Neeta Pandit-Taskar

Phase I pharmacokinetic and biodistribution study with escalating doses of 223Ra-dichloride in men with castration-resistant metastatic prostate cancer

Purpose223Ra-Dichloride (223Ra) is a novel bone-seeking alpha-emitter that prolongs survival in patients with castration-resistant metastatic prostate cancer. We conducted a study to better profile the pharmacokinetics, pharmacodynamics, and biodistribution of this agent.MethodsTen patients received either 50, 100, or 200xa0kBq of 223Ra per kilogram of body weight. Subsequently, six of these ten patients received a second dose of 50xa0kBq/kg. Pharmacokinetics and biodistribution were assessed by serial blood sampling, planar imaging, and whole-body counting. Pharmacodynamic assessment was based on measurements of prostate-specific antigen, bone alkaline phosphatase, and serum N-telopeptide. Safety was also assessed.ResultsPharmacokinetic studies showed rapid clearance of 223Ra from the vasculature, with a median of 14xa0% (range 9–34xa0%), 2xa0% (range 1.6–3.9xa0%), and 0.5xa0% (range 0.4–1.0xa0%) remaining in plasma at the end of infusion, after 4xa0h, and after 24xa0h, respectively. Biodistribution studies showed early passage into the small bowel and subsequent fecal excretion with a median of 52xa0% of administered 223Ra in the bowel at 24xa0h. Urinary excretion was relatively minor (median of 4xa0% of administered 223Ra). Bone retention was prolonged. No dose-limiting toxicity was observed. Pharmacodynamic effects were observed (alkaline phosphatase and serum N-telopeptides) in a significant fraction of patients.Conclusion223Ra cleared rapidly from plasma and rapidly transited into small bowel, with fecal excretion the major route of elimination. Administered activities up to 200xa0kBq/kg were associated with few side effects and appeared to induce a decline in serum indicators of bone turnover.

A Phase I/II Study for Analytic Validation of 89Zr-J591 ImmunoPET as a Molecular Imaging Agent for Metastatic Prostate Cancer

Purpose: Standard imaging for assessing osseous metastases in advanced prostate cancer remains focused on altered bone metabolism and is inadequate for diagnostic, prognostic, or predictive purposes. We performed a first-in-human phase I/II study of 89Zr-DFO-huJ591 (89Zr-J591) PET/CT immunoscintigraphy to assess performance characteristics for detecting metastases compared with conventional imaging modalities (CIM) and pathology. Experimental Design: Fifty patients with progressive metastatic castration-resistant prostate cancers were injected with 5 mCi of 89Zr-J591. Whole-body PET/CT scans were obtained, and images were analyzed for tumor visualization. Comparison was made to contemporaneously obtained bone scintigraphy and cross-sectional imaging on a lesion-by-lesion basis and with biopsies of metastatic sites. Results: Median standardized uptake value for 89Zr-J591–positive bone lesions (n = 491) was 8.9 and for soft-tissue lesions (n = 90), it was 4.8 (P < 0.00003). 89Zr-J591 detected 491 osseous sites compared with 339 by MDP and 90 soft-tissue lesions compared with 124 by computed tomography (CT). Compared with all CIMs combined, 89Zr-J591 detected an additional 99 osseous sites. Forty-six lesions (21 bone and 25 soft tissue) were biopsied in 34 patients; 18 of 19 89Zr-J591–positive osseous sites and 14 of 16 89Zr-J591–positive soft tissue sites were positive for prostate cancer. The overall accuracy of 89Zr-J591 was 95.2% (20 of 21) for osseous lesions and 60% (15 of 25) for soft-tissue lesions. Conclusions: 89Zr-J591 imaging demonstrated superior targeting of bone lesions relative to CIMs. Targeting soft-tissue lesions was less optimal, although 89Zr-J591 had similar accuracy as individual CIMs. This study will provide benchmark data for comparing performance of proposed prostate-specific membrane antigen (PSMA) targeting agents for prostate cancer. Clin Cancer Res; 21(23); 5277–85. ©2015 AACR.

89Zr-huJ591 immuno-PET imaging in patients with advanced metastatic prostate cancer

PurposeGiven the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. 89Zr-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection.MethodsTen patients with metastatic prostate cancer received 5xa0mCi of 89Zr-huJ591. Four whole-body scans with multiple whole-body count rate measurements and serum activity concentration measurements were obtained in all patients. Biodistribution, clearance, and lesion uptake by 89Zr-huJ591 immuno-PET imaging was analyzed and dosimetry was estimated using MIRD techniques. Initial assessment of lesion targeting of 89Zr-huJ591 was done. Optimal time for imaging post-injection was determined.ResultsThe dose was well tolerated with mild chills and rigors seen in two patients. The clearance of 89Zr-huJ591 from serum was bi-exponential with biological half-lives of 7 ± 4.5xa0h (range 1.1–14xa0h) and 62 ± 13xa0h (range 51–89xa0h) for initial rapid and later slow phase. Whole-body biological clearance was 219 ± 48xa0h (range 153–317xa0h). The mean whole-body and liver residence time was 78.7 and 25.6xa0h, respectively. Dosimetric estimates to critical organs included liver 7.7 ± 1.5xa0cGy/mCi, renal cortex 3.5 ± 0.4xa0cGy/mCi, and bone marrow 1.2 ± 0.2xa0cGy/mCi. Optimal time for patient imaging after injection was 7 ± 1xa0days. Lesion targeting of bone or soft tissue was seen in all patients. Biopsies were performed in 8 patients for a total 12 lesions, all of which were histologically confirmed as metastatic prostate cancer. One biopsy-proven lesion was not positive on 89Zr-huJ591, while the remaining 11 lesions were 89Zr-huJ591 positive. Two biopsy-positive nodal lesions were noted only on 89Zr-huJ591 study, while the conventional imaging modality was negative.Conclusion89Zr-huJ591 PET imaging of prostate-specific membrane antigen expression is safe and shows good localization of disease in prostate cancer patients. Liver is the critical organ for dosimetry, and 7 ± 1xa0days is the optimal imaging time. A larger study is underway to determine lesion detection in an expanded cohort of patients with metastatic prostate cancer.

Indium 111-labeled J591 anti-PSMA antibody for vascular targeted imaging in progressive solid tumors

BackgroundJ591 is a monoclonal antibody that targets the external domain of the prostate-specific membrane antigen (PSMA). Besides prostate cancer cells, it also targets the neovasculature of non-prostate solid tumors. We provide an analysis of the antibody mass-dose dependency of lesion uptake and normal tissue retention, together with an assessment of lesion detectability using 111In-J591 imaging, compared with conventional imaging in patients with a variety of solid tumors.MethodsTwenty patients in six cohorts received fixed amounts (5, 10, 20, 40, 60, and 100 mg) of J591 in a phase I trial. A maximum of four administrations per patient was given, with each administration separated by 3 weeks. All antibody administrations included 370 MBq (10 mCi) of 111In labeled to 2 mg of J591 via the chelating agent DOTA. Three whole body (WB) gamma camera scans with at least one SPECT scan, along with multiple WB count-rate measurements and blood samples, were obtained for all patients. The effect of escalating antibody mass on lesion uptake and normal tissue retention was evaluated using lesion, liver, serum, and WB residence times and ratios thereof for each treatment cycle. Lesion detectability using 111In-J591 imaging was compared to the standard imaging on a lesion-by-lesion basis.ResultsA total of 170 lesions in 20 patients were detected by standard or 111In-J591 imaging. 111In-J591 targeted both skeletal and soft tissue diseases in all tumor types. 111In-J591 imaging identified 74% (20/27) of skeletal lesions, 53% (18/34) of nodes, and 64% (70/109) of other soft tissue/organ lesions. There was increasing 111In-J591 uptake in lesions with increasing antibody mass-dose, coupled with decreasing retention in the liver for increments up to 20 mg, and no significant change at higher antibody mass.ConclusionsRadiolabeled J591 antibody has potential as a targeting agent for solid tumor vasculature and lesion detection. Bone and soft tissue lesions arising from tumors of diverse origin were targeted by the anti-PSMA antibody J591. For the detection of lesions in these tumors by J591 antibody scans, an antibody mass of 20 mg is adequate. The optimal time of imaging is 5 to 7 days post-injection.

Radionuclide therapy of adrenal tumors

Adrenal tumors arising from chromaffin cells will often accumulate radiolabeled metaiodobenzylguanidine (MIBG) and thus are amenable to therapy with I‐131 MIBG. More recently, therapy studies have targeted the somatostatin receptors using Lu‐177 or Y‐90 radiolabeled somatostatin analogs. Because pheochromocytoma (PHEO)/paraganglioma (PGL) and neuroblastoma (NB), which often arise from the adrenals, express these receptors, clinical trials have been performed with these reagents. We will review the experience using radionuclide therapy for targeting PHEO/PGL and NBs. J. Surg. Oncol. 2012; 106:632–642.

Molecular Imaging of Biomarkers in Breast Cancer

The success of breast cancer therapy is ultimately defined by clinical endpoints such as survival. It is valuable to have biomarkers that can predict the most efficacious therapies or measure response to therapy early in the course of treatment. Molecular imaging has a promising role in complementing and overcoming some of the limitations of traditional biomarkers by providing the ability to perform noninvasive, repeatable whole-body assessments. The potential advantages of imaging biomarkers are obvious and initial clinical studies have been promising, but proof of clinical utility still requires prospective multicenter clinical trials.

I-131 Metaiodobenzylguanidine Therapy of Pheochromocytoma and Paraganglioma☆

Pheochromocytomas and paragangliomas are rare tumors arising from chromaffin cells. Available therapeutic modalities consist of chemotherapy, tyrosine kinase inhibitors, and I-131 metaiodobenzylguanidine (MIBG). I-131 MIBG is taken up via specific receptors and localizes into many but not all pheochromocytomas and paragangliomas. Because these tumors are rare, most therapy studies are retrospective presentations of clinical experience. Numerous retrospective studies and a few prospective studies have shown favorable responses in this disease, including symptomatic, biochemical, and objective responses. In this report, we review the experience of using I-131 MIBG therapy for targeting pheochromocytoma and paragangliomas.

Repetitively dosed docetaxel and ¹⁵³samarium-EDTMP as an antitumor strategy for metastatic castration-resistant prostate cancer.

β‐emitting bone‐seeking radiopharmaceuticals have historically been administered for pain palliation whereas docetaxel prolongs life in patients with metastatic castration‐resistant prostate cancer (mCRPC). In combination, these agents simultaneously target the bone stroma and cancer cell to optimize antitumor effects. The toxicity and efficacy when each agent is combined at full, recommended doses, in a repetitive fashion is not well established.

Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial

BACKGROUNDnDiffuse intrinsic pontine glioma is one of the deadliest central nervous system tumours of childhood, with a median overall survival of less than 12 months. Convection-enhanced delivery has been proposed as a means to efficiently deliver therapeutic agents directly into the brainstem while minimising systemic exposure and associated toxic effects. We did this study to evaluate the safety of convection-enhanced delivery of a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen in children with diffuse intrinsic pontine glioma.nnnMETHODSnWe did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients were aged 3-21 years and had diffuse intrinsic pontine glioma as diagnosed by consensus of a multidisciplinary paediatric neuro-oncology team; a Lansky (patients <16 years of age) or Karnofsky (patients ≥16 years) performance score of at least 50 at study entry; a minimum weight of 8 kg; and had completed external beam radiation therapy (54·0-59·4 Gy at 1·8 Gy per fraction over 30-33 fractions) at least 4 weeks but no more than 14 weeks before enrolment. Seven dose-escalation cohorts were planned based on standard 3u2008+u20083 rules: patients received a single infusion of 9·25, 18·5, 27·75, 37, 92·5, 120·25, or 148 MBq, respectively, at a concentration of about 37 MBq/mL by convection-enhanced delivery of the radiolabelled antibody [124I]-8H9. The primary endpoint was identification of the maximum tolerated dose. The analysis of the primary endpoint was done in the per-protocol population (patients who received the full planned dose of treatment), and all patients who received any dose of study treatment were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01502917, and is ongoing with an expanded cohort.nnnFINDINGSnFrom April 5, 2012, to Oct 8, 2016, 28 children were enrolled and treated in the trial, of whom 25 were evaluable for the primary endpoint. The maximum tolerated dose was not reached as no dose-limiting toxicities were observed. One (4%) of 28 patients had treatment-related transient grade 3 hemiparesis and one (4%) had grade 3 skin infection. No treatment-related grade 4 adverse events or deaths occurred. Estimated volumes of distribution (Vd) were linearly dependent on volumes of infusion (Vi) and ranged from 1·5 to 20·1 cm3, with a mean Vd/Vi ratio of 3·4 (SD 1·2). The mean lesion absorbed dose was 0·39 Gy/MBq 124I (SD 0·20). Systemic exposure was negligible, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1200.nnnINTERPRETATIONnConvection-enhanced delivery in the brainstem of children with diffuse intrinsic pontine glioma who have previously received radiation therapy seems to be a rational and safe therapeutic strategy. PET-based dosimetry of the radiolabelled antibody [124I]-8H9 validated the principle of using convection-enhanced delivery in the brain to achieve high intra-lesional dosing with negligible systemic exposure. This therapeutic strategy warrants further development for children with diffuse intrinsic pontine glioma.nnnFUNDINGnNational Institutes of Health, The Dana Foundation, The Cure Starts Now, Solving Kids Cancer, The Lyla Nsouli Foundation, Cookies for Kids Cancer, The Cristian Rivera Foundation, Battle for a Cure, Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering Cancer Center.

Targeted Therapy for Bone Metastasis

Bone metastases markedly reduce the quality of life due to bone pain, pathologic fractures, loss of mobility, and hypercalcemia. A graded three step approach, as recommended by WHO, is used to treat pain according to its severity. Usually nonsteroidal anti-inflammatory drugs are used in patients with mild to moderate pain. When pain persists or increases a weak opioid, such as codeine or hydrocodone is added. Higher doses or more potent opioids are used if the pain persists or becomes more severe. Bisphosphonates are useful in the treatment of osteoporosis and metastatic disease by decreasing the resorption of bone. They bind to bone mineral and directly interfere with the activation of osteoclasts. Bisphosphonates are internalized in the osteoclasts and inhibit specific biochemical and metabolic pathways in these cells. Bisphosphonates reduce skeletal complications and reduce the rate of development of new lesions and delay progression in bone metastases. External beam radiation therapy is effective for localized bone pain due to bone metastasis. It provides rapid pain relief that can start as early as 48 h after the commencement of therapy. Radiation destroys viable tumor cells and enables osteoblastic repair of damaged bone. Radiotherapy may be given as a single dose or multifractionated dose. There is preferential use of the multifractionated dose method in USA. Therapy with bone-seeking radiopharmaceuticals is efficacious to reduce pain in patients with widespread painful bone metastases. Beta-emitting nuclide phosphorus-32 (32P) sodium phosphate or orthophosphate, strontium-89 (89Sr) chloride, and samarium-153 ethylene diamine tetramethylene phosphonic acid (153Sm-EDTMP) have been approved for clinical use in the USA. All agents have advantages and side effects. Moreover, the sources of radiation within bone differ with the radiopharmaceutical used. The metallic chelated radiotracers tend to chemically absorb to the trabecular surface, whereas 32P-sodium orthophosphate and 89Sr-chloride distribute more widely throughout bone. 89Sr-chloride is one of the two FDA-approved radiopharmaceuticals that has largely replaced 32P-sodium orthophosphate in the treatment of metastatic bone pain. The onset of pain relief commonly occurs within 7–21 days, and mean duration of relief is about 2–6 months. Retreatment can be given after 90 days, although multiple xadtherapies may lead to greater marrow toxicity. 89Sr-chloride has been extensively used, mainly in the treatment of bone pain from breast and prostate cancer. Radionuclide therapy can be administered in association with chemotherapy. The combination may enhance pain relief and delay the onset of new painful metastases. 153Sm-EDTMP is a stable complex that selectively accumulates in skeletal tissue. Bone metastasis may contain 3–5 times more 153Sm-EDTMP than healthy bone tissue. The low energy of the beta particle reduces the radiation burden to bone marrow. Hematological side effects are generally mild. Pain relief is generally noted within 5–10 days and can last up to 4 months. Repeated dosing of 153Sm-EDTMP is feasible if pain returns or increases. Patients referred for bone pain therapy have multiple painful bone metastases confirmed by a bone scan which shows multiple focal sites of increased radiopharmaceutical uptake and who is experiencing worsening of bone pain, in spite of narcotic pain medication. In patients with established bone metastases, hormonal or chemotherapy can palliate symptoms, but rarely produces durable control. Recent data offer a compelling rationale to combine chemotherapy with bone-seeking radiopharmaceuticals for prolonging survival and enhance quality of life.