Neoplasms

All Conditions

Rare Diseases

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Antibodies, Monoclonal

Vaccines

Temozolomide

Immunoglobulins

Antineoplastic Agents, Alkylating

Alkylating Agents

Patients will receive TMZ at a target dose of 150-200 mg/m\^2/d for 5 days every 4 (+2) weeks for up to 12 cycles. DC vaccines will be administered in equal amounts to both inguinal regions. DC vaccines #1-3 occur every 2 weeks and all subsequent vaccines (up to 10) occur monthly. Group 1 patients will receive autologous unpulsed DC vaccines administered to a single side of the groin and saline administered to the contralateral side the day prior to the 4th DC vaccine as pre-conditioning.

Patients will receive TMZ at a target dose of 150-200 mg/m\^2/d for 5 days every 4 (+2) weeks for up to 12 cycles. DC vaccines will be administered in equal amounts to both inguinal regions. DC vaccines #1-3 occur every 2 weeks and all subsequent vaccines (up to 10) occur monthly. Group 2 patients will receive a single dose of Td toxoid administered to a single side of the groin and saline administered to the contralateral side the day prior to the 4th DC vaccine, which is always given bilaterally at the groin site.

Patients will receive TMZ at a target dose of 150-200 mg/m\^2/d for 5 days every 4 (+2) weeks for up to 12 cycles. DC vaccines will be administered in equal amounts to both inguinal regions. DC vaccines #1-3 occur every 2 weeks and all subsequent vaccines (up to 10) occur monthly. Group 3 patients will receive the first 3 DC vaccines every 2 weeks, same as Groups 1 and 2, but they will also receive varlilumab intraveneously (IV) 7 days before vaccine #1 and again at the same visit as vaccine #1, as well as 7 days before every DC vaccine except vaccine #2. Prior to the 4th vaccine, patients will receive a single dose of Td toxoid administered to a single side of the groin and saline administered to the contralateral side.

2x10\^7 human CMV pp65-LAMP mRNA-pulsed autologous DCs are given intradermally and bilaterally at the groin site (divided equally to both inguinal regions). Patients will receive up to a total of 10 DC vaccines.

Human CMV pp65-LAMP mRNA-pulsed autologous DCs

Temozolomide is a standard chemotherapy given to all enrolled patients at a targeted dose of 150-200mg/m2/d for 5 days every 4 (+ 2) weeks for up to 12 cycles (patients with unmethylated MGMT gene promoter will receive only cycle 1)

Varlilumab is an agonist anti-CD27 monoclonal antibody

Varlilumab

A single dose of Td toxoid (1 flocculation unit, Lf, in 0.4 mLs) administered to a single side of the groin given intradermally

Patients in Group I will receive 1 x 10\^6 autologous unpulsed DCs in saline administered to a single side of the groin intradermally 1 day before the fourth vaccine.

Unpulsed DCs

Annick Desjardins, MD, FRCPC

Patients with newly diagnosed glioblastoma will be consented following tumor resection then undergo leukapheresis for harvest of peripheral blood leukocytes for generation of dendritic cells. Subjects will then receive standard of care (planned 6 weeks) radiation therapy (RT) and concurrent temozolomide (TMZ) at a standard targeted dose of 75 mg/m2/day.

The study cycle of TMZ comprises a targeted dose of 150-200mg/m2/day for 5 days every 4 (+2) weeks for up to 12 cycles (patients with unmethylated MGMT gene promoter will receive only cycle 1). All patients will receive up to a total of 10 DC vaccines called pp65 CMV dendritic cells (DC). Dendritic Cell (DC) vaccines #1-3 will be given every two weeks, thus delaying the initiation of TMZ cycle 2 for patients receiving TMZ. All remaining TMZ/vaccine cycles will be 4 (+2) weeks in length.

After the first 3 DC vaccines given during Cycle 1 of TMZ, the remaining DC vaccine injections are given on Day 21 (+/- 2 days) of each TMZ cycle. Subjects with unmethylated MGMT will only receive one cycle of adjuvant TMZ; however, their vaccine schedule will follow the same 4 (+ 2) week TMZ cycle schedule.

Following RT, patients will be randomized into 1 of 3 groups. Groups 1 and 2 will be blinded. The groups differ in the type of pre-conditioning received prior to DC vaccine #4; additionally, Group 3 will be receiving infusions of varlilumab 7 days prior to and with vaccine #1 and 7 days prior to vaccine #3+. The pre-conditioning for each group is as follows: Group 1: Unpulsed DC pre-conditioning prior to DC vaccine #4; Group 2: Tetanus-diphtheria (Td) pre-conditioning prior to DC vaccine #4; Group 3: Td pre-conditioning prior to DC vaccine #4 and varlilumab infusion at 7 days prior to each DC vaccine (except DC vaccine #2) with Td pre-conditioning prior to vaccine #4.

Human cytomegalovirus (CMV) is a common endemic β-Herpesvirus, and over half of adults have been infected with CMV. CMV does not usually cause significant clinical disease but can cause health problems for people with weakened immune systems. Expression of proteins unique to human CMV has been reported within a large proportion of malignant gliomas (MGs), including detection of the human CMV immunodominant protein pp65-LAMP (pp65-lysosomal-associated membrane protein). Human CMV antigens were not detected in surrounding normal brain samples. The presence of highly-immunogenic human CMV antigens within MGs affords a unique opportunity to target these tumors immunologically.

Dendritic cells (DCs) are antigen-presenting cells in the immune system. DCs are activated then migrate to the lymph nodes to interact with T cells and B cells, which initiates the adaptive immune response. This study generates autologous DCs from peripheral blood leukocytes obtained from the subject during leukapheresis. RNA transfection is the method used in this study for loading antigens onto DCs. DCs are pulsed with human CMV pp65-LAMP mRNA.

Tetanus-diphtheria (Td) toxoid is used for active immunization in children and adults against infection with the bacteria Clostridium tetani and Corynebacterium diphtheria. It is thought that Td toxoid induces an inflammatory milieu within the intradermal vaccine site, thereby promoting the migration of injected tumor-specific DCs. Additionally, in the context of vaccinating the host with tumor-derived peptides, conditioning the vaccine site with Td toxoid has demonstrated enhanced immunogenicity with these peptides. Previous trials have suggested that giving the Td prior to immunotherapy may help improve the effectiveness of the DC vaccine by activating the immune response. This study will further examine whether Td helps activate the immune response by comparing subjects who receive Td pre-conditioning to subjects who receive autologous unpulsed DCs as pre-conditioning.

Varlilumab is a fully human monoclonal antibody (mAb) that targets CD27, a critical molecule in the activation pathway of lymphocytes. Varlilumab is an agonist anti-CD27 mAb that has been shown to activate human T cells in the context of T cell receptor stimulation. In pre-clinical models, varlilumab has been shown to mediate anti-tumor effects and may be particularly effective in combination with other immunotherapies. Anti-CD27 mAb has emerged as a novel costimulatory immune modulator that depletes TRegs without impairing activated effector T cells to improve antitumor immunity. We hypothesize that TReg inhibition through Varlilumab may increase polyfunctional immune responses to CMV.

Assignment to Groups 1 and 2 is blinded, and neither the study team nor the subject knows which pre-conditioning regimen is given. Assignment to Group 3 is not blinded, and the subject and study team know that Td preconditioning and Varlilumab is given.

DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab

OS is defined as the time in months between randomization and death, or last follow-up if alive (Groups 1 and 2). Kaplan-Meier methods will be used to estimate median OS

Percentage of patients with unacceptable toxicity (all Groups)

Change between baseline and nadir before the 2nd cycle of TMZ (Combined Groups 1 and 2, Group 3)

OS is defined as the time in months between randomization and death, or last follow-up if alive (Group 3). Kaplan-Meier methods will be used to estimate median OS

PFS is defined as the time between randomization and initial failure (disease progression or death) (all Groups). If the patient remains alive without disease progression, PFS will be censored at the time of last follow-up. Kaplan-Meier methods will be used to estimate median PFS

CCL3 levels in serum 24, 48, and 72 hours after pre-conditioning by multiplex. The median CCL3 level will be presented

Celldex Therapeutics

Annick Desjardins, MD

Assistant Professor of Neurosurgery

Symptoms and General Pathology

Nervous System Diseases

Neoplasm Metastasis

Brain Neoplasms

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Kimberly L Blackwell, MD

This clinical trial is being done to learn more about how different types of cancer treatments affect cancer cells when they spread to the brain. Many cancer treatments are not able to make their way into the brain or into spinal fluid of the central nervous system. This is because they cannot cross what is called the "blood-brain barrier" or "BBB". The BBB is like a protective shield that only allows certain materials pass through to reach the brain but not others. This study is being initiated to help researchers learn more about what types of cancer treatments make it through the BBB to attack cancer cells within the brain, and what treatments do not make it through the BBB. Learning more about this may help future researchers develop more effective cancer drugs that better fight cancer cells that have spread to the brain.

Very little is known about the penetration of systemic therapies through the normal blood brain barrier and the ways in which a brain metastasis or radiation would impact the permeability of the blood brain barrier. This study would be one of the first to examine the concentrations of systemic cancer therapies in the cerebrospinal fluid (CSF) with matched serum samples. Additionally, the concentration of these therapies in brain metastasis surgical specimens would be of particular interest to correlate with serum and CSF levels, length of time on therapy, and latency to developing brain metastases in future studies.

As participants in this study, patients scheduled for a lumbar puncture per their standard of care treatment will be subject to a withdrawal of 15cc's of cerebrospinal fluid for pharmacokinetic analysis. They will also have a blood draw of 5mL within 2 hours of the lumbar puncture for serum pharmacokinetics. If the patient is eligible for and elects to proceed with surgical resection of a brain metastasis, optional CSF and serum samples would be drawn at the time of resection.

Blood samples and cerebrospinal fluid samples are to be collected for pharmacokinetic analysis by blood draw and lumbar puncture, respectively.

Pharmacokinetics of Systemic Anti-Cancer Therapies in the Cerebrospinal Fluid (CSF) of Patients With Advanced Cancer

CSF Pharmacokinetics of Systemic Anti-Cancer Therapies in Patients With Advanced Cancer

CSF pharmacokinetics of systemic anti-cancer therapies, as measured by the concentration of their metabolites in the cerebrospinal fluid, will be obtained via lumbar puncture. The lumbar puncture will take place within 2 half-lives of the last dose of systemic therapy. Because a wide variety of anti-cancer therapies will be studied in this trial, there is significant variability in the half-lives of these therapies. Some will take place 2-24 hours after the last dose of systemic therapy. Some will take place 1-6 days after the last dose of systemic therapy. Some will take place 1-3 weeks after the last dose of systemic therapy. The time of the lumbar puncture procedure will depend greatly on the identity of the systemic therapy with which the subject is being treated. In patients undergoing surgical resection of a brain metastasis, an additional CSF sample is optional.

CSF and serum pharmacokinetics of systemic anti-cancer therapies, as measured by the concentration of their metabolites, will be obtained via lumbar puncture and blood draw, respectively. The lumbar puncture and blood draw will take place together within 2 half-lives of the last dose of systemic therapy. Because a wide variety of anti-cancer therapies will be studied in this trial, there is significant variability in the half-lives of these therapies. Some will take place 2-24 hours after the last dose of systemic therapy. Some will take place 1-6 days after the last dose. Some will take place 1-3 weeks after the last dose. The time of the lumbar puncture procedure will depend greatly on the identity of the systemic therapy with which the subject is being treated. In patients undergoing surgical resection of a brain metastasis, an additional matched CSF and serum sample is optional.

Duke University

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Trastuzumab

Pertuzumab

Antineoplastic Agents, Immunological

Four cohorts will enroll in a dose escalation of pertuzumab and a consistent dose of trastuzumab. The cohorts will be assigned as follows:

Cohort: Intrathecal Dose:

1. 10mg pertuzumab, 80mg trastuzumab
2. 20mg pertuzumab, 80mg trastuzumab
3. 40mg pertuzumab, 80mg trastuzumab
4. 80mg pertuzumab, 80mg trastuzumab

Pertuzumab will be administered intrathecally via a lumber puncture. The dosing cohorts are described above in the arm description.

Trastuzumab will be administered intrathecally via a lumber puncture. The dosing cohorts are described above in the arm description.

Kimberly Blackwell, MD

The purpose of this research study is to determine how well pertuzumab and trastuzumab works in treating breast cancer that has spread to the brain. Pertuzumab and trastuzumab are treatments that stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2).

Pertuzumab and trastuzumab have been found to be very effective for HER2-positive breast cancer and are FDA approved for treatment of metastatic breast cancer outside of the brain when given through the vein. This suggests that pertuzumab and trastuzumab may help shrink or stabilize HER2-positive breast cancer that has spread to the brain in this research study.

In this research study, the investigators are looking to see whether pertuzumab and trastuzumab will work to decrease the size of or stabilize breast cancer that has spread to the brain.

Intrathecal administration of pertuzumab and trastuzumab will occur via lumbar puncture (spinal tap) under fluoroscopic guidance by interventional radiology at Duke University Medical Center. The spinal needle will be inserted into the spinal column and 7 mL of cerebrospinal fluid (CSF) will be collected. Once the CSF is removed, the intrathecal pertuzumab and trastuzumab will be administered using aseptic technique. At certain time points the CSF will be analyzed for free cell DNA. If subjects consent, the CSF fluid will also be stored for additional future research.

Patients will be treated using a 3+3 dose-escalation design. Patients will not be accrued to the next cohort (dose escalation) until at least one patient on the previous cohort has been followed for six weeks. If a dose limiting toxicity (DLT) is seen in a patient then the cohort will be expanded by an additional 3 patients to allow for 1 in 6 patients per cohort to have a DLT before dose escalation. Dose limiting toxicity will be assessed weekly during the first six weeks of the treatment.

Patients will be treated weekly for the first six weeks and then every 3 weeks (q21 days). Once the maximum tolerated dose is reached, an additional 12 patients will be enrolled in the cohort at the maximum tolerated dose. The maximum number of enrolled patients is 36. Dosing is as follows: Cohort 1 - 80mg IT trastuzumab, 10mg IT pertuzumab, cohort 2 - 80mg IT trastuzumab, 20mg IT pertuzumab, cohort 3 - 80mg IT trastuzumab, 40mg IT pertuzumab, cohort 4 - 80mg IT trastuzumab, 80mg IT pertuzumab. If the lowest dose level is found to be too toxic, the trial will stop without finding a maximum tolerated dose.

Intrathecal Pertuzumab and Trastuzumab in Patients With New Untreated Asymptomatic or Low Symptomatic Brain Metastasis in HER2 Positive Breast Cancer

Phase I Dose Escalation Trial of Intrathecal Pertuzumab and Trastuzumab in Patients With New Untreated Asymptomatic or Low Symptomatic Brain Metastasis

Adverse events will be closely monitored and assessed for all subjects on study treatment. The main observational portion of study will be complete at 36 weeks. However, subjects will be allowed to continue on treatment for as long as they are receiving clinical benefit and any adverse events occurring during this time will be assessed. Following discontinuation of study treatment, patient follow-up will take place every 3 months.

Toxicity will be graded according to the NCI-CTC version 4 and will be assessed weekly for the first six weeks of treatment and then every 21 days. A DLT is defined as any grade 3 or higher non-hematologic toxicity or grade 4 hematologic toxicity that occurs within the first 6 weeks of treatment that is assessed as possibly related to the intrathecal therapy. Any treatment delays occurring during the first six weeks of treatment that are due to study treatment-related toxicity will also be considered a DLT.

The main portion of study will be complete at 36 weeks. However, subjects will be allowed to continue on treatment for as long as they are receiving clinical benefit.

Response assessed:

Complete Response (CR): Radiographic complete response (RCR), 100% reduction in tumor, with complete clearing of MRI scan evidence of disease on 2 consecutive scans 6 weeks apart with stable or improved clinical function.

Partial Response (PR): Radiographic stability of disease (RSD), \> 50% but \< 100% reduction in tumor, with improved clinical function.

Stable Disease (SD): Radiographic stability of disease (RSD), \< 50% reduction in tumor or \< 25% increase in size of tumor, with stable clinical function.

Progressive Disease (PD): Radiographic progressive disease (RPD), \> 25% increase in size of tumor, and/or the presence of declining clinical function attributable to the CNS metastasis. Other indications of progression include development of new CNS metastases or increase in size of previous CNS metastasis. Changes in size of previous CNS metastasis must measure \> 25% increase in the largest unidimensional measurement in the absence of new neurologic symptoms.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
DC Migration Study to Evaluate TReg Depletion In GBM Patients With and Without Varlilumab	NCT03688178	Glioblastoma	Human CMV pp65-... Temozolomide Varlilumab Td Unpulsed DCs	18 Years -	Duke University
Pharmacokinetics of Systemic Anti-Cancer Therapies in the Cerebrospinal Fluid (CSF) of Patients With Advanced Cancer	NCT02580045	Metastatic Canc... Advanced Cancer Brain Metastasi...		18 Years -	Duke University
Intrathecal Pertuzumab and Trastuzumab in Patients With New Untreated Asymptomatic or Low Symptomatic Brain Metastasis in HER2 Positive Breast Cancer	NCT02598427	HER2 Positive U... Asymptomatic or...	Pertuzumab Trastuzumab	18 Years -	Duke University
Intrathecal Pertuzumab and Trastuzumab in Patients With New Untreated Asymptomatic or Low Symptomatic Brain Metastasis in HER2 Positive Breast Cancer	NCT02598427	HER2 Positive U... Asymptomatic or...	Pertuzumab Trastuzumab	18 Years -	Duke University

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