Study of Niraparib, TSR-022, Bevacizumab, and Platinum-Based Doublet Chemotherapy in Combination With TSR-042
Condition: 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
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis
Intervention: Niraparib; TSR-042; Carboplatin-Paclitaxel; Bevacizumab; TSR-022; Carboplatin-Pemetrexed; Carboplatin-Nab-Paclitaxel
Intervention description: 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.; 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).; 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.; 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.; 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.; 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; 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.
Intervention MeSH terms: Paclitaxel; Albumin-Bound Paclitaxel; Bevacizumab; Carboplatin; Pemetrexed; Niraparib; Dostarlimab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 58.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

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 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.