A Phase II Study of Rindopepimut/GM-CSF in Patients with Relapsed EGFRvIII-Positive Glioblastoma (The “ReACT” Study)
This is a Phase II study of rindopepimut/GM-CSF in patients with relapsed, EGFRvIII-positive glioblastoma. Two groups of patients will be enrolled as follows: â?¢ Group 1: Bevacizumab naÃ¯ve: Group 1 will consist of bevacizumab naÃ¯ve patients who will be randomized (in a 1:1 ratio) to receive either rindopepimut/GM-CSF or control (KLH), in combination with bevacizumab. These patients will receive rindopepimut/GM-CSF or control (KLH) in a blinded fashion. â?¢ Group 2: Refractory to bevacizumab: Group 2 will consist of patients who have experienced recurrence or progression of glioblastoma while on (or within two months after discontinuing) bevacizumab therapy. These patients will be treated with rindopepimut/GM-CSF and bevacizumab in an open-label fashion. â?¢ An additional cohort (Group 2C) with up to 73 patients with measurable disease at study entry who have experienced recurrence or progression of glioblastoma while on (or within two months after discontinuing) bevacizumab therapy will be enrolled in order to verify the potentially promising, but preliminary tumor responses observed among the patients enrolled previously in Group 2. The enrollment of patients in this confirmatory cohort will be carried out in two stages so that enrollment may terminate early if the results in this cohort are not sufficiently promising to warrant further study (see Group 2C sample size considerations below). Rindopepimut/GM-CSF or KLH as a blinded control (hereinafter referred to as â??study vaccinationâ??) will be intradermally administered. Three initial â??primingâ?? vaccinations will be given at Days 1, 15 and 29, and then monthly (every 28 days) until progression of disease or intolerance. Bevacizumab infusions will begin on Day 1 and will be administered every two weeks until progression of disease or intolerance. Humoral immunologic response will be measured at baseline and at selected times following vaccination and at the time of disease progression. HLA typing will also be performed at baseline. Safety will be evaluated throughout the trial by the incidence of adverse events (AEs), physical examination findings, vital signs and clinical laboratory test results. AEs will be graded for severity using NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0, and collection of new AEs will continue until 28 days after the last dose of trial treatment or until the initiation of subsequent anticancer treatment, whichever occurs first. Any SAE occurring any time after the reporting period must be promptly reported if a causal relationship to study vaccination is suspected. Patients will undergo brain MRI every 8 weeks until disease progression, and whenever progression is suspected based on clinical symptoms. Tumor response will be assessed using the RANO response criteria for high-grade gliomas (Wen, Macdonald et al. 2010), which considers radiologic imaging, clinical status, and steroid dosing. The investigatorâ??s assessment of tumor response will guide clinical management and eligibility for continuation of study treatment in individual patients. For the purpose of final study analyses, tumor response will be assessed by an independent review committee (IRC). Whenever clinically appropriate, stereotactic biopsy or resection will be performed in accordance with standard of care for patients with progressive disease. To differentiate true progression from potentially toxic or therapeutic inflammatory responses presenting as radiographic or clinical changes, histologic verification of progression will be performed whenever feasible and appropriate (observing the recommendation to avoid surgery within 28 days of bevacizumab dosing). Tumor tissue may also be examined to assess persistence of EGFRvIII expression and other tumor or immune markers. At the time of tumor progression, patients may receive alternate anti-cancer therapy at the discretion of the treating oncologist, including continuation of bevacizumab dosing if clinically appropriate. These therapies will be documented, and patients will be followed for survival every eight weeks until study closure.
Inclusion Criteria 1. Age ï¿½18 years of age. : 2. Histologic diagnosis of glioblastoma (WHO Grade IV). 3. Previous treatment must include surgery (biopsy, partial resection, or full surgical resection), conventional radiation therapy and temozolomide (TMZ). 4. First or second relapse of de novo glioblastoma, or first diagnosis or first relapse of secondary (transformed) glioblastoma. Patients enrolled with secondary (transformed) glioblastoma must have received treatment with temozolomide and radiation for glioma prior to entry, and may be eligible for enrollment upon diagnosis of transformed glioblastoma if temozolomide or radiation are not appropriate at their stage of disease. Patients to be enrolled to Group 2 and Group 2C must have had progression of glioblastoma (including clinical or radiographic progression in accordance with RANO criteria) while receiving bevacizumab or within two months of discontinuing treatment with bevacizumab. 5. Screening MRI must be obtained at least 4 weeks after any salvage surgery, and at least 12 weeks after radiation therapy (to minimize the potential fofor MRI changes related to radiation necrosis that might be misdiagnosed as disease progression) or at least 4 weeks after radiation for a new lesion outside the prior primary radiation field. 6. If prior therapy with gamma knife or other focal high-dose radiation, must have subsequent histologic documentation of local relapse, or relapse with new lesion outside the irradiated field. 7. Evaluable disease (as per RANO criteria). Patients enrolled to Group 2C must have measurable disease that can be followed serially as ï¿½Targetï¿½ disease per RANO . 8. Documented EGFRvIII positive tumor status, determined by polymerase chain reaction (PCR) assay on glioblastoma tissue, performed at a sponsor-designated central laboratory. A tumor sample from either the initial diagnosis or more recent relapse will be acceptable; however, the most recent sample is preferred. 9. Resolution of all chemotherapy or radiation-related toxicities ï¿½ CTCAE Grade 1 severity, except for alopecia and hematologic toxicity. 10. If applicable, systemic corticosteroid therapy must be at a dose of ï¿½ 4 mg of dexamethasone or equivalent per day during the week prior to Day 1. 11. Acceptable screening clinical laboratory values: ï¿½ Absolute neutrophil count (ANC) greater than 1,500/Î¼l ï¿½ Platelet count greater than 100,000/Î¼l ï¿½ Total bilirubin less than 1.6 mg/dl ï¿½ Aspartate aminotransferase (AST) / Alanine aminotransferase (ALT) ï¿½ 2.5 x ULN ï¿½ Creatinine less than 1.2 x ULN ï¿½ Urine protein/creatinine ratio ï¿½ 1.0 ï¿½ International normalized ratio (INR) less than 1.5 ï¿½ Activated partial thromboplastin time (APTT) less than 1.5 x ULN 12. KPS of ï¿½ 70%. 13. Life expectancy greater than 12 weeks. 14. Both men and women enrolled in this trial must use adequate birth control measures during the course of the trial and for at least three months after discontinuing study treatment, defined as double barrier contraception (ie, condom plus spermicide in combination with a female condom, diaphragm, cervical cap or intrauterine device), implants, injectables, combined oral contraceptives, sexual abstinence (abstinence from intercourse during the ovulation period) or vasectomised partner. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement. 15. Personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of and agreed with all pertinent aspects of the study. Exclusion Criteria 1. Subjects unable to undergo an MRI with contrast. : 2. Contrast-enhancing tumor component crossing the midline (unless patient is felt to be an appropriate study candidate after discussion with, and agreement by, the Celldex Medical Monitor) or tumor dissemination (subependymal or leptomeningeal) 3. Presence of diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease 4. History, presence, or suspicion of metastatic disease 5. Prior receipt of vaccination against EGFRvIII or other EGFRvIII-targeted agents. 6. Any known contraindications to receipt of study drugs, including known allergy or hypersensitivity to keyhole limpet hemocyanin (KLH), GM-CSF (sargramostim; LEUKINEÂ®), polysorbate 80 or yeast derived products, or a history of anaphylactic reactions to shellfish proteins. 7. Applicable only for patients to be randomized to Group 1: Prior receipt of bevacizumab or other VEGF- or VEGF receptor-targeted agents (Note: patients who have received one dose of bevacizumab according to standard of care may be eligible for enrollment to Group 1, provided that study Day 1 will occur within 18 days after initiation of bevacizumab, and a MRI performed prior to initiation of bevacizumab is available and suitable for use as the screening assessment.) 8. Known contraindication or hypersensitivity to any component of bevacizumab. 9. Prior treatment with prolifeprospan 20 with carmustine wafer, unless wafers were placed over one year prior to entry and believed fully dissolved with no resulting artifact impacting interpretation of the baseline MRI. 10. Prior therapeutic intracerebral agents (agents used for diagnosis, imaging or visualization, even if investigational, are not exclusionary). 11. Use of non-protein based investigational therapy within 14 days prior to Day 1 or use of antibody-based investigational therapy within 28 days prior to Day 1. 12. Clinically significant increased intracranial pressure (e.g., impending herniation), uncontrolled seizures, or requirement for immediate palliative treatment 13. Evidence of recent hemorrhage on screening MRI of the brain with the following exceptions: presence of hemosiderin; resolving hemorrhagic changes related to surgery; presence of punctate hemorrhage in the 22. Active infection requiring treatment or an unexplained febrile ( greater than 101.5o31 F) illness. Infection controlled by therapy will not be exclusionary provided it is not consistent with exclusion criterion . 23. Known immunosuppressive disease, active systemic autoimmune diseases such as lupus, receipt of systemic immunosuppressive therapy, human immunodeficiency virus (HIV) infection, Hepatitis B or Hepatitis C 24. Uncontrolled hypertension, blood pressure of greater than 150 mmHg systolic and greater than 100 mmHg diastolic, or history of hypertensive encephalopathy 25. Stroke, transient ischemic attack, unstable angina, myocardial infarction or congestive heart failure (New York Heart Association Grade II or greater) within the past 12 months or serious uncontrolled cardiac arrhythmia. 26. Concurrent neurodegenerative disease, dementia or significantly altered mental status that would prohibit the understanding or rendering of informed consent and compliance with the requirements of the protocol. 27. Unstable or severe intercurrent medical conditions such as lung (FEV1 28. Women who are pregnant or lactating. All female patients with reproductive potential must have a negative pregnancy test prior to Day 1. less than 50%) disease, chronic renal disease, or uncontrolled diabetes mellitus. 29. History of any malignancy (other than glioblastoma) during the last three years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer, cured early-stage prostate cancer in a patient with Prostate Surface Antigen (PSA) level. 30. Evidence of current drug or alcohol abuse. 31. Any other acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with trial participation or trial drug administration or could interfere with the interpretation of trial results and, in the judgment of the investigator
Gliomas, tumors that arise from glial cells, represent a histologically heterogeneous spectrum of tumors, ranging from benign tumors to malignant and highly aggressive tumors accounts for over half of all gliomas, which, in turn, account for 80% of all malignant brain and central nervous system (CNS) tumors. In European and North American countries, the incidence rate is approximately 2 to 3 new cases per 100,000 people per year. Composed of poorly differentiated neoplastic astrocytes, glioblastomas primarily affect adults, and they are located preferentially in the central hemispheres. Much less commonly, glioblastoma can affect the brain stem in children and the spinal cord. These tumors may develop from lower-grade astrocytomas (WHO grade II) or anaplastic astrocytomas (WHO grade III), but, more frequently, they manifest without evidence of a less malignant precursor lesion. The first-line treatment of glioblastoma is usually surgery, either to confirm the diagnosis with a biopsy or to remove as much of the tumor as possible. Standard adjuvant treatment includes radiotherapy with TMZ chemotherapy. Bevacizumab monotherapy is an FDA-approved therapeutic option following initial therapy, for patients with progressive or recurrent glioblastoma. However, regardless of the treatment regimen, the aggressive infiltration of glioblastoma throughout the brain typically produces progressive disability and ultimately leading to death in nearly all cases. This is principally because conventional therapy is severely constrained by the need to eradicate tumor cells that are hidden behind a restrictive blood-brain barrier or that have invaded eloquent brain tissue. As a result, surgery and radiation must be curtailed to avoid incapacitating collateral damage, and chemotherapy becomes toxic to rapidly dividing extracerebral normal tissues before eliminating all intracerebral tumor cells. The immune system, however, has the capacity to eliminate altered neoplastic cells with incredible specificity. Although the CNS is considered to be an immune privileged site, under certain circumstances CNS antigens are capable of generating strong immune responses (eg, multiple sclerosis or encephalitis). Theoretically, disruption of the blood brain barrier due to tumor infiltration or in the post-operative or post-radiation setting or following treatment with chemotherapy could allow the immune system to gain access to antigens in the brain. It is possible that an acutely ruptured blood brain barrier could reveal an area to which a patientï¿½s immune system has had only limited exposure, providing an ideal setting to generate de novo immune responses in the absence of pre-existing immune regulatory elements. Furthermore, it appears that the immune system regenerating from a cytotoxic insult may be hyperacutely activated and particularly responsive due both to increased stimulatory cytokines within the environment and reduced regulatory elements. Rindopepimut is a vaccine designed to generate an immune response against the tumor-specific antigen EGFRvIII. The epidermal growth factor receptor (EGFR) gene is involved in the control of cell proliferation and is either amplified or overexpressed in more than one-third of glioblastomas . The EGFR mutant EGFRvIII, which is present in 25-30% of glioblastomas, has been associated with poor long term survival and a prognosis independent of previously identified prognostic factors, including gross total resection. The mutation, which results in a continuously activated receptor, has also been shown to correlate with increased tumorigenicity in mouse models. EGFRvIII may be an ideal candidate for targeted vaccine therapy since it is expressed by glioblastoma cells and reported to be present in a number of other human tumors, but not expressed in normal tissues and thus is less likely to induce autoimmunity or muted immune responses due to self tolerance. The lack of expression of EGFRvIII in normal tissues suggests that this tumor antigen may be particularly applicable for active immunization. Unlike the case with many tumor-associated antigens, patients may not have developed significant tolerance to this antigen, which will not have been previously exposed to their immune system. Furthermore, eliciting a potent EGFRvIII-specific immune response is not likely to impact healthy tissues, as can be observed with EGFR targeting agents. As described in protocol, rindopepimut/GM-CSF has been administered as an intradermal vaccine to a total of 125 patients with glioblastoma. These trials have shown that rindopepimut/GM-CSF has a good tolerability profile, with promising indications of clinically meaningful activity. In all three phase II trials, progression-free survival (PFS) and overall survival (OS) were significantly increased for patients treated with rindopepimut/GM-CSF as compared to a cohort of EGFRvIII-positive historical controls matched for major trial eligibility requirements, as well as to published results for adjuvant radiation and temozolomode.
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