Phase II NKTR-102 In Bevacizumab-Resistant High Grade Glioma
Condition: Anaplastic Astrocytomas; Anaplastic Oligodendrogliomas; Glioblastomas (GBM)
MeSH terms: Glioblastoma; Astrocytoma; Oligodendroglioma
Intervention: Etirinotecan pegol
Intervention MeSH terms: Etirinotecan pegol
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      High Grade Gliomas, including anaplastic astrocytomas, anaplastic oligodendrogliomas and
      glioblastomas (GBM), are the most common and most aggressive primary brain tumors. Prognosis
      for patients with high-grade gliomas remains poor. The estimated median survival for patients
      with GBM is between 12 to 18 months. Recurrence after initial therapy with temozolomide and
      radiation is nearly universal. Since May 2009, the majority of patients in the US with an
      initial recurrence of high-grade glioma receive bevacizumab, a monoclonal antibody against
      vascular endothelial growth factor (VEGF), which is thought to prevent angiogenesis in these
      highly vascular tumors. BEV has response rates from 32-62% and has improved overall median
      survival in patients with recurrent high-grade gliomas1. However, the response is short
      lived, and nearly 100% of patients eventually progress despite bevacizumab. No
      chemotherapeutic agent administered following progression through bevacizumab has made a
      significant impact on survival. Patients progress to death within 1-5 months after resistance
      develops. Therefore, patients with high-grade gliomas who have progressed through bevacizumab
      represent a population in dire need of a feasible and tolerable treatment.

      NKTR-102 is a topoisomerase I inhibitor polymer conjugate that was engineered by attaching
      irinotecan molecules to a polyethylene glycol (PEG) polymer using a biodegradable linker.
      Irinotecan released from NKTR-102 following administration is further metabolized to the
      active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN38), that causes DNA damage through
      inhibition of topoisomerase. The goal in designing NKTR-102 was to attenuate or eliminate
      some of the limiting side effects of irinotecan while improving efficacy by modifying the
      distribution of the agent within the body. The size and structure of NKTR-102 results in
      marked alteration in pharmacokinetic (PK) profile for the SN38 derived from NKTR-102 compared
      to that following irinotecan: the maximal plasma concentration (Cmax) is reduced 5- to
      10-fold and the half-life (t1/2 ) of SN38 is increased from 2 days to approximately 50 days.
      This altered profile leads to constant exposure of the tumor to the active drug. In addition,
      the large NKTR-102 molecule does not freely pass out of intact vasculature, which may account
      for relatively higher concentrations of the compound and the active metabolites in tumor
      tissues in in vivo models, where the local vasculature may be relatively more permeable. A
      145 mg/m2 dose of NKTR-102, the dose intended for use in this phase II clinical trial (and
      being used in the phase III clinical program), results in approximately the same plasma
      exposure to SN38 as a 350 mg/m2 dose of irinotecan, but exposure is protracted, resulting in
      continuous exposure between dosing cycles and lower Cmax. NKTR-102 was therefore developed as
      a new chemotherapeutic agent that may improve the clinical outcomes of patients.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Pathologically proven high-grade glioma (WHO III or IV) with astrocytic component and
             must be in recurrence after treatment with bevacizumab

          -  Patients must have received conventional radiation therapy of total radiation dosage
             (ranging from 5400 to 6000 cGy administered in daily fractions of 150 to 200 cGy over
             6 weeks) with concurrent temozolomide.

        Patients must have received bevacizumab and be in recurrence after bevacizumab treatment.

          -  Patients must be at least 28 days from last administration of cytotoxic chemotherapy
             and at least 14 days from the last administration of bevacizumab.

               -  Patients must be >18 years of age.

               -  Patients must have a life expectancy > 6 weeks

               -  Patients must have a Karnofsky Performance Score (KPS) >=50

               -  If female, patients of childbearing potential must have a negative serum beta-hCG
                  pregnancy test and must agree to use hormonal or barrier birth control with
                  spermicidal gel to avoid pregnancy during the study

               -  Adequate organ function (obtained within 14 days prior to randomization and
                  analyzed by the central laboratory) as evidenced by:

                    1. Absolute neutrophil count (ANC) >=1.5 X 10^9/L without myeloid growth factor
                       support for 7 days preceding the lab assessment;

                    2. Hemoglobin (Hgb) >= 9 g/dL (90 g/L); < 9 g/dL (< 90 g/L) is acceptable if
                       hemoglobin is corrected to >= 9 g/dL (90 g/L) as by growth factor or
                       transfusion prior to randomization;

                    3. Platelet count >=100 X 10^9/L without blood transfusions for 7 days
                       preceding the lab assessment;

                    4. Bilirubin <= 1.5 X upper limit of normal (ULN), except for patients with
                       documented history of Gilbert's disease;

                    5. Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <= 2.5
                       X ULN

                    6. Alkaline phosphatase (AP) <= 3 X ULN

                    7. Serum creatinine <= 1.5 mg/dL (133 µmol/L) or calculated creatinine
                       clearance >= 50 mL/min (using Cockcroft-Gault formula);

                    8. Women of childbearing potential (WCBP): negative serum pregnancy test (this
                       test is required of all women unless post-menopausal, defined as 12
                       consecutive months since last regular menses, or surgically sterile).

               -  Patients must be willing and able to comply with the protocol and provide written
                  informed consent prior to study-specific screening procedures.

        Exclusion Criteria:

        Patients who meet any of the following criteria must not be permitted entry to the study.

          -  Patients who have had chemotherapy within 28 days, radiotherapy within 28 days,
             biological therapy within 14 days, and investigational therapy within 21 days prior to
             first dose of experimental drug.

          -  Patients who have received prior treatment for cancer with a camptothecin derivative
             (eg, irinotecan, topotecan, and investigational agents including but not limited to
             exatecan, rubitecan, gimatecan, karenitecan, SN38 investigational agents, EZN-2208,
             SN-2310, and AR-67).

          -  Patients with the following co-morbid disease or incurrent illness:

               1. Patients with chronic or acute GI disorders resulting in diarrhea of any severity
                  grade; patients who are using chronic anti-diarrheal supportive care (more than 3
                  days/week) to control diarrhea in the 28 days prior to first dose of
                  investigational drug.

               2. Patients with known cirrhosis diagnosed with Child-Pugh Class A or higher liver
                  disease.

               3. Prior malignancy except for non-melanoma skin cancer and carcinoma in situ (of
                  the cervix or bladder), unless diagnosed and definitively treated more than 3
                  years prior to first dose of investigational drug.

               4. Severe/uncontrolled inter-current illness within the previous 28 days prior to
                  first dose of investigational drug.

               5. Significant known cardiovascular impairment (NYHA CHF > grade 2, unstable angina,
                  myocardial infarction within the previous 6 months prior to first dose of
                  investigational drug, or existing serious cardiac arrhythmia).

               6. Patients who require daily use of oxygen supplementation in the 28 days prior to
                  first dose of investigational drug.

               7. Any other significant co-morbid conditions that in the opinion of the
                  Investigator would impair study participation or cooperation.

          -  Patients with a known allergy or hypersensitivity to any of the components of the
             investigational therapy, including PEG or topoisomerase inhibitors.

          -  Patients receiving the following medications at the time of first dose of
             investigational drug:

               -  Pharmacotherapy for hepatitis B or C, tuberculosis, or HIV.

               -  enzyme inducing anti-epileptic medications (EIAEDs)

               -  other chemotherapy, other investigational agents , or biologic agents for

               -  the treatment of cancer including antibodies(eg, bevacizumab,

               -  trastuzumab, or pertuzumab) or any investigational agent(s).

          -  Pregnant or nursing patients will be excluded from the study.

          -  Patients receiving active treatment for HIV will be excluded from this study because
             non-nucleoside reverse transcriptase inhibitors, protease inhibitors and maraviroc (a
             CCR5-antagonist) are extensively metabolized by the cytochrome P450 system.
             Interactions with these drugs may induce or inhibit irinotecan or SN38 metabolism,
             leading to over or under-dosing.