Papers by M Wayne Saville
Annals of Oncology, Sep 1, 2021
Annals of Oncology, Sep 1, 2021
Journal of Clinical Oncology, Aug 1, 1995
A phase I/II study of oral all-trans-retinoic acid (ATRA; tretinoin), administered every other we... more A phase I/II study of oral all-trans-retinoic acid (ATRA; tretinoin), administered every other week alone and then in combination with interferon (IFN) alfa-2a, was undertaken to evaluate the activity, toxicity, and pharmacokinetics of this regimen in patients with human immunodeficiency virus (HIV)-associated Kaposi's sarcoma (KS). Thirteen patients with HIV-associated KS, eight of whom had more than 100 CD4 cells/microL, were entered. The protocol initially called for patients to receive 150 mg/m2/d of ATRA every other week. However, this regimen was associated with headaches, and the initial dose of ATRA was reduced to 40 mg/m2/d orally in three divided doses, increasing to a maximum of 100 mg/m2/d. After 12 weeks, IFN alfa-2a could be added. The principal toxicities from ATRA were headaches (12 patients) and dry skin or lip (seven patients). Of 12 assessable patients, 10 had progressive disease and two had stable disease on ATRA alone. One of eight assessable patients who went on to receive ATRA plus IFN alfa-2a had partial response (PR). There were no overall changes in the serum HIV p24 antigen (Ag) level or CD4 count during treatment with ATRA alone. Peak ATRA levels decreased during the week of continuous ATRA therapy, but rebounded when treatment was resumed after a week without the drug. Intermittent ATRA therapy was reasonably well tolerated and provided a means to circumvent the low plasma exposure found with continuous ATRA therapy. However, we were unable to document antitumor activity in patients with HIV-associated KS.
Journal of Clinical Oncology, 2005
We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with... more We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer. Patients and Methods A total of 561 eligible patients were randomly assigned to receive paclitaxel alone or in combination with carboplatin. Results The response rate was 17% in the paclitaxel arm and 30% in the carboplatin-paclitaxel arm (P Ͻ .0001). Median failure-free survival was 2.5 months in the paclitaxel arm and 4.6 months in the carboplatin-paclitaxel arm (P ϭ .0002). Median survival times were 6.7 months (95% CI, 5.8 to 7.8) and 8.8 months (95% CI, 8.0 to 9.9), and 1-year survival rates were 32% (95% CI, 27% to 38%), and 37% (95% CI, 32% to 43%), respectively. The overall survival distributions were not statistically different: hazard ratio ϭ 0.91 (95% CI, 0.77 to 1.17; P ϭ .25). Hematological toxicity and nausea were more frequent in the combination arm, but febrile neutropenia and toxic deaths were equally low in both arms. There was no significant survival difference in elderly patients. Performance status 2 patients treated with combination chemotherapy had a better survival rate than those treated with single-agent therapy (P ϭ .019). Conclusion Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy, but there was no statistically significant difference in the primary end point of overall survival. The results in elderly patients were similar to younger patients. Performance status 2 patients had a superior outcome when treated with combination chemotherapy.
Journal of Clinical Oncology, Jun 20, 2006
15532 Objective: To report a cohort of patients with lymphoid tumors of the orbit whose disease r... more 15532 Objective: To report a cohort of patients with lymphoid tumors of the orbit whose disease responded to immunotherapy with rituximab alone or rituximab followed by Zevalin (yttrium-90 ibritumomab tiuxetan). Methods: Between October 2002 and June 2005, 9 patients with indolent non-Hodgkin’s lymphoma and 1 with orbital benign lymphoid hyperplasia were treated with monoclonal antibodies against CD20. 6 patients with orbital lymphoma (3 follicular B-cell, 2 MALT, and 1 mantle cell lymphoma) received rituximab followed by Zevalin. 2 patients with indolent orbital lymphoma (one with follicular B cell and the other with small lymphocytic lymphoma) and 1 patient with benign lymphoid hyperplasia received rituximab alone. 3 out of the 6 patients who received Zevalin were part of a prospective trial evaluating the efficacy of Zevalin for indolent B-cell lymphoma of the orbit; the rest were treated in other trials at M. D. Anderson. Clinical records and imaging studies were reviewed to document response. Results: 4 men and 5 women were between23 and 83 years old (median age, 63 years). Of the 8 patients with orbital lymphoma, 4 had stage IE, 4 had stage IV, and 6 had previously untreated disease. All 9 patients experienced resolution of the orbital tumor in response to monoclonal antibodies against CD20. Follow-up time ranged from 6 to 32 months (mean, 12 months) after completion of immunotherapy. There were no serious systemic or ocular side effects during the study period. The most common side effect was mild fatigue. All 6 patients treated with Zevalin had transient pancytopenia which normalized within 3 months. Conclusions: Rituximab and Zevalin may be considered as alternative treatment modalities to radiotherapy for indolent B-cell lymphoma or MALT of the orbit. Systemic targeted immunotherapy may potentially have the advantage of lower rate of distant (out-of-field) relapse and less ocular toxicity compared with radiotherapy; these potential advantages would have to be verified in long-term studies and in larger number of patients. [Table: see text]
Blood, Nov 20, 2009
Background: CD80 is a member of the B7 family of immune coregulatory proteins that mediate both i... more Background: CD80 is a member of the B7 family of immune coregulatory proteins that mediate both immune activation and suppression. CD80 in particular has recently been shown to play an important role in supporting immune suppression through interactions with B7-H1. CD80 has been identified as a therapeutic target in non-Hodgkin lymphoma (NHL) based on limited immunohistochemical studies of CD80 expression. Clinical studies have shown that the anti-CD80 antibody galiximab is safe and clinically efficacious in follicular NHL. However, the mechanisms through which targeting CD80 inhibits tumor progression remain poorly understood. Methods: To further define the potential of CD80 as a therapeutic target in NHL, CD80 expression was evaluated by multicolor flow cytometric analysis of primary lymphoma cell suspensions generated from 241 diagnostic biopsies of patients with NHL. Results: CD80 was expressed on malignant B cells in essentially all cases of follicular lymphoma (97%; n 5 115), the majority of cases of diffuse large B-cell lymphoma (90%; n 5 69), marginal zone lymphoma (91%; n 5 22), mantle cell lymphoma (75%; n 5 12), and in about half of small lymphocytic lymphoma cases (43%; n 5 23). CD80 was also present on tumor-infiltrating T lymphocytes in nearly all cases. Additionally, CD80 was expressed by non-B, non-T cells in 68 and 44% of cases of follicular and diffuse large B-cell NHL, respectively. Conclusions: CD80 is expressed on both malignant cells and the nonmalignant cells in NHL. Therapeutic targeting of CD80 will therefore modulate the complex intercellular interactions that define the tumor microenvironment in NHL. V
Blood, 1996
Herpesvirus-like DNA sequences (KSHV/HHV-8) have recently been described in AIDS-associated Kapos... more Herpesvirus-like DNA sequences (KSHV/HHV-8) have recently been described in AIDS-associated Kaposi's sarcoma (KS) lesions. Many questions remain regarding the role of this virus in KS and the therapeutic implications of this finding. In the current study, KSHV/HHV-8 DNA was detected in peripheral blood mononuclear cells (PBMCs) from human immunodeficiency virus (HIV)-infected patients with KS (34/98) more often than in HIV-infected individuals without KS (12/64, P = .03). The detection of KSHV/HHV-8 DNA did not correlate with the CD4 lymphocyte count. Five patients demonstrated KSHV/HHV-8 DNA in their PBMCs during administration of intravenous foscarnet and/or ganciclovir. The continued detection of KSHV/HHV-8 DNA in the PBMCs of patients receiving these anti-herpesvirus drugs has potential implications regarding the virus-cell relationship of KSHV/HHV-8, as well as for the value of these drugs in treating or preventing KS, but additional studies are needed.
Journal of Investigative Medicine, 2007
Journal of Clinical Oncology, 2002
This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of iri... more This phase II, multicenter, open-label, single-arm study evaluated the efficacy and safety of irinotecan and gemcitabine as combination chemotherapy for previously untreated patients with unresectable or metastatic pancreatic cancer. Patients received repeated 21-day cycles at starting doses of gemcitabine 1,000 mg/m(2) over 30 minutes followed immediately by irinotecan 100 mg/m(2) over 90 minutes, both given intravenously on days 1 and 8. Patients were evaluated for objective tumor response, changes in the serum tumor marker CA 19-9, time to tumor progression (TTP), survival, and safety. Forty-five patients were treated. Eleven patients (24%) had 50% or greater reductions in tumor area. These were confirmed one cycle later in nine patients (response rate, 20%; 95% confidence interval, 8% to 32%). Among 44 patients with baseline CA 19-9 determinations, CA 19-9 decreased during therapy in 22 patients (50%) and was reduced by 50% or more in 13 patients (30%). Median TTP was 2.8 months (range, 0.3 to 10.8 months). There were significant (P <.001) correlations between proportional changes in CA 19-9 and radiographic changes in tumor area with regard to extent of change (r =.67), timing of minimum on-study values (r =.85), and tumor progression (r =.89). Median survival was 5.7 months (range, 0.4 to 19.4+ months), and the 1-year survival rate was 27%. Severe toxicities were uncommon and primarily limited to grade 4 neutropenia (2%), grade 4 vomiting (2%), and grade 3 diarrhea (7%). Irinotecan/gemcitabine is a new combination that offers encouraging activity in terms of radiographic and CA 19-9 response and notable 1-year survival in pancreatic cancer. The regimen was well tolerated, with minimal grade 3 and 4 toxicities and excellent maintenance of planned dose-intensity.
Bone, 2011
A199 for Chinese journals, were searched through to Dec. 31th, 2014. RESULTS: In 2010, incidence ... more A199 for Chinese journals, were searched through to Dec. 31th, 2014. RESULTS: In 2010, incidence and mortality of lung cancer in China are 46.08/105 and 37.00/105. DALYs (disability adjusted life years) and economic burden of lung cancer are extremely high in both Beijing and Shanghai. DALYs of lung cancer are 42219.38 and 91962.18 in Beijing and Shanghai respectively. And average hospitalization expenditures per lung cancer inpatient are ¥38595.00 and ¥50026.65, among which average drug costs per inpatient are as high as ¥18139.65(46.97%) and ¥30356.00(60.68%). CONCLUSIONS: Lung cancer has made Chinese patients incur great loss in both DALYs and money, which is a conspicuous reminder to policy makers to pay more attention to management of the raging disease. And early prevention and screening of lung cancer should be priorities to slow increasing speed of disease burden.
OBJECTIVE: To review the in vitro, animal, and clinical data on immune-based therapies for treatm... more OBJECTIVE: To review the in vitro, animal, and clinical data on immune-based therapies for treatment of HIV infection. DATA SOURCF.s: An extensive MEDLINE search was performed for interleukins, interferons, immunotoxins, tumor necrosis factor (TNF)-directed agents, vaccines, and gene therapy. STIJDY SELEcnON: In vitro experiments with immune-based agents in cell lines infected with HIV were included. In addition, all human studies and case reports that used these agents in patients infected with HIV were selected. Additional literature included abstracts from international meetings on HIV and AIDS. DATA EXTRACTION: Data regarding activity, efficacy, and toxicity were extracted from in vitro and in vivo studies. When conflicting data were observed, both viewpoints were stated to give an unbiased analysis. Because HIV research involves multiple social, ethical, and scientific issues, perspectives on these problems were addressed,
Experimental and Molecular Therapeutics, 2021
Clinical Trials, 2021
Conventional chemotherapeutic agents are effective for a broad array of patients, but have limite... more Conventional chemotherapeutic agents are effective for a broad array of patients, but have limited dosing capabilities, lack specificity, and often result in systemic toxicity. Conversely, newer cancer immunotherapies have been successful but benefit only a subset of patients and have varying response rates across different tumors. Here we present SQ3370, a novel approach that activates doxorubicin (Dox) at the tumor site while avoiding systemic toxicities commonly associated with the therapy, and may also activate an immune response against the tumor. SQ3370 is based on a local intratumoral injection of a prodrug-capturing biomaterial (SQL70) followed by 5 daily systemic infusions of an attenuated form of Dox (SQP33). Mutually-reactive click chemistry groups in the 2 components allow the release of active Dox at the tumor site. While conventional Dox is known to induce immune activation [1] and enhance tumor responsiveness to checkpoint inhibitors [2], its benefit is limited by ach...
Journal for ImmunoTherapy of Cancer
BackgroundConventional chemotherapeutics lack specificity for tumor tissue and usually have anarr... more BackgroundConventional chemotherapeutics lack specificity for tumor tissue and usually have anarrow therapeutic index. SQ3370, a novel therapy that activates doxorubicin (Dox) at the tumor sitewhile minimizing systemic exposure, is based on intratumoral injection of a protodrug-activatinghyaluronic acid-based biopolymer (SQL70) followed by five daily intravenous (IV) doses of an attenuatedprotodrug of Dox (SQP33). SQ3370 utilizes Shasqi’s proprietary Click Activated Protodrugs AgainstCancer (CAPAC) platform where mutually-reactive click chemistry groups in the two components allowrelease of active Dox specifically at the tumor site. In animals, SQ3370 allowed for an 8.95-fold increase in dosing with minimal systemic adverse eventsand no cardiotoxicity. SQ3370 treatment of mouse tumor models showed improved overall survival,enhanced T-cell infiltration, and a robust anti-tumor response against both biopolymer-injected andnon-injected lesions,1 suggesting that SQ3370 promotes activati...
Blood
Background: MGd is a novel anti-cancer agent that selectively accumulates in tumor cells and disr... more Background: MGd is a novel anti-cancer agent that selectively accumulates in tumor cells and disrupts redox dependent pathways by targeting oxidative stress related proteins such as thioredoxin reductase and metallothioneins. MGd induces apoptosis in lymphoma cells and is additive or synergistic with radiation, chemotherapy and rituximab in pre-clinical studies. In solid tumor clinical trials, there has been no evidence of hematopoietic toxicity with MGd at doses of 5 mg/kg x 10 days. In rituximab-refractory follicular NHL, single-agent Zevalin® produces a response rate (RR) of 74% (15% complete response [CR]). We reasoned that MGd and Zevalin® would be synergistic and provide higher response rates that are more durable. Method: To test this hypothesis, we are conducting a phase I/II dose escalation trial for patients with relapsed/refractory NHL using fixed dose 90Yttrium-Zevalin (0.4 mCi/kg) with increasing doses of MGd (2.5 mg/kg, 3.5 mg/kg and 5.0 mg/kg) based on a modified Fibo...
Journal for ImmunoTherapy of Cancer
BackgroundCancer immunotherapies have been very successful in recent times; however, they benefit... more BackgroundCancer immunotherapies have been very successful in recent times; however, they benefit only a subset of patients and have varying response rates across tumor types. Conversely, conventional chemotherapies are effective in a large group of patients, but have limited dosing capabilities, lack specificity, and often result in systemic adverse events. Here, we present SQ3370, a novel approach that activates doxorubicin (Dox) at the tumor site while avoiding systemic toxicities commonly associated with the therapy, and also potentially activates an immune response against tumors. SQ3370 is based on a local intratumoral injection of a prodrug-capturing biomaterial (SQL70) followed by 5 daily systemic infusions of an attenuated form of Dox (SQP33). Mutually-reactive click chemistry groups in the 2 components allow the capture and release of active Dox at the tumor site. While conventional Dox is known to induce immune activation1 and enhance tumor responsiveness to checkpoint in...
Blood
Ytrrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) is indicated for the treatment of relapsed or re... more Ytrrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) is indicated for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL at relapse or upon confirmation of refractory disease. Long-term responses in excess of 6 years have been observed following ibritumomab tiuxetan administration, underscoring the efficacy of this selective treatment modality. Dosing guidelines for 90Y ibritumomab tiuxetan were established in phase 1/2 trials and are dependent on body mass and platelet count, with the maximum recommended dose being 32 mCi. Biodistribution is evaluated by whole-body imaging prior to the delivery of the therapeutic dose using the gamma emitter indium 111 (111In) as the imaging radioimmunoconjugate. Current imaging methodology for the ibritumomab tiuxetan regimen has several limitations. First, the correlation between 111In ibritumomab tiuxetan dosimetry and either toxicity or tumor response is poor, and clinical parameters such as platelet count, pat...
Blood
Recently, it has been suggested that concordant but not discordant BM involvement is a negative p... more Recently, it has been suggested that concordant but not discordant BM involvement is a negative predictor of outcome in DLBCL patients treated with CHOP (Chung et al, Blood 2007). The significance of BM involvement in pts treated in the current era of therapy including rituximab has not been fully examined. We evaluated the prognostic impact of BM involvement in DLBCL patients treated with the current standard of care, R-CHOP. Patients: We identified 282 patients with biopsy proven de novo DLBCL treated in British Columbia (BC) with an R-CHOP regimen between 01/01/2001 and 01/01/2005 with complete clinical information and staging bone marrows available for review. Cases were identified using the Lymphoid Cancer Database of the BC Cancer Agency. Median follow-up is 44 mos (range 1–77). Results: 234/282 (83%) had a negative staging BM, 27 pts (10%) had a positive BM with concordant histology (Con-BM) and 21 (7%) had a positive BM with discordant histology (Dis-BM) with predominantly s...
Blood, 2004
Ytrrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) is indicated for the treatment of relapsed or re... more Ytrrium 90 (90Y) ibritumomab tiuxetan (Zevalin®) is indicated for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL at relapse or upon confirmation of refractory disease. Long-term responses in excess of 6 years have been observed following ibritumomab tiuxetan administration, underscoring the efficacy of this selective treatment modality. Dosing guidelines for 90Y ibritumomab tiuxetan were established in phase 1/2 trials and are dependent on body mass and platelet count, with the maximum recommended dose being 32 mCi. Biodistribution is evaluated by whole-body imaging prior to the delivery of the therapeutic dose using the gamma emitter indium 111 (111In) as the imaging radioimmunoconjugate. Current imaging methodology for the ibritumomab tiuxetan regimen has several limitations. First, the correlation between 111In ibritumomab tiuxetan dosimetry and either toxicity or tumor response is poor, and clinical parameters such as platelet count, patient weight, and percentage lymphomatous bone marrow involvement have been much more accurate. Further, while gamma (or PET/SPECT) imaging provides a visual evaluation of uptake in the blood pool and relevant organs, it cannot resolve biodistribution to the cellular level. This is particularly relevant for discriminating between radioisotope uptake in malignant and nonmalignant tissues. In order to assess the uniformity of cellular localization of 90Y ibritumomab tiuxetan, we performed autoradiographic analyses of lymph node tissue and bone marrow sampled after ibritumomab tiuxetan therapy. We also proposed to semi-quantify the energy doses delivered to lymphomatous tissue in an effort to better understand mechanisms of cellular sensitivity or resistance to this form of radioimmunotherapy. Following standard delivery of the ibritumomab tiuxetan regimen, bone marrow and lymph node tissues were sampled from a patient who presented with CD20+ NHL, bulky peripheral lymph nodes, and positive bone marrow involvement. Samples were collected 4 days after the administration of 90Y ibritumomab tiuxetan and immediately processed. Prepared sections were stained with hematoxylin and eosin (H&E) for histologic examination and then submitted for autoradiographic preparation with Kodak NBT-3 nuclear emulsion at 42o C, Kodak D-19 developer, and sodium thiosulphate fixative. Within lymph node tissue, radioisotope uptake was preferentially localized to lymphoma cells. An absence of significant localization in the histologically normal sections of bone marrow was also noted. The observed distribution patterns in the lymph node suggested that distribution of 90Y ibritumomab tiuxetan was localized to the cell membrane of lymphoma cells, with limited stromal and intravascular involvement. We are currently quantifying the density of radioisotope aggregation within malignant cells to assess whether a sufficient quantity of nuclide is recruited to achieve a crossfire effect on neighboring, unlabeled cells. Our results confirm that in vivo,90Y ibritumomab tiuxetan selectively targets tumor tissue with little binding to normal bone marrow and lymph node tissue, including stroma and vasculature. Additional patients with CD20+ NHL are being studied to verify the cellular localization pattern of 90Y ibritumomab tiuxetan.
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Papers by M Wayne Saville