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William A Wegener - One of the best experts on this subject based on the ideXlab platform.

  • anti cd22 90y epratuzumab Tetraxetan combined with anti cd20 veltuzumab a phase i study in patients with relapsed refractory aggressive non hodgkin lymphoma
    Haematologica, 2014
    Co-Authors: Thomas E Witzig, William A Wegener, Michael B Tomblyn, Jamal Misleh, Robert M. Sharkey, David M. Goldenberg
    Abstract:

    A lingering criticism of radioimmunotherapy in non-Hodgkin lymphoma is the use of cold anti-CD20 antibody along with the radiolabeled anti-CD20 antibody. We instead combined radioimmunotherapy with immunotherapy targeting different B-cell antigens. We evaluated the anti-CD22 90Y-epratuzumab Tetraxetan with the anti-CD20 veltuzumab in patients with aggressive lymphoma in whom at least one prior standard treatment had failed, but who had not undergone stem cell transplantation. Eighteen patients (median age 73 years, median of 3 prior treatments) received 200 mg/m2 veltuzumab once-weekly for 4 weeks, with 90Y-epratuzumab Tetraxetan at planned doses in weeks 3 and 4, and 111In-epratuzumab Tetraxetan in week 2 for imaging and dosimetry. Veltuzumab effectively lowered levels of B cells in the blood prior to the radioimmunotherapy doses. No significant immunogenicity or change in pharmacokinetics of either agent occurred in combination. 111In imaging showed tumor targeting with acceptable radiation dosimetry to normal organs. For 90Y-epratuzumab Tetraxetan, transient myelosuppression was dose-limiting with 6 mCi/m2 (222 MBq/m2) × 2 being the maximal tolerated dose. Of 17 assessable patients, nine (53%) had objective responses according to the 2007 revised treatment response criteria, including three (18%) complete responses (2 relapsing after 11 and 13 months, 1 continuing to be clinically disease-free at 19 months), and six (35%) partial responses (1 relapsing after 14 months, 5 at 3 – 7 months). Responses occurred in patients with different lymphoma histologies, treated at different 90Y dose levels, and with a predicted risk of poor outcome, most importantly including five of the six patients treated with the maximal tolerated dose (2 of whom achieved durable complete responses). In conclusion, the combination of 90Y-epratuzumab Tetraxetan and veltuzumab was well-tolerated with encouraging therapeutic activity in this difficult-to-treat population.

  • bcr abl1 molecular remission after 90y epratuzumab Tetraxetan radioimmunotherapy in cd22 ph b all proof of principle
    European Journal of Haematology, 2013
    Co-Authors: Patrice Chevallier, Caroline Bodetmilin, Tan Eugene, Nelly Robillard, Martine Escoffrebarbe, Audrey Menard, Claire Le Houerou, Jean Delaunay, Thierry Guillaume, William A Wegener
    Abstract:

    Although targeted therapies are used increasingly in hematologic malignancies, we are unaware of any prior studies of radioimmunotherapy (RAIT) in B-acute lymphoblastic leukemia (ALL), even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Here, we report a patient with Philadelphia chromosome-positive B-ALL in third relapse who received RAIT with 90yttrium (90Y)-labeled anti-CD22 epratuzumab Tetraxetan. Seven weeks after initiating therapy, the patient achieved a BCR-ABL1 molecular remission documented by RT-qPCR, which is now continuing at 6 months while awaiting an allogeneic hematopoietic stem cell transplant. 90Y-Epratuzumab Tetraxetan may be a promising therapeutic option for CD22+ B-ALL patients.

  • BCR-ABL1 Molecular Remission After 90y-Epratuzumab Tetraxetan Radioimmunotherapy In CD22+ Ph+ B-ALL: A Potential New Treatment Paradigm
    Blood, 2013
    Co-Authors: Patrice Chevallier, Tan Eugene, Nelly Robillard, Audrey Menard, Claire Le Houerou, Caroline Bodet-milin, Martine Escoffre-barbe, Jean Delaunay, Thierry Guillaume, William A Wegener
    Abstract:

    Introduction Targeted therapies are increasingly becoming treatment options for many hematological diseases. While immuno/chemoimmunotherapy is a recent area of research in acute lymphoblastic leukemia (ALL) (Raetz, JCO, 2008; Advani, Blood, ASH Meeting 2012, abstract 2603), we are unaware of any published studies in ALL using radioimmunotherapy (RAIT), where a potent radionuclide conjugated to an antibody can deliver radiation selectively to the tumor. CD22 is highly expressed in B-ALL. As such, the anti-CD22 humanized antibody, epratuzumab (Immunomedics, Inc., Morris Plains, NJ), which has been studied extensively in non-Hodgkin lymphoma, is also under active investigation in adult and pediatric ALL (see references above). Here we report a patient with Ph+ B-ALL who presented in third relapse and who received RAIT with 90yttrium (90Y)-labeled anti-CD22 epratuzumab Tetraxetan, resulting in an outstanding response. Patient and Methods A 57-year-old woman was diagnosed in July 2004 with Ph+ B-ALL. She was documented with a first (meningeal) relapse in September 2009, then a second (bone marrow) relapse in July 2012. Because of no suitable stem-cell donor, the patient was never allografted when achieving first, second, or third complete remission (CR). Previous treatments included various chemotherapy regimens as well all the three available generations of targeted BCR-ABL1 protein fusion tyrosine kinase inhibitors. A third (bone marrow) relapse occurred in December 2012. The peripheral blood showed normal levels of hemoglobin, leukocytes and platelets, with no circulating leukemic blasts, the bone marrow showed 60% blast infiltration, and BCR-ABL1/ABL1 ratios in blood and bone marrow were 22.4% and 13%, respectively. Taking advantage of the patient’s good performance status (ECOG 1) and the high CD22 expression (100%) in the blast population, we decided to treat this patient by RAIT alone. We reduced the treatment dose to be conservative, since we had no prior experience in ALL and the bone marrow showed 60% blast infiltration, which is above the 25% cutoff for standard RAIT dosing in lymphoma. Accordingly, the patient received 2 cycles of 2 doses of 185 MBq/m2 90Y-epratuzumab Tetraxetan administered intravenously one week apart. The Nantes ethics committee approved the treatment plan, and signed informed consent was obtained from the patient. Results Cycle 1: The patient completed both doses of 185 MBq/m2 90Y-epratuzumab Tetraxetan without infusion reactions. Two weeks after starting treatment, she developed Grade 4 neutropenia and thrombocytopenia that subsequently recovered to Grade 1 levels at weeks 7 and 8, respectively. Grade 3 anemia developed 4 weeks after starting treatment and recovered to Grade 1 at week 7. Phenotypic minimal residual disease (MRD) was negative at 4 and 7 weeks. At 4 weeks, BCR-ABL1 transcript was detectable but not quantifiable (

  • bcr abl1 molecular remission after 90y epratuzumab Tetraxetan radioimmunotherapy in cd22 ph b all a potential new treatment paradigm
    Blood, 2013
    Co-Authors: Patrice Chevallier, Caroline Bodetmilin, Tan Eugene, Nelly Robillard, Martine Escoffrebarbe, Audrey Menard, Claire Le Houerou, Jean Delaunay, Thierry Guillaume, William A Wegener
    Abstract:

    Introduction Targeted therapies are increasingly becoming treatment options for many hematological diseases. While immuno/chemoimmunotherapy is a recent area of research in acute lymphoblastic leukemia (ALL) (Raetz, JCO, 2008; Advani, Blood, ASH Meeting 2012, abstract 2603), we are unaware of any published studies in ALL using radioimmunotherapy (RAIT), where a potent radionuclide conjugated to an antibody can deliver radiation selectively to the tumor. CD22 is highly expressed in B-ALL. As such, the anti-CD22 humanized antibody, epratuzumab (Immunomedics, Inc., Morris Plains, NJ), which has been studied extensively in non-Hodgkin lymphoma, is also under active investigation in adult and pediatric ALL (see references above). Here we report a patient with Ph+ B-ALL who presented in third relapse and who received RAIT with 90yttrium (90Y)-labeled anti-CD22 epratuzumab Tetraxetan, resulting in an outstanding response. Patient and Methods A 57-year-old woman was diagnosed in July 2004 with Ph+ B-ALL. She was documented with a first (meningeal) relapse in September 2009, then a second (bone marrow) relapse in July 2012. Because of no suitable stem-cell donor, the patient was never allografted when achieving first, second, or third complete remission (CR). Previous treatments included various chemotherapy regimens as well all the three available generations of targeted BCR-ABL1 protein fusion tyrosine kinase inhibitors. A third (bone marrow) relapse occurred in December 2012. The peripheral blood showed normal levels of hemoglobin, leukocytes and platelets, with no circulating leukemic blasts, the bone marrow showed 60% blast infiltration, and BCR-ABL1/ABL1 ratios in blood and bone marrow were 22.4% and 13%, respectively. Taking advantage of the patient’s good performance status (ECOG 1) and the high CD22 expression (100%) in the blast population, we decided to treat this patient by RAIT alone. We reduced the treatment dose to be conservative, since we had no prior experience in ALL and the bone marrow showed 60% blast infiltration, which is above the 25% cutoff for standard RAIT dosing in lymphoma. Accordingly, the patient received 2 cycles of 2 doses of 185 MBq/m2 90Y-epratuzumab Tetraxetan administered intravenously one week apart. The Nantes ethics committee approved the treatment plan, and signed informed consent was obtained from the patient. Results Cycle 1: The patient completed both doses of 185 MBq/m2 90Y-epratuzumab Tetraxetan without infusion reactions. Two weeks after starting treatment, she developed Grade 4 neutropenia and thrombocytopenia that subsequently recovered to Grade 1 levels at weeks 7 and 8, respectively. Grade 3 anemia developed 4 weeks after starting treatment and recovered to Grade 1 at week 7. Phenotypic minimal residual disease (MRD) was negative at 4 and 7 weeks. At 4 weeks, BCR-ABL1 transcript was detectable but not quantifiable (<0.01%) in blood sample and positive at 0.017% in bone marrow. Finally, at 7 weeks, BCR-ABL1 transcript was no longer detectable in both samples. No renal or liver toxicities were observed. Cycle 2: Eight weeks after starting the initial treatment, the same treatment was repeated. The patient again completed both doses of 185 MBq/m2 90Y-epratuzumab Tetraxetan with no infusion reactions. No Grade 3-4 hematologic toxicity was observed. Contrary to cycle 1, no transfusions or cytokine support was given. Again, no renal or liver toxicities occurred. Most importantly, evaluations 7 weeks after retreatment and now 6 months (June 2013) from the beginning of RAIT confirmed the persistence of complete phenotypic and molecular responses. Conclusion We report here, for the first time, the feasibility as well as the unexpected efficacy of 90Y-labeled anti-CD22 RAIT in a CD22+, Ph+, B-ALL patient in third relapse. This novel targeted-radiation approach may be a promising therapeutic option for other CD22+ B-ALL patients. We are now conducting a phase I/II study testing this strategy (clinicaltrials no. [NCT01354457][1]). Disclosures: Wegener: Immunomedics: Employment, stock options, stock options Patents & Royalties. Goldenberg: Immunomedics: Employment, stock options, stock options Patents & Royalties. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01354457&atom=%2Fbloodjournal%2F122%2F21%2F3910.atom

  • BCR-ABL1 molecular remission after 90Y-epratuzumab Tetraxetan radioimmunotherapy in CD22+ Ph+ B-ALL: proof of principle.
    European Journal of Haematology, 2013
    Co-Authors: Patrice Chevallier, Tan Eugene, Nelly Robillard, Audrey Menard, Claire Le Houerou, Caroline Bodet-milin, Martine Escoffre-barbe, Jean Delaunay, Thierry Guillaume, William A Wegener
    Abstract:

    Although targeted therapies are used increasingly in hematologic malignancies, we are unaware of any prior studies of radioimmunotherapy (RAIT) in B-acute lymphoblastic leukemia (ALL), even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Here, we report a patient with Philadelphia chromosome-positive B-ALL in third relapse who received RAIT with 90yttrium (90Y)-labeled anti-CD22 epratuzumab Tetraxetan. Seven weeks after initiating therapy, the patient achieved a BCR-ABL1 molecular remission documented by RT-qPCR, which is now continuing at 6 months while awaiting an allogeneic hematopoietic stem cell transplant. 90Y-Epratuzumab Tetraxetan may be a promising therapeutic option for CD22+ B-ALL patients.

Allyson J Ocean - One of the best experts on this subject based on the ideXlab platform.

  • 90y clivatuzumab Tetraxetan with or without low dose gemcitabine a phase ib study in patients with metastatic pancreatic cancer after two or more prior therapies
    European Journal of Cancer, 2015
    Co-Authors: Vincent J Picozzi, Ramesh K Ramanathan, Maeve A Lowery, Allyson J Ocean, Edith P Mitchel, Bert H Oneil, Michael J Guarino, Paul R Conkling, Steven J Cohen, Nathan Bahary
    Abstract:

    Abstract Background For patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering 90Y-clivatuzumab Tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine. Methods Fifty-eight patients with three (2–7) median prior treatments were treated on Arm A (N = 29, 90Y-clivatuzumab Tetraxetan, weekly 6.5 mCi/m2 doses × 3, plus gemcitabine, weekly 200 mg/m2 doses × 4 starting 1 week earlier) or Arm B (N = 29, 90Y-clivatuzumab Tetraxetan alone, weekly 6.5 mCi/m2 doses × 3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated. Results Cytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3–9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan–Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29–0.86; P = 0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4 months with multiple cycles (HR 0.32, P = 0.004), including three patients in Arm A surviving >1 year. Conclusions Clinical studies of 90Y-clivatuzumab Tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting.

  • abstract b98 final results of a randomized phase ib study of fractionated 90y clivatuzumab Tetraxetan in patients with metastatic pancreatic cancer having at least two prior therapies
    Cancer Research, 2015
    Co-Authors: Vincent J Picozzi, Ramesh K Ramanathan, Maeve A Lowery, Allyson J Ocean, Bert H Oneil, Michael J Guarino, Paul R Conkling, Steven J Cohen, Edith P Mitchell, Nathan Bahary
    Abstract:

    Background: Prior clinical studies in the first and second line setting showed radioimmunotherapy (RAIT) is a promising therapy for pancreatic cancer that avoids the side effects of further chemotherapy. This multicenter study evaluated the contribution of low radiosensitizing doses of gemcitabine (GEM) to fractionated doses of 90 Y-clivatuzumab Tetraxetan in patients with metastatic pancreatic ductal cancer after having received at least 2 prior systemic therapies. Methods: Fifty-eight patients (33 males, 25 females; median age 63.5 years), 1.6 median years from diagnosis and with a median of 3 (2-7) prior treatments, were randomized to Arm A (N=29, 4-week cycles: 200 mg/m 2 GEM, weekly, combined with 6.5 mCi/m 2 90 Y-clivatuzumab Tetraxetan, weekly the last 3 weeks) or Arm B (N=29, 3-week cycles: 6.5 mCi/m 2 90 Y-clivatuzumab Tetraxetan alone, once-weekly), repeating cycles after 4-week delays. Safety and efficacy were evaluated. Results: None of the patients had infusion reactions, and as expected, cytopenias (predominantly thrombocytopenia) were the only significant toxicities, but mostly transient and manageable with infrequent hematologic support and little evidence of increased infection or bleeding. Patients terminated treatment cycles due to disease progression or clinical deterioration, not treatment toxicity. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ≥1 full treatment cycle and thus were evaluable for efficacy, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including 7 (6 Arm A, 1 Arm B; 12%) given 3-7 cycles. Two patients in Arm A had PRs by RECIST criteria. Karnofsky performance status (90-100 v 70-80), number of prior therapies, and tumor burden estimates (summed length of index lesions, serum CA 19-9 levels) correlated with overall survival (OS), but appear balanced between arms. Kaplan-Meier median OS was 3.9 months (1.0-16.7) in Arm A v 2.8 months (0.9-9.4) in Arm B (hazard ratio 0.54, 95% CI: 0.27-0.87; P=0.020, log-rank). The median OS for Arm A v Arm B increased to 7.9 v 3.4 months with multiple cycles (P= 0.004) and 3 patients in Arm A still being observed (11 – 17 months). Conclusions: This randomized trial demonstrated the feasibility of performing clinical studies in metastatic pancreatic cancer patients after having at least 2 prior therapies (3rd line and beyond). With significant survival advantage and favorable safety profile, fractionated RAIT with 90 Y-clivatuzumab Tetraxetan and low-dose GEM appears promising in this difficult population, supporting Phase 3 studies of this combination now being initiated. Citation Format: Vincent J. Picozzi, Ramesh K. Ramanathan, Maeve A. Lowery, Allyson J. Ocean, Edith P. Mitchell, Bert H. O9Neil, Michael J. Guarino, Paul R. Conkling, Steven J. Cohen, Nathan Bahary, Richard C. Frank, Tomislav Dragovich, Benjamin B. Bridges, Marie Lee, Ronald L. Korn, Neeta Pandit-Taskar, Stanley J. Goldsmith, Charles M. Intenzo, Arif Sheikh, Timothy C. Manzone, Michael L. Miller, Michael Yu, Judith M. Joyce, Edward B. Strauss, Susan Passalaqua, Ronald V. Dorn, III, Michael J. Anderson, Michael Holt, Fadi S. Braiteh, Fa-Chyi Lee, Thomas E. Gribbin, Donald A. Richards, Alexander N. Starodub, Wegener A. William, Eileen M. O9Reilly, Daniel D. Von Hoff, David M. Goldenberg. Final results of a randomized phase Ib study of fractionated 90Y-clivatuzumab Tetraxetan in patients with metastatic pancreatic cancer having at least two prior therapies. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B98.

  • feasibility and results of a randomized phase ιb study of fractionated 90υ clivatuzumab Tetraxetan in patients with metastatic pancreatic cancer having two or more prior therapies
    Journal of Clinical Oncology, 2014
    Co-Authors: Vincent J Picozzi, Ramesh K Ramanathan, Maeve A Lowery, Allyson J Ocean, Bert H Oneil, Michael J Guarino, Paul R Conkling, Steven J Cohen, Edith P Mitchell, Nathan Bahary
    Abstract:

    4026 Background: Radioimmunotherapy (RAIT) is an option to avoid side effects of further chemotherapy for advanced metastatic pancreatic ductal cancer (mPC). This multicenter, phase Ib study aimed at determining the contribution of low radiosensitizing doses of gemcitabine (GEM) to fractionated doses of 90Y-clivatuzumab Tetraxetanin pts with mPC after ≥ 2prior GEM- or 5FU-containing regimens. Methods: Pts were randomized to Arm A (4-week cycles: 200 mg/m2 GEM, weekly, combined with 6.5 mCi/m2 90Y-clivatuzumab Tetraxetan, once-weekly the last 3 weeks) or Arm B (3-week cycles: 6.5 mCi/m2 90Y-clivatuzumab Tetraxetan alone, once-weekly), repeating cycles after 4-week delays until unacceptable toxicity or pt deterioration. Safety and efficacy were evaluated. Results: Fifty-eight pts (33M/25F; median age 63.5) were treated on arm A (N=29) or B (N=29), 1.6 median years from diagnosis with a median of 3 (2-7) prior treatments. The main toxicity was transient myelosuppression, as expected, with dose reductions for...

  • fractionated radioimmunotherapy with 90y clivatuzumab Tetraxetan and low dose gemcitabine is active in advanced pancreatic cancer
    Cancer, 2012
    Co-Authors: Allyson J Ocean, Michael J Guarino, K Pennington, Tanios Bekaiisaab, Seza Gulec, Arif Sheikh, Aldo N Serafini, Max W Sung, Stanley J Goldsmith, Timothy Manzone
    Abstract:

    BACKGROUND It has been demonstrated that the humanized clivatuzumab Tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease.

  • o 0003 phase i ii study of 90y clivatuzumab Tetraxetan 90y hpam4 combined with gemcitabine gem in advanced pancreatic cancer apc
    Annals of Oncology, 2012
    Co-Authors: Edith P Mitchell, William A Wegener, David M. Goldenberg, Allyson J Ocean, Michael J Guarino, K Pennington, David V Gold, Gregory M Springett, Bekaiisaab Tanio, Heather Horne
    Abstract:

    ABSTRACT Introduction Clivatuzumab (hPAM4) is a humanized monoclonal antibody targeting an epitope in the MUC1 antigen expressed in most pancreatic cancers. Methods Fractionated radioimmunotherapy (RAIT) with 90Y-labeled humanized mAb (90Y-hPAM4) plus Gem as first-line therapy in Stage 3-4 APC with Gem weekly x 4 with 90Y-hPAM4 on wks 2, 3 and 4. 90Y doses were escalated with Gem fixed 200 mg/m2, then Gem increased up to 1000 mg/m2, with 90Y fixed at 12 mCi/m2 for cycle 1. Results Of 100 pts, 10 withdrew early; 90 (73 stage IV) received 1-4 cycles. In Part I, 38 pts received 90Y-hPAM4 weekly x 3 at 6.5, 9, 12, or 15 mCi/m2, with the same cycle repeated 1-3 times in 13 pts. By CT-RECIST, 6 pts (16%) had PRs and 16 (42%) had stabilization (58% disease control). After cycle 1, 52% (13/25) with PET-avid images had >25% SUV reduction, and 33% (9/27) with elevated CA19-9 levels decreased by >50%. The median OS was 7.7 mo., but 11.8 mo. for retreated pts [46% (6/13) survived1 yr.], and with improved efficacy at higher 90Y doses. NCI-CTCv3 Grade 3-4 platelets or ANC developed in 20/38 (53%) after cycle 1 (all reversible to Grade 1) and in all retreated pts (irreversible in 4/9 pts at 12 or 15 mCi/m2). In Part II, 52 pts received increased Gem without evidence of improved efficacy, while 13 pts were retreated with more acceptable toxicity at lower 90Y doses of 6.5 or 9 mCi/m2. No infusion reactions occurred. Infections requiring IV antibiotics occurred at a low rate (bacteremia/sepsis, 7% febrile neutropenia, 4% ascending cholangitis, 3% pneumonia, 2% others 1%). One case of bleeding occurred, due to rectal tumor invasion. Anecdotal reports of good performance and decreased pain medication requirements require further validation. Conclusion Fractionated RAIT with 90Y-hPAM4 combined with low-dose 200 mg/m2 GEM appears promising as treatment regimen for APC. Hematologic toxicity was dose limiting. A 90Y-hPAM4 dose of 12 mCi/m2 for cycle 1 and 6.5 mCi/m2 for cycle 2 have been selected as suitable for further clinical development. PET scans are useful for assessment.

Simone Krebs - One of the best experts on this subject based on the ideXlab platform.

  • comparison of 68ga dota jr11 pet ct with dosimetric 177lu satoreotide Tetraxetan 177lu dota jr11 spect ct in patients with metastatic neuroendocrine tumors undergoing peptide receptor radionuclide therapy
    European Journal of Nuclear Medicine and Molecular Imaging, 2020
    Co-Authors: Simone Krebs, Joseph A Odonoghue, Evan Biegel, Bradley J Beattie, Diane Lauren Reidy, Serge K Lyashchenko, Jason S Lewis, Lisa Bodei, Wolfgang A Weber, Neeta Pandittaskar
    Abstract:

    PURPOSE: Paired imaging/therapy with radiolabeled somatostatin receptor (SSTR) antagonists is a novel approach in neuroendocrine tumors (NETs). The aim of this study was to compare tumor uptake of 68Ga-DOTA-JR11 and 177Lu-satoreotide Tetraxetan (177Lu-DOTA-JR11) in patients with NETs. METHODS: As part of a prospective clinical trial, 20 patients with metastatic NETs underwent 68Ga-DOTA-JR11 PET/CT and serial imaging with 177Lu-satoreotide Tetraxetan. PET/CT and SPECT/CT parameters for lesion uptake and absorbed dose of 177Lu-satoreotide Tetraxetan in lesions were compared using linear regression analysis and Pearson correlation. RESULTS: A total of 95 lesions were analyzed on 68Ga-DOTA-JR11 PET/CT and 177Lu-satoreotide Tetraxetan SPECT/CT. SUVs and tumor-to-normal-tissue ratios on PET/CT and SPECT/CT were significantly correlated (p < 0.01), but the degree of correlation was modest with Pearson correlation coefficients ranging from 0.3 to 0.7. Variation in intrapatient lesional correlation was observed. Nevertheless, in all patients, the lesion SUVpeak uptake ratio for 177Lu-satoreotide Tetraxetan vs. 68Ga-DOTA-JR11 was high; even in those with low uptake on 68Ga-DOTA-JR11 PET/CT (SUVpeak ≤ 10), a ratio of 8.0 ± 5.2 was noted. Correlation of SUVpeak of 68Ga-DOTA-JR11 with projected 177Lu-satoreotide tetratexan-absorbed dose (n = 42) was modest (r = 0.5, p < 0.01), while excellent correlation of SUVpeak of 177Lu-satoreotide Tetraxetan with projected 177Lu-satoreotide Tetraxetan-absorbed dose was noted (r = 0.9, p < 0.0001). CONCLUSION: Our study shows that 68Ga-DOTA-JR11 PET can be used for patient selection and PRRT and that low tumor uptake on PET should not preclude patients from treatment with 177Lu-satoreotide Tetraxetan. The ability to use single time-point SPECT/CT for absorbed dose calculations could facilitate dosimetry regimens, save costs, and improve patient convenience.

  • Comparison of ^68Ga-DOTA-JR11 PET/CT with dosimetric ^177Lu-satoreotide Tetraxetan (^177Lu-DOTA-JR11) SPECT/CT in patients with metastatic neuroendocrine tumors undergoing peptide receptor radionuclide therapy
    European Journal of Nuclear Medicine and Molecular Imaging, 2020
    Co-Authors: Simone Krebs, Evan Biegel, Bradley J Beattie, Diane Lauren Reidy, Serge K Lyashchenko, Jason S Lewis, Lisa Bodei, Wolfgang A Weber, Joseph A. O’donoghue, Neeta Pandit-taskar
    Abstract:

    Purpose Paired imaging/therapy with radiolabeled somatostatin receptor (SSTR) antagonists is a novel approach in neuroendocrine tumors (NETs). The aim of this study was to compare tumor uptake of ^68Ga-DOTA-JR11 and ^177Lu-satoreotide Tetraxetan (^177Lu-DOTA-JR11) in patients with NETs. Methods As part of a prospective clinical trial, 20 patients with metastatic NETs underwent ^68Ga-DOTA-JR11 PET/CT and serial imaging with ^177Lu-satoreotide Tetraxetan. PET/CT and SPECT/CT parameters for lesion uptake and absorbed dose of ^177Lu-satoreotide Tetraxetan in lesions were compared using linear regression analysis and Pearson correlation. Results A total of 95 lesions were analyzed on ^68Ga-DOTA-JR11 PET/CT and ^177Lu-satoreotide Tetraxetan SPECT/CT. SUVs and tumor-to-normal-tissue ratios on PET/CT and SPECT/CT were significantly correlated ( p  

  • Comparison of 68Ga-DOTA-JR11 PET/CT with dosimetric 177Lu-satoreotide Tetraxetan (177Lu-DOTA-JR11) SPECT/CT in patients with metastatic neuroendocrine tumors undergoing peptide receptor radionuclide therapy.
    European Journal of Nuclear Medicine and Molecular Imaging, 2020
    Co-Authors: Simone Krebs, Evan Biegel, Bradley J Beattie, Diane Lauren Reidy, Serge K Lyashchenko, Jason S Lewis, Lisa Bodei, Wolfgang A Weber, Joseph A. O'donoghue, Neeta Pandit-taskar
    Abstract:

    PURPOSE: Paired imaging/therapy with radiolabeled somatostatin receptor (SSTR) antagonists is a novel approach in neuroendocrine tumors (NETs). The aim of this study was to compare tumor uptake of 68Ga-DOTA-JR11 and 177Lu-satoreotide Tetraxetan (177Lu-DOTA-JR11) in patients with NETs. METHODS: As part of a prospective clinical trial, 20 patients with metastatic NETs underwent 68Ga-DOTA-JR11 PET/CT and serial imaging with 177Lu-satoreotide Tetraxetan. PET/CT and SPECT/CT parameters for lesion uptake and absorbed dose of 177Lu-satoreotide Tetraxetan in lesions were compared using linear regression analysis and Pearson correlation. RESULTS: A total of 95 lesions were analyzed on 68Ga-DOTA-JR11 PET/CT and 177Lu-satoreotide Tetraxetan SPECT/CT. SUVs and tumor-to-normal-tissue ratios on PET/CT and SPECT/CT were significantly correlated (p 

  • phase i trial of well differentiated neuroendocrine tumors nets with radiolabeled somatostatin antagonist 177lu satoreotide Tetraxetan
    Clinical Cancer Research, 2019
    Co-Authors: Diane Reidylagunes, Simone Krebs, Joseph A Odonoghue, Serge K Lyashchenko, Jason S Lewis, Neeta Pandittaskar, Kevin Staton, Mithat Gonen, Christian Lohrmann
    Abstract:

    Purpose: Radiolabeled somatostatin receptor 2 (SSTR2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than somatostatin agonists in preclinical models of NETs. We performed a phase I study to evaluate the safety and efficacy of SSTR2 antagonist 177Lu-satoreotide Tetraxetan. EXPERIMENTAL DESIGN: Twenty patients with advanced SSTR2 positive NETs were treated with 177Lu-satoreotide Tetraxetan. Patients first underwent a dosimetry study with 177Lu-satoreotide Tetraxetan to determine the therapeutic activity that could be safely administered. This activity was split into two equal cycles to be delivered three months apart. The maximum activity was 7.4 GBq per cycle. Results: Of 20 NET patients (1 lung, 7 small bowel, 9 pancreatic, 1 gastric, 1 rectal, 1 kidney; mean prior treatments: 3), 6 received one cycle of 177Lu- satoreotide Tetraxetan and 14 received two cycles. Hematologic toxicity after cycle 1 was mild-moderate and reversed before cycle 2. However, grade 4 hematologic toxicity occurred in 4/7 (57%) patients after cycle 2 of 177Lu-satoreotide Tetraxetan. The study was suspended, and the protocol modified to limit the cumulative absorbed bone marrow dose to 1Gy and to reduce prescribed activity for cycle 2 by 50%. The best overall response rate was 45% (5% complete response (1/20), 40% partial response (8/20)); with 40% stable disease (8/20) and 15% progression of disease (3/20). Median progression-free survival (PFS) was 21.0 months (95% CI: 13.6-NR). Conclusion: In this trial of heavily treated NETs, preliminary data are promising for the use of 177Lu-satoreotide Tetraxetan. Additional studies are on-going to determine optimal therapeutic dose/schedule.

Patrice Chevallier - One of the best experts on this subject based on the ideXlab platform.

  • 90y labelled anti cd22 epratuzumab Tetraxetan in adults with refractory or relapsed cd22 positive b cell acute lymphoblastic leukaemia a phase 1 dose escalation study
    The Lancet Haematology, 2015
    Co-Authors: Patrice Chevallier, Tan Eugene, Nelly Robillard, Francoise Isnard, Martine Escoffrebarbe, Francoise Huguet, Mathilde Hunault, Antoine Marcais, Franck E Nicolini, Joelle Gaschet
    Abstract:

    Summary Background Prognosis of patients with relapsed or refractory acute lymphoblastic leukaemia is poor and new treatments are needed. We aimed to assess the feasibility, tolerability, dosimetry, and efficacy of yttrium-90-labelled anti-CD22 epratuzumab Tetraxetan ( 90 Y-DOTA-epratuzumab) radioimmunotherapy in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia in a standard 3 + 3 phase 1 study. Methods Adults (≥18 years) with relapsed or refractory B-cell acute lymphoblastic leukaemia (with CD22 expression on at least 70% of blast cells) were enrolled at six centres in France. Patients received one cycle of 90 Y-DOTA-epratuzumab on days 1 and 8 (give or take 2 days) successively at one of four dose levels: 2·5 mCi/m 2 (92·5 MBq/m 2 ; level 1), 5·0 mCi/m 2 (185 MBq/m 2 ; level 2), 7·5 mCi/m 2 (277·5 MBq/m 2 ; level 3), and 10·0 mCi/m 2 (370 MBq/m 2 ; level 4). The primary objective was to identify the maximum tolerated dose of 90 Y-DOTA-epratuzumab. We assessed safety during infusions and regularly after radioimmunotherapy over a 6-month period. Analyses included only patients who received radioimmunotherapy. The trial is closed to inclusion and is registered at ClinicalTrials.gov, NCT01354457. Findings Between Aug 25, 2011, and June 11, 2014, 17 patients (median age 62 years; range 27–77) were treated (five at level 1, three at level 2, three at level 3, and six at level 4). Radioimmunotherapy infusion was overall well tolerated. One dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the maximum tolerated dose was not reached. The most common grade 3–4 adverse events were pancytopenia (one patient at level 2, one at level 3, and six at level 4) and infections (three at level 1, one at level 2, and five at level 4). Interpretation 90 Y-DOTA-epratuzumab radioimmunotherapy is well tolerated. We recommend the dose of 2 × 10·0 mCi/m 2 1 week apart per cycle for phase 2 studies. Funding Immunomedics and Direction de la Recherche Clinique of Nantes.

  • phase 1 dose escalation study of 90 yttrium labeled anti cd22 epratuzumab Tetraxetan in adults with refractory relapsed cd22 b cell acute lymphoblastic leukemia b all
    Blood, 2014
    Co-Authors: Patrice Chevallier, Tan Eugene, Nelly Robillard, Francoise Isnard, Martine Escoffrebarbe, Francoise Huguet, Mathilde Hunault, Antoine Marcais, Franck E Nicolini, Thierry Guillaume
    Abstract:

    Background : Prognosis of relapsed/refractory acute lymphoblastic leukemia (ALL) in adults is dismal. CD22 is highly expressed in patients with B-ALL. Epratuzumab (hLL2) is a humanized monoclonal antibody targeting CD22 surface antigen. We performed a standard 3+3 phase 1 study to assess the feasibility, tolerability, and efficacy of a 90 yttrium-labeled anti-CD22 epratuzumab Tetraxetan ( 90 Y-DOTA-hLL2) radioimmunotherapy (RIT) in adults with refractory/relapsed CD22 + B-ALL. Methods : After premedication with corticosteroid, 90 Y-DOTA-hLL2 was administered twice on days 1 and 8 (+2), successively at 2.5 (level 1), 5.0 (level 2), 7.5 (level 3), and 10.0 (level 4) mCi/m². The first two patients also received 4 infusions of DOTA-hLL2 360 mg/m²/day before the RIT. This “cold phase” was terminated after observing no efficacy and full saturation of the CD22 target on the leukemic cells. Minimal residual disease (MRD) was assessed either by flow cytometry or by RQ-PCR for BCR-ABL1 analyses in Philadelphia chromosome positive (Ph + ) B-ALL patients. Dose-limiting toxicity (DLT) was defined as any non-reversible grade >3 non-hematological toxicity or grade 4 pancytopenia with hypocellular bone marrow lasting for >6 weeks. Maximum tolerated dose (MTD) was defined as the dose level at which 2 of 3 or 2 of 6 patients experienced a DLT. Dosimetry, organ distribution and elimination of the radiotracer were studied between the two RIT infusions in all but one patient, using whole-body scintigraphy recorded after 111 Indium-epratuzumab Tetraxetan injection and blood pharmacokinetics. Patients were evaluated for response between 4 and 6 weeks following the first infusion of RIT. Findings : Between October 2011 and June 2014, 20 patients were enrolled. Three patients were not considered for analyses because of disease progression (n=2) or persistent non-blastic pancytopenia (n=1) before RIT. Overall, 17 cases were treated (5 at level 1 including 2 previously treated with the cold phase, 3 at level 2, 3 at level 3, and 6 at level 4). There were 10 males and 7 females with a median age of 62 years (range: 27-77). Two patients had primary refractory B-ALL; 10, 3 and 2 were in first, second or third relapse, respectively. Median percentage of blasts in the bone marrow was 75%. Karyotypes were as follows: Ph + B-ALL n=6, complex n=3, MLL rearrangement n=1, hyperdiploidy n=1, hypodiploidy n=1, near-triploidy n=1, del4q (+ikaros mutation) n=1, normal (but ikaros mutation) n=1, and unknown n=2. Four patients were previously allotransplanted. Median interval between diagnosis and RIT was 16.5 months. Five patients presented immediate infusion reactions (3 grade 1, 1 grade 2 and 1 grade 3 in a patient with a previous history of severe allergic reactions) after the first RIT infusion, but received the second infusions without toxicities. All examined patients showed expected uptake of the radiotracer on potential disease sites (blood, spleen, liver, and bone marrow). No response was seen at levels 1 and 3. One molecular complete response was documented at level 2 (54-year old woman in third relapse of Ph + B-ALL). At level 4, 2 patients achieved complete remissions (1 Ph + ALL and 1 Ph - ALL), while all 6 cases presented with grade 4 hematologic toxicity. One DLT was documented at level 4 (non-blastic pancytopenia lasting 8 weeks), but MTD was not reached. Two patients in response received a second RIT cycle. Currently, only one non-responder is alive, while 2 of 3 responders are alive. One relapsed at 1 year and died of progression (level 2), while the two remaining are in persistent CR at 6 months post RIT, with low positive MRD. Interpretation : 90 Y-DOTA-hLL2 RIT is well-tolerated and induced complete remissions even in heavily pre-treated CD22 + relapsed/refractory B-ALL patients, thus appearing to be a promising targeted therapy for CD22 + B-ALL. We recommend the dose of 10 mCi/m² given twice, one week apart/cycle, for phase 2 studies. The trial is registered at http://clinicaltrials.gov/ct no. NCT01354457 . Funding: Immunomedics, Inc. Disclosures Goldenberg: immunomedics: Employment. Wegener: immunomedics: Employment.

  • Phase 1 Dose-Escalation Study of 90 yttrium-Labeled Anti-CD22 Epratuzumab Tetraxetan in Adults with Refractory/Relapsed CD22 + B-Cell Acute Lymphoblastic Leukemia (B-ALL)
    Blood, 2014
    Co-Authors: Patrice Chevallier, Tan Eugene, Nelly Robillard, Francoise Isnard, Francoise Huguet, Mathilde Hunault, Antoine Marcais, Martine Escoffre-barbe, Franck E Nicolini, Thierry Guillaume
    Abstract:

    Background : Prognosis of relapsed/refractory acute lymphoblastic leukemia (ALL) in adults is dismal. CD22 is highly expressed in patients with B-ALL. Epratuzumab (hLL2) is a humanized monoclonal antibody targeting CD22 surface antigen. We performed a standard 3+3 phase 1 study to assess the feasibility, tolerability, and efficacy of a 90 yttrium-labeled anti-CD22 epratuzumab Tetraxetan ( 90 Y-DOTA-hLL2) radioimmunotherapy (RIT) in adults with refractory/relapsed CD22 + B-ALL. Methods : After premedication with corticosteroid, 90 Y-DOTA-hLL2 was administered twice on days 1 and 8 (+2), successively at 2.5 (level 1), 5.0 (level 2), 7.5 (level 3), and 10.0 (level 4) mCi/m². The first two patients also received 4 infusions of DOTA-hLL2 360 mg/m²/day before the RIT. This “cold phase” was terminated after observing no efficacy and full saturation of the CD22 target on the leukemic cells. Minimal residual disease (MRD) was assessed either by flow cytometry or by RQ-PCR for BCR-ABL1 analyses in Philadelphia chromosome positive (Ph + ) B-ALL patients. Dose-limiting toxicity (DLT) was defined as any non-reversible grade >3 non-hematological toxicity or grade 4 pancytopenia with hypocellular bone marrow lasting for >6 weeks. Maximum tolerated dose (MTD) was defined as the dose level at which 2 of 3 or 2 of 6 patients experienced a DLT. Dosimetry, organ distribution and elimination of the radiotracer were studied between the two RIT infusions in all but one patient, using whole-body scintigraphy recorded after 111 Indium-epratuzumab Tetraxetan injection and blood pharmacokinetics. Patients were evaluated for response between 4 and 6 weeks following the first infusion of RIT. Findings : Between October 2011 and June 2014, 20 patients were enrolled. Three patients were not considered for analyses because of disease progression (n=2) or persistent non-blastic pancytopenia (n=1) before RIT. Overall, 17 cases were treated (5 at level 1 including 2 previously treated with the cold phase, 3 at level 2, 3 at level 3, and 6 at level 4). There were 10 males and 7 females with a median age of 62 years (range: 27-77). Two patients had primary refractory B-ALL; 10, 3 and 2 were in first, second or third relapse, respectively. Median percentage of blasts in the bone marrow was 75%. Karyotypes were as follows: Ph + B-ALL n=6, complex n=3, MLL rearrangement n=1, hyperdiploidy n=1, hypodiploidy n=1, near-triploidy n=1, del4q (+ikaros mutation) n=1, normal (but ikaros mutation) n=1, and unknown n=2. Four patients were previously allotransplanted. Median interval between diagnosis and RIT was 16.5 months. Five patients presented immediate infusion reactions (3 grade 1, 1 grade 2 and 1 grade 3 in a patient with a previous history of severe allergic reactions) after the first RIT infusion, but received the second infusions without toxicities. All examined patients showed expected uptake of the radiotracer on potential disease sites (blood, spleen, liver, and bone marrow). No response was seen at levels 1 and 3. One molecular complete response was documented at level 2 (54-year old woman in third relapse of Ph + B-ALL). At level 4, 2 patients achieved complete remissions (1 Ph + ALL and 1 Ph - ALL), while all 6 cases presented with grade 4 hematologic toxicity. One DLT was documented at level 4 (non-blastic pancytopenia lasting 8 weeks), but MTD was not reached. Two patients in response received a second RIT cycle. Currently, only one non-responder is alive, while 2 of 3 responders are alive. One relapsed at 1 year and died of progression (level 2), while the two remaining are in persistent CR at 6 months post RIT, with low positive MRD. Interpretation : 90 Y-DOTA-hLL2 RIT is well-tolerated and induced complete remissions even in heavily pre-treated CD22 + relapsed/refractory B-ALL patients, thus appearing to be a promising targeted therapy for CD22 + B-ALL. We recommend the dose of 10 mCi/m² given twice, one week apart/cycle, for phase 2 studies. The trial is registered at http://clinicaltrials.gov/ct no. NCT01354457 . Funding: Immunomedics, Inc. Disclosures Goldenberg: immunomedics: Employment. Wegener: immunomedics: Employment.

  • phase 1 dose escalation study of 90yttrium labeled anti cd22 epratuzumab Tetraxetan in adults with refractory relapsed cd22 b cell acute lymphoblastic leukemia b all
    Blood, 2014
    Co-Authors: Patrice Chevallier, Tan Eugene, Nelly Robillard, Francoise Isnard, Martine Escoffrebarbe, Francoise Huguet, Mathilde Hunault, Antoine Marcais, Franck E Nicolini, Thierry Guillaume
    Abstract:

    Background : Prognosis of relapsed/refractory acute lymphoblastic leukemia (ALL) in adults is dismal. CD22 is highly expressed in patients with B-ALL. Epratuzumab (hLL2) is a humanized monoclonal antibody targeting CD22 surface antigen. We performed a standard 3+3 phase 1 study to assess the feasibility, tolerability, and efficacy of a 90 yttrium-labeled anti-CD22 epratuzumab Tetraxetan ( 90 Y-DOTA-hLL2) radioimmunotherapy (RIT) in adults with refractory/relapsed CD22 + B-ALL. Methods : After premedication with corticosteroid, 90 Y-DOTA-hLL2 was administered twice on days 1 and 8 (+2), successively at 2.5 (level 1), 5.0 (level 2), 7.5 (level 3), and 10.0 (level 4) mCi/m². The first two patients also received 4 infusions of DOTA-hLL2 360 mg/m²/day before the RIT. This “cold phase” was terminated after observing no efficacy and full saturation of the CD22 target on the leukemic cells. Minimal residual disease (MRD) was assessed either by flow cytometry or by RQ-PCR for BCR-ABL1 analyses in Philadelphia chromosome positive (Ph + ) B-ALL patients. Dose-limiting toxicity (DLT) was defined as any non-reversible grade >3 non-hematological toxicity or grade 4 pancytopenia with hypocellular bone marrow lasting for >6 weeks. Maximum tolerated dose (MTD) was defined as the dose level at which 2 of 3 or 2 of 6 patients experienced a DLT. Dosimetry, organ distribution and elimination of the radiotracer were studied between the two RIT infusions in all but one patient, using whole-body scintigraphy recorded after 111 Indium-epratuzumab Tetraxetan injection and blood pharmacokinetics. Patients were evaluated for response between 4 and 6 weeks following the first infusion of RIT. Findings : Between October 2011 and June 2014, 20 patients were enrolled. Three patients were not considered for analyses because of disease progression (n=2) or persistent non-blastic pancytopenia (n=1) before RIT. Overall, 17 cases were treated (5 at level 1 including 2 previously treated with the cold phase, 3 at level 2, 3 at level 3, and 6 at level 4). There were 10 males and 7 females with a median age of 62 years (range: 27-77). Two patients had primary refractory B-ALL; 10, 3 and 2 were in first, second or third relapse, respectively. Median percentage of blasts in the bone marrow was 75%. Karyotypes were as follows: Ph + B-ALL n=6, complex n=3, MLL rearrangement n=1, hyperdiploidy n=1, hypodiploidy n=1, near-triploidy n=1, del4q (+ikaros mutation) n=1, normal (but ikaros mutation) n=1, and unknown n=2. Four patients were previously allotransplanted. Median interval between diagnosis and RIT was 16.5 months. Five patients presented immediate infusion reactions (3 grade 1, 1 grade 2 and 1 grade 3 in a patient with a previous history of severe allergic reactions) after the first RIT infusion, but received the second infusions without toxicities. All examined patients showed expected uptake of the radiotracer on potential disease sites (blood, spleen, liver, and bone marrow). No response was seen at levels 1 and 3. One molecular complete response was documented at level 2 (54-year old woman in third relapse of Ph + B-ALL). At level 4, 2 patients achieved complete remissions (1 Ph + ALL and 1 Ph - ALL), while all 6 cases presented with grade 4 hematologic toxicity. One DLT was documented at level 4 (non-blastic pancytopenia lasting 8 weeks), but MTD was not reached. Two patients in response received a second RIT cycle. Currently, only one non-responder is alive, while 2 of 3 responders are alive. One relapsed at 1 year and died of progression (level 2), while the two remaining are in persistent CR at 6 months post RIT, with low positive MRD. Interpretation : 90 Y-DOTA-hLL2 RIT is well-tolerated and induced complete remissions even in heavily pre-treated CD22 + relapsed/refractory B-ALL patients, thus appearing to be a promising targeted therapy for CD22 + B-ALL. We recommend the dose of 10 mCi/m² given twice, one week apart/cycle, for phase 2 studies. The trial is registered at http://clinicaltrials.gov/ct no. NCT01354457 . Funding: Immunomedics, Inc. Disclosures Goldenberg: immunomedics: Employment. Wegener: immunomedics: Employment.

  • bcr abl1 molecular remission after 90y epratuzumab Tetraxetan radioimmunotherapy in cd22 ph b all proof of principle
    European Journal of Haematology, 2013
    Co-Authors: Patrice Chevallier, Caroline Bodetmilin, Tan Eugene, Nelly Robillard, Martine Escoffrebarbe, Audrey Menard, Claire Le Houerou, Jean Delaunay, Thierry Guillaume, William A Wegener
    Abstract:

    Although targeted therapies are used increasingly in hematologic malignancies, we are unaware of any prior studies of radioimmunotherapy (RAIT) in B-acute lymphoblastic leukemia (ALL), even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Here, we report a patient with Philadelphia chromosome-positive B-ALL in third relapse who received RAIT with 90yttrium (90Y)-labeled anti-CD22 epratuzumab Tetraxetan. Seven weeks after initiating therapy, the patient achieved a BCR-ABL1 molecular remission documented by RT-qPCR, which is now continuing at 6 months while awaiting an allogeneic hematopoietic stem cell transplant. 90Y-Epratuzumab Tetraxetan may be a promising therapeutic option for CD22+ B-ALL patients.

David M. Goldenberg - One of the best experts on this subject based on the ideXlab platform.

  • anti cd22 90y epratuzumab Tetraxetan combined with anti cd20 veltuzumab a phase i study in patients with relapsed refractory aggressive non hodgkin lymphoma
    Haematologica, 2014
    Co-Authors: Thomas E Witzig, William A Wegener, Michael B Tomblyn, Jamal Misleh, Robert M. Sharkey, David M. Goldenberg
    Abstract:

    A lingering criticism of radioimmunotherapy in non-Hodgkin lymphoma is the use of cold anti-CD20 antibody along with the radiolabeled anti-CD20 antibody. We instead combined radioimmunotherapy with immunotherapy targeting different B-cell antigens. We evaluated the anti-CD22 90Y-epratuzumab Tetraxetan with the anti-CD20 veltuzumab in patients with aggressive lymphoma in whom at least one prior standard treatment had failed, but who had not undergone stem cell transplantation. Eighteen patients (median age 73 years, median of 3 prior treatments) received 200 mg/m2 veltuzumab once-weekly for 4 weeks, with 90Y-epratuzumab Tetraxetan at planned doses in weeks 3 and 4, and 111In-epratuzumab Tetraxetan in week 2 for imaging and dosimetry. Veltuzumab effectively lowered levels of B cells in the blood prior to the radioimmunotherapy doses. No significant immunogenicity or change in pharmacokinetics of either agent occurred in combination. 111In imaging showed tumor targeting with acceptable radiation dosimetry to normal organs. For 90Y-epratuzumab Tetraxetan, transient myelosuppression was dose-limiting with 6 mCi/m2 (222 MBq/m2) × 2 being the maximal tolerated dose. Of 17 assessable patients, nine (53%) had objective responses according to the 2007 revised treatment response criteria, including three (18%) complete responses (2 relapsing after 11 and 13 months, 1 continuing to be clinically disease-free at 19 months), and six (35%) partial responses (1 relapsing after 14 months, 5 at 3 – 7 months). Responses occurred in patients with different lymphoma histologies, treated at different 90Y dose levels, and with a predicted risk of poor outcome, most importantly including five of the six patients treated with the maximal tolerated dose (2 of whom achieved durable complete responses). In conclusion, the combination of 90Y-epratuzumab Tetraxetan and veltuzumab was well-tolerated with encouraging therapeutic activity in this difficult-to-treat population.

  • o 0003 phase i ii study of 90y clivatuzumab Tetraxetan 90y hpam4 combined with gemcitabine gem in advanced pancreatic cancer apc
    Annals of Oncology, 2012
    Co-Authors: Edith P Mitchell, William A Wegener, David M. Goldenberg, Allyson J Ocean, Michael J Guarino, K Pennington, David V Gold, Gregory M Springett, Bekaiisaab Tanio, Heather Horne
    Abstract:

    ABSTRACT Introduction Clivatuzumab (hPAM4) is a humanized monoclonal antibody targeting an epitope in the MUC1 antigen expressed in most pancreatic cancers. Methods Fractionated radioimmunotherapy (RAIT) with 90Y-labeled humanized mAb (90Y-hPAM4) plus Gem as first-line therapy in Stage 3-4 APC with Gem weekly x 4 with 90Y-hPAM4 on wks 2, 3 and 4. 90Y doses were escalated with Gem fixed 200 mg/m2, then Gem increased up to 1000 mg/m2, with 90Y fixed at 12 mCi/m2 for cycle 1. Results Of 100 pts, 10 withdrew early; 90 (73 stage IV) received 1-4 cycles. In Part I, 38 pts received 90Y-hPAM4 weekly x 3 at 6.5, 9, 12, or 15 mCi/m2, with the same cycle repeated 1-3 times in 13 pts. By CT-RECIST, 6 pts (16%) had PRs and 16 (42%) had stabilization (58% disease control). After cycle 1, 52% (13/25) with PET-avid images had >25% SUV reduction, and 33% (9/27) with elevated CA19-9 levels decreased by >50%. The median OS was 7.7 mo., but 11.8 mo. for retreated pts [46% (6/13) survived1 yr.], and with improved efficacy at higher 90Y doses. NCI-CTCv3 Grade 3-4 platelets or ANC developed in 20/38 (53%) after cycle 1 (all reversible to Grade 1) and in all retreated pts (irreversible in 4/9 pts at 12 or 15 mCi/m2). In Part II, 52 pts received increased Gem without evidence of improved efficacy, while 13 pts were retreated with more acceptable toxicity at lower 90Y doses of 6.5 or 9 mCi/m2. No infusion reactions occurred. Infections requiring IV antibiotics occurred at a low rate (bacteremia/sepsis, 7% febrile neutropenia, 4% ascending cholangitis, 3% pneumonia, 2% others 1%). One case of bleeding occurred, due to rectal tumor invasion. Anecdotal reports of good performance and decreased pain medication requirements require further validation. Conclusion Fractionated RAIT with 90Y-hPAM4 combined with low-dose 200 mg/m2 GEM appears promising as treatment regimen for APC. Hematologic toxicity was dose limiting. A 90Y-hPAM4 dose of 12 mCi/m2 for cycle 1 and 6.5 mCi/m2 for cycle 2 have been selected as suitable for further clinical development. PET scans are useful for assessment.

  • fractionated radioimmunotherapy of non hodgkin lymphoma with 90 y labeled anti cd22 antibody epratuzumab Tetraxetan
    2012
    Co-Authors: Francoise Kraeberbodere, William A Wegener, Amandine Pallardy, Caroline Bodetmilin, Alain Faivrechauvet, Jeanfrancois Chatal, David M. Goldenberg
    Abstract:

    Radioimmunotherapy (RIT) efficacy has been demonstrated in hematology, in particular in B cell non-Hodgkin lymphoma (NHL). RIT can be applied in clinical practice using non-ablative activity of murine anti-CD20 131I-tositumomab and 90Y-ibritumomab tiuxetan. Today, different approaches are explored to improve efficacy of RIT in NHL: myeloablative RIT, RIT as consolidation after chemotherapy, RIT in first-line treatment, fractionated RIT, RIT using other antigen targets or other monoclonal antibody. This chapter reviews current advances in the fractionated radioimmunotherapy, in particular the use of Epratuzumab Tetraxetan, a 90-Y-labeled anti-CD22 antibody in the treatment of non-Hodgkin lymphoma. We present especially the result of a phase I/II, multi center, dose-escalation trial assessing 90Y-hLL2 administered once weekly for 2 or 3 weeks, achieving high rates of durable complete responses with manageable hematological toxicity in NHL relapsing patients.

  • Combination Radioimmunotherapy and Chemoimmunotherapy Involving Different or the Same Targets Improves Therapy of Human Pancreatic Carcinoma Xenograft Models
    Molecular Cancer Therapeutics, 2011
    Co-Authors: Robert M. Sharkey, Habibe Karacay, Serengulam V. Govindan, David M. Goldenberg
    Abstract:

    Chemoimmunotherapy with antibody–drug conjugates (ADC) is emerging as a promising therapy for solid tumors, whereas radioimmunotherapy (RAIT) of solid tumors has been relatively ineffective because of their resistance to radiation. We developed antibody–SN-38 conjugates that have significant antitumor activity in xenograft models at nontoxic doses. The goal of this study was to determine if an ADC could be combined with RAIT to enhance efficacy without a commensurate increase in host toxicity. Nude mice bearing human pancreatic cancer xenografts (Capan-1 and BxPC-3) were treated with a single dose of 90Y-labeled antimucin antibody (hPAM4; clivatuzumab Tetraxetan) alone or in combination with an anti-Trop-2–SN-38 conjugate, typically administered twice weekly over 4 weeks. The combination, even at RAIT's maximum tolerated dose, controlled tumor progression and cured established xenografts significantly better than the individual treatments without appreciable toxicity. The ADC could be started 1 week after or up to 2 weeks before RAIT with similar enhanced responses, but delaying RAIT for 2 weeks after the ADC was less effective. A nonspecific ADC provided additional benefit over using free drug (irinotecan), but the response was enhanced with the specific ADC. When targeting Capan-1 with ample mucin, hPAM4 could be used as the RAIT and the ADC agent without losing effectiveness, but in BxPC-3 with less mucin, targeting of different antigens was preferred. These studies show the feasibility of combining ADC and RAIT for improved efficacy without increased toxicity. Mol Cancer Ther; 10(6); 1072–81. ©2011 AACR .

  • Effect of combination radioimmunotherapy (RAIT) and chemoimmunotherapy on therapeutic response and toxicity in xenograft models of human pancreatic carcinoma: First experimental studies.
    Journal of Clinical Oncology, 2011
    Co-Authors: Robert M. Sharkey, Habibe Karacay, Serengulam V. Govindan, Sung-ju Moon, Ali A. Mostafa, David M. Goldenberg
    Abstract:

    206 Background: Preclinical and early clinical data with RAIT involving a 90Y-labeled antibody to a pancreatic mucin antigen (hPAM4, clivatuzumab Tetraxetan) have shown promising therapeutic activity in combination with gemcitabine. Selective targeting of therapeutic drugs using antibody-drug conjugates (ADC) might be useful in pancreatic cancer therapy. Methods: ADCs composed of SN-38 coupled to an internalizing anti-TROP-2 antibody, an antigen found on many epithelial cancers, or to the non-internalizing anti-mucin humanized IgG, were prepared (6 SN-38/IgG). Nude mice bearing s.c. Capan-1 or BxPC3 xenografts (∼0.35 cm3) were given multiple ADC doses (twice weekly, 4 weeks) or appropriate controls of a non-targeting IgG-SN-38 conjugate or irinotecan. Other groups of animals were treated with the ADC conjugates and RAIT, using RAIT at 60% and 100% of its MTD. The endpoint was time to progress to 3.0 cm3 (TTP), with animals monitored up to 22 weeks. Results: ADCs alone were each able to inhibit tumor growt...