Oral Pazopanib Plus Oral Topotecan Metronomic Antiangiogenic Therapy for Recurrent Glioblastoma Multiforme (A) Without Prior Bevacizumab Exposure and (B) After Failing Prior Bevacizumab

Phase 2

Completed

Conditions: Brain Neoplasms
Glioblastoma
Glioblastoma Multiforme
Gliosarcoma
Central Nervous System Neoplasms

Interventions: Drug: topotecan
Drug: pazopanib

Registration Number: NCT01931098

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

Glioblastoma is the most common and most aggressive type of malignant brain tumor. The drug pazopanib is used to treat people with a type of kidney cancer. Topotecan is used to treat lung cancer. Both topotecan and pazopanib have individually been used to treat patients with glioblastoma and some anti-tumor activity has been found. Researchers want to see if these two drugs together may be able to help people with glioblastoma.

Objectives:

To learn if pazopanib with topotecan can help control glioblastoma. Also, to study the safety of this drug combination.

Eligibility:

Adults at least 18 years old whose glioblastoma has returned after treatment.

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

Brain computed tomography (CT) or magnetic resonance imaging (MRI) For these, participants lay in a machine that takes pictures.

Chest CT scan or x-ray

Heart electrocardiogram (EKG)

A questionnaire about quality of life

Participants will be assigned to a study group.

Participants will take the study drugs for 28-day cycles for up to 1 year. They will take capsules of topotecan by mouth once every day. They will take tablets of pazopanib by mouth once every day.

Participants will write in a diary the times they take the study drugs.

Participants will have several study visits during each cycle. These may include

Blood pressure measurement

Blood and urine tests

EKG

Physical exam and/or neurological exam

Brain MRI or CT scan to check the status of the disease

A symptom questionnaire

At the end of treatment, participants will have a physical exam. They may have blood drawn.

Participants will have follow-up calls once every 3 months to check.

Detailed Description: Background

* 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.

* 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%.

* Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGFR), Platelet-derived growth factor receptors (PDGFR), and c-Kit, and was recently Food and Drug Administration (FDA) approved for advanced renal cell carcinoma.

* Topotecan is an orally bioavailable topoisomerase I and Hypoxia-inducible factor 1 (HIF-1) alpha inhibitor with reasonably high central nervous system (CNS)/cerebrospinal fluid (CSF) penetration

* 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 Deoxyribonucleic acid (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

* The combination of Topotecan and Pazopanib has been directly demonstrated as active in

animal models

Objectives

* 6 month progression free survival rate for recurrent glioblastoma (rGBM) patients with no prior bevacizumab exposure treated with pazopanib and topotecan (Group A).

* 3 month progression free survival rate for rGBM patients with prior bevacizumab exposure treated with pazopanib and topotecan (Group B).

Eligibility

* Histologically proven intracranial glioblastoma multiforme (GBM) or gliosarcoma (GS) with evidence of progression on MRI or CT scan.

* Patient must have failed prior chemoradiation with temozolomide and any other therapies except Bevacizumab (BEV) (group A), or must have failed primary chemoradiation and a BEVincorporating treatment (group B).

* Patients must be greater than 12 weeks following completion of chemoradiation.

* Archived tumor tissue must be available for confirmation of the diagnosis

* Patients must be \> 18 years old.

* Patients must have a Karnofsky performance status of \> 60.

* Patients must have adequate organ function.

* No pregnancy or lactation.

* Patients must not have any significant medical illnesses that in the investigators opinion cannot be adequately controlled with appropriate therapy or would compromise the patients ability to tolerate this therapy.

* 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.

* No clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, or the absorption of the medications.

* 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).

* No evidence of active bleeding or bleeding diathesis.

* No known endobronchial lesions and/or lesions infiltrating major pulmonary vessels.

* No serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subjects safety, provision of informed consent, or compliance to study procedures.

* No ongoing toxicity from prior anti-cancer therapy that is \> Grade 1 and/or that is progressing in severity, except alopecia.

* No ongoing use of enzyme-inducing anti-epileptic agents (EIAEDs), unless 2 week washout has elapsed form last dose of EIAED.

* No known hypersensitivity to pazopanib or topotecan or to their excipients.

* No total daily dose of dexamethasone greater than 16 mg/day.

* No prior therapy with topotecan, pazopanib, or related drugs such as tyrosine kinase inhibitors, VEGF inhibitors (except bevacizumab). Prior treatment with Tyrosine kinase inhibitors (TKIs) that do not impact VEGFR -1, -2, or -3, Platelet Derived Growth Factor Receptor Alpha (PDGFRa) Platelet Derived Growth Factor Receptor Beta (-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 na(SqrRoot) ve patients and progression free survival (PFS) at 3 months for patients with prior bevacizumab treatment.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 35

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Glioblastoma or Gliosarcoma With No Prior Bevacizumab Exposure	topotecan	Topotecan .25 mg and pazopanib 600 mg are administered orally daily until progression, up to one year.
Glioblastoma or Gliosarcoma With No Prior Bevacizumab Exposure	pazopanib	Topotecan .25 mg and pazopanib 600 mg are administered orally daily until progression, up to one year.
Glioblastoma or Gliosarcoma With Prior Bevacizumab Exposure	topotecan	Topotecan .25 mg and pazopanib 600 mg are administered orally daily until progression, up to one year.
Glioblastoma or Gliosarcoma With Prior Bevacizumab Exposure	pazopanib	Topotecan .25 mg and pazopanib 600 mg are administered orally daily until progression, up to one year.

Primary Outcome Measures

Name	Time	Method
Proportion of Patients That Have Progressive Survival (PFS) at Six Months From Patient Registration for Bevacizumab Naive Patients and PFS at 3 Months for Patients With Prior Bevacizumab Treatment	six months from patient registration for bevacizumab naive patients, and 3 months from patient registration for patients with prior bevacizumab treatment	PFS was evaluated using the Kaplan-Meier product-limit survival curve methodology. For participants with no prior bevacizumab exposure, PFS is defined as 2 or more participants who are progression free at 6 months. For participants with prior bevacizumab exposure, PFS is defined as 1 or more participants who are progression free at 3 months. Progression is a 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) or clear worsening of evaluable disease or the appearance of any new lesions.

Secondary Outcome Measures

Name	Time	Method
Mean Symptom Interference Score Between Responders and Non-responders at Baseline and by Cycle	Baseline, and Cycles 1-6	Responders and Non-Responders symptom interference was assessed by the M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) questionnaire that determined how much general activity, mood, work inside and outside the home, relations with other people, walking and enjoying life interfered with a participant's life rated on an scale (0-10); 0 being not present and 10 being the worst. Responders were defined as patients with stable disease (SD) and partial response (PR) as their best response, and Non-responders were defined as patients with disease progression (PD) as their best response. Partial response is greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesion. Progressive disease is a 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease). And stable disease does not qualify for complete response, partial response or progression.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Date treatment consent signed to date off study, approximately 20 months and 18 days for the first Arm/Group, and 28 months and 23 days for the second Arm/Group.	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Overall Survival	From date of registration to date of death due to any cause, up to 5 years.	OS was evaluated using the Kaplan-Meier product-limit survival curve methodology and is defined as the time from date of registration to date of death due to any cause.
Mean Symptom Severity Score Between Responders and Non-responders at Baseline and by Cycle	Baseline, and Cycles 1-6	Responders and Non-Responders symptom presence and severity were assessed by the M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) questionnaire using an scale of (0-10); 0 being not present and 10 being the worst, and Responders were defined as patients with stable disease (SD) and partial response (PR) as their best response, and Non-responders were defined as patients with disease progression (PD) as their best response. Partial response is greater than or equal to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesion. Progressive disease is a 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease). And stable disease does not qualify for complete response, partial response or progression.