Dose-Escalation Study of RRx-001 in Combination With Whole Brain Radiation in Subjects With Brain Metastases (BRAINSTORM)

A Phase 1 Dose-Escalation Study of RRx-001 in Combination With Whole Brain Radiation in Subjects With Brain Metastases (BRAINSTORM)

In this dose-escalation study, the safety and tolerability of escalating dose levels of RRx-001 administered intravenously twice a week in subjects with brain metastases receiving whole brain radiation therapy (WBRT) will be assessed. Once a maximum tolerated dose is identified, further (up to approximately 30) participants will be recruited. The study will use MRI to monitor changes in tumor blood flow associated with RRx-001.

Study Overview

• Status: Completed
• Conditions: Brain Metastases
• Intervention / Treatment: Drug: RRx-001 + WBRT

Detailed Description

The purpose of this research study is to test the safety and activity of whole brain radiation therapy with RRx-001, an experimental radiation sensitizer, in participants with brain metastases. As a radiation sensitizer, RRx-001 may increase the effect of whole brain radiation, the standard of care for brain metastases, on cancer cells in a specific target area while reducing damage to normal healthy cells. The ability to sensitize the cancer cells to radiation sets off a 'domino effect' of free radical damage in the tumor from a given amount or dose of radiation.

This study, which is called BRAINSTORM, since RRx-001 is associated with the development of a "free radical storm" in the brain tumors, is divided into two stages. In the first stage, approximately 3 participants at a time will be entered at a particular dose level of RRx-001 and then observed in order to see whether that dose results in side effects with radiation. If no bad side effects are observed, a second group of approximately 3 subjects will be given a slightly higher dose of RRx-001 and also monitored for side effects with radiation. This process will be repeated until a dose is reached, which has the most activity against the cancer cells without unacceptable side effects. At this point, more participants will be entered at this dose level until a maximum enrollment of approximately 30 participants has been reached.

RRx-001 releases a gas called nitric oxide, which widens the diameter of blood vessels, and allows the delivery of more oxygen to tumors. The presence of oxygen in tumors is critical for the effectiveness of radiation therapy, since cancer cells are about two to three times more vulnerable to radiation when oxygen is present. The reason that cancer cells are so much more vulnerable to the effects of radiation when oxygen is present is that radiation relies on the formation of harmful molecules known as free radicals that damage proteins and genetic material (DNA); without oxygen lower levels of free radicals are produced. Changes in the diameter go blood vessels will be studied by magnetic resonance imaging.

Unlike chemotherapies or other radiation sensitizers, RRx-001 does not have to enter the tumor to be effective because nitric oxide, as a gas, is able to spread or diffuse from the bloodstream into cancer cells.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Santa Monica, California, United States, 90404
      • Providence Saint John's Health Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Jackson, Michigan, United States, 49201
      • Allegiance Health
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • The Cancer Institute of New Jersey (Rutgers University)

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:

• Written informed consent
• Age ≥18 years
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• One or more brain metastases
• Prior radiation therapy to the brain is allowed with the exception of whole brain irradiation
• Subjects must be neurologically stable for at least 14 days prior to first dose of study drug;
• Male and female subjects who are not surgically sterile or post-menopausal must agree to use reliable methods of birth control for the duration of the study and for 90 days after the last dose of study drug administration; male partners of female subjects should use condoms for the duration of the study, and for 90 days after the last dose of study drug administration

Exclusion Criteria:

• Pregnant or lactating females
• Any evidence of severe or uncontrolled diseases
• Inadequate bone marrow reserve
• Previous whole brain radiotherapy
• Prior RRx-001 therapy
• Insufficient recovery from all side effects of previous anticancer therapies
• Evidence of blood clotting or bleeding abnormalities

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: RRx-001 + WBRT; RRx-001 administered intravenously twice a week (10, 17, 33, 55 mg) in subjects with brain metastases receiving whole brain radiation therapy (WBRT).	Drug: RRx-001 + WBRT; Subjects will receive a combination of RRx-001 and whole brain radiotherapy.; Other Names: Whole brain radiotherapy and RRx-001

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number, frequency and type of adverse events	To identify the maximum tolerated dose (MTD) of RRx-001 in combination with WBRT, defined as the dose of RRx-001 associated with a 20% probability of dose-limiting toxicity (DLT) in subjects with brain metastases	42 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate	To assess the Objective Response Rate of RRx-001 in combination with WBRT using modified Response Evaluation Criteria in Solid Tumors	4 months
Clinical Benefit Rate	To assess the Clinical Benefit Rate of RRx-001 in combination with WBRT using modified Response Evaluation Criteria in Solid Tumors	4 months
Intracranial Progression Free Survival	To obtain a preliminary estimate of the efficacy of RRx-001 in combination with WBRT in prolonging intracranial Progression Free Survival in subjects with brain metastases	4 months
Overall Survival	Overall Survival in subjects with brain metastases treated with WBRT and RRx-001	10 months
Brain Imaging Parameters	To evaluate changes in imaging parameters of the brain as a surrogate measure of pharmacologic activity and neurocognitive outcome	6 weeks

Collaborators and Investigators

• Sponsor: EpicentRx, Inc.
• Investigators: Principal Investigator: Michelle Kim, MD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2015
• Primary Completion (Actual): November 28, 2016
• Study Completion (Actual): November 12, 2020

Study Registration Dates

• First Submitted: August 11, 2014
• First Submitted That Met QC Criteria: August 11, 2014
• First Posted (Estimate): August 13, 2014

Study Record Updates

• Last Update Posted (Actual): November 3, 2021
• Last Update Submitted That Met QC Criteria: November 1, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasm Metastasis; Brain Neoplasms
• Other Study ID Numbers: RRx001-22-01