A prospective non-randomized study of 131I-L19SIP Radioimmunotherapy (RIT) in combination with Whole Brain Radiation Therapy (WBRT) in patients with multiple brain metastases from solid tumors - 131I-L19SIP RIT plus External Beam Radiation in brain metastases

Start Date28 May 2010

Sponsor / Collaborator-

NCT01124812 / TerminatedPhase 1

A Prospective Non-randomized Study of 131I-L19SIP Radioimmunotherapy (RIT) in Combination With External Beam Radiotherapy (EBRT) and Concurrent Chemotherapy in Patients With Inoperable, Locally-advanced (Stage III) NSCLC

The aim of this feasibility study is to determine the therapeutic potential of the L19SIP antibody, labeled with the radionuclide 131I in combination with radiochemotherapy, for the treatment of patients with newly diagnosed, unresectable, locally-advanced NSCLC following the promising results with this agent in previous clinical studies.
The L19SIP antibody is a fully human antibody, capable of preferential localization around tumor blood vessels while sparing normal tissues. The formation of new blood vessels is a rare event in the adult (with the exception of the female reproductive tract), but it is a characteristic pathological feature for most types of aggressive cancer.

Start Date01 May 2010

Sponsor / Collaborator

Philogen SpA

EUCTR2009-013002-13-IT / Not yet recruitingNot Applicable

A prospective non-randomized study of 131I-L19SIP Radioimmunotherapy (RIT) in combination with Whole Brain Radiation Therapy (WBRT) in patients with multiple brain metastases from solid tumors - 131I-L19SIP Radioimmunotherapy (RIT) in combination with External Beam Radiation in patients with mu

Start Date25 Sep 2009

Sponsor / Collaborator

Philogen SpA

100 Clinical Results associated with 131 I-L19-small immunoprotein(Philogen SpA)

100 Translational Medicine associated with 131 I-L19-small immunoprotein(Philogen SpA)

100 Patents (Medical) associated with 131 I-L19-small immunoprotein(Philogen SpA)

Literatures (Medical) associated with 131 I-L19-small immunoprotein(Philogen SpA)

01 Mar 2016·Bone Marrow TransplantationQ3 · MEDICINE

Nivolumab in a patient with refractory Hodgkin’s lymphoma after allogeneic stem cell transplantation

Q3 · MEDICINE

Letter

Author: Kessler, T ; Rebber, E ; Berdel, W E ; Schliemann, C ; Weckesser, M ; Lutz, M ; Stegger, L ; Schulze, A B ; Lenz, G ; Stelljes, M ; Schäfers, M ; Groth, C ; Angenendt, L

Allogeneic stem cell transplantation (alloSCT) is still one of the most powerful tools for the treatment of hematol. malignancies.¹ The immune-mediated graft-vs.-tumor (GVT) effect endows it with the potential to cure malignancies refractory to all other treatments.Nevertheless, it is associated with the risk of donor cell-mediated graft-vs.-host disease (GVHD), which mainly contributes to its relevant morbidity and lethality.In theory, the GVT effect might be enhanced by immune checkpoint inhibitors such as ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4), nivolumab (anti-programmed cell death 1, PD1) or pembrolizumab (anti-PD1), by releasing the brakes on GVT conveying tumor-suppressed lymphocytes.² Nevertheless, severe graft-vs.-host (GVH) reactions might be unleashed as well.While preliminary data demonstrated no significantly increased GVHD in patients treated with ipilimumab post alloSCT,³ there is still substantial concern regarding the safety of PD1 inhibitors in this setting.In fact, increased GVHD-related lethality has been demonstrated in a murine model of acute GVHD when blocking PD-L1.⁴ Recently, a report on a patient receiving pembrolizumab for malignant melanoma about 20 years after alloSCT reported no development of GVHD.⁵ However, there were no data on donor chimerism reported and lack of donor immune cells might be a reasonable cause for lack of GVHD development.Hodgkin's lymphoma (HL) is a neoplastic disease of lymphoid origin, that can initially be cured in >75% of patients using chemotherapy, often followed by consolidating radiation.⁶ Relapsed or refractory (r/r) patients might be salvaged by high-dose therapy and autologous stem cell transplantation.After high-dose therapy, the antibody-drug conjugate brentuximab vedotin (BV) demonstrated very promising results both as consolidation and salvage treatment and is approved in this setting.^7, ⁸ In highly refractory cases alloSCT is considered as a therapeutic option in eligible patients.⁹ Recently, checkpoint inhibition by nivolumab demonstrated a remarkable overall response rate of 87% including 17% complete remissions (CR) in 23 patients with r/r HL.¹⁰ The benefit of PD1 inhibition in this setting is furthermore supported by preliminary results of pembrolizumab in 15 r/r patients achieving similar responses.¹¹ While the latter trial allows the inclusion of patients 5 years post alloSCT, no such patient has been reported yet.Here, we report the first patient to our knowledge successfully treated with nivolumab after alloSCT.In May 2012 an 18-yr-old man was diagnosed with classical HL involving mediastinal and hilar lymph nodes as well as the middle lobe of the lung corresponding to a stage IV B (fever).Risk factors according to the German Hodgkin Study Group classification system included an erythrocyte sedimentation rate above 30 mm/h with B symptoms, a mediastinal mass on chest X-ray measuring more than one-third of the thoracic diameter (21/31 cm) and extranodal involvement (lung).Following prephase treatment with prednisolone, the patient received six cycles BEACOPP-escalated (bleomycin, etoposide, adriamycin, cyclophopshamide, vincristine, prednisolone and procarbazine).In Oct. 2012, final examination by ¹⁸F-fluorodeoxyglucose (FDG)-positron emission tomog. (PET)/computed tomog. (CT) demonstrated a CR of the mediastinal and hilar lymph nodes, but metabolically active paramediastinal residuals in the middle lobe.Unfortunately, the disease immediately progressed even before consolidating radiotherapy could be initiated.The patient received two cycles of DHAP (dexamethasone, high-dose cytarabine and cisplatin) complemented by two cycles of Dexa-BEAM (dexamethasone, carmustine, etoposide, cytarabine and melphalan) due to insufficient response on interim staging, followed by high-dose BEAM and autologous stem cell transplantation.This achieved a partial remission with residual metabolically active lesions in the mediastinum and in the right lung that were subjected to radiotherapy with 30.6 Gy.Only 3 wk after completion of radiotherapy in August 2013, the patient was again submitted to our department with fever.Staging demonstrated multifocal progressive disease, which was histol. confirmed by mediastinoscopic lymphadenectomy.At that point, a search for a matched unrelated donor for alloSCT was initiated.As a bridge to transplant the patient received five cycles of BV, resulting in a mixed response on ¹⁸F-FDG-PET/CT with regressive nodal disease, but progressing lymphoma lesions in the lung.In Dec. 2013, following conditioning with treosulfan (3 × 14 g/m²), fludarabine (5 × 30 mg/m²) and antithymocyte globulin (2 × 20 mg/kg), the patient was transplanted from an HLA-matched unrelated donor.There was no development of acute or chronic GVHD post transplantation.However, after an initial minor response, his disease already progressed 2 mo after transplantation.Considering this short response, we decided against the use of donor lymphocyte infusions (DLI).Treatment with BV was resumed with no response after 3 cycles.In July 2014, an exptl. treatment with a single dose of the vascular-targeting radioimmunoconjugate ¹³¹I-L19-SIP (2.2 GBq) that has previously demonstrated marked responses in refractory cases of HL (reference12) led to a good response of the preexistent lesions, but multiple new lesions at previously non-involved sites developed.The patient was treated with CEVD (lomustine, etoposide, vindesine, dexamethasone) chemotherapy, again leading to a mixed response with regressive intrathoracic and retroperitoneal lesions, but new liver and bone lesions.At that time, the patient's general condition progressively deteriorated accompanied with nausea, loss of appetite, severe B symptoms and significant loss of weightHe was bedridden most of the time, corresponding to a Karnofsky performance index of only 30%.Considering the high response rates in r/r HL, recently reported by Ansell et al.,¹⁰ we decided to initiate an off-label therapy with the anti-PD1 antibody nivolumab.The patient consented and received a single dose of nivolumab at 3 mg/kg (approximated to 200 mg absolute) in June 2015.Treatment was well tolerated with mild fever during the first 2 h after application being the only side effects.Within the first week after infusion, the patient's B symptoms disappeared and his clin. condition drastically improved over the following weeks (Karnofsky performance index 90%).Most importantly, there was no clin. evidence of GVHD induction.An ¹⁸F-FDG-PET/CT performed 4 wk after infusion revealed a complete metabolic response (Figure 1) and therapy with nivolumab is currently being continued.Of note, there was an unspecific FDG uptake in some parts of the colon after nivolumab.Although this could have many causes, including enteritis or even physiol. peristalsis, an unspecific T-cell activation causing a subclin. GVH reaction in the gut cannot be excluded.¹³ Chimerism analyses showed a complete donor cell chimerism (100%) in peripheral blood during the whole treatment period after alloSCT.Despite the generally favorable prognosis of HL, the prognosis of primary refractory patients, including those relapsing within 3 mo after first-line treatment, is poor, with a 5-yr overall survival of only 26%.⁶ Nevertheless, some of them can still profit from alloSCT with reduced intensity conditioning, mainly due to a GVT or 'graft-vs.-Hodgkin's-lymphoma' effect.^6, ^9, ¹⁴ Patients relapsing after alloSCT might be treated with DLI and/or BV, but supporting evidence is scarce.⁹ Recently, some studies demonstrated enhanced expression of PD-L1 in HL due to 9p24.1 amplification, chromosomal rearrangements and Epstein-Barr virus infection.² This conceivably results in suppression of an anticancer immune response, as supported by the impressive therapeutic potential of PD1 inhibitors in r/r HL patients.^10, ¹¹ However, while it appears particularly appealing to reverse the suppression of allogeneic GVT effects with PD1 inhibition in the situation of HL relapse after alloSCT, special caution has to be taken in the context of an allogeneic immune system given the role of the PD1 axis in the pathophysiol. of GVHD as well.⁴ In the presented case of a patient with HL refractory to multiple lines of therapy including alloSCT and BV, nivolumab achieved a remarkable and fast response, suggesting PD1 inhibition to be a powerful means for unleashing the GVT effect in the immunosuppressive microenvironment of HL.However, we did not perform mechanistic studies and another potential cause might be a disruption of the HL supporting infiltrating leukocytes independent of a GVT effect.Importantly, despite recent concerns, there were no signs of GVHD induction in our patient.While the mice in the study of Saha received PD1/PD-L1 inhibition from day one after transplantation,⁴ our patient received nivolumab 19 mo after alloSCT.Thus, GVHD might be more responsive to PD1/PD-L1 inhibition during the early phase of transplantation potentially triggering severe GVH reactions in the context of conditioning-related inflammation of host tissues.In addition, our patient had never developed signs of GVHD post transplantation and patients with a history of GVHD might be at higher risk of GVHD exacerbation by releasing the brakes on existing alloreactive cells.Furthermore, follow-up is short and it is entirely conceivable that GVHD might still occur after months of treatment, similar to immune-related adverse events of checkpoint inhibition in non-transplanted patients.¹⁵ Nevertheless, more established post-alloSCT treatments such as DLIs are also associated with the risk of GVHD exacerbation.¹⁶ Thus, it seems reasonable to investigate nivolumab in a larger group of patients in this desperate situation.However, its regular use in this setting cannot be recommended on the basis of a single experience.

01 Mar 2016·Medical HypothesesQ4 · MEDICINE

Nanotrastuzumab in combination with radioimmunotherapy: Can it be a viable treatment option for patients with HER2-positive breast cancer with brain metastasis?

Q4 · MEDICINE

Article

Author: Shen, Songjie ; Xu, Yali ; Huang, Likun ; Wang, Xuefei ; Sun, Qiang

Brain metastasis of primary breast cancer (BCBM) has been rising during the last couple of decades. Approximately 25% of the patients with BCBM have a hormone receptor-negative, HER2-positive disease. Given the short life expectancy in patients with BCBM, researchers have tried many new approaches, including cesium-131(131Cs) brachytherapy, radretumab radioimmunotherapy and nanoparticles. Novel biological drug delivery techniques have successfully delivered nanobioconjugates across the blood-brain barrier (BBB). However, nanobioconjugates have significant toxicities and other drawbacks that prevent therapeutic concentrations of the active drug from being delivered to the brain lesions. Radretumab radioimmunotherapy combined with nanotrastruzumab can theoretically overcome this challenge. Radiotherapy can increase the BBB permeability, which can promote the transport and effect of nanotrastuzumab, reduce radretumab radioimmunotherapy dose and target patients with HER2-positive BCBM lesions more specifically. In this article, we propose that nanotrastuzumab in combination with radioimmunotherapy could be a viable treatment option for patients with HER2-positive breast cancer with brain metastasis.

01 Jan 2014·Journal of Cancer Research and Clinical OncologyQ3 · MEDICINE

Abundant in vitro expression of the oncofetal ED-B-containing fibronectin translates into selective pharmacodelivery of 131I-L19SIP in a prostate cancer patient

Q3 · MEDICINE

Article

Author: Giovannoni, Leonardo ; Bombardieri, Emilio ; Erba, Paola A. ; Menssen, Hans D. ; Locher, Ricarda ; Hirsch, Burkhard ; Duerkop, Horst ; Neri, Dario

PURPOSEThe extradomain B of fibronectin (ED-B) is a promising vascular target for selective pharmacodelivery in cancer patients. We analyzed a large series of prostatectomies from patients with prostate cancer, hyperplastic prostate disease, and normal prostates to study extent and tumor-selectivity of ED-B expression.METHODSUsing immunohistology, 68 adenocarcinomas of the prostate or prostate cancer-inflicted lymph nodes, 4 samples of benign prostatic hyperplasia, and 6 normal prostate glands were studied for ED-B expressing newly formed blood vessels. Further, we treated an advanced prostate cancer patient with the anti-ED-B antibody (131)I-L19SIP to study in vivo target accessibility.RESULTSED-B-positive blood vessels were found significantly more frequent in prostate cancers as compared with peritumoral prostate tissues or normal prostate glands, independent of tumor differentiation. The ED-B-positive blood vessels' density was 97 (±23), 65 (±9), and 59 (±9)/mm(2) in G3, G2, and G1 prostate cancers, respectively, and 7 (±5)/mm(2) in normal prostate glands. In high-grade (G3) prostate cancers, also the peritumoral tissue showed a higher density of ED-B vessels than normal prostate glands. Similar results were obtained when ED-B-positive vessel density was expressed as a fraction of CD34-positive vessel density. Finally, selective uptake of ED-B-binding (131)I-L19SIP to tumor lesions was found in an advanced prostate cancer patient by whole-body planar scintigraphy.CONCLUSIONSED-B-positive blood vessels were found to a large extent in prostate cancer tissues, but only rarely in normal prostates or benign prostatic hyperplasia. Whole-body planar scintigraphy in a prostate cancer patient confirmed selective uptake of (131)I-L19SIP in the prostate cancer tissues, qualifying ED-B as a promising target for selective pharmacodelivery of anticancer agents in prostate cancer.

100 Deals associated with 131 I-L19-small immunoprotein(Philogen SpA)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Locally Advanced Lung Non-Small Cell Carcinoma	Phase 2	IT	Philogen SpA	01 May 2010
Non-small cell lung cancer stage III	Phase 2	IT	Philogen SpA	01 May 2010
Brain Cancer	Phase 2	IT	Philogen SpA	-
Brain Cancer	Phase 2	GB	Philogen SpA	-
Hodgkin's Lymphoma	Phase 2	-	Philogen SpA	-
Solid tumor	Phase 2	EU	Philogen SpA	-

Clinical Result

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Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


Pubmed \| Cancer Immunol Res	Not Applicable	Brain metastases	-	Radretumab RIT	oizqvvvlnt(hxijmnujwd) = dbzipkxkzn sldkpivjbz (nbfsszenwy )	-	01 Aug 2013
ASCO2010	Phase 1	Solid tumor \| X-Linked Lymphoproliferative Disorder	-	<sup>131</sup>I-L19SIP	(ecqwjpdwax) = rbqhvpmeyx xvyhdcvprk (ogqmosbtvg )	-	20 May 2010
ASCO2010	Phase 1/2	Neoplasms	12	131I-L19SIP	zaxyieldra(ctyropwmhd) = nqtvwxmcub jhbqlztnyy (tbkpxboaic )	-	20 May 2010
ASCO2008	Phase 1	Solid tumor \| Lymphoproliferative Disorders	37	<sup>131</sup>I-L19-SIP	bxjmjxgkph(hpydjbcimo) = yjmrgusjer vdbdqbrtvo (ykbefltuog ) View more	-	20 May 2008

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