Abbreviated Title: Ph II Pazopanib Topotecan Version Date: 10/11/2019 Page 1 of 93 BRAIN TUMOR TRIALS COLLABORATIVE (BTTC) Abbreviated Title: Ph II Pazopanib Topotecan NCI Protocol #: 16C0034 Amendment Letter: B Version Date: 10/11/2019 BTTC Protocol #: BTTC12-01 NCT Number: NCT01931098 Title: A Phase II Trial of Oral Pazopanib plus Oral Topotecan Metronomic Antiangiogenic Therapy for Recurrent Glioblastoma Multiforme (A) without Prior Bevacizumab Exposure and (B) after Failing Prior Bevacizumab Coordinating Center: NCI BTTC Coordinating Center, Center for Cancer Research NCI Principal Investigator: Mark Gilbert, M.D. Neuro Oncology Branch (NOB), CCR, NCI 9030 Old Georgetown Road, Building 82, Room 235 Bethesda, MD 20892 Phone: 301-402-6383 Fax: 301-480-2246 Email: [email protected] Investigational Agents: None Commercial Agents: Pazopanib and Oral Topotecan Abbreviated Title: Ph II Pazopanib Topotecan Version Date: 10/11/2019 Page 2 of 93 A DISCLAIMER STATEMENT FOR BTTC PROTOCOLS This is a research protocol of the Brain Tumor Trials Collaborative describing an experimental treatment procedure. It is a privileged document and is not intended to be circulated or used for other purposes. The Brain Tumor Trials Collaborative assumes no responsibility for its use outside of the constraints of this research protocol or by investigators other than those approved by the Consortium. Abbreviated Title: Ph II Pazopanib Topotecan Version Date: 10/11/2019 Page 3 of 93 PRÉCIS Background x Glioblastoma (GBM) is the most common primary brain tumor. With optimal treatment, consisting of focal radiotherapy with concurrent chemotherapy, followed by adjuvant chemotherapy, median survival is 14.6 months. Most patients have evidence of tumor progression within one year of diagnosis despite treatment. At progression, treatment options are limited and mostly ineffective. x Recently, bevacizumab was approved for recurrent GBM patients who fail bevacizumab indicate a short survival, on the order of 10 weeks, an approximate PFS 3 and 6 months of 0%. x Pazopanib is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit, and was recently FDA approved for advanced renal cell carcinoma. x Topotecan is an orally bioavailable topoisomerase I and HIF-1 alpha inhibitor with reasonably high CNS/CSF penetration x Recent pre-clinical reports have begun to argue for the clinical testing of metronomic chemotherapy administration in various cancers. The theory of improved activity of Pazopanib + Topotecan administered metronomically is based on targeting tumor vasculature (both existing capillary endothelial cells and circulating bone marrow derived endothelial cell precursors), immune modulation, as well as tumor cell HIF-1 alpha inhibition, and the induction of DNA damage. Further support for the combination comes from recent data tying drug-induced VEGF inhibition to the induction of HIF-1 alpha activity in GBM suggesting possible synergy between Pazopanib and Topotecan x The combination of Topotecan and Pazopanib has been directly demonstrated as active in animal models Objectives x 6 month progression free survival rate for recurrent glioblastoma (rGBM) patients with no prior bevacizumab exposure treated with pazopanib and topotecan (Group A). x 3 month progression free survival rate for rGBM patients with prior bevacizumab exposure treated with pazopanib and topotecan (Group B). Eligibility x Histologically proven intracranial glioblastoma multiforme (GBM) or gliosarcoma (GS) with evidence of progression on MRI or CT scan. x Patient must have failed prior chemoradiation with temozolomide and any other therapies except BEV (group A), or must have failed primary chemoradiation and a BEV- incorporating treatment (group B). x Patients must be greater than 12 weeks following completion of chemoradiation. x Archived tumor tissue must be available for confirmation of the diagnosis x Patients must be > 18 years old. Abbreviated Title: Ph II Pazopanib Topotecan Version Date: 10/11/2019 Page 4 of 93 x Patients must have a Karnofsky performance status of > 60. x Patients must have adequate organ function. x No pregnancy or lactation. x Patients must not have any significant medical illnesses that in the investigator’s opinion cannot be adequately controlled with appropriate therapy or would compromise the patient’s ability to tolerate this therapy. x No history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix), unless in complete remission and off of all therapy for that disease for a minimum of 3 years are eligible. x No clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, or the absorption of the medications. x No prior major surgery or trauma within 28 days and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major). x No evidence of active bleeding or bleeding diathesis. x No known endobronchial lesions and/or lesions infiltrating major pulmonary vessels. x No serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures. x No ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is progressing in severity, except alopecia. x No ongoing use of enzyme-inducing anti-epileptic agents (EIAEDs), unless 2 week washout has elapsed form last dose of EIAED. x No known hypersensitivity to pazopanib or topotecan or to their excipients. x No total daily dose of dexamethasone greater than 16 mg/day. x No prior therapy with topotecan, pazopanib, or related drugs such as tyrosine kinase inhibitors, VEGF inhibitors (except bevacizumab). Prior treatment with TKIs that do not impact VEGFR -1, -2, or -3, PDGFR –a, -b of cKIT could be allowed. Design This is a 2 arm phase II trial of the combination of topotecan and pazopanib in patients with recurrent GBM or GS. Patients will be enrolled into one of the following groups: (A) Glioblastoma or gliosarcoma with no prior bevacizumab exposure: (B) Glioblastoma or gliosarcoma with prior bevacizumab exposure. Topotecan and pazopanib are administered orally daily. The primary efficacy endpoint is progression free survival (PFS) at six months from patient registration for bevacizumab naïve patients and PFS at 3 months for patients with prior bevacizumab treatment. Abbreviated Title: Ph II Pazopanib Topotecan Version Date: 10/11/2019 Page 5 of 93 TABLE OF CONTENTS PRÉCIS........................................................................................................................................... 3 TABLE OF CONTENTS ................................................................................................................ 5 INTRODUCTION .................................................................................................................. 8 Objectives ......................................................................................................................... 8 Background ...................................................................................................................... 8 ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 11 Eligibility Criteria .......................................................................................................... 11 Pretreatment Evaluation ................................................................................................. 16 Registration Procedures.................................................................................................. 17 Descriptive Factors ......................................................................................................... 19 STUDY IMPLEMENTATION ............................................................................................ 19 Study Design .................................................................................................................. 19 Drug Administration ...................................................................................................... 19 Dose Modifications: ....................................................................................................... 19 On Study Evaluation ...................................................................................................... 25 Questionnaires ................................................................................................................ 26 Study Calendar ............................................................................................................... 26 Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 28 CONCOMITANT MEDICATIONS/MEASURES .............................................................. 29 G-CSF Administration ................................................................................................... 29 Corticosteroids ............................................................................................................... 29 Anti-seizure medications ................................................................................................ 29 Febrile neutropenia ......................................................................................................... 29 Anti-emetics ..................................................................................................................