Clinical Trials /

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

NCT03307785

Description:

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.

Related Conditions:
  • Cancer
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of Niraparib, TSR-022, Bevacizumab, and Platinum-Based Doublet Chemotherapy in Combination With TSR-042
  • Official Title: Phase 1b Dose-Finding Study of Niraparib, TSR-022, Bevacizumab, and Platinum-Based Doublet Chemotherapy in Combination With TSR-042 in Patients With Advanced or Metastatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: 3000-01-002
  • NCT ID: NCT03307785

Conditions

  • Metastatic Cancer
  • Advanced Cancer
  • Solid Tumor
  • Non Small Cell Lung Cancer Metastatic
  • Non Small Cell Lung Cancer Stage IIIB
  • Non Small Cell Lung Cancer

Interventions

DrugSynonymsArms
NiraparibZejulaPart A: Dose Finding
TSR-042Part A: Dose Finding
Carboplatin-PaclitaxelPart B: Safety and Tolerability Evaluation
BevacizumabAvastinPart C: Dose Finding
TSR-022Part F: Safety and Tolerability Evaluation
Carboplatin PemetrexedPart E:Safety and Tolerability Evaluation
Carboplatin-Nab-PaclitaxelPart G: Safety and Tolerability Evaluation

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.

Trial Arms

NameTypeDescriptionInterventions
Part A: Dose FindingExperimentalTest safety and tolerability of combination therapy of Niraparib with TSR-042. To establish a Phase 2 dose (RP2D).
  • Niraparib
  • TSR-042
Part B: Safety and Tolerability EvaluationExperimentalTest the safety and tolerability of combination therapy of Carboplatin-Pacitaxel with TSR-042. To establish a Phase 2 dose (RP2D).
  • TSR-042
  • Carboplatin-Paclitaxel
Part C: Dose FindingExperimentalTest safety and tolerability of combination therapy of Niraparib and Bevacizumab with TSR-042. To establish a Phase 2 dose (RP2D).
  • Niraparib
  • TSR-042
  • Bevacizumab
Part D: Safety and Tolerability EvaluationExperimentalTest the safety and tolerability of combination therapy of Carboplatin-Paclitaxel and Bevacizumab with TSR-042. To establish a Phase 2 dose (RP2D).
  • TSR-042
  • Carboplatin-Paclitaxel
  • Bevacizumab
Part E:Safety and Tolerability EvaluationExperimentalTest the safety and tolerability of combination therapy of Carboplatin-Pemetrexed with TSR-042. To establish a Phase 2 dose (RP2D).
  • TSR-042
  • Carboplatin Pemetrexed
Part F: Safety and Tolerability EvaluationExperimentalTest the safety and tolerability of combination therapy of Carboplatin-Pemetrexed and TSR-022 with TSR-042. To establish a Phase 2 dose (RP2D).
  • TSR-042
  • TSR-022
  • Carboplatin Pemetrexed
Part G: Safety and Tolerability EvaluationExperimentalTest the safety and tolerability of combination therapy of Carboplatin-nab-Paclitaxel with TSR-042. To establish a Phase 2 dose (RP2D).
  • TSR-042
  • Carboplatin-Nab-Paclitaxel
Part H: Safety and Tolerability EvaluationExperimentalTest the safety and tolerability of combination therapy of Carboplatin-nab-Paclitaxel, TSR-022 with TSR-042. To establish a Phase 2 dose (RP2D).
  • TSR-042
  • TSR-022
  • Carboplatin-Nab-Paclitaxel
Part I: Safety and Tolerability EvaluationExperimentalTest the safety and tolerability of combination therapy of Carboplatin-Paclitaxel, TSR-022 with TSR-042. To establish a Phase 2 dose (RP2D).
  • TSR-042
  • Carboplatin-Paclitaxel
  • TSR-022

Eligibility 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 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and tolerability of TSR-042 and niraparib combination treatment using Common Terminology Criteria for Adverse Events (CTCAE v.4.03) in patients with advanced or metastatic cancer
Time Frame:Part A: Safety and Tolerability Evaluation - Approximately 2-Years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:Duration of response (DOR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:Disease control rate (DCR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:Progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:Anti-Drug Antibodies (ADA)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:To evaluate anti-drug antibodies (ADAs) of TSR-042 during Part A: TSR-042 and niraparib combination treatment or Part B: TSR-042 and carboplatin-paclitaxel combination treatment or Part C: TSR-042, niraparib and bevacizumab combination treatment or Part D: TSR-042, carboplatin-pacitaxel and bevacizumab combination treatment or Part E: TSR-042, carboplatin-pemetrexed combination treatment or Part F: TSR-042, TSR-022, carboplatin-pemetrexed combination treatment or Part G: TSR-042, carboplatin-nab-paclitaxel combination treatment or Part H: TSR-042, TSR-022, carboplatin-nab-paclitaxel combination treatment or Part I: TSR-042, TSR-022, carboplatin-paclitaxel combination treatment.
Measure:PK Parameter: AUC, 0-last assessment
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:PK Parameter: AUC, 0 to infinity
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:PK Parameter: AUC at steady state
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:PK Parameter: Minimum Concentration (Cmin)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:PK Parameter: Maximum Concentration (Cmax)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:PK Parameter: Clearance (CL)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:PK Parameter: Cmin at steady state (Cmin,ss)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:PK Parameter: Cmax at steady state (Cmax, ss)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:PK Parameter: Volume of Distribution (Vz)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:
Measure:PK Parameter: terminal half-life (t1/2)
Time Frame:Part A, Part B, Part C, Part D, Part E, Part F, Part G, Part H and Part I - Approximately 4 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Tesaro, Inc.

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