Maximum Tolerated Dose, Safety, and Efficacy of Rhenium Nanoliposomes in Recurrent Glioblastoma
| Status: | Recruiting |
|---|---|
| Conditions: | Brain Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 3/17/2019 |
| Start Date: | March 2015 |
| End Date: | January 2020 |
| Contact: | Epp Goodwin |
| Email: | ctrcreferral@uthscsa.edu |
| Phone: | 450-5798 |
A Dual Phase 1/2, Investigator Initiated Study to Determine the Maximum Tolerated Dose, Safety, and Efficacy of Rhenium Nanoliposomes in Recurrent Glioblastoma
While radiation is an essential component to the treatment of glioblastoma, it's use is
limited due to toxicity when higher doses are attempted. Rhenium is a compund which releases
radiation in small particles that are absorbed after only a fraction of an inch. This limited
penetration means that high doses potentially can be given without the toxicity of other
forms of radiation. In order for the radiaiton to be retained within the tumor, it has been
packaged in microscopic fat like particles termed nanoliposomes. These facilitate the uptake
of the radiation particles by the tumor. In order to better characterize this form of
radiation therapy, it is being administered in patients who have failed other forms of
therapy for glioblastoma. The treatment is administered by tubing inserted into the center of
the tumor in the operating room. There are two portionms to this study. The first involves
progressively increasing doses until the most tolerable dose can be identified. The second
portion of the study involves a larger number of patients being treated at the determined
most tolerable dose to better evalaute how well the treatment works.
limited due to toxicity when higher doses are attempted. Rhenium is a compund which releases
radiation in small particles that are absorbed after only a fraction of an inch. This limited
penetration means that high doses potentially can be given without the toxicity of other
forms of radiation. In order for the radiaiton to be retained within the tumor, it has been
packaged in microscopic fat like particles termed nanoliposomes. These facilitate the uptake
of the radiation particles by the tumor. In order to better characterize this form of
radiation therapy, it is being administered in patients who have failed other forms of
therapy for glioblastoma. The treatment is administered by tubing inserted into the center of
the tumor in the operating room. There are two portionms to this study. The first involves
progressively increasing doses until the most tolerable dose can be identified. The second
portion of the study involves a larger number of patients being treated at the determined
most tolerable dose to better evalaute how well the treatment works.
Rhenium-186 (186Re) (half-life 90 hours) is a reactor produced isotope with great potential
for medical therapy. It is in the same chemical family as Technetium-99m (99mTc), a
radioactive tracer that is the most commonly used isotope for diagnostic scintigraphic
imaging in nuclear medicine. Like 99mTc, rhenium is not taken up by bone and is readily
cleared by the kidneys. 186Re emits both therapeutic beta particles and every 10 isotope
decays is associated with a gamma photon. The average 186Re beta particle path length in
tissue of 2mm is ideal for treatment of solid tumors. Additionally, the emitted gamma photons
have similar photon energy to those emitted by 99mTc, therefore allowing for imaging of the
isotope within the body on standard nuclear imaging machines available in routine medical
practice. Therefore, the 186Re isotope has great potential in CED applications of local
therapy of solid tumors. However, a carrier is needed to deliver the isotope to the brain and
maintain its localization at the desired site, as otherwise it would quickly disperse and be
carried away from the site of injection by the circulatory system.
Liposomes are spontaneously forming lipid nanoparticles that have been well studied for over
30 years. Although larger liposomes can be manufactured, the most useful size range for drug
carrier applications is 80-100 nm. Liposomes of this size are often referred to as
nanoliposomes and have the ability to facilitate retention at the site of injection. A method
for the efficient loading of liposomes with the to very high levels of specific activity has
been developed. These rhenium-labeled nanoliposomes (186RNL) have shown great promise in
preclinical studies 186RNL of glioblastoma that surpassed results typically seen with
currently standard treatment modalities such as oral temozolomide or intravenous bevacizumab.
This is a single center, sequential cohort, open-label, dose-escalation study of the safety,
tolerability, and distribution of 186RNL given by convection enhanced delivery to patients
with recurrent or progressive malignant glioma after standard surgical, radiation, and/or
chemotherapy treatment.
for medical therapy. It is in the same chemical family as Technetium-99m (99mTc), a
radioactive tracer that is the most commonly used isotope for diagnostic scintigraphic
imaging in nuclear medicine. Like 99mTc, rhenium is not taken up by bone and is readily
cleared by the kidneys. 186Re emits both therapeutic beta particles and every 10 isotope
decays is associated with a gamma photon. The average 186Re beta particle path length in
tissue of 2mm is ideal for treatment of solid tumors. Additionally, the emitted gamma photons
have similar photon energy to those emitted by 99mTc, therefore allowing for imaging of the
isotope within the body on standard nuclear imaging machines available in routine medical
practice. Therefore, the 186Re isotope has great potential in CED applications of local
therapy of solid tumors. However, a carrier is needed to deliver the isotope to the brain and
maintain its localization at the desired site, as otherwise it would quickly disperse and be
carried away from the site of injection by the circulatory system.
Liposomes are spontaneously forming lipid nanoparticles that have been well studied for over
30 years. Although larger liposomes can be manufactured, the most useful size range for drug
carrier applications is 80-100 nm. Liposomes of this size are often referred to as
nanoliposomes and have the ability to facilitate retention at the site of injection. A method
for the efficient loading of liposomes with the to very high levels of specific activity has
been developed. These rhenium-labeled nanoliposomes (186RNL) have shown great promise in
preclinical studies 186RNL of glioblastoma that surpassed results typically seen with
currently standard treatment modalities such as oral temozolomide or intravenous bevacizumab.
This is a single center, sequential cohort, open-label, dose-escalation study of the safety,
tolerability, and distribution of 186RNL given by convection enhanced delivery to patients
with recurrent or progressive malignant glioma after standard surgical, radiation, and/or
chemotherapy treatment.
Inclusion Criteria:
1. Planned stereotactic biopsy as standard of care (ie, for confirmation of disease
progression)
2. At least 18 years of age
3. Ability to understand the purposes and risks of the study and has signed a written
informed consent form approved by the investigator's IRB/Ethics Committee
4. Histologically confirmed glioblastoma
5. Progression following both standard combined modality treatment with radiation and
temozolomide chemotherapy, as well as anti-angiogenic therapy (ie, bevacizumab;
patients not eligible for or refusing antiangiogenic therapy will also be allowed)
6. For cohorts 1-3, tumor volumes limited to 1.5cc, as calculated under 4.1 Inclusion
criteria.
7. Recovered from toxicities of prior therapy to grade 0 or 1
8. ECOG performance status of 0 to 2
9. Life expectancy of at least 2 months
10. Acceptable liver function:
- Bilirubin ≤ 1.5 times upper limit of normal
- AST (SGOT) and ALT (SGPT) ≤ 3.0 times upper limit of normal (ULN);
11. Acceptable renal function:
- Serum creatinine ≤1.5xULN
12. Acceptable hematologic status (without hematologic support):
- ANC ≥1000 cells/uL
- Platelet count ≥75,000/uL
- Hemoglobin ≥9.0 g/dL
13. All women of childbearing potential must have a negative serum pregnancy test and male
and female subjects must agree to use effective means of contraception (surgical
sterilization or the use or barrier contraception with either a condom or diaphragm in
conjunction with spermicidal gel or an IUD) with their partner from entry into the
study through 6 months after the last dose
Exclusion Criteria:
- The subject has evidence of acute intracranial or intratumoral hemorrhage either by
MRI or computerized tomography (CT) scan. Subjects with resolving hemorrhage changes,
punctate hemorrhage, or hemosiderin are eligible.
- The subject is unable to undergo MRI scan (eg, has pacemaker).
- The subject has not recovered to National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) v4.0 Grade ≤ 1 from AEs (except alopecia, anemia
and lymphopenia) due to surgery, antineoplastic agents, investigational drugs, or
other medications that were administered prior to study drug.
- The subject is pregnant or breast-feeding.
- The subject has serious intercurrent illness, such as:
- hypertension (two or more blood pressure [BP] readings performed at screening of
> 150 mmHg systolic or > 100 mmHg diastolic) despite optimal treatment
- Non-healing wound, ulcer, or bone fracture
- Significant cardiac arrhythmias
- Untreated hypothyroidism
- Unhealed rectal or peri-rectal abscess
- Uncontrolled active infection
- Symptomatic congestive heart failure or unstable angina pectoris within 3 months
prior study drug
- Myocardial infarction, stroke, transient ischemic attack within 6 months
- Gastrointestinal perforation, abdominal fistula, intra- abdominal abscess within
1 year
- History or clinical evidence of pancreatitis within 2 years
- The subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding
- The subject has received any of the following prior anticancer therapy:
- Non-standard radiation therapy such as brachytherapy, systemic radioisotope
therapy (RIT), or intra-operative radiotherapy (IORT) to the target site. SRS is
allowed as long as the target lesion for this study has not been the treatment
target.
- Targeted therapy (including investigational agents and small-molecule kinase
inhibitors) or non-cytotoxic hormonal therapy (eg, tamoxifen) within 7 days or 5
half-lives, whichever is shorter, prior first dose of study drug
- Biologic agents (antibodies, immune modulators, vaccines, cytokines) within 21
days prior to first dose of study drug
- Nitrosoureas or mitomycin C within 42 days, or metronomic/protracted low-dose
chemotherapy within 14 days, or other cytotoxic chemotherapy within 28 days,
prior to first dose of study drug
- Prior treatment with carmustine wafers
We found this trial at
1
site
San Antonio, Texas 78229
Principal Investigator: Andrew J Brenner, M.D., Ph.D.
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