Evidence Of Clinical Response Research Articles

VAX014 for instillation in subjects with nonmuscle-invasive bladder cancer.

488 Background: VAX014 is a novel tumor targeted oncolytic agent for intravesical administration. It is comprised of recombinant bacterial minicells, that actively target a3b1 and a5b1 integrins expressed on NMIBC and deliver an active cytotoxic/oncolytic protein payload, perfringolysin O. VAX014 is being investigated for the intravesical treatment of NMIBC in an ongoing multi-center Phase 1 marker lesion trial in subjects with low grade Ta disease (NCT 03854721). Methods: Subjects with up to 5 pathologically confirmed TaG1 lesions ≥ 5mm but ≤ 15mm are eligible to receive six (6) weekly intravesical instillations of VAX014. Subjects with presence or history of high-grade bladder cancer are ineligible. Phase 1a will establish the MTD using a 3+3 design. After the DSMB establishes the RP2D, a Phase 1b expansion will use this dose to treat an additional 10 patients. Results: No serious adverse events or dose limiting toxicities have been recorded through two dose cohorts (3 + 3 design) and evidence of clinical response has been observed. Treatment related adverse events have been limited to Grade 1/2 hematuria, dysuria, and urgency. Preclinical studies indicate the pharmacodynamic activity of VAX014 following weekly intravesical administration to immune competent mice bearing bladder tumors is immune dependent and synergizes with systemic PD-L1 blockade to eliminate organ confined tumors and extravesical tumors. Surviving mice are capable of rejecting tumor rechallenge due to development of protective antitumor immunologic memory in response to therapy. Exploratory immunohistochemical target validation studies in bladder tumor biopsy specimens from subjects with more advanced stage tumors (T1-T3), indicate overexpression of VAX014’s target integrins, a3b1 and a5b1, in most samples tested. Conclusions: These clinical and preclinical data support the further development of VAX014 for the intravesical treatment of NMIBC and set a foundation for combination therapy with systemically administered immune checkpoint blockade in subjects with advanced disease. Clinical trial information: NCT03854721.

Real Life Treatment Alterations of Frontline Therapies in Classic Hodgkin's Lymphoma

Introduction Classic Hodgkin's lymphoma (cHL) is a highly curable lymphoid malignancy. Most of the patients receive either bleomycin or brentuximab vedotin (BV) based therapies as a frontline treatment. Treatment alterations are common and can be related to toxicity, patient's preference, and/or clinical evidence of response. The aim of our study is to explore the frequency and characteristics of treatment alterations, especially bleomycin and BV, in frontline therapies used in newly diagnosed cHL. Methods This single center study included patients with a diagnosis of cHL who were first seen at The University of Texas MD Anderson Cancer Center between January 1,2016 and May 28, 2020 for either newly diagnosed cHL or relapsed/refractory (R/R) cHL. Patients' charts were reviewed to assess frequency of treatment discontinuation at the time of frontline therapy and underlying reasons for any treatment alterations. The primary aims were to assess the frequency of treatment alterations and its effects on overall survival (OS), and progression-free survival (PFS). Descriptive statistics including mean, standard deviation, median, and range for continuous variables such as age, and lab measurements, and frequency counts and percentages for categorical variables such as race, gender, and response were analyzed. The Kaplan-Meier method was used for time-to-event analysis including PFS and OS. Median time to event in months with 95% confidence interval (CI) was calculated. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for statistical analyses. Results In the studied period, 644 patients met the inclusion criteria. The median age at diagnosis was 33 years (range:9-85) with 52% males. Advanced stage (stages III and IV) occurred in 45% of patients. Ninety-seven percent of patients had 0-1 Eastern Cooperative Oncology Group (ECOG) performance status. Histological subtype was predominately nodular sclerosis (83%). International prognostic index at the time of diagnosis was ≥4 in 13% of patients. Most of the patients received doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) based therapy (77%). Other therapies included brentuximab vedotin (BV)(13%) and checkpoint inhibitors (CPIs) (6%, as a part of clinical trial). Patient's demographics are outlined in Table.1. Treatment alteration, which included either addition or omission of drug/s, occurred in 26% of patients. The most common discontinued drugs were bleomycin (79%), and BV (15%). Of the patients who were started on ABVD based therapy, the frequency of bleomycin discontinuation was 26% (116 of 455 patients). The most common reasons for bleomycin discontinuation were: treatment response as per the RATHL study (49%), pulmonary toxicity (27%) and other treatment-related toxicity (9%). Of the patients who were started on frontline BV based therapy, the frequency of BV discontinuation was 26% (20 of 78 patients). The most common reasons for BV discontinuation were: peripheral neuropathy (65%), skin rash (10%) and other treatment-related toxicity (25%). Patients who discontinued bleomycin due to adverse events (AEs) had a higher chance of primary refractory disease at the end of frontline treatment (19% vs. 15%, p-value: 0.005) while patients who discontinued bleomycin due to treatment response had similar rates of primary refractory disease (13% vs. 15%, p-value: 0.57). The median cycles number of bleomycin based therapy were the same (6 cycles) among all the groups (those who continued bleomycin without AEs or discontinuation, patients who discontinued bleomycin for treatment response and patients who discontinued bleomycin for AEs) . Patients who discontinued BV due to AEs had similar outcome to the patients who continued the treatment without alterations. Conclusions Frontline treatment alterations in cHL are common. Positron emission tomography treatment response based bleomycin discontinuation was not associated with worse PFS or OS. However bleomycin discontinuation secondary to AEs was associated with a statistically significant higher rate of primary refractory disease and subsequent worse PFS and OS. BV discontinuation secondary to AEs didn't result in worse outcomes. Disclosures Parmar: Cellenkos Inc.:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.Iyer:CRISPR:Research Funding;Spectrum:Research Funding;Merck:Research Funding;Afffimed:Research Funding;Rhizen:Research Funding;Seattle Genetics, Inc.:Research Funding;Legend Biotech:Consultancy;Daiichi Sankyo:Consultancy;Trillium:Research Funding;Curio Biosciences:Honoraria;Target Oncology:Honoraria.Nieto:Affimed:Consultancy, Other: Grant Support;Novartis:Other: Grant Support;Secura Bio:Other: Grant Support;Astra Zeneca:Other: Grant Support.Chuang:Sage-Evidence=Based Medicine & Practice:Consultancy.Wang:Lu Daopei Medical Group:Honoraria;Pulse Biosciences:Consultancy;Molecular Templates:Research Funding;BioInvent:Research Funding;VelosBio:Research Funding;Beijing Medical Award Foundation:Honoraria;Juno:Consultancy, Research Funding;Oncternal:Consultancy, Research Funding;AstraZeneca:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Celgene:Consultancy, Other: Travel, accommodation, expenses, Research Funding;InnoCare:Consultancy;Loxo Oncology:Consultancy, Research Funding;Verastem:Research Funding;Acerta Pharma:Research Funding;Pharmacyclics:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Janssen:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;MoreHealth:Consultancy;OncLive:Honoraria;Kite Pharma:Consultancy, Other: Travel, accommodation, expenses, Research Funding;Nobel Insights:Consultancy;Guidepoint Global:Consultancy;Dava Oncology:Honoraria;OMI:Honoraria, Other: Travel, accommodation, expenses;Targeted Oncology:Honoraria.Lee:Celgene:Research Funding;Guidepoint Blogal:Consultancy;Bristol-Myers Squibb:Consultancy, Research Funding;Aptitude Health:Speakers Bureau;Oncternal Therapeutics:Research Funding;Seattle Genetics:Research Funding;Takeda:Research Funding.

PS1212 UPDATED RESULTS FROM PHASE I TRIALS ASSESSING A NKG2D CAR T‐CELL APPROACH IN RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROME PATIENTS

Background:CYAD‐01 cells are chimeric antigen receptor (CAR) T cells based on the NKG2D receptor fused to the intracellular domain of CD3ζ, and bind ligands (MICA/B, ULBP1–6) expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).Aims:A comprehensive clinical program was developed with the objective to define the optimal CYAD‐01 treatment in relapsed/refractory (r/r) AML/MDS patients (pts).Methods:The Phase I THINK trial (NCT03018405) assesses the safety and clinical activity of multiple CYAD‐01 infusions without preconditioning chemotherapy in various malignancies, including r/r AML, MDS and multiple myeloma (MM). 3 dose levels (DL) were evaluated in the dose escalation segment (3x108, 1x109 and 3x109 T‐cells/inf.). 1st cycle of treatment consists of 3 CYAD‐01 infusions every 2 weeks and a 2nd cycle of 3 CYAD‐01 infusions with a 2 week‐interval in case of no progressive disease (PD) after the 1st cycle. Additional cohorts aim to provide a dense treatment schedule at the same DL (3x 1 CYAD‐01 every week + 3x 1 CYAD‐01 every 2 weeks). The Phase I/II DEPLETHINK study (NCT03466320) evaluates the safety and preliminary efficacy of 1 CYAD‐01 infusion administered after preconditioning with cyclophosphamide and fludarabine to pts with r/r AML/MDS. A 2nd cycle of 3 CYAD‐01 without preconditioning is administered in case of no PD after 1st treatment. 3 DL (1x108, 3x108 and 1x109 cells/inf.) and 2 intervals between preconditioning and CYAD‐01 infusion are evaluated in the dose escalation segment. Data as of February 20, 2019 are presented.Results:THINK study: 16 pts were enrolled in the dose‐escalation segment of the hematological cohort, now completed. 4 pts were enrolled in cohorts with the dense schedule. In total, 7 pts experienced grade (G) 3/4 treatment‐related adverse events (AEs). Cytokine release syndrome (CRS) occurred in 10 pts with only 2 G3 CRS (at DL2) and 1 G4 CRS (at DL3), which resolved with early tocilizumab treatment. No treatment‐related neurotoxicity AEs have been observed.Out of 12 pts who received at least 3 CYAD‐01 infusions in the dose‐escalation segment, 2 pts with MM did not have evidence of clinical response. For pts with r/r AML/MDS, 4/10 pts had overall response (OR) at D29 with 1 complete remission (CR) with partial hematologic recovery (CRh) for 16 months in a r/r AML pt at DL‐1, 2 CR with incomplete hematologic recovery (CRi) for 1 month in AML pts at DL‐1 and DL‐3, and 1 marrow CR (mCR) for 1 month in an MDS pt at DL‐3. 2 AML pts at DL‐2 had stable disease (SD) with bone marrow (BM) blast percentage decrease upon 1st treatment cycle and further reduction upon 2nd treatment cycle. Two other AML pts in DL‐3 achieved SD for at least 2 months. 2 AML pts did not show evidence of clinical response.DEPLETHINK study: 6 pts were enrolled in the first 2 cohorts which evaluated 1x108 cells/inf. In total, there were 3 G3/4 treatment‐related AE observed in the same pt. Five CRS occurred in 4 pts: 3 G1/2 after the 1st infusion and 2 CRS during 2nd cycle (1 G4 CRS and 1 G1), which resolved with tocilizumab treatment. At the 1st cohort, 2 pts reached a stable disease (SD) at D36, allowing the initiation of the 2nd cycle of 3 CYAD‐01 infusions.Summary/Conclusion:Altogether, results obtained to date in both phase 1 trials demonstrate the safety of CYAD‐01 with or without preconditioning chemotherapy in patients with r/r hematological malignancies. A promising OR rate of 40% at D29 was seen in pts with r/r AML/MDS in the THINK study. The DEPLETHINK study is still accruing.image

Targeting the PD-1/PD-L1 axis for the treatment of non-small-cell lung cancer.

Lung cancer is the leading cause of cancer-specific death among Canadians, with non-small-cell lung cancer (nsclc) being the most common histologic variant. Despite advances in the understanding of the molecular biology of nsclc, the survival rate for this malignancy is still poor. It is now understood that, to evade detection and immune clearance, nsclc tumours overexpress the immunosuppressive checkpoint protein programmed death ligand 1 (PD-L1). Inhibiting the PD-1/PD-L1 axis with monoclonal antibodies has significantly changed the treatment landscape in nsclc during the last 5 years. Despite evidence of clinical response in some patients, only approximately 20% of patients obtain any durable benefit, and many of the patients who do respond ultimately relapse with drug-resistant disease. The identification of patients who are most likely to benefit from such therapy is therefore important. In the present review, we cover the basics of the PD-1/PD-L1 axis and its clinical significance in nsclc, biomarkers that are predictive of treatment response, relevant clinical trials of PD-1/PD-L1 blockade completed to date, and proposed mechanisms of acquired therapeutic resistance.

Tofacitinib, an Oral Janus Kinase Inhibitor, in the Treatment of Ulcerative Colitis: Open-Label, Long-term Extension Study

Introduction: Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated for ulcerative colitis (UC). The efficacy and safety of tofacitinib was demonstrated as induction and maintenance therapy in 3 Phase 3, randomized, placebo-controlled studies (OCTAVE Induction 1, NCT01465763; OCTAVE Induction 2, NCT01458951; OCTAVE Sustain, NCT01458574) in patients (pts) with moderate to severe UC.1 Methods: We present interim safety and efficacy data up to 3 yrs of treatment (as of July 8, 2016) from an ongoing Phase 3, multicenter, open-label, long-term extension study (OLE; NCT01470612) in pts who had completed or demonstrated treatment failure in OCTAVE Sustain, or who were non-responders after completing OCTAVE Induction 1 or 2. Pts in remission at Week 52 of OCTAVE Sustain received tofacitinib 5 mg twice daily (BID); all others received 10 mg BID. At Month 2, all pts underwent endoscopy, and non-responders from induction were mandated to withdraw if no evidence of clinical response was shown. Remission was defined by a Mayo score ≤2 with no individual subscore >1, and rectal bleeding subscore of 0. Binary efficacy endpoints were derived from Mayo score, based on local-read endoscopic subscore. Results: 914 pts (5 mg BID, N=156 [17.1%]; 10 mg BID, N=758 [82.9%]) received ≥1 dose of study drug; 381 pts (41.7%) discontinued. The most frequent AE leading to discontinuation was worsening of UC. Serious and severe AEs occurred in 10.4% and 7.8% of pts, respectively (dose groups combined). The most frequent treatment-emergent AEs by system organ classes (both doses) were ‘infections/infestations' and ‘gastrointestinal disorders', and by preferred term were ‘nasopharyngitis' and ‘worsening of UC'. Serious infections AEs were reported in 4 (2.6%) and 14 (1.8%) pts with 5 and 10 mg BID, respectively. Malignancies excl. NMSC were reported in 9 (1.2%) pts in the 10 mg BID group (no clustering of malignancy type); none were reported in the 5 mg BID group. No new safety risks were identified. Data ‘as observed' for remission and mucosal healing at Months 2, 12, and 24 are shown.Table: Table. Summary of safety and efficacy in the OLE studyConclusion: In pts with moderate to severe UC who remained in the OLE study, no new safety concerns emerged compared with those observed with tofacitinib in rheumatoid arthritis. Efficacy results from this OLE study support sustained efficacy with tofacitinib 5 and 10 mg BID. Funded by Pfizer Inc.

Recurrent pleural effusions and cardiac tamponade as possible manifestations of pseudoprogression associated with nivolumab therapy– a report of two cases

BackgroundCheckpoint inhibitors are a class of agents that employ host’s adaptive immune defenses in fighting cancer. With many new indications and several ongoing clinical trials in a variety of malignancies,...

Modified Dose Escalation Of Ruxolitinib: A Feasible Therapeutic Approach In The Management Of Myelofibrosis

Ruxolitinib, is a JAK1/2 inhibitor approved for the treatment of intermediate and high risk myelofibrosis (MF). The recommended starting doses for ruxolitinib, are 20 mg PO BID or 15 mg PO BID if platelet (PLT) counts are ≥200 x109/L or 100 to 200 x109/L, respectively. However, drug related side effects which includes grade 3/4 anemia (45.2%), thrombocytopenia (12.9%), fatigue (25.2%) and diarrhea (23.2%) are common using standard dosing. Moreover 70% of patients (pts) started on the standard regimen require dose reduction because of drug related toxicities. Although hematologic side effects are generally expected during early phases of ruxolitinib therapy and reversible in most cases, a therapeutic approach that can avoid myelosuppression while still providing adequate clinical responses is warranted. Therefore, to obviate toxicities and achieve symptom improvement in pts with MF, we employed a dose escalation (DE, starting at 5 mg QOD) approach for ruxolitinib and compared outcomes with another group that previously received standard regimens (SR, 15 or 20 mg BID). In addition to baseline characteristics, clinical data including hematologic parameters, bone marrow (BM) results, Dynamic International Prognostic Scoring System-Plus (DIPSS-plus) risk, and transfusion (TF) requirement were collected. Hematologic and non-hematologic side effects based on CTCAEv.4 and evidence of clinical response (reduction of splenomegaly by palpation) were assessed at 8, 12 and 16 weeks after starting treatment (post-Tx). Descriptive data were summarized as frequency of counts and percentages and continuous data were presented as mean and ranges and the comparison between two groups was performed. Survival outcomes were analyzed using the Kaplan-Meier method. Plasma concentrations for interleukins (IL) including IL1A, IL1B, IL2, IL4, IL6, IL8, IL10, IL12, IL17A, INFg, TNFa and GM-CSF were also measured pre and post- ruxolitinib treatment using a Multi-Analyte ELISArray Kits (SABiosciences)A total of 42 pts seen in our MPN clinic were studied, including 23 females (54%) and 19 males (46%). The median age of the cohort was 69 (43-83 years). Disease subtypes include 23 PMF, 10 post-PV MF, 6 post-ET MF and, 1 CMML-1. Based on the DIPSS-plus risk score, there were 17 high, 16 intermediate-2, and 8 intermediate-1 risk pts. Thirty-two pts (76%) were JAK2V617F mutant and 10 were wild type. The mean duration of treatment was 8 mos (range, 3-17) and follow up was 11 mos (4-36). Twenty-six pts started on DE and 16 received SR. The mean ruxolitinib dose in the whole cohort was 10 mg BID (range; 5mg QOD-25mg BID). The mean maintenance dose in the DE cohort was 5mg BID while in the SR cohort was 15mg BID. In terms of clinical response, the mean pre and post-Tx spleen size was 13.69 cm and 6.8 cm in the DE cohort compared to 17.68 cm and 13.07 cm in SR cohort (p = .03). In terms of hematological side effects, the DE approach resulted in less frequent grade 3-4 or any grade anemia compared to SR (G3-4: 3% vs. 18%, p =.02; overall anemia: 14% vs. 50%, p =.04). In pts treated with DE and SR, 57% and 75% were TF dependent pre-Tx. Post-Tx, 35% of pts treated with DE became transfusion independent vs 0% in the SR group. The DE approach also resulted in less frequent grade 3-4 or any grade thrombocytopenia compared to SR (G3-4: 11% vs. 31%, p= .04; overall thrombocytopenia: 23% vs. 43%, p=.06). There was no difference in the frequency or degree of neutropenia between the DE and SR treated pts. Non-hematologic side effects were also less frequent in the DE group compared to the SR group (bruising: 36 vs 75%, diarrhea: 28 vs 56%, lower extremity edema: 21% vs 50%, and dizziness: 15 vs 31%). In 3 pts treated with DE, the degree of reticulin fibrosis reduced from MF3 to MF2 confirmed with bone marrow biopsy performed 6-12 months post-Tx. We also compared the differences in cytokine profile between the patients treated with DE (n=2) and SR (N=2). No difference in the degree of reduction of MF relevant cytokines including IL-1A, IL-1B, IL-2, IL-4, IL-6, IL-12, TNF-α and GM-CSF were observed between both groups (p=0.2). At the time of analysis, 38 pts are still alive and no difference in survival were observed between DE and SR treated patients (log rank p=0.69). In conclusion, a dose escalation approach for ruxolitinib therapy is better tolerated and with preserved clinical responses compared to the standard dosing regimen in MF patients. Disclosures:No relevant conflicts of interest to declare.

Imaging Features of Extramedullary, Relapsed, and Refractory Multiple Myeloma involving the Liver Across Treatment With Cyclophosphamide, Lenalidomide, Bortezomib, and Dexamethasone

A 55-year-old white woman presented in June 2003 with stage IIIA Durie-Salmon immunoglobulin (Ig) G κ multiple myeloma (MM) and was initially treated with thalidomide and dexamethasone followed by cyclophosphamide, with concurrent bisphosphonate (zoledronic acid), and intensified by autologous stem-cell transplant (ASCT) after high-dose melphalan conditioning. She remained in complete remission until December 2008, when she experienced relapse with occipital plasmacytoma and symptomatic extramedullary disease (EMD) arising from her skeleton. She was treated with an experimental second-generation proteasome inhibitor (NPI-0052, 0.7 mg/m2 administered intravenously [IV]), combined with low-dose weekly oral dexamethasone. She had evidence of clinical response (disease stabilization and symptomatic improvement). Treatment was completed after 6 months, and she declined maintenance options other than bisphosphonate.

Abstract 1692: Expression of argininosuccinate synthetase protein and correlation with response to the novel therapeutic pegylated arginine deiminase (ADI-PEG20) in osteosarcoma

Abstract The amino acid arginine is involved in protein synthesis and tumor metabolism and is essential for the growth of human cancer cells. Pegylated arginine deiminase (ADI-PEG20) is a novel therapy that lowers extracellular arginine levels and has shown evidence of clinical response and low toxicity in patients with tumors lacking argininosuccinate synthetase (ASS1) protein expression, including melanoma and hepatocellular carcinoma. Recently it has been shown that ASS1 expression was deficient in 63% (39/62) of Japanese osteosarcoma patient samples, and reduced ASS1 was associated with pulmonary metastases. In addition, they showed that ASS1 deficient, but not ASS1 expressing, osteosarcoma cells lines did not grow in arginine-deficient media, and recommended evaluation of arginine depletion with ADI-PEG20 in osteosarcoma. Because ADI-PEG20 efficacy appears to correlate with ASS1 protein expression, a cohort of osteosarcoma tissue sections (n=171) was stained immunohistochemically to determine the presence or absence of ASS1 protein. Sixty-four percent (n=109) indicated negligible or no staining for ASS1 protein suggesting further that osteosarcoma might be a candidate for ADI-PEG20 sensitivity. Western blots were performed on patient-derived osteosarcoma cell lines (n=18) to determine levels of ASS1 protein expression prior to treatment with ADI-PEG20. Of the 18 cell lines studied, four cell lines had noticeably diminished ASS1 protein expression. The remaining 13 cell lines exhibited varying amounts of ASS1 protein expression with five of these cell lines appearing strongly positive indicating possible overexpression of ASS1 protein. Cytotoxicity assays were performed on a subset of cell lines representing both elevated and decreased ASS1 protein expression to determine the in vitro effectiveness of ADI-PEG20 in patient-derived osteosarcoma cell lines and its correlation with ASS1 protein expression. Some of the ASS1 deficient cell lines showed decreased cell viability in response to arginine depletion with ADI-PEG 20. These findings suggest that arginine depletion with ADI-PEG 20 may be a potential targeted treatment for osteosarcoma patients deficient in ASS1 expression. In addition, further preclinical studies are ongoing, including xenograft models, to understand better the mechanism of this agent in osteosarcoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1692. doi:1538-7445.AM2012-1692

A phase I study of INNO-406, a dual inhibitor of Abl and Lyn kinases, in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory, or intolerant of imatinib

7046 Background: INNO-406 is an orally available, dual Abl/Lyn kinase inhibitor that is up to 55-times more potent than imatinib in Bcr-Abl cell lines. Numerous Bcr-Abl mutant proteins (not T315I) are sensitive to INNO-406 in vitro. INNO-406 demonstrates specific Src kinase activity against Lyn kinase. Methods: In this phase I study, patients with imatinib-resistant or intolerant Philadelphia (Ph+) chromosome- positive leukemias were eligible for treatment with INNO-406 once a day, orally. Results: 14 pts [median age: 58 yrs (range 18–74); 7 male, 7 female; median CML duration: 53 mo. (range 14–266); and median time on imatinib 45 months (range 12–129); chronic phase CML (8 pts), accelerated phase CML (2 pts), blast phase CML (1 pt), Ph+ ALL (3 pts); previous treatment with nilotinib (5 pts), dasatinib (6 pts)] have been enrolled in the following dose cohorts (mg/day): 30 (3 pts), 60 (3), 120 (6) and 240 mg (2), and have been on treatment between 7 and 123 days. 3 pts remain on study; 10 pts discontinued with disease progression [data unmonitored]. 6 patients who have completed >1 month of treatment, 3 have evidence of clinical response. Patient 5, a chronic phase CML treated with imatinib for 69 mo. before developing resistant disease with an Y253H mutation, had a minimal cytogenetic response after 1 month of INNO-406 therapy. Patient 4, an accelerated phase CML treated with imatinib and nilotinib for 16 and 6 mo., respectively, before becoming intolerant to nilotinib due to thrombocytopenia, has maintained a complete hematologic response following 4.5 months of INNO-406 therapy at a dose of 120 mg/day. Patient 1, a chronic phase CML treated with imatinib for 51 mo. before developing resistant disease without a mutation, has maintained stable white cell counts after 4 months of therapy at a dose of 30–60 mg/day, with a 55-fold reduction in Bcr-Abl transcript levels after 1 month of INNO-406 therapy. Conclusions: INNO-406 is well tolerated in patients at a dose of 240 mg/day, with encouraging evidence of clinical activity in imatinib-resistant and nilotinib-intolerant patients. In the absence of dose limiting toxicity, dose escalation continues. No significant financial relationships to disclose.

Anti-tumor activity of recombinant human Interleukin-21 (rIL-21): Preliminary data from a phase 2a study in patients with stage IV malignant melanoma (MM) without prior treatment

3055 Background: rIL-21 is a pleiotropic class I cytokine that activates CD8+ T cells and NK cells. The safety and pharmacologic profile of rIL-21 was characterized in two phase 1 dose escalation studies including patients with MM, performed in Australia and the US, respectively. Two dosing schedules were tested: “5+9” (5 days of dosing followed by 9 days of rest) and “3/wk” (dosing 3 times per week for 6 weeks). The maximum tolerated dose (MTD) was determined to be 30 μg/kg for both dosing regimens and two complete remissions (at the 30 μg/kg dose level) were observed in the MM patients. A phase 2a study was initiated to estimate the preliminary efficacy of rIL-21 in patients with advanced MM. Methods: The phase 2a study design is an open-label, two-stage trial. Primary objective: antitumor efficacy as determined by response rate. Secondary objectives: safety, effects on blood biomarkers, and measurement of anti-rIL-21 antibodies. Eligible patients had unresectable MM with measurable disease, no prior systemic therapy (adjuvant interferon was permitted), adequate major organ function, good performance status, no brain metastases, and no evidence of significant autoimmune disease. rIL-21 was administered by i.v. bolus injection using the “5+9” regimen for 6 weeks (= three cycles) at 30 μg/kg dose level. Results: At the time of writing (January 2007), all 14 patients have entered the first stage of the phase 2a study and currently seven patients are evaluable for response after completion of 3 treatment cycles (6 weeks). One patient had a complete remission, five patients had stable disease, and one patient had progressive disease. So far, six patients have gone on to receive further treatment with rIL-21. Similar to the phase 1 experience, treatment with rIL-21demonstrated an acceptable safety profile. Updated interim study results, including response data, will be presented. Conclusions: rIL-21 administered at 30 μg/kg/day using the “5+9” regimen is well tolerated by patients with MM. Preliminary evidence of clinical response has been observed and the second stage of the two-stage phase 2a study has opened for accrual. [Table: see text]

Elevated body mass index does not increase the risk of palmar–plantar erythrodysesthesia in patients receiving pegylated liposomal doxorubicin

Objectives. The dose-limiting toxicity of pegylated liposomal doxorubicin (PLD) is palmar–plantar erythrodysesthesia (PPE). Some physicians are reluctant to use this drug in overweight patients, postulating that larger size increases the likelihood of PPE. We sought to determine whether a correlation exists between body mass index (BMI) and the frequency or severity of skin reactions during PLD chemotherapy. Methods. The records of all patients receiving PLD chemotherapy for gynecologic malignancy at our institution were reviewed for chemotherapy history, BMI at start of treatment, dose, infusion time, and adverse outcomes. Skin reaction sites, grade, and treatments were recorded. Possible predisposing factors were extracted, as well as the reason for drug discontinuation. Results. Over 7 years, 103 patients were treated with PLD for gynecologic malignancies. 429 cycles were given, and PPE occurred in 36% of patients treated. Of those with PPE, reactions were grades 1, 2, or 3 in 54%, 32%, and 14% of patients, respectively. The BMI of patients with PPE (29.0) was not significantly different from that of patients without PPE (28.8). Analysis using finer subsets of weight also revealed no association. Finally, logistic regression revealed no relationship between BMI and rash grade. Conclusions. Elevated BMI does not appear to correlate with occurrence of PPE in our population. Of interest, among patients discontinuing PLD due to skin toxicity, 25% had clinical evidence of response. The identification of predisposing risk factors may help guide treatment decisions; however, elevated BMI does not appear to be such a risk factor.

Accurate response assessment of breast cancer bone metastasis using computed tomography and new response criteria

568 Background: The lack of accurate criteria for assessing the response of bone metastases from breast cancer has led to bone disease being considered unmeasurable. Criteria from the UICC and the WHO based on radiography (XR) and skeletal scintigraphy (SS) are not satisfactory for clinical use. Criteria for computed tomography (CT) and magnetic resonance imaging (MR) have yet to be validated. We recently proposed a set of CT- and MR-inclusive criteria (MDA) to assess bone response (JCO 22:2942, 2004). Here we retrospectively reviewed image sets to evaluate the accuracy of MDA criteria (vs UICC, WHO) and the accuracy of each imaging modality for assessing bone response. Methods: XR, SS, CT, and MR images from patients with breast cancer and bone-only metastases were reviewed by musculoskeletal radiologists at baseline and after treatment (early: 2–6 mo, late: 11–13 mo). Responses were characterized as complete or partial, or stable or progressive disease (CR, PR, SD or PD) according to the 3 sets of criteria (MDA, WHO, UICC). Results from each imaging modality were compared with clinical evidence of response (symptoms, tumor markers, imaging). Results: We reviewed 180 image sets from 47 patients and analyzed images from 41 patients. At the early phase, we found that CT was more sensitive (77%; 95% CI 54–99; P=0.03) than SS (36%; 95% CI 11–61), and MDA criteria were more sensitive (87%; 95% CI 69–100; P=0.02) than WHO (40%; 95% CI 15–65) for detecting response. Specificity was no different among modalities or criteria. Those with CR or PR by MDA criteria early in treatment may have had better overall survival than nonresponders (SD+PD) (HR 0.4; 95% CI 0.17–1.14; P=0.09), with no difference by WHO criteria (HR 1.0; 95% CI 0.38–2.56; P=0.98). We could not examine XR, MR, or UICC criteria because too few XR and MR images were available. Conclusions: CT is more sensitive than SS for showing clinical response of bone lesions from breast cancer. The MDA criteria is more likely to be appropriate than WHO criteria for assessing bone metastases from breast cancer. Prospective studies are warranted to determine whether use of the CT- and MR-inclusive MDA criteria improves the ability to detect and quantify responses in bone metastases. No significant financial relationships to disclose.

Phase II study of all-trans retinoic acid in the accelerated phase or early blastic phase of chronic myeloid leukemia: A study of the Eastern Cooperative Oncology Group (E1993)

The aims of this study were to evaluate the safety and efficacy of all-trans retinoic acid (ATRA) in the treatment of the accelerated and blastic phase of chronic myeloid leukemia (CML) and to evaluate in vitro correlates of biological activity. ATRA was administered in an intermittent schedule to patients with CML in the accelerated or blastic phases for a 6 week induction period, which was continued if there was evidence of clinical response or stable disease. If the patient was progressing at 6 weeks, interferon-α could be added to the ATRA. Laboratory correlative studies were performed prior to treatment and at intervals during treatment to evaluate effects on maturation and differentiation, and on CML progenitor cell growth by assessment of colony-forming cells (CFC). Eighteen patients were enrolled. There was 1 complete response, 1 partial response and 2 with hematological improvement. A fifth patient was stable on ATRA and interferon for several months. Laboratory data for the responders demonstrated high sensitivity of primary CFC to ATRA prior to treatment and low serial CFC counts on ATRA therapy. ATRA demonstrated clinical and hematological activity in 5 of 18 patients with the accelerated phase of CML, and there was evidence of a biological effect in laboratory studies of 3 of the 5 patients' progenitor cells. Combination therapy with other differentiating agents may be useful in this disease.

Phospho-Akt Overexpression in Non–Small Cell Lung Cancer Confers Significant Stage-Independent Survival Disadvantage

Akt is a signal transduction protein that plays a central role in inhibiting apoptosis in a variety of cell types including human cancer cells. In cell lines derived from human non-small cell lung cancers (NSCLCs), Akt has been shown to confer chemoresistance by inhibition of apoptosis in response to different chemotherapeutic agents including platinum-based agents, which are often the first-line therapy for NSCLCs. Only 20% to 30% of patients with NSCLC treated with chemotherapy have clinical evidence of response. The purpose of this study is to determine whether or not overexpression of activated Akt [i.e., phosphorylated Akt (pAkt)] is correlated with survival. We studied tumors from 61 patients with NSCLC in three tissue microarrays. All patients were followed for a period of 10 years or until death. The arrays were studied immunohistochemically with antibodies against pAkt, p53, and Ki-67. There was a statistically significant difference in survival between the 14 patients with strong pAkt staining and the 47 patients with weak to absent pAkt staining both by log-rank (P = 0.0416) and Breslow analysis (P = 0.0446). Difference in survival time with respect to pAkt status was also statistically significant even after accounting for stage at diagnosis (P = 0.004). Neither p53 nor Ki-67 was a statistically significant prognostic factor. Overexpression of pAkt is an independent prognostic factor. Additional studies of human NSCLCs are warranted to drive the development of targeted tumor-specific antineoplastic therapies.

Monoclonal Antibodies in Cancer Treatment

Research advances and promising clinical outcomes with immunotherapeutics has led to a resurgence of incorporating monoclonal antibodies in cancer treatment. Unconjugated, conjugated and multi-target constructs are emerging as a conventional form of therapy along with the classical trio of surgery, radiation and chemotherapy. The recent major accomplishments in monoclonals include: first, the development of human and chimeric structures negating the induction of humoral responses to murine counterparts which limited use; second, protein engineering has improved the affinity and specificity of the antibody to its target; third, technics have been designed to select monoclonal antibodies imparting a biological consequence (function) following binding; and, lastly, recombinant proteins are being created with multiple epitopic specificities and/or fusion with other biologically active proteins such as toxins and cytokines/growth factors. Clinical efficacy in the treatment of haematological malignancies has secured a role for monoclonals in routine treatment. Evidence of clinical responses in patients with metastatic solid tumours is leading to the next generation of trials in the adjuvant setting. This paper presents an overview of the clinical experience with monoclonal antibodies in cancer treatment over the past 5 years. Our aim is to highlight the successes and advances, as well as noting limitations of antibody therapeutics. The advances seen support a continued effort to optimise the creation, selection and use of immunotherapeutics in the battle against cancer.

Bryostatin 1-tamoxifen combinations show synergistic effects on the inhibition of growth of P388 cells in vitro.

This study shows that combinations of bryostatin 1, a novel modulator of protein kinase C currently under clinical evaluation, with the anti-oestrogenic agent tamoxifen caused a large synergistic enhancement of growth inhibition in P388 cells in vitro. The growth-inhibitory effects of bryostatin 1 in the presence of non-inhibitory concentrations of tamoxifen were increased by approximately 200-fold, whereas growth inhibition by tamoxifen in the presence of non-inhibitory concentrations of bryostatin 1 were increased over 30-fold. These data have been confirmed by isobologram analysis. The precise mechanism underlying this effect is unknown, although preliminary data implicating protein kinase C is presented. The magnitude of this synergistic effect, together with evidence of clinical responses seen when these agents were given sequentially in ovarian cancer, merits further study.

1275 Preliminary clinical results of active immunization with interleukin-4 gene transfected allogeneic melanoma cells in metastatic melanoma patients

From May 1994 to February 1995 five HLA-A2 patients affected with melanoma metastases were treated with active immunization with IL4 transfected, irradiated, HLA-A2 + allogeneic melanoma cells. They were injected with 50 × 106 cells at day 1, 13, 26, 55. Two patients received 4 vaccinations, 1 patient 3 vaccinations and 2 patients (actually not evaluables) were injected 2 times. According to the WHO toxicity grading 2 patients presented grade 2 local toxicity and 3 patients had grade 1. No systemic toxicity was recorded. No evidence of clinical response was obtained. At the present, 4 patients are alive with disease and 1 patient is alive without disease after surgical excision of a cutaneous metastasis. From May 1994 to February 1995 five HLA-A2 patients affected with melanoma metastases were treated with active immunization with IL4 transfected, irradiated, HLA-A2 + allogeneic melanoma cells. They were injected with 50 × 106 cells at day 1, 13, 26, 55. Two patients received 4 vaccinations, 1 patient 3 vaccinations and 2 patients (actually not evaluables) were injected 2 times. According to the WHO toxicity grading 2 patients presented grade 2 local toxicity and 3 patients had grade 1. No systemic toxicity was recorded. No evidence of clinical response was obtained. At the present, 4 patients are alive with disease and 1 patient is alive without disease after surgical excision of a cutaneous metastasis.

Environmentally responsive temperature instability in pediatric spinal cord injury

OBJECTIVE To study the frequency and clinical implications of environmentally responsive temperature instability in hospitalized pediatric patients with spinal cord injury (SCI). SETTING A tertiary level SCI rehabilitation unit located in a free standing children's hospital in Wilmington, DE, USA. STUDY DESIGN Temperature data and corresponding clinical responses were collected prospectively between January 1991 and June 1993. Fifty-four consecutive patients with SCI levels at or above T6 were admitted to the pediatric spinal cord injury rehabilitation unit over that time (4059 SCI days). METHODS Hypothermic events were defined as oral temperatures less than 35.0 degrees C or rectal temperatures less than 35.6 degrees C. Hyperthermic events were defined as oral temperatures greater than 38.0 degrees C or rectal temperatures greater than 38.4 degrees C. The events and the clinical responses were reviewed retrospectively and were used for subsequent analysis if there was evidence of clinical response to environmental manipulation within 4 hours of case identification, and other potential etiologies of temperature fluctuation could be excluded. RESULTS Sixty-five events of hypothermia (1.60%) and 14 events of hyperthermia (0.34%) were analyzed. Twelve patients (22%) accounted for all 79 events. Subjects with environmentally responsive temperature instability were more recently injured (P<0.001), had longer lengths of stay (P<0.001) and were more likely to be ventilator dependent (P<0.002) than those who did not have environmentally responsive temperature instability. There was no significant difference between the two groups in age, gender, level or etiology of the SCI. There were no adverse clinical outcomes as a result of the environmentally responsive temperature instability. CONCLUSIONS Environmentally responsive temperature instability affects a select subset of pediatric aged spinal cord injured persons. Early recognition of the potential contribution of the environment to temperature fluctuation in this group has led to the successful utilization of a temperature instability protocol on our SCI unit.