Repeat Radiation, Minocycline and Bevacizumab in Patients With Recurrent Glioma (RAMBO)

A Phase 1b/2 Study of Repeat rAdiation, Minocycline, and Bevacizumab in Patients With Recurrent gliOma (RAMBO)

The primary objective of step 1 is the rate of adverse events of minocycline and bevacizumab during reirradiation and of step 2 is the response rate to bevacizumab, reirradiation, and minocycline. The secondary objectives are the response rate, Progression Free Survival (PFS)-3, PFS-6, and effects on quality of life and cognition from repeat radiation and bevacizumab.

Study Overview

• Status: Completed
• Conditions: Recurrent Glioma
• Intervention / Treatment: Drug: Bevacizumab; Drug: Minocycline; Radiation: Radiation

Detailed Description

After providing informed consent, patients will undergo screening for eligibility to participate in the study. Screening will start within 21 days prior to dosing.

Subjects will have an MRI within 21 days of starting radiation. QOL and cognition measures will be performed within 21 days of starting radiation. Radiation will be given with parameters determined on an individual basis by the radiation oncologist. Bevacizumab will be continued at 10mg/kg IV every 2 weeks. Minocycline will be given twice a day starting at 100mg PO bid. MRI, QOL, and cognitive tests will be obtained 1, 3 and 6 months after the end of radiation.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients ≥18 years old with a life expectancy of at least 8 weeks
2. Radiographically proven recurrent (≥ first relapse), intracranial glioma
3. Previous treatment with external beam radiation
4. Radiographic progression on current or prior bevacizumab treatment
5. Women of child-bearing potential must have a negative pregnancy test within 7 days of initiation of dosing and must agree to use an acceptable method of birth control while on study drug and for 3 months after the last dose. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year. Men of child-bearing potential must also agree to use an acceptable method of birth control while on study drug, and for 3 months after the last dose.
6. Karnofsky performance status of ≥50
7. Adequate hematologic, hepatic, and renal function (absolute neutrophil count ≥1.0 x 109/L, Hgb >9 g/dL, platelet count ≥50 x 109/L, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤2.5x ULN, creatinine ≤1.5x ULN)
8. Willing and able to provide written informed consent prior to any study related procedures and to comply with all study requirements
9. Systolic blood pressure ≤ 160 mg Hg or diastolic pressure ≤ 90 mg Hg within 14 days prior to study registration
10. Prothrombin time/international normalized ratio (PT INR) < 1.4 for patients not on warfarin confirmed by testing within 14 days prior to study registration
11. Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight (LMW) heparin) must have no active bleeding or pathological condition that carries a high risk of bleeding, and must be on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin

Exclusion Criteria:

1. Use of an investigational drug within 14 days or within 5 half-lives of teh investigational drug, whichever is shorter
2. Progression within 3 months of previous radiation by Radiographic Assessment in Neurooncology (RANO) criteria
3. History of Grade 2 (CTCAE v4) or greater acute intracranial hemorrhage
4. A concurrent active cancer that requires non-surgical therapy (e.g. chemotherapy, radiation, adjuvant therapy).
5. Patients with serious illnesses, uncontrolled infection, medical conditions, or other medical history including abnormal laboratory results, which in the investigator's opinion would be likely to interfere with a patient's participation in the study, or with the interpretation of the results
6. Women of child-bearing potential who are pregnant or breast feeding
7. Unstable angina and/or congestive heart failure in the last 6 months, transmural myocardial infarction within the last 6 months, New York Heart Association grade II or higher congestive heart failure requiring hospitalization within 12 months prior to registration, evidence of recent myocardial infarction by EKG performed within 14 days of registration, serious or inadequately controlled cardiac arrhythmia, significant vascular and peripheral vascular disease, evidence of bleeding diathesis or coagulopathy
8. History of stroke, cerebral vascular accident (CVA) or transient ischemic attack within 6 months
9. Serious or non-healing wound, ulcer, or bone fracture or history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to registration, with the exception of the craniotomy for tumor resection
10. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration
11. Active connective tissue disorders, such as lupus or scleroderma, that in the opinion of the treating physician may put the patient at high risk for radiation toxicity

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Level 0: 100 mg bid; Patients receiving minocycline 100 mg bid, bevacizumab, and radiation therapy.	Drug: Bevacizumab; Bevacizumab will be administered in accordance with the FDA-approved dose for gliomas, 10mg/kg IV every 2 weeks. Bevacizumab will be continued every two weeks as long as tolerated. One cycle of bevacizumab will be 28 days, with treatments on day1 and day 15.; Other Names: Avastin; Drug: Minocycline; Minocycline will be given by mouth twice a day at the assigned dose level. Minocycline will be started on the day prior to radiation and continued until progression or intolerance.; Radiation: Radiation; Radiation planning will be individualized by the radiation oncologist based on the location of the current radiation field relative to prior radiation doses. The length and fractionation will be determined individually by the radiation oncologist.
Experimental: Dose Level 1: 200 mg bid; Patients receiving minocycline 200 mg bid, bevacizumab, and radiation therapy.	Drug: Bevacizumab; Bevacizumab will be administered in accordance with the FDA-approved dose for gliomas, 10mg/kg IV every 2 weeks. Bevacizumab will be continued every two weeks as long as tolerated. One cycle of bevacizumab will be 28 days, with treatments on day1 and day 15.; Other Names: Avastin; Drug: Minocycline; Minocycline will be given by mouth twice a day at the assigned dose level. Minocycline will be started on the day prior to radiation and continued until progression or intolerance.; Radiation: Radiation; Radiation planning will be individualized by the radiation oncologist based on the location of the current radiation field relative to prior radiation doses. The length and fractionation will be determined individually by the radiation oncologist.
Experimental: Dose Level 2: 400 mg bid; Patients receiving minocycline 400 mg bid, bevacizumab, and radiation therapy.	Drug: Bevacizumab; Bevacizumab will be administered in accordance with the FDA-approved dose for gliomas, 10mg/kg IV every 2 weeks. Bevacizumab will be continued every two weeks as long as tolerated. One cycle of bevacizumab will be 28 days, with treatments on day1 and day 15.; Other Names: Avastin; Drug: Minocycline; Minocycline will be given by mouth twice a day at the assigned dose level. Minocycline will be started on the day prior to radiation and continued until progression or intolerance.; Radiation: Radiation; Radiation planning will be individualized by the radiation oncologist based on the location of the current radiation field relative to prior radiation doses. The length and fractionation will be determined individually by the radiation oncologist.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events	Adverse Events were assessed from start of minocycline treatment (one day prior to start of radiation therapy) until 28 days following the end of radiation therapy. Adverse events were assessed using the Common Terminology for Adverse Events (CTCAE) version 4.0. Each event was assigned a grade (1-5), with lower grades indicating milder events. Events were categorized as severe (grade 3-4) or non-severe (grade 1-2). All adverse events were recorded, regardless of attribution to study treatment. Reported below are the number of patients who experienced any non-severe AE and the number of patients who experienced any severe AE. A full listing of AEs (severe and non-severe) are listed in the Adverse Events module of the Results section.	From first dose of study treatment to 28 days following radiation therapy (7-8 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) at 3 Months	Proportion of patients who have not progressed 12 weeks after the end of radiation therapy. Radiographic Assessment in Neurooncology (RANO) criteria will be used to assess progression and response. Estimates were done by Kaplan-Meier methods to account for patients whose data was censored prior to progression.	From start of study treatment until 12 weeks after radiation therapy (15-16 weeks)
Progression Free Survival (PFS) at 6 Months	Proportion of patients who have not progressed 26 weeks after the end of radiation therapy. Radiographic Assessment in Neurooncology (RANO) criteria will be used to assess progression and response. Estimates were done by Kaplan-Meier methods to account for patients whose data was censored prior to progression.	From start of study treatment until 26 weeks after radiation therapy (29-30 weeks)
Tabulation of Tumor Best Responses	Tabulation of the best tumor response participants achieved from baseline through 26 weeks after the end of radiation therapy. Radiographic Assessment in Neurooncology (RANO) criteria will be used to assess progression and response.	From start of study treatment until 26 weeks after radiation therapy (29-30 weeks)
Quality of Life Change Over Time	The M. D. Anderson Symptom Inventory - Brain Tumors (MDASI-BT) scale was used to assess patients at baseline, 4 weeks post-radiation, 12 weeks post-radiation, and 26 weeks post-radiation. Means and standard deviations from baseline and 26 post-radiation are reported here. MDASI-BT is a 28 item assessment using a 0-10 scale. Part 1 contains 22 items and assesses severity of symptoms, with a score range from 0 to 220. Part 2 contains 6 items and assesses the degree to which symptoms interfere with daily life, with a score range from 0 to 60. The Total score adds Part 1 and Part 2 together to assess total symptom burden, with a score range from 0 to 280. For all parts of the assessment, higher scores indicate a lower quality of life and worse symptom burden.	From start of study treatment until 26 weeks after radiation therapy (29-30 weeks)
Cognitive Change Over Time - DET	The Cogstate software was used to assess cognitive function at baseline, 4 weeks post-radiation, 12 weeks post-radiation, and 26 weeks post-radiation. Mean scores and standard deviations from baseline and 26 weeks post-radiation are reported here. Detection Test (DET) measures sensory registration, vigilance, and reaction time. DET is scored based on the speed of performance: mean of the log10 transformed reaction time for correct responses [measured in log10 milliseconds (MS)]. Lower scores meant a better performance.	From start of study treatment until 26 weeks after radiation therapy (29-30 weeks)
Cognitive Change Over Time - IDN	The Cogstate software was used to assess cognitive function at baseline, 4 weeks post-radiation, 12 weeks post-radiation, and 26 weeks post-radiation. Mean scores and standard deviations from baseline and 26 weeks post-radiation are reported here. Identification Test (IDN) measures basic information processing and decision speed. IDN is scored based on the speed of performance: mean of the log10 transformed reaction time for correct responses [measured in log10 milliseconds (MS)]. Lower scores meant a better performance.	From start of study treatment until 26 weeks after radiation therapy (29-30 weeks)
Cognitive Change Over Time - OCLT	The Cogstate software was used to assess cognitive function at baseline, 4 weeks post-radiation, 12 weeks post-radiation, and 26 weeks post-radiation. Mean scores and standard deviations from baseline and 26 weeks post-radiation are reported here. One Card Learning Test (OCLT) measures visuoperceptual learning and memory. OCLT is a score defined as the arcsine transformation of the square root of the proportion of correct responses to 80 OCLT questions. The transformed score ranges from 0 to 1.5708 where a higher score means better performance.	From start of study treatment until 26 weeks after radiation therapy (29-30 weeks)
Cognitive Change Over Time - GMLT	The Cogstate software was used to assess cognitive function at baseline, 4 weeks post-radiation, 12 weeks post-radiation, and 26 weeks post-radiation. Mean scores and standard deviations from baseline and 26 weeks post-radiation are reported here. Groton Maze Learning Test (GMLT) measures special learning and executive functioning, including working memory, error monitoring, and ability to integrate feedback to modify problem solving. GMLT score is the number of errors made (lower score indicates better performance).	From start of study treatment until 26 weeks after radiation therapy (29-30 weeks)

Collaborators and Investigators

• Sponsor: University of Utah
• Investigators: Principal Investigator: Adam Cohen, MD, University of Utah

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2012
• Primary Completion (Actual): January 12, 2018
• Study Completion (Actual): May 15, 2018

Study Registration Dates

• First Submitted: March 6, 2012
• First Submitted That Met QC Criteria: April 18, 2012
• First Posted (Estimate): April 19, 2012

Study Record Updates

• Last Update Posted (Actual): August 16, 2019
• Last Update Submitted That Met QC Criteria: August 9, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: glioma
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Recurrence; Glioma; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Bevacizumab; Minocycline
• Other Study ID Numbers: HCI55264

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No