Dose‐finding study of <sup>153</sup>Sm‐EDTMP in patients with poor‐prognosis osteosarcoma

Loeb, David M.; Garrett‐Mayer, Elizabeth; Hobbs, R.; Prideaux, Andrew; Sgouros, George; Shokek, Ori; Wharam, Moody D.; Scott, Tammy; Schwartz, Cindy L.

doi:10.1002/cncr.24286

Cited by 50 publications

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“…In a subsequent phase II study designed to study the safety and response of high-risk osteosarcoma to a high dose of 153 Sm-EDTMP, 11 of 13 patients who participated in the phase I study were found eligible to receive a second high dose (tandem dose) of 153 Sm-EDTMP. The clinical trial details and the treatment plan have been described by Loeb et al (2,3). Briefly, patients were included in the study if they had a positive 99m Tc-methylene diphosphonate bone scan finding; autologous hematopoietic stem cells were collected before the first treatment with 153 Sm-EDTMP (low dose).…”

Section: Methodsmentioning

confidence: 99%

Tumor Dosimetry and Response for ¹⁵³Sm-Ethylenediamine Tetramethylene Phosphonic Acid Therapy of High-Risk Osteosarcoma

et al. 2012

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153Sm-ethylenediamine tetramethylene phosphonic acid (153Sm-EDTMP) therapy for osteosarcoma is being investigated. In this study, we analyzed the influence of 153Sm-EDTMP administered activity (AA), osteosarcoma tumor density, mass, and the shape of the tumor on absorbed dose (AD). We also studied the biologic implication of the nonuniform tumor AD distribution using radio-biologic modeling and examined the relationship between tumor AD and response. Methods Nineteen tumors in 6 patients with recurrent, refractory osteosarcoma enrolled in a phase I or II clinical trial of 153Sm-EDTMP were analyzed using the 3-dimensional radiobiologic dosimetry (3D-RD) software package. Patients received a low dose of 153Sm-EDTMP (37.0–51.8 MBq/kg), followed on hematologic recovery by a second, high dose (222 MBq/kg). Treatment response was evaluated using either CT or MRI after each therapy. SPECT/CT of the tumor regions were obtained at 4 and 48 h or 72 h after 153Sm-EDTMP therapy for 3D-RD analysis. Mean tumor AD was also calculated using the OLINDA/EXM unit-density sphere model and was compared with the 3D-RD estimates. Results On average, a 5-fold increase in the AA led to a 4-fold increase in the mean tumor AD over the high- versus low-dose–treated patients. The range of mean tumor AD and equivalent uniform dose (EUD) for low-dose therapy were 1.48–14.6 and 0.98–3.90 Gy, respectively. Corresponding values for high-dose therapy were 2.93–59.3 and 1.89–12.3 Gy, respectively. Mean tumor AD estimates obtained from OLINDA/EXM were within 5% of the mean AD values obtained using 3D-RD. On an individual tumor basis, both mean AD and EUD were positively related to percentage tumor volume reduction (P = 0.031 and 0.023, respectively). Conclusion The variations in tumor density, mass, and shape seen in these tumors did not affect the mean tumor AD estimation significantly. The tumor EUD was approximately 2- and 3-fold lower than the mean AD for low-and high-dose therapy, respectively. A dose–response relationship was observed for transient tumor volume shrinkage.

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Section: Methodsmentioning

confidence: 99%

Tumor Dosimetry and Response for ¹⁵³Sm-Ethylenediamine Tetramethylene Phosphonic Acid Therapy of High-Risk Osteosarcoma

et al. 2012

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“…For more detail on CRM designs and for applications published in clinical journals, please see additional references (28, 29). …”

Section: Overviewmentioning

confidence: 99%

Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

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et al. 2010

Clinical Cancer Research

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The goals and objectives of phase 1 clinical trials are changing to include further evaluation of endpoints such as molecular targeted effects, in addition to dose/toxicity profile of the investigational agent. Because of these changes in focus, the National Cancer Institute/Investigational Drug Steering Committee’s Task Force on Clinical Trial Design met to evaluate the most efficient ways to design and implement early clinical trials with novel therapeutics. Clinical approaches discussed included the conventional 3 + 3 cohort expansion phase 1 design, multi-institutional phase 1 studies, accelerated titration designs, continual reassessment methods, the study of specific target patient populations and phase 0 studies. Each of these approaches uniquely contributes to some aspect of the phase 1 study, with all focused on dose and schedule determination, patient safety, and limited patient exposure to ineffective doses of investigational agent. The benefit of labor-intensive generation of preliminary biomarker evidence of target inhibition, as well as the value of molecular profiling of the study population, is considered. New drug development is expensive and the failure rate remains high. By identifying patient populations expected to respond to the study agent and tailoring the treatment with a novel drug, investigators will be one step closer to personalizing cancer treatment. The ‘fail early and fast’ approach is acceptable if the appropriate patient population is evaluated in the phase 1 trial. The approaches outlined in this overview address the merits, advantages, disadvantages and obstacles encountered during first in human studies.

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“…This study illustrates how pediatric trial consortia could develop this model ( 9 ). A new radionucleotide therapy for pediatric osteosarcoma (Samarium-153-EDTMP) has already been tested using this trial design ( 10 ). The Pediatric Brain Tumor Consortium has also used a modified CRM to evaluate a gamma-secretase inhibitor (NOTCH pathway) in CNS tumors ( 11 ).…”

Section: Identifying a Safe Dosementioning

confidence: 99%

Challenges of Clinical Trial Design for Targeted Agents Against Pediatric Leukemias

et al. 2015

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The past 40 years have seen significant improvements in both event-free and overall survival for children with acute lymphoblastic and acute myeloid leukemia (ALL and AML, respectively). Serial national and international clinical trials have optimized the use of conventional chemotherapeutic drugs and, along with improvements in supportive care that have enabled the delivery of more intensive regimens, have been responsible for the major improvements in patient outcome seen over the past few decades. However, the benefits of dose intensification have likely now been maximized, and over the same period, the identification of new cytotoxic drugs has been limited. Therefore, challenges remain if survival is to be improved further. In pediatric ALL, 5-year-survival rates of over 85% have been achieved with risk-stratified therapy, but a notable minority of patients will still not be cured. In pediatric AML, different challenges remain. A slower improvement in overall survival has taken place in this patient population. Despite the obvious morphological heterogeneity of AML blasts, biological stratification is comparatively limited, and translation into risk-stratified therapeutic approaches has only best characterized by the use of retinoic acid for t(15;17)-positive AML. Even where prognostic markers have been identified, limited therapeutic options or multi-drug resistance of AML blasts has limited the impact on patient benefit. For both, the acute morbidities of current treatment remain significant and may be life-threatening alone. In addition, the Childhood Cancer Survivor Study (CCSS) highlighted many leukemia survivors develop one or more chronic medical conditions attributable to treatment (1, 2). As the biology of leukemogenesis has become better understood, key molecules and intracellular pathways have been identified that offer the possibility of targeting directly the leukemia cells while sparing normal cells. Consequently, there is now a drive to develop novel leukemia-specific or “targeted” therapies. These new classes of drugs will have mechanisms of action, toxicities, and therapeutic indices quite different from conventional cytotoxic drugs previously encountered, thus rendering current clinical trial methodologies inappropriate. Clinical trial methods will need to be adapted to accommodate these features of these new classes of drugs. This review will address the challenges and some of the techniques for developing clinical trials for targeted therapies.

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Dose‐finding study of ¹⁵³Sm‐EDTMP in patients with poor‐prognosis osteosarcoma

Cited by 50 publications

References 11 publications

Tumor Dosimetry and Response for ¹⁵³Sm-Ethylenediamine Tetramethylene Phosphonic Acid Therapy of High-Risk Osteosarcoma

Tumor Dosimetry and Response for ¹⁵³Sm-Ethylenediamine Tetramethylene Phosphonic Acid Therapy of High-Risk Osteosarcoma

Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

Challenges of Clinical Trial Design for Targeted Agents Against Pediatric Leukemias

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Dose‐finding study of 153Sm‐EDTMP in patients with poor‐prognosis osteosarcoma

Cited by 50 publications

References 11 publications

Tumor Dosimetry and Response for 153Sm-Ethylenediamine Tetramethylene Phosphonic Acid Therapy of High-Risk Osteosarcoma

Tumor Dosimetry and Response for 153Sm-Ethylenediamine Tetramethylene Phosphonic Acid Therapy of High-Risk Osteosarcoma

Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee

Challenges of Clinical Trial Design for Targeted Agents Against Pediatric Leukemias

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Dose‐finding study of ¹⁵³Sm‐EDTMP in patients with poor‐prognosis osteosarcoma

Tumor Dosimetry and Response for ¹⁵³Sm-Ethylenediamine Tetramethylene Phosphonic Acid Therapy of High-Risk Osteosarcoma

Tumor Dosimetry and Response for ¹⁵³Sm-Ethylenediamine Tetramethylene Phosphonic Acid Therapy of High-Risk Osteosarcoma