: - Niraparib

Niraparib is a potent, orally active PARP1 and PARP2 inhibitor being developed as a treatment for patients with tumors that harbor defects in the homologous recombination DNA repair pathway or that are driven by PARP-mediated transcription factors.

Drug: - TSR-042

TSR-042 is a humanized monoclonal antibody that binds with high affinity to PD-1 resulting in inhibition of binding to programmed death receptor ligands 1 and 2 (PD-L1 and PD-L2).

Drug: - Carboplatin-Paclitaxel

Carboplatin in combination with paclitaxel is a chemotherapy treatment that has been shown to be efficacious against a variety of different tumor types, including non-small cell lung cancer [NSCLC], ovarian cancer, endometrial cancer, and head and neck cancer.

Drug: - Bevacizumab

Bevacizumab is a chemotherapy treatment that has been shown to be efficacious against a variety of different cancer types, including colon cancer, lung cancer, glioblastoma, and renal-cell carcinoma. Bevacizumab is in the angiogenesis inhibitor and monoclonal antibody families of medication. It works by slowing the growth of new blood vessels.

Drug: - TSR-022

TSR-022 is a monoclonal antibody against TIM-3 (also called HAVCR2), an immune checkpoint receptor. Immune checkpoint proteins are molecules that help to regulate the immune system so it does not mistakenly attack healthy cells. However, they can also keep immune cells from recognizing and killing cancer cells. TIM-3 is found on the surface of certain T-cells, including tumor-infiltrating T-cells, that have left the bloodstream and migrated into the tumor environment. By binding to and blocking TIM-3, TRS-022 allows for T-cells to become activated so as to enhance T-cell-mediated attacks on tumors. These attacks reduce their growth.

Drug: - Carboplatin-Pemetrexed

Pemetrexed and platinum therapy in combination with pembrolizumab (anti-PD-1 antibody) has proven to be efficacious in a first line setting for nonsquamous NSCLC patients

Drug: - Carboplatin-Nab-Paclitaxel

Nab-paclitaxel is a formulation of paclitaxel that is indicated for locally advanced or metastatic NSCLC, as first-line treatment in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy. Nab-paclitaxel has shown increased ORR and time to progression in metastatic breast cancer compared with solvent-based paclitaxel and has shown antitumor activity and improved ORR compared with solvent-based paclitaxel as first-line therapy in patients with NSCLC.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

GSK Investigational Site, Scottsdale, Arizona

Status

Address

GSK Investigational Site

Scottsdale, Arizona, 85258

GSK Investigational Site, Encinitas, California

Status

Address

GSK Investigational Site

Encinitas, California, 92024

GSK Investigational Site, Sarasota, Florida

Status

Address

GSK Investigational Site

Sarasota, Florida, 34232

GSK Investigational Site, Canton, Ohio

Status

Address

GSK Investigational Site

Canton, Ohio, 44718

GSK Investigational Site, Cleveland, Ohio

Status

Address

GSK Investigational Site

Cleveland, Ohio, 44106

GSK Investigational Site, Nashville, Tennessee

Status

Address

GSK Investigational Site

Nashville, Tennessee, 37203

GSK Investigational Site, Houston, Texas

Status

Address

GSK Investigational Site

Houston, Texas, 77030

GSK Investigational Site, San Marcos, Texas

Status

Address

GSK Investigational Site

San Marcos, Texas, 92069

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