Safety and feasibility of rhenium-186 nanoliposome (186RNL) in recurrent glioma: The ReSPECT phase 1 trial.

2061 Background: While external beam radiation therapy (EBRT) remains a central component of the management of primary brain tumors, it is limited by tolerance of the surrounding normal brain tissue. Rhenium-186 NanoLiposome (186RNL) permits the delivery of beta-emitting radiation of high specific activity with excellent retention in the tumor. We report the results of the phase 1 study in recurrent glioma. Methods: A Phase 1 dose-escalation study of 186RNL in recurrent glioma utilizing a standard 3+3 design was undertaken to determine the maximum tolerated dose of 186RNL. 186RNL is administered by convection enhanced delivery (CED). Infusion is followed under whole body planar imaging and SPECT/CT. Repeat SPECT/CT imaging is performed immediately following, and at 1, 3, 5, and 8 days after 186RNL infusion to obtain dosimetry and distribution. Subjects were followed until disease progression by RANO criteria. Results: Eighteen subjects were treated across 6 cohorts. The mean tumor volume was 9.4 mL (range 1.1 – 23.4). The infused dose ranged from 1.0 mCi to 22.3 mCi and the volume of infusate ranged from 0.66 mL to 8.80 mL. From 1 – 4 CED catheters were used. The maximum catheter flow rate was 15 µl/min. The mean absorbed dose to the tumor volume was 239 Gy (CI 141 – 337; range 9 - 593), to normal brain was 0.72 Gy (CI 0.34 – 1.09; range 0.005 – 2.73), and to total body was 0.07 Gy (CI 0.04 – 0.10; range 0.001 – 0.23). The mean absorbed dose to the tumor volume when the percent tumor volume in the treatment volume was 75% or greater (n = 10) was 392 Gy (CI 306 – 478; range 143 – 593). Scalp discomfort and tenderness related to the surgical procedure did occur in 3 subjects. The therapy has been well tolerated, no dose-limiting toxicity has been observed, and no treatment-related serious adverse events have occurred despite markedly higher absorbed doses typically delivered by EBRT in patients with prior treatment. Responses have been observed supporting the clinical activity. Final results from the dose escalation will be presented. Conclusions: 186RNL administered by CED to patients with recurrent glioma results in a much higher absorbed dose of radiation to the tumor compared to EBRT without significant toxicity. The recommended Phase 2 dose is 22.3 mCi in 8.8 mL of infusate. Clinical trial information: NCT01906385. [Table: see text]

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RADT-24. HIGH ABSORBED DOSES OF RHENIUM-186 NANOLIPOSOMES (RNL) IN RECURRENT GBM: A PHASE 1 STUDY

Neuro-Oncology ◽

10.1093/neuonc/noaa215.777 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii186-ii186

Author(s):

Andrew Brenner ◽

John Floyd ◽

Ande Bao ◽

William Phillips ◽

Vibhudutta Awasthi ◽

...

Keyword(s):

Phase 1 ◽

High Specific Activity ◽

Absorbed Dose ◽

External Beam Radiation ◽

Whole Body ◽

Recurrent Glioma ◽

Normal Brain ◽

Beam Radiation ◽

Absorbed Doses ◽

The Mean

Abstract INTRODUCTION While external beam radiation therapy (EBRT) remains a central component of the management of primary brain tumors, it is limited by tolerance of the surrounding normal brain tissue. Nanoliposomal BMEDA-chelated-186Rhenium (RNL™) permits the delivery of beta-emitting radiation of high specific activity with excellent retention in the tumor. We report on the phase 1 results in recurrent glioma. METHODS A phase 1 dose-escalation study of RNL in recurrent glioma utilizing a standard 3 + 3 design was undertaken to determine the maximum tolerated dose of RNL following stereotactic biopsy. RNL is administered with the BrainLab Flexible Catheter by convection enhanced delivery (CED) with placement guided using iPlan Flow and the Varioguide system. Infusion is followed under whole body planar imaging and SPECT/CT. Repeat SPECT/CT imaging is performed immediately following, and at 1, 3, 5, and 8 days after RNL infustion to obtain dosimetry and distribution. RESULTS Thirteen patients have been treated to-date, 12 were recurrent glioblastoma, and 54% failed treatment with bevacizumab. The infused dose was progressively increased from 1.0 mCi to 13.4 mCi and the volume of infusate from 1.0 mL to 5.28 mL using 1 – 2 CED catheters. The mean absorbed dose to the distribution volume was 175 Gy (CI 97 – 254). The maximum absorbed dose to the tumor volume was 593 Gy. The mean retention of the administered dose at 24 hours was 61.4% (CI 45.4 – 77.5). The therapy has been well tolerated and no dose-limiting toxicity has been observed with no treatment related adverse effects despite markedly higher absorbed doses than EBRT in patients with prior treatment. The plan is to increase the dose to 22.3 mCi and the infusate volume to 8.8 mL. CONCLUSION Intratumoral RNL can deliver up to twenty times the absorbed dose of radiation administered by EBRT without significant toxicity.

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EPCT-18. A TWO-PART, PHASE 1 STUDY OF RHENIUM-186 NANOLIPOSOME (186RNL) DELIVERED BY CONVECTION ENHANCED DELIVERY FOR RECURRENT, REFRACTORY, OR PROGRESSIVE EPENDYMOMA AND HIGH-GRADE GLIOMA (HGG) AND NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Neuro-Oncology ◽

10.1093/neuonc/noab090.204 ◽

2021 ◽

Vol 23 (Supplement_1) ◽

pp. i50-i51

Author(s):

Ashley Plant ◽

Stewart Goldman ◽

Sandi Lam ◽

Michael DeCuypere ◽

Gregory Stein ◽

...

Keyword(s):

Specific Activity ◽

Phase 1 ◽

High Specific Activity ◽

External Beam Radiation ◽

Central Component ◽

Normal Brain ◽

Newly Diagnosed ◽

Convection Enhanced Delivery ◽

Beam Radiation ◽

Dose Limiting Toxicity

Abstract Ependymoma, HGG, and DIPG are gliomas that are often difficult to treat, frequently aggressive, and often carry an extremely poor prognosis. While external beam radiation therapy (EBRT) remains a central component of the management of pediatric gliomas, it is limited by tolerance of the surrounding normal brain tissue. Rhenium-186 NanoLiposome (186RNL) permits the selective delivery of beta-emitting radiation of high specific activity with excellent retention in the tumor. In a Phase 1 trial in adults with recurrent glioblastoma (NCT01906385), the mean absorbed dose to the tumor when coverage was 75% or greater (n=10) was 392 Gy (CI 306 – 478). Thus far, the therapy has been well tolerated, no dose-limiting toxicity has been observed, and no treatment-related serious adverse events have occurred despite markedly higher absorbed doses than typically delivered by EBRT (n=18). Methods This is a two-part, Phase 1 dose-finding study followed by an expansion cohort to explore efficacy. Part 1 will enroll up to 18 subjects to determine the maximum feasible dose (MFD) of 186RNL administered by convection enhanced delivery (CED). Tumor size will be limited to a diameter of 4 cm in the longest axis and a volume of 34 mL. The dose limiting toxicity period (DLT) is 28 days post infusion. Part 2 will independently evaluate 186RNL in 3 different cohorts: Cohort A: up to 12 subjects with a diagnosis of recurrent, refractory, or progressive ependymoma; Cohort B: up to 12 subjects with a diagnosis of recurrent, refractory, or progressive HGG; Cohort C: up to 15 subjects with newly diagnosed DIPG. The primary endpoint is overall response rate (ORR) by Radiographic Assessment in Pediatric Neuro-Oncology (RAPNO) criteria. Secondary endpoints are PFS-24 and OS-24 in Cohort A and PFS-12 and OS-12 in Cohorts B and C. Planned enrollment will begin in H2 2021.

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Neuroimaging and quality-of-life outcomes in patients with brain metastasis and peritumoral edema who undergo Gamma Knife surgery

Journal of Neurosurgery ◽

10.3171/jns/2008/109/12/s15 ◽

2008 ◽

Vol 109 (Supplement) ◽

pp. 90-98 ◽

Cited By ~ 26

Author(s):

Hung-Chuan Pan ◽

Ming-Hsih Sun ◽

Clayton Chi-Chang Chen ◽

Chun-Jung Chen ◽

Chen-Hui Lee ◽

...

Keyword(s):

Quality Of Life ◽

Brain Metastasis ◽

Gamma Knife ◽

Tumor Volume ◽

Gamma Knife Surgery ◽

External Beam Radiation ◽

Peritumoral Edema ◽

Beam Radiation ◽

The Mean

Object Gamma Knife surgery (GKS) has been shown to be effective for treating many patients with brain metastasis. Some brain metastases demonstrate significant peritumoral edema; radiation may induce cerebral edema or worsening preexisting edema. This study was conducted to evaluate the imaging and neurobehavioral outcomes in patients with preexisting peritumoral edema who then undergo GKS. Methods Between August 2003 and January 2008, 63 cases of brain metastasis with significant peritumoral edema (> 20 cm3) were prospectively studied. The study inclusion criteria were as follows: 1) a single metastatic lesion with significant edema (perilesional edema signal volume on FLAIR > 20 cm3); and 2) inclusion of only 1 lesion > 20 cm3 in the study (in cases of multiple lesions noted on FLAIR images). All patients received MR imaging with pulse sequences including T1-weighted imaging and FLAIR with or without contrast and T2-weighted imaging at an interval of 3 months. A neurological assessment and Brain Cancer Module (BCM-20) questionnaire were obtained every 2–3 months. Kaplan–Meier, Cox regression, and logistic regression were used for analysis of survival and associated factors. Results At the time of GKS, the median Karnofsky Performance Scale (KPS) score was 70 (range 50–90), and the mean BCM-20 score was 45.5 ± 6.1. The mean tumor volume (± standard deviation) was 5.2 ± 4.6 cm3 with corresponding T2-weighted imaging and FLAIR volumes of 59.25 ± 37.3 and 62.1 ± 38.8 cm3, respectively (R2 = 0.977, p < 0.001). The mean edema index (volume of peritumoral edema/tumor volume) was 17.5 ± 14.5. The mean peripheral and maximum GKS doses were 17.4 ± 2.3 and 35 ± 4.7 Gy, respectively. The median survival was 11 months. The longer survival was related to KPS scores ≥ 70 (p = 0.008), age < 65 years (p = 0.022), and a reduction of > 6 in BCM-20 score (p = 0.007), but survival was not related to preexisting edema or tumor volume. A reduction in BCM-20 score of > 6 was related to decreased volume in T1-weighted and FLAIR imaging (p < 0.001). Thirty-eight (79.2%) of 48 patients demonstrated decreased tumor volume and accompanied by decreased T2-weighted imaging and FLAIR volume. Eight (16.7%) of the 48 patients exhibited increased or stable tumor volume. A margin dose > 18 Gy was more likely to afford tumor reduction and resolution of peritumoral edema (p = 0.005 and p = 0.006, respectively). However, prior external-beam radiation therapy correlated with worsened preexisting peritumoral edema (p = 0.013) and longer maintenance of corticosteroids (p < 0.001). Conclusions Patients demonstrating a reduction in the BCM-20 score > 6, age < 65 years, and KPS score ≥ 70 exhibited longer survival. Significant preexisting edema did not influence the tumor response or clinical outcome. The resolution of edema was related to better quality of life but not to longer survival.

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Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma

Blood ◽

10.1182/blood-2003-12-4264 ◽

2004 ◽

Vol 104 (3) ◽

pp. 642-648 ◽

Cited By ~ 27

Author(s):

David A. Rizzieri ◽

Gamal Akabani ◽

Michael R. Zalutsky ◽

R. Edward Coleman ◽

Scott D. Metzler ◽

...

Keyword(s):

Stem Cell ◽

Phase 1 ◽

Absorbed Dose ◽

Whole Body ◽

Hematologic Toxicity ◽

Blocking Antibody ◽

Non Hodgkin Lymphoma ◽

Body Activity ◽

The Mean ◽

Administered Activity

AbstractWe report a phase 1 study of pharmacokinetics, dosimetry, toxicity, and response of 131I anti-tenascin chimeric 81C6 for the treatment of lymphoma. Nine patients received a dosimetric dose of 370 MBq (10 mCi). Three patients received an administered activity of 1480 MBq (40 mCi), and 2 developed hematologic toxicity that required stem cell infusion. Six patients received an administered activity of 1110 MBq (30 mCi), and 2 developed toxicity that required stem cell infusion. The clearance of whole-body activity was monoexponential with a mean effective half-life of 110 hours (range, 90-136 hours) and a mean effective whole-body residence time of 159 hours (range, 130-196 hours). There was rapid uptake within the viscera; however, tumor uptake was slower. Activity in normal viscera decreased proportional to the whole body; however, tumor sites presented a slow clearance (T1/2, 86-191 hours). The mean absorbed dose to whole-body was 67 cGy (range, 51-89 hours), whereas the dose to tumor sites was 963 cGy (range, 363-1517 cGy). Despite lack of a “blocking” antibody, 1 of 9 patients attained a complete remission and 1 a partial remission. These data demonstrate this radiopharmaceutical to be an encouraging agent for the treatment of lymphoma particularly if methods to protect the normal viscera are developed.

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Fractionated Dosing of CLR 131 in Patients with Relapsed or Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood-2019-131014 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 144-144 ◽

Cited By ~ 1

Author(s):

Sikander Ailawadhi ◽

Patrick J. Stiff ◽

Emad Ibrahim ◽

Anusha Vallurupalli ◽

Elizabeth H. Cull ◽

...

Keyword(s):

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

External Beam Radiation ◽

Cell Transplant ◽

Phase 2 ◽

Eligibility Criteria ◽

Beam Radiation ◽

Phase 1 Trial ◽

Phase 2 Trial

Background: CLR 131 is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Based on initial preclinical and clinical experience and the radiosensitivity of MM, fractionated dosing of CLR 131 is being examined in RRMM in a Phase 1 trial (NCT02278315) and a Phase 2 trial, CLOVER-1 (NCT02952508). Methods: Both the Phase 1 and Phase 2 trials of CLR 131 aim to determine efficacy and safety in RRMM. Eligibility criteria include progressive or relapsed MM that is refractory to at least 1 proteasome inhibitor (PI) and 1 immunomodulatory (IMiD) drug with no upper limit to the number of prior lines of therapy. Prior autologous stem cell transplant (ASCT) and external beam radiation therapy are allowed (< 20% of total marrow irradiated). The Phase 1 trial was a single and fractionated ascending dose escalation safety study and the Phase 2 trial is evaluating 3 doses: a bolus dose and 2 fractionated doses. The fractionated doses of CLR 131 included infusion of either 31.25 mCi/m2 CLR 131 or 37.5 mCi/m2 CLR 131 (administered as 15.625 mCi/m2 or 18.75 mCi/m2, respectively, on day 1 and day 7 (± 1 day)) administered as a 30-minute intravenous infusion is reported here. Adverse events (AEs) are graded by NCI-CTCAE v4.03. Responses were determined using IMWG criteria as assessed by the investigator. Results: As of 30Jul2019, 10 subjects have received fractionated 31.25 mCi/m2 and 6 subjects fractionated 37.5 mCi/m2 CLR 131. In addition, 1 subject was scheduled to receive fractionated 37.5 mCi/m2 CLR 131 but died due to progressive disease prior to administration of the second dose; this subject is not included in the analyses below as they did not receive both fractionated doses. There is no upper age limit for enrollment and the median age for the 16 RRMM patients was 71 (range 51-83), including 6 females and 10 males with a median of 4 prior therapies (range 2 to 13). Seven patients had prior ASCT. CLR 131 demonstrated 100% disease control rate in subjects receiving either fractionated dose of CLR 131. The overall response rate (ORR) in the fractionated 37.5 mCi/m2 cohort is 50%. Three subjects in the cohort experienced a partial responses (PR), median time to response 43 days, and the other three had minimal responses (MR) with an average 39% reduction in m-protein. In this cohort, 80% of the subjects were either quad- or penta-refractory; all 80% were refractory to daratumumab. There were two subjects in the 31.25 mCi/m2 cohort with non-secretory disease and their status was followed by FDG-PET imaging. Both have been excluded from the evaluation of efficacy as their disease does not meet with IMWG criteria for response. No patients in this cohort achieved a PR or better however a majority of the subjects experienced a minimal response. The primary AEs include thrombocytopenia, anemia, neutropenia, and fatigue (Table 2). The hematologic AEs were expected, manageable and followed a predictable timeline to nadir (average. 40 days) and subsequent recovery (average 17 days post nadir). Conclusions: CLR 131 is a unique, first in class targeted radiotherapeutic for RRMM. Preliminary data for CLR 131 administered as a fractionated dose shows an acceptable and expected safety profile in this patient population. Fractionated dosing at 37.5 mCi/m2 has shown an efficacy signal and has been adopted as the standard for CLR 131 dosing in ongoing and future trials. Dose escalation to determine the highest tolerated dose is ongoing in the Phase 1 study and is currently examining a fractionated infusion of 40 mCi/m2 administered as 20 mCi/m2 CLR 131 on day 1 and day 7 (± 1 day). Based upon these data enrollment to the fractionated 37.5 mCi/m2 cohort of the Phase 2 trial continues. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Stiff:Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding. Ibrahim:Cellectar: Honoraria, Research Funding; Incyte: Research Funding; Pfeizer: Research Funding; Puma: Research Funding; Eli Lilly: Research Funding; Hoffman-LaRoche: Research Funding; Spectrum: Research Funding; Takeda: Research Funding. Cull:Celgene: Speakers Bureau; ADC Therapeutics: Research Funding. Green:GSK: Consultancy; Seattle Genetics: Research Funding; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Oliver:Cellectar Biosciences: Employment. Longcor:Cellectar Biosciences: Employment, Equity Ownership.

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Phase 1, Open-Label, Dose Escalation Study of I-131-CLR1404 (CLR 131) in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2019-131806 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1864-1864

Author(s):

Jarrod Longcor ◽

Kate Oliver

Keyword(s):

Multiple Myeloma ◽

Dose Level ◽

Cancer Cell ◽

Dose Escalation ◽

Proteasome Inhibitor ◽

Phase 1 ◽

External Beam Radiation ◽

Beam Radiation ◽

Selective Uptake ◽

Refractory Multiple Myeloma

Background: CLR 131 [18-(p-[131I]-iodophenyl)octadecyl phosphocholine] is an investigational, radioiodinated cancer therapy that exploits the selective uptake and retention of phospholipid ethers (PLEs) and PLE analogs by malignant cells [Mollinedo 2010, Weichert 2014]. To produce CLR 131, the core PLE analog is radioiodinated with the radioisotope iodine-131 (I-131). CLR 131 provides targeted delivery of radiation to malignant tumor cells, thus minimizing radiation exposure to normal tissues. The mechanistic basis for the cancer-cell selective uptake involves interaction with lipid raft regions of the plasma membrane. Imaging studies with CLR 124 [18-(p-[124I]-iodophenyl)octadecyl phosphocholine], which is chemically and structurally identical to CLR 131, have demonstrated cancer-cell selective uptake and retention in all but 3 of over 60 tumor cell models assessed to date [Weichert 2014]. Using a MM1.S myeloma xenograft murine model, highly selective uptake of CLR 124 was documented using I-124 PET imaging (Figure 1). Similarly, using CLR 124 in a disseminated MM1.S myeloma model, PET-CT documented selective uptake of CLR1404 in anatomic regions of dense myelomatous involvement (Figure 2). CLR 131 activity was assessed in NOD scid gamma mice bearing 200 mm3 MM1.S flank tumors who received a single tail vein injection of CLR 131 (100 µCi) or a mass equivalent dose of CLR1404. As anticipated, a single dose of CLR 131 produced tumor growth delay (Figure 3). Study Design and Methods: This Phase 1 trial (NCT02278315) is assessing CLR 131 in patients with relapsed or refractory multiple myeloma (RRMM). The primary objective is to determine the safety and tolerability of CLR 131 as a single or multiple dose, with and without concurrent weekly dexamethasone, in patients with RRMM who have previously been treated with, or are intolerant of, an immunomodulator and a proteasome inhibitor. Secondary objectives include identifying the recommended Phase 2 dose and schedule, and determining therapeutic activity. Eligibility criteria include progressive, RRMM, and at least one previous exposure to proteasome inhibitor and immunomodulatory drugs with no limit to the number of prior lines of therapy. Patients are to have at least 5% plasma cell involvement and measurable disease (by m-protein or FLC, although non-secretors are considered on a case-by-case basis). Patients are excluded if they have had prior radioisotope therapy, prior total body or hemi-body irradiation, or prior external beam radiation therapy resulting in greater than 20% of total bone marrow receiving greater than 20 Gy. Patients receive CLR 131 as a fractionated infusion of CLR 131 at increasing doses administered on day 1 and day 7 (± 1 day) as a 30-minute intravenous infusion with 40 mg concurrent weekly dexamethasone. All patients take thyroid protection medication starting the day prior to CLR 131 infusion and continuing for 14 days after the last CLR 131 infusion. Following the CLR 131 infusions, patients are followed for a total of 12 weeks to assess safety and efficacy. At least 3 to 4 patients are enrolled in each dose level. Patients who discontinue prior to the day 64 assessment can be replaced. A Data Monitoring Committee evaluates each dose level for safety and tolerability and provides recommendations for dose escalation, de-escalation, or expansion. Current Status As of 31-Jul-2019, 28 subjects have been enrolled; 18 patients received a single infusion of CLR 131 and 10 patients have received fractionated doses of CLR 131. Enrollment in the 40 mCi/m2 fractionated dose level is ongoing. Disclosures Longcor: Cellectar Biosciences: Employment, Equity Ownership. Oliver:Cellectar Biosciences: Employment.

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EQUIVALENT UNIFORM DOSE SENSITIVITY TO CHANGES IN ABSORBED DOSE DISTRIBUTION

International Journal of Biomathematics ◽

10.1142/s1793524512500696 ◽

2013 ◽

Vol 06 (01) ◽

pp. 1250069

Author(s):

FRANCISCO CUTANDA-HENRÍQUEZ ◽

SILVIA VARGAS-CASTRILLÓN

Keyword(s):

Treatment Planning ◽

Dose Distribution ◽

Absorbed Dose ◽

Target Volume ◽

Simple Expression ◽

External Beam Radiation ◽

Equivalent Uniform Dose ◽

Beam Radiation ◽

Dose Volume Histograms ◽

Small Change

Treatment planning in external beam radiation therapy (EBRT) utilizes dose volume histograms (DVHs) as optimization and evaluation tools. They present the fraction of planning target volume (PTV) receiving more than a given absorbed dose, against the absorbed dose values, and a number of radiobiological indices can be computed with their help. Equivalent uniform dose (EUD) is the absorbed dose that, uniformly imparted, would yield the same biological effect on a tumor as the dose distribution described by the DVH. Uncertainty and missing information can affect the dose distribution, therefore DVHs can be modeled as samples from a set of possible outcomes. This work studies the sensitivity of the EUD index when a small change in absorbed dose distribution takes place. EUD is treated as a functional on the set of DVHs. Defining a Lévy distance on this set and using a suitable expansion of the functional, a very simple expression for a bound on the variation of EUD when the dose distribution changes is found. This bound is easily interpreted in terms of standard treatment planning practice.

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