bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of sagopilone (ZK-EPO), a novel synthetic epothilone, with significant activity in metastatic melanoma
Authors: Daud A. , Weber J. , Urbas P. , Andrews S. , Maker N. , Sondak V. K. , DeConti R. C. 
Published: August 2020

9031 Background: Sagopilone (ZK-Epothilone) is a novel, fully synthetic epothilone with promising preclinical activity in several cancer models. This phase II study aims to define the efficacy and safety of sagopilone in patients with metastatic melanoma, as well as perform pharmacokinetic evaluation of this dose and schedule. Methods: Patients with unresectable stage III or IV malignant melanoma, with up to 2 prior chemotherapy and any prior immunotherapy regimens with measurable disease were eligible. Sagopilone was administered at 16 mg/m2 as a 3-hour IV infusion every 21 days. The primary end point of the trial was response rate, and secondary endpoints included time to progression, overall survival, and tolerability. Pharmacokinetic analysis was done on the first 10 patients. A total of 37 patients were to be accrued to have 33 evaluable patients. The trial had a 0.90 power and assumed α of 0.03. Results: Thirty four patients have been enrolled to date. Sagopilone appears to be well tolerated: The most common side effects seen have been sensory neuropathy, (55%, 19/34, 5 Grade 2, 14Grade 1) motor neuropathy (23%, 8/34, All Grade 1); anemia (26 %, 9/34) neutropenia (14%, 5/34 1 Grade 2, 4 Grade 1) thrombocytopenia (14%, 5/34) and fatigue (38%, 13/34). Two patients have shown grade 3 events (syncope and mental status changes, respectively, possibly related to therapy), both of which resolved and an additional patient had a pulmonary embolism which was considered unlikely to be related to therapy. Responses have been seen in 4 patients (3 RECIST confirmed PR, 1 unconfirmed PR). Stable disease was seen for at least 12 weeks in an additional 10 patients for a clinical benefit rate (CR+PR+SD) of 44%. No grade 4 events have been reported. Conclusions: Unlike the epothilone analogs patupilone or ixabepilone, sagopilone appears to be an active drug in advanced melanoma. The side effect profile seen to date at 16 mg/m2 given over 3 hours repeated every 3 weeks appears to be notably free of myelosuppression indicating that it could be combined with other drugs active in melanoma. Pharmacokinetic studies show a prolonged terminal half life, probably due to release from deep tissue compartments. [Table: see text]
Phase II clinical trial with a second generation, GM-CSF encoding, oncolytic herpesvirus in unresectable metastatic melanoma
Authors: Senzer N. N. , Kaufman H. , Amatruda T. , Nemunaitis M. , Daniels G. , Glaspy J. , Goldsweig H. , Coffin R. S. , Nemunaitis J. 
Published: August 2020

9035 Background: OncoVEXGM-CSF is a an oncolytic HSV, encoding GM-CSF . We recently completed a phase II trial involving 50 advanced melanoma patients (stage IIIc and IV) with at least one injection accessible lesion, including by ultrasound. Methods: Patients received a single IT injection of 106 pfu/ml apportioned between 10 or less injectable tumors, followed 3 wks later by 24 or less sequential injections of 108 pfu/ml every 2 wks until clinically significant disease progression, or overall or injectable lesion complete response. Response (RECIST modified to allow progression before response and biopsy of residual masses) and survival were monitored. Results: All 50 pts have been enrolled and are evaluable (Stage IIIc, n=10; IV M1a, n=16; IV M1b, n=4; IV M1c, n=20). A median of 6 injections were administered. Adverse effects were limited and generally involved transient flu-like symptoms. Both injected and uninjected regional and distant disease demonstrated response including clearly documented responses at uninjected visceral sites. The overall response rate was 26% (8 CR, 5 PR); 10 responses have been maintained for >6 months and 2 are ongoing at <6months, the longest currently being at 35 months from first dose. 93% of patients (14 of 15) with PR, CR or surgical CR remain alive. Ten additional patients had SD for >3 months. Kaplan Meier one year survival is 61% overall, 58% stage IV only, 48% for Stage IV M1c. The median OS is 16+ months. Conclusions: The 1-year survival and durable objective response rate are encouraging. Responses of distant and visceral disease provide further compelling evidence of systemic effectiveness. This, combined with a limited toxicity profile, suggests OncoVEXGM-CSF is a promising treatment for metastatic melanoma. A phase III clinical trial is planned. [Table: see text]
Efficacy of ipilimumab 10 mg/kg in advanced melanoma patients (pts) with good and poor prognostic factors
Authors: Wolchok J. D. , de Pril V. , Linette G. , Waterfield W. , Gajewski T. , Chiarion-Sileni V. , Ibrahim R. , Chin K. , Hoos A. , Hamid O. 
Published: August 2020

9036 Background: Ipilimumab is a fully human monoclonal antibody against cytotoxic T-lymphocyte antigen-4. In total, ∼50% of metastatic melanoma pts treated with 10 mg/kg ipilimumab are alive at 1 year (Wolchok et al. CRI-CVC annual meeting 2008. Oral presentation), and identifying prognostic factors may help select pts most likely to benefit from treatment. Factors predictive of poorer prognosis in melanoma include advanced stage of disease (ie, M1c), age 60+, gender (male), elevated baseline lactate dehydrogenase (LDH) levels, and lack of a prior response to therapy. In this pooled analysis, potential prognostic factors in pts with advanced melanoma treated with ipilimumab 10 mg/kg in 2 phase II studies (CA184–008, N=155 and -022, N=72) were explored. Methods: Ipilimumab 10 mg/kg was given every 3 weeks (Q3W) × 4 (induction); eligible pts could continue to receive ipilimumab Q12W starting at week (Wk) 24 (maintenance). Response was based on modified World Health Organization criteria. Each variable was analyzed separately. Results: Disease control rate (complete/partial response [CR/PR] and stable disease) seems not to be associated with age (<65 yrs: 25.2%; ≥65 yrs: 32.9%), gender (male: 22.6%; female: 34.0%), M stage (M0: 33.3%; M1a: 41.0%; M1b: 26.4%; M1c: 23.6%), response to prior systemic therapy (yes: 32.5%; no: 26.7%), prior immunotherapy (yes: 21.6%; no: 35.3%), LDH >upper normal limit (UNL) (yes: 25.9%; no: 29.7%), or LDH >2×UNL (yes: 15.9%; no: 30.6%). Best overall response rate (CR or PR) was not associated with age (<65 yrs: 7.3%; ≥65 yrs: 7.9%), gender (male: 4.0%; female: 11.7%), M stage (M0: 8.3%; M1a: 15.4%; M1b: 5.7%; M1c: 5.7%), response to prior systemic therapy (yes: 12.5%; no: 6.4%), prior immunotherapy (yes: 3.2%; no: 12.7%), LDH >UNL (yes: 8.6%; no: 6.3%), or LDH >2×UNL (yes: 4.5%; no: 8.2%). Overall survival was not associated with age (median OS: <65 yrs: 11.6 mo; ≥65 yrs: 7.59 mo), M stage (median OS: M0: 21.9 mo; M1a: 15.7 mo; M1b: 15.4 mo; M1c: 6.6 mo), or response to prior systemic therapy (median OS: yes: 11.6 mo; no: 10.7 mo). Conclusions: Ipilimumab demonstrates clinical activity independent of negative prognostic factors, and may even benefit those pts with the worst prognosis. [Table: see text]
Long-term survival of patients (pts) with advanced melanoma treated with ipilimumab with or without dacarbazine
Authors: Hersh E. , Weber J. , Powderly J. , Pavlik A. , Nichol G. , Yellin M. , Cranmer L. , Urba W. , O'Day S. 
Published: August 2020

9038 Background: Ipilimumab is a fully human monoclonal antibody targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4). Here, we report updated survival of pts with advanced melanoma treated with ipilimumab in 2 completed studies. Methods: Seventy-two chemotherapy-naïve pts were randomized to receive 3 mg/kg ipilimumab every 4 weeks (Q4W) × 4 alone or with ≤6 × 5-day courses of DTIC 250 mg/m2/day (ipilimumab, n = 37; ipilimumab + DTIC, n = 35) in the multicenter, open- label Phase II study MDX010–08 (Sep 2002-Aug 2004)(Hersh E et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 9022)). In the phase I/II dose-ranging study MDX010–15, 23 pts were treated with 10 mg/kg ipilimumab every 3 weeks (Q3W) × 4 (induction) (Jun 2004- Jul 2006) (Urba W et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 3018)). No maintenance ipilimumab was administered in either study. Long-term survival was determined under a follow-up protocol (MDX010–28) from May 2007-Jan 2008. Results: Long-term data are available for 62 pts for MDX010–08 and 22 pts for MDX010–15. For MDX010–08, the median follow-up was 4.3 years (range, 4.0–4.7 years); it was 2.2 years (range, 2.0–2.4 years) for MDX010–15. Survival rates are reported in the Table . Conclusions: Ipilimumab monotherapy, administered at 3 mg/kg and without maintenance dosing, resulted in survival rates better than those observed with historical controls (Korn EJ et al. J Clin Oncol 26:527–34; 2008). Adding DTIC to ipilimumab did not suppress the effect of ipilimumab (as might have been predicted), but enhanced it still further. Consistent with previously reported response data showing that 10 mg/kg is the recommended dose (study CA184022) (Hamid O et al. J Clin Oncol 26: 2008 (May 20 suppl; abstr 9025)), there was a trend toward better survival with the higher dose (eg, a 2-year survival rate of 36% vs. 22% for 10 mg/kg vs. 3 mg/kg). [Table: see text] [Table: see text]
Adjuvant vaccination with melanoma antigen pulsed dendritic cells (DCs) in stage III melanoma patients
Authors: Markowicz S. , Nowecki Z. I. , Rutkowski P. , Lipkowski A. W. , Jakubowska-Mucka A. , Switaj T. , Biernacka M. , Misicka A. , Walewski J. A. , Ruka W. 
Published: August 2020

9039 Background: This is a pilot study evaluating of high-risk melanoma patients (pts) treated with peptide-DC vaccine after lymphadenectomy (LND). DC vaccination was designed to induce the immune response against melanoma antigens in melanoma pts who remain at high risk of dissemination after LND. Methods: DCs were generated from the bone marrow with the use GM-CSF, SCF, FLT3-L and TNFa or from peripheral blood adherent monocytes with GM-CSF and IL-4. DCs pulsed with HLA-A2-binding TYR, MART-1 and gp100 peptides and/or HLA-A1-binding MAGE-1, MAGE-3 peptides, tumor lysate if available, or with tracer antigen keyhole limpet hemocyanin (KLH), were injected sc 9 times within 8 months (mos). Boost injections were performed after 12 and 24 mos. Vaccinated pts were matched to unvaccinated controls (22 of 587) by sex, number of metastatic lymph nodes, extracapsular involvement, completion or therapeutic LND, Breslow stage (T), and ulceration. Results: HLA-A2+, -A1+ or -A3+ melanoma pts (n=22), stage III, N1b-N3, enrolled between Sept. 2002 and Apr. 2004, received 5–16 vaccinations (median: 11) within 2 yrs. Cutaneous delayed type hypersensitivity (DTH) to melanoma peptides was induced in 12 of 22 pts. Peptide-specific IFNg producing CD8+ cells were detected in peripheral blood of 13 of 19 pts after vaccination. At least one of these responses to melanoma antigens was elicited in 17 of 22 pts. DTH to KLH was positive in 15 of 22 pts. Nine vaccinated pts are free of disease, and 1 is stable by Dec. 2008 (follow up is 58–76 mos after LND). Survival analysis for vaccinated pts and matched controls is presented in the Table . Conclusions: The DC/peptide vaccine elicited immune responses to melanoma antigens. Vaccinated pts had clinically substantially longer overall survival (OS) and disease free survival (DFS) than matched control. OS was associated with the immune responsiveness to melanoma antigens and to KLH. [Table: see text] No significant financial relationships to disclose.
Prognostic factors in metastatic melanoma patients treated with biochemotherapy and maintenance immunotherapy
Authors: Minor D. R. , Kashani-Sabet M. , Moore D. , Kim C. , Venna S. S. , Wang W. , Boasberg P. D. , O'Day S. 
Published: August 2020

9051 Background: Patients with stage IV metastatic melanoma are usually felt to be incurable with a median survival of 6.4 months and a 5-year survival of only 2%. Biochemotherapy has shown promise with long-term survival in selected patients. We felt the study of prognostic factors would determine which patients might benefit the most from this intensive therapy. Methods: 135 consecutive patients with stage IV melanoma treated with decrescendo biochemotherapy followed by maintenance immunotherapy at one melanoma treatment center were studied to determine the most important prognostic factors; these factors were then validated by analysis of 133 patients treated in a multi-center trial at other institutions. Patients were treated using the inpatient regimen of O'Day (JCO23:710s,2005 abstract). Results: Median overall survival (OS) was 16.6 months with 1-year survival of 70% and 5-year survival of 28%. Median progression-free survival (PFS) was 7.6 months with 15% progression-free at 5 years. PFS curves showed no relapses after 30 months, so remissions were durable. For OS performance status 0, normal LDH, stage M1a, and non-visceral sites of metastases were favorable prognostic factors. For PFS performance status 0, normal LDH, female sex, age <50 and stage M1a were favorable prognostic factors Multivariate analysis demonstrated two important prognostic factors for survival: normal serum LDH and the presence of either skin or nodes as one of the sites of metastatic disease. The group with normal LDH and skin or node metastases had a relatively good prognosis with median survival of 44 months and a 5-year survival of 38%. Conversely patients with elevated LDH without any skin or nodal metastases had a poor prognosis, with no long-term survivors. Conclusions: Metastatic melanoma patients treated with biochemotherapy and maintenance immunotherapy that have either a normal LDH or skin or nodes as one of their metastatic sites may have durable remissions of their disease, and this therapy should be studied further in these groups. [Table: see text]
Long-term survival of patients with metastatic melanoma (MM) treated with dacarbazine (DTIC) or temozolomide (TMZ)
Authors: Kim C. , Lee C. W. , Klasa R. , Shah A. , Savage K. J. 
Published: August 2020

9054 Background: Patients with metastatic melanoma (MM) generally have a poor prognosis, with a median survival of 6 to 9 months. There is a small proportion of patients who achieve long term survival (LTS), however, it is unclear whether LTS reflects sensitivity to systemic therapy, indolent tumor biology or host immune factors. Dacarbazine (DTIC) is the only approved chemotherapy for the treatment of MM, although temozolomide (TMZ) has similar efficacy. There is limited information as to the frequency of complete response (CR) following DTIC or TMZ, duration of response and whether LTS occurs only in patients who achieve a CR. We sought to identify all patients with MM treated with either DTIC (alone or in combinations) or TMZ at the BC Cancer Agency (BCCA) who achieved LTS defined as survival ≥ 18 months from the time of administration of chemotherapy. Methods: All patients with MM treated with either DTIC or TMZ from January 1, 1988 to February 1, 2006 were identified in the BCCA pharmacy database. The BCCA surveillance and outcomes unit (SAO) was utilized to identify cases of LTS. CR was defined as disappearance of all disease by diagnostic imaging. Given the retrospective nature of the analysis, progressive disease (PD) was defined as any tumor growth, and partial response or stable disease (PR/SD) were combined. Results: In the 18-year period reviewed, 397 patients with MM were treated with DTIC (n= 349) or TMZ (n=48). Of these, 45 patients met the criterion of LTS and had the following characteristics: median age 53 (range 22–86); male 67 %; ocular primary 7%; non-pulmonary visceral metastases 38%; DTIC 11.7% (41/349), TMZ 8.3% (4/48). The best response to DTIC or TMZ documented was: CR 18%, PR/SD 67%, PD 13%. The 5-year overall and progression-free survival rates were 33% and 12%, respectively. Eleven patients survived > 5 years (range 5–27.5), and 6 patients remain in remission (5 CR, 1 PR). Disease progression occurred in 5 patients in < 1 year however, they remain alive for at least 5 years (range 5.2–17.9). Conclusions: LTS occurs in patients with MM treated with either DTIC or TMZ. However, a minority have a sustained response following chemotherapy, and most cases of LTS are likely the result of indolent disease or host biology. No significant financial relationships to disclose.
Chemoablation of melanoma with intralesional rose bengal (PV-10)
Authors: Agarwala S. S. , Thompson J. , Smithers M. , Ross M. , Coventry B. , Minor D. , Scoggins C. , Hersey P. , Wachter E. 
Published: August 2020

9060 Background: Intralesional rose bengal (PV-10, a sterile 10% solution in saline) can elicit selective ablation of solid tumors and an apparent bystander response in untreated lesions. In phase 1 testing in 20 subjects with AJCC Stage III (19 subjects) or IV (1 subject) melanoma, a single injection of PV-10 into 1–20 lesions led to durable objective response (OR) at 12–24 weeks in 40% of subjects (20% CR + 20% PR by modified RECIST) and locoregional disease control (CR + PR + SD) in 75% of subjects. Untreated bystander lesions achieved an OR in 15% of subjects, and all subjects with an OR of their injected lesions achieved disease control of their bystander lesions. PV-10 was well tolerated, with only one Grade 3 adverse event (photosensitivity reaction). The most common AEs were transient pain at the treatment site (75% of subjects), followed by local inflammation or infection (25%). Methods: Expanded phase 2 testing commenced in late 2007 in up to 80 subjects with measurable Stage III or IV melanoma. After an initial treatment of 1–20 cutaneous, subcutaneous or nodal lesions, new or incompletely responsive lesions can be retreated at weeks 8, 12 or 16, with follow-up to 52 weeks. An additional 1–2 lesions, including visceral lesions, remain untreated for assessment of bystander response. Seven centers in Australia and the USA are enrolling subjects, with completion of enrolment expected by mid-2009. A modified Fleming design allows interim assessment of safety and OR at weeks 4 and 24, respectively, after treatment of the 20th and 40th subjects. The primary end-point is OR of injected lesions in the intent-to-treat population; secondary endpoints include OR of bystander lesions and PFS. Results: Interim safety data for the first 40 subjects treated is comparable to phase 1, with transient mild to moderate locoregional pain, vesicles or edema most common; Grade 3 AEs have been rare (1 case each of vesicles and skin flap necrosis), with no Grade 4 or 5 AEs attributed to PV-10. Interim efficacy for the first 20 subjects is also comparable to that of phase 1 (15% CR + 15% PR); efficacy data for the first 40 subjects will be presented at the meeting. Conclusions: The safety and efficacy profile of intralesional therapy with PV-10 compares favorably with available therapeutic options for this patient population. No significant financial relationships to disclose.
Selective internal radiation therapy (SIRT) as salvage therapy for uveal melanoma (UM) hepatic metastases
Authors: Gonsalves C. F. , Eschelman D. J. , Sullivan K. L. , Anne P. R. , Doyle L. , Sato T. 
Published: August 2020

9066 Background: The liver is the first site of metastasis in >80% of patients with UM. Transarterial chemoembolization (TACE) has been used to control hepatic metastases, however, patients eventually progress through or experience complications related to TACE. We report our results using SIRT as salvage therapy for patients with UM liver metastases who are no longer candidates for TACE. Methods: Patients with UM liver metastases previously treated with TACE were treated with SIRT. Patients were followed 1-month post-SIRT for acute toxicity then every 3 months for tumor response evaluation and for complications of delayed toxicity. Common Toxicity Criteria 3.0 (CTC) was used for toxicity assessment. Best radiographic tumor response was determined by MRI using RECIST criteria. Results: Five men and 7 women, ages 48–81 (median 65) with UM liver metastases were treated with SIRT after tumor progression post-TACE (n=9), complications of TACE (n=1) or patient preference (n=2). Pretreatment whole liver tumor burdens were as follows: <25% (n=10), 25–50% (n=1) and >50% (n=1). Patients had both hepatic lobes treated on separate occasions (n=7), one lobe (n=3) or whole liver (n=2) therapy. Treatment dose per patient was reduced by 25% due to prior TACE procedures. The mean total SIRT dose delivered was 1.0 GBq (0.62–1.47 GBq). Five patients had an increase in hepatic enzymes (Grade 1–4) at 1-month follow-up. No procedure related deaths or serious adverse events were experienced. Best tumor response was as follows: CR (n=0), PR (n=0), SD (n=8), PD (n=4), with a median follow-up of 7.8 months (1.0–16.0). The median time to liver progression was 7.0 months (1.0- 15.5). Nine of the 12 patients, including 2 patients with >25% pretreatment tumor burden, died due to progression of liver disease (n=6), extrahepatic disease (n=1) or both (n=2). Post-SIRT, median overall patient survival was 10.8 months (1.0–19.0). Three patients (ECOG 0 performance status) are still alive at 13.5–19.0 months (median 16.2 months) following SIRT. Conclusions: SIRT was safely used and showed a potential clinical benefit for patients previously treated with TACE. Further investigation is warranted to determine if SIRT should be employed as a first line therapy for patients with UM liver metastases. No significant financial relationships to disclose.
Characteristics of first relapse in stage III melanoma patients with no evidence of disease (NED): Guidelines for follow-up
Authors: Romano E. , Scordo M. , Chapman P. 
Published: August 2020

9069 Background: Follow up (F/U) of patients (pts) with AJCC stage III melanoma but with NED is currently empiric with respect to frequency of clinical exams, F/U duration, and diagnostic tests. Data-based F/U guidelines are needed. Methods: Clinical records of 429 pts with stage III NED pts seen at MSKCC between 1998 and 2002 and who ultimately relapsed were reviewed retrospectively to evaluate: site and date of 1st relapse, interval between the stage III NED and 1st relapse; how the 1st relapse was detected, date of death or last F/U. We also determined the overall 5 yr relapse-free survival (RFS) of all stage III pts seen at MSKCC during this period. Results: The overall 5 yr RFS for stage IIIA, B, and C patients at MSKCC was: 52%, 29%, and 15%, respectively. Among the relapsing pts, 280 had adequate F/U to be evaluable for all parameters (35 stage IIIA, 155 stage IIIB, 90 stage IIIC). The site of 1st relapse was local/in-transit (28%), regional nodal (20%), or systemic sites (52%). The most common sites of 1st systemic relapse were lung, liver, brain. There were significant differences among substages. First relapses were detected by the pt or family, MD, or by screening radiological tests in 52%, 19%, and 29% of cases, respectively. Multivariate analysis revealed better overall survival (OS) was not associated with time to relapse but was associated with younger age and if 1st relapse was: a) local/in-transit or nodal, b) asymptomatic, or c) resectable. By noting when the risk for 1st local/intransit, nodal, or systemic (lung, liver, brain) relapse became sufficiently low (<5%) for each substage, we generated tentative F/U guidelines ( Table ). Conclusions: Our data suggest that F/U strategies for stage III should be adapted by substage and indicate time ranges beyond which more prolonged F/U would be unlikely to benefit pts. Whether frequent F/U within these time ranges can increase the chances of complete surgical resection or improve OS is not known. [Table: see text] No significant financial relationships to disclose.