Glenn J. Lesser, M.D. - US grants

RSR 13 is a synthetic allosteric modifer of hemoglobin. It decreases the oxygen affinity of hemoglobin and augments oxygen unloading in the microvasculature which increases the oxygen diffusion gradient to the tissues. By increasing tissue oxygenation, RSR 13 may reduce tumor hypoxia and enhance the cytotoxic effects of radiation therapy used to treat cancer patients with solid tumors. This study will therefore evaluate the safety and toxicity of this new agent and its efficacy.

This phase I protocol will evaluate the safety and toxicity of escalating doses of oral phenylbutyrate in adult ambulatory patients with refractory or recurrent malignant glioma. Phenylbutyrate, a potential tumor differentiating agent and possible cytotoxic agent, has safely been given for many years to adults and children with urea cycle disorders where it acts as a sink for glutamine and thereby enhances nitrogen loss and prevents hyperammonemia. Phase I and II studies of phenylbutyrate and its metabolite phenylacetate (phenylacetate is formed by oxidation of phenylbutyrate) are ongoing in patients with a variety of malignancies. Both preclinical and early clinical data suggests that phenylacetate and phenylbutyrate are active against malignant gliomas. Preliminary results of a completed trial of intravenous phenylacetate in patients with malignant gliomas described radiographic responses and stable disease in a small number of patients. In this trial, the safety and toxicity of incrementally increasing doses of oral phenylbutyrate will be tested. OBJECTIVES: + To determine the maximum tolerated dose of sodium phenylbutyrate taken orally three times a day in patients with refractory CNS tumors until evidence of tumor progression. + To describe the pharmacokinetic parameters of oral phenylbutyrate and to escalate the dose of phenylbutyrate in an attempt to achieve plasma levels of 2-6 mmol/L while evaluating patient tolerability on the continuous oral exposure schedule. + To seek preliminary evidence of therapeutic activity of phenylbutyrate when administered on this schedule to patients with refractory CNS tumors. + To correlate any observed responses and toxicity with results of bioassaya and tissue sampling for phenylbutyrate activity.

The purpose of this study is to determine the efficacy, safety, pharmacokinetics and pharmacodynamics of multiple daily IV infusions of RSR13 at a therapeutically relevant daily dose (100 mg/kg) administered immediately prior to radiation therapy in patients with glioblastoma multiforme. This tumor is almost never cured with surgery, radiation therapy or chemotherapy. This research study is designed to look for evidence that RSR13 may improve results of radiation therapy for treatment of this type of tumor and to evaluate the safety and tolerance of RSR13 when given with radiation therapy. RSR13 is an investigational drug that increases the amount of oxygen released from the blood into the tissues. Lack of oxygen in a tumor can reduce the effectiveness of radiation therapy, therefore, RSR13 may improve the effectiveness of radiation therapy by increasing oxygen delivery to the tumor.

DESCRIPTION (provided by applicant): The primary aim of this proposal is to further our efforts to improve the treatment and care of adult patients with malignant brain tumors through continued participation as a fully funded member in the Phase I and II clinical investigations of the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. This consortium utilizes the resources, expertise and patient populations of 10 outstanding medical institutions with experienced, multidisciplinary brain tumor programs and demonstrated ability to evaluate novel therapeutic agents and modalities in this challenging patient population. During our past 6 years of partially funded provisional membership in NABTT, Wake Forest University has demonstrated: (1) an outstanding ability to accrue adult patients with newly diagnosed or recurrent high grade astrocytomas to Phase I and II clinical trials of novel therapeutic agents; (2) an outstanding ability to collect, collate, monitor and transmit all manners of clinical data, including tissue samples, and to do so in an exemplary and timely fashion; and (3) scientific leadership in the conception, development and implementation of new treatment paradigms for patients with malignant brain tumors. This effort is an extension of the sustained tradition of excellence in clinical research and trial design on the part of the NCI-designated Comprehensive Cancer Center of Wake Forest University which has demonstrated expertise in concept development, biostatistics, pharmacology, data management and patient accrual over the past 25 years. A second aim of this proposal is to share our institutional interest in and ability to collect, utilize and distribute brain tumor specimens and other clinical material with institutions interested in the molecular events responsible for glioma development and progression, and the immunohistochemical and molecular prognostic markers of tumor behavior and response to therapy. We continue to expect that the novel observations which arise from these efforts will lead to improvements in both the overall survival and quality of life of our patients afflicted with these tumors.

The overarching goal of the Wake Forest NCORP Cancer Center Research Base (WF NCORP RB) is to improve patient well-being and the quality of cancer care by developing, implementing and successfully completing innovative and feasible Cancer Control and Cancer Care Delivery (CCDR) clinical research studies. For nearly two decades as a CCOP and now NCORP Research Base, Wake Forest has maintained an exclusive focus on Cancer Control and CCDR studies and has emphasized efficient operational processes and extensive interactions with our NCORP Community Site and Minority Underserved Community Site partners. During the first 4 years of the NCORP network, the WF NCORP RB: opened 7 Cancer Control and 3 CCDR studies; enrolled 1,140 participants on WF NCORP RB studies; obtained approval for 5 additional concepts and protocols bringing the total remaining and planned accrual for active and pending trials to over 4,420 participants; and achieved a 33% accrual rate of racial/ethnic minority participants, as well as 68% women, 14% rural residents and 26% age 65 or greater. Over the next 6 years, we will build on and strengthen this highly successful platform by accomplishing the following Specific Aims: Specific Aim 1: Extend our cancer control clinical research activities in the following areas: cardiovascular complications of cancer therapy; radiation and chemotherapy-induced neurocognitive toxicities; and additional cancer and treatment-related symptoms and related-outcomes prioritized by NCI steering committees and those commonly associated with novel emerging treatment paradigms. Specific Aim 2: Elucidate and intervene upon patient, family, clinician, and organizational factors that influence cancer care delivery, emphasizing survivorship care, informal cancer caregivers and implementation of evidence-based supportive care services. Specific Aim 3: Illuminate biological mechanisms underlying cancer and treatment-related symptoms and toxicities in new and innovative multidisciplinary collaborative studies taking advantage of our growing biobank of blood, urine and salivary fluid specimens. Specific Aim 4: Identify and address determinants of cancer disparities via disparities-focused studies, integrated aims focused on underserved populations, and targeted recruitment of racial and ethnic minority and underserved populations across all Wake Forest NCORP research investigations. Specific Aim 5: Train the next generation of Cancer Control and CCDR researchers through mentoring and involvement of early career faculty, oncology trainees, post-doctoral fellows, and students in WF NCORP activities. Our ongoing and proposed Cancer Control and CCDR studies will continue to improve oncology care by informing best practices for symptom and late effect management as well as efficient, patient-centered, evidence-based cancer care delivery for diverse patient populations. In the next funding period, the WF NCORP RB will help accelerate the translation of knowledge in cancer control and cancer care delivery through close partnership with community and minority underserved sites and studies designed for future dissemination and implementation.

? DESCRIPTION (provided by applicant): Glioblastoma (GBM) is among the most aggressive and common primary brain tumors in adults. GBM patients have an extremely poor prognosis, and current treatments (including surgery, radiation therapy, and chemotherapy) have failed to extend median survival beyond 15 months. Therefore, the need for an effective GBM therapy is urgent. To achieve this goal, we need to understand the molecular machinery that drives GBM. Recent studies indicate that GBMs are heterogeneous, and four major subtypes have been identified by The Cancer Genome Atlas (TCGA) program. To further understand the molecular heterogeneity of GBM, we recently characterized a panel of 20 patient-derived glioblastoma xenografts (PDGX) at the proteomic level and compared each with the proteome of its corresponding parent tumor. An examination of the proteomic profiling of 20 PDGX revealed that 7 of them have activated epidermal growth factor receptor (EGFR) arising from both wild-type EGFR amplification and EGFRvIII. Such data is consistent with the observation that EGFR dysfunction is seen in a large proportion of GBMs. Furthermore, we found these specific PDGX with activated EGFR have elevated phosphorylation of several other proteins, including HER2, which only underscores the importance of testing an EGFR tyrosine kinase inhibitor (EGFR-TKI), such as AZD9291, since it has been proven to inhibit both EGFR and HER2. Another key characteristic of AZD9291 is its good brain penetration. Previous studies of EGFR-TKI in GBM patients have failed because of two fatal flaws: 1) the trial included all GBM patients, instead of just those with activated EGFR originating from a specific EGFR genotype, and 2) the EGFR-TKI had poor brain penetration. Both flaws have been removed from this proposed study. In fact, the proposed study will subdivide GBM patients with activated EGFR into two groups: 1) patients whose activated EGFR is wild-type; and 2) patients whose activated EGFR is EGFRvIII. This segregation is warranted because our data show that activated EGFR from wild-type and EGFRvIII utilize different signaling pathways. The focus of the UH2 part (stage 1) of this application is to test AZD9291 in preclinical models of GBM with activated EGFR originating from either wild-type EGFR with gene amplification or EGFRvIII (Aim 1). A positive response in the proposed preclinical studies will lead to the second goal of the UH2 part, which will involve phase 1b studies (Aim 2) to determine whether AZD9291, at safe doses, reaches the tumor, engages the target, and inhibits downstream signaling. A positive response from phase 1b studies will lead to UH3 part (stage 2), which will assess the efficacy of AZD9291 in phase 2a trials (Aim 3) consisting of control (standard of care) and treated arm (AZD9291 plus standard of care). Because of AZD9291's unique properties, our molecularly-defined preclinical models, and our inclusion of only those GBM patients expressing the target, the proposed studies will be the first to properly evaluate whether or not an EGFR-TKI can control GBM growth in patients whose tumor is driven by specific abnormalities in EGFR. To successfully complete the proposed study, we have assembled a well-rounded team consisting of Drs. Kwatra (PI), Lesser (PI), and Gilbert (director of the Brain Tumor Trials Collaborative).