bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial of carboplatin (C) and nab-paclitaxel (ABI-007-nab-P) in patients with unresectable stage IV melanoma: Final data from N057E
Authors: Markovic S. N. , Suman V. J. , Kottschade L. A. , Amatruda T. , McWilliams R. R. , Dakhil S. R. , Nikcevich D. A. , Morton R. F. , Fitch T. R. , Jaslowski A. J. 
Published: August 2020

9055 Background: There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). Nab-P is an albumin-bound paclitaxel with ability to bind SPARC (secreted protein acid rich in cysteine), that is overexpressed in MM and associated with poor prognosis. This study explores the clinical activity of the combination of nab-P and C in patients (pts) with stage IV melanoma and SPARC correlatives. Methods: A parallel phase II trial was conducted in pts with unresectable stage IV melanoma, who were either chemotherapy naïve (CN) or were previously treated (PT). A treatment regimen consisting of nab-P (100 mg/m2) and C (AUC 2) was administered on days 1, 8, and 15 of a 28 day cycle. The primary aim of this study was to assess whether tumor response rate (CR + PR by RECIST) was ≤15% vs ≥35% in the CN group and ≤5% vs ≥ 20% in the PT cohort. Major eligibility criteria: ≥18 years of age, ECOG PS ≤2, adequate organ function, platinum or taxane naive, peripheral neuropathy < grade 2, and no untreated brain metastasis; no pregnant and/or nursing women. Tumor tissue was tested for SPARC and level 3 immunohistochemical staining was considered positive. Results: 76 pts (41-CN and 35 PT) enrolled from 11/2006 - 7/2007, 3 pts (2-CN, 1-PT) cancelled prior to starting treatment. The median number of cycles administered was 4 (range 1–18-CN and 1–10-PT). There were 11 (28.2%) confirmed responses (1 CR and 10 PRs) in the CN cohort (90% CI: 16.7–42.3%) and 3 (8.8%) confirmed responses (3 PRs) in the PT cohort (90% CI: 2.5–21.3%). Median PFS was 4.5 months (CN) and 4.1 months (PT). Median OS was 11.1 months (CN) and 10.9 months (PT).The most common severe toxicities in both groups (CTCAE ≥ grade 3) included neutropenia, thrombocytopenia, neuro-sensory, fatigue, nausea, and vomiting. PFS was not affected by SPARC positivity; however, based on limited data there is some evidence that OS may be longer with tumoral SPARC positivity (10.0 vs 12.8 mo; SPARC negative vs SPARC positive). Conclusions: The weekly combination of nab-P and C appears to be well tolerated with promising clinical activity as front line or salvage therapy in pts with MM. SPARC positivity may be associated with improved OS. No significant financial relationships to disclose.
A phase II trial of imatinib mesylate in Merkel cell carcinoma (neuroendocrine carcinoma of the skin): A Southwest Oncology Group Study (S0331)
Authors: Samlowski W. E. , Moon J. , Tuthill R. J. , Heinrich M. C. , Balzer-Haas N. S. , Merl S. A. , DeConti R. C. , Thompson J. A. , Flaherty L. E. , Sondak V. K. 
Published: August 2020

9056 Background: Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) frequently stains strongly for c-KIT (CD-117) expression. We therefore evaluated imatinib mesylate as a treatment for MCC. Methods: Eligibility included patients with measurable metastatic or unresectable MCC with CD117 expression by immunostaining. A Zubrod performance status of 0–2, adequate hematologic, renal, and hepatic function was also required. Imatinib 400 mg daily was administered orally in 28-day cycles. Results: A total of 25 patients were accrued to this trial from 13 institutions, with 6 accrued through Intergroup participation by the Eastern Cooperative Oncology Group. Two patients were ineligible (one was found not to express CD117 on central pathology review, and one lacked measurable disease). These 23 patients were included in the analysis. Imatinib was well tolerated with Grade 1 or 2 nausea, diarrhea, and hematologic toxicity as the most frequent side effects. There were no complete responses (0%) and 1 confirmed partial response (4%) in the 23 evaluable patients (4% objective response rate, CI 0 -22%). In addition, stable disease was observed in 3 patients (9, 4 and 3 months). Median progression-free survival was 1 month (95% CI: 1–2 months). Estimated 6 month PFS was 4%. Median overall survival was 5 months (95% CI 2–8 months). The estimated one-year overall survival was 17% (95% CI: 0% - 33%). There were three on-study deaths. All were attributed to tumor progression. One patient achieved a partial response and another had prolonged disease stabilization while receiving treatment. DNA sequencing of c-KIT was performed on tumor tissue from on a non- responding patient and the one patient with long-term stable disease (9 months). Neither demonstrated an activating mutation in c-KIT. Unfortunately, the patient with partial response withdrew consent for the study and DNA sequencing could not be performed. Conclusions: The majority of patients progressed rapidly within 1–2 cycles of treatment. The observed progression-free survival and overall survival were not adequate to conclude that this agent was active in advanced MCC. The planned second stage of patient accrual was not opened. No significant financial relationships to disclose.
In vivo molecular changes in patients (pts) with metastatic melanoma treated with EMD121974 (selective antagonist of avβ3 integrin)
Authors: Joseph R. W. , Prieto V. G. , Papadopolus N. , Papadopolus N. , Bedikian A. , Colevas A. D. , Kim K. 
Published: August 2020

9058 Background: αvβ3 integrin promotes the proliferation of tumor-associated endothelial ells and potentiates the survival of melanoma cells through activation of downstream kinases. Here we report the molecular changes of downstream kinases in tumors of pts with metastatic melanoma treated with cilengitide, a selective antagonist of αvβ3, in a phase II study. Methods: In this study, 26 pts were treated, and all tissues were embedded in OCT and immediately frozen in liquid nitrogen at -80° C until further analysis. Immunohistochemical staining was performed for the expression of αvβ3, pFAK, pERK1/2 and pAKT. Results: There were 1 pt with a partial response (PR) and 3 pts with stable disease (SD) in the study. All 26 pts had pre-treatment biopsies, and 18 underwent second biopsy on day 8. Adequate paired tumor samples were available in 16 pts for αvβ3, 11 pts for pAKT, and 9 pts for pERK1/2 and pFAK. Six (23%) of 26 pts had intratumoral expression of αvβ3 (defined as ≥25% of tumor cells stained positive) pre-treatment. The sole responder and 2 of 3 pts with SD did not express avβ3 at baseline. Cilengitide decreased the expression of αvβ3 (p = 0.04), but not the expression of the downstream kinases. The decreased expression of αvβ3 with treatment was correlated with the decrease in pERK1/2 expression (p = 0.03) but not with pAKT or pFAK. Conclusions: Although cilengitide decreased melanoma expression of αvβ3, its clinical efficacy was minimal in this study. These data suggest that the benefit of cilengitide in pts with disease control (PR+SD) was secondary to anti-angiogenic activity rather than direct anti-tumoral effect. Supported in part by NCI grant N01 CM-17003 and CA16672. [Table: see text] No significant financial relationships to disclose.
Phase I/II study of the association of sorafenib and temozolomide (extended schedule) in patients with metastatic melanoma: A new clinical response profile with massive tumor necroses
Authors: Robert C. , Lazar V. , Lacroix L. , Farace F. , Lassau N. , Dromain C. , Poirier V. , Zitvogel L. , Soria J. , Mateus C. 
Published: August 2020

9062 Background: Recent progress in melanoma research identified a wide variety of different melanomas in term of biology, clinical behavior and chemosensitivity profiles. This phase I/II study of association of sorafenib (SOR) and temozolomide (TMZ) evaluates the safety and efficacy of this association in patients with metastatic melanoma and tries to correlate clinical responses to early biological and imaging parameters. We report the ph I results and preliminary results of the ph II (still recruiting pts). Methods: Safety was the primary objective of the phase I and three escalating dose levels were tested. Primary objective of the phase II is PFS at 12 weeks and 32 patients were recruited at the recommended (45 planned). Secondary objectives evaluate tumour vascularization by dynamic contrast enhanced ultrasonography (DCE-US), PK profile of TMZ, number and function of circulating lymphocytes, melanoma RNA expression profiles and mutational status (BRAF, NRAS, c-KIT, PTEN, PI3K, βcat), circulating endothelial and progenitor cells. Results: 13 evaluable pts were included in the phase I. The recommended doses are SOR: 400 mg bid and TMZ: 150 mg/m2 /d every other week. Toxicity was manageable. SOR did not influence TMZ PK. RECIST evaluation showed 1 CR (+ 12 months), 1 PR (+ 13 months), 3 SD, 8 PD. Among the 23 evaluable pts included in the phase II, 1 PR, 11 SD and 11 PD were observed. Five pts presented rapid and massive metastases necrosis with obvious tumour cavitation on CT which is very unusual during the course of melanoma treatment. Devascularization seen on DCE-US after 1 month was predictive of tumour response. Integrated correlative biological parameters are being analyzed and will be presented. Conclusions: SOR+TMZ association is well tolerated and gives promising results in some patients with metastatic melanoma. Unexpected major tumour necrosis has been observed in 5 patients. Early tumour devascularization observed by DCE-US seems predictive for tumour response. Extensive biological studies are being performed and might give useful clues allowing the identification of melanoma subtypes that are sensitive to this treatment regimen. No significant financial relationships to disclose.
A phase I study of systemic sorafenib in combination with isolated limb infusion with melphalan (ILI-M) in patients (pts) with locally advanced in-transit melanoma
Authors: McMahon N. , Beasley G. M. , Sanders G. , Augustine C. , Padussis J. , Coleman A. , Selim M. A. , Peterson B. , Brady M. S. , Tyler D. S. 
Published: August 2020

9065 Background: Sorafenib is a multi-kinase inhibitor that may also enhance the cytotoxicity of concurrently administered chemotherapy. In a preclinical model of regionally advanced melanoma, the combination of systemic Sorafenib and regional melphalan led to augmented tumor responses. Methods: A Phase I multicenter study was performed to evaluate the safety and pharmacokinetics (PK) of systemic Sorafenib in combination with ILI-M in patients with measurable in-transit melanoma of the extremity. Sorafenib dose escalation cohorts consisted of 200mg, 300mg, and 400mg administered systemically twice daily for one week prior and one week after a standard dose ILI-M corrected for ideal body weight. Tumor biopsies pre-therapy and pre-ILI were obtained to assess molecular changes associated with Sorafenib pretreatment. Response was defined at 3 months using RECIST. Results: Nine pts with high disease burden, including 7 previous ILI-M alone failures, have been treated; 3 in the first cohort and 6 in the second cohort. There were no grade 5 toxicities. Four patients had CTCAE Grade 4 toxicities including neutropenia (2), CPK elevation (1), and skin ulceration (1). In the remaining 5 patients, there were no >grade 3 toxicities. The maximally tolerated dose (MTD) has not yet been defined. Initial in field response determination in 6 of the 9 patients out at least 3 months includes 2 partial responses and 4 disease progressions. Conclusions: Systemic Sorafenib administered pre and post ILI-M is a well tolerated, novel targeted therapy approach to regionally advanced melanoma. An additional 10 patients will be enrolled to define the MTD. Correlation of response with drug PK, Sorafenib downregulation of pErk and Mcl1, and a melphalan resistance signature is in progress. No significant financial relationships to disclose.
Utility of routine PET/CT and MRI staging in patients with sentinel lymph node positive melanoma
Authors: Meyers M. O. , Yeh J. J. , Amos K. D. , Long P. , Frank J. , Ollila D. W. 
Published: August 2020

9071 Background: The utility of routine radiographic staging in sentinel lymph node (SLN) positive stage III melanoma is unclear. Although body computed tomography (CT) has proven unlikely to identify occult metastasis at the time of diagnosis, there is some suggestion that whole body positron emission tomography combined with computed tomography (PET/CT) may be more sensitive in the detection of clinically unsuspected metastatic melanoma. We evaluated the ability of routine PET/CT and brain MRI to detect occult metastatic disease at the time of diagnosis in patients with SLN positive stage III melanoma. Methods: All clinically node- negative patients with cutaneous melanoma and a positive SLN who completed staging with PET/CT from 2003 through 2008 were identified from a prospective, IRB-approved, single-institution database. Data were analyzed to determine the positive (PPV) and negative (NPV) predictive values of PET/CT in detecting occult metastatic disease. Results: 72 patients had a positive SLN and were staged with PET/CT and 61 with brain MRI. There were 41 men and 31 women. Median age was 55 years. Median Breslow depth was 2.50 mm. 5 patients were T1, 25 T2, 22 T3, and 20 T4. 46 % were ulcerated. MRI was negative in all 61 patients. PET/CT was interpreted as suspicious for metastasis in 8 patients (11%) and negative in 64 (92%). 6 (8%) of the suspicious PET/CT scans were subsequently proven to be negative for malignancy and 1 (1.4%) proven to be an incidental thyroid cancer. Only 1 patient (1.4%) was found to have metastatic melanoma, an in transit metastasis that was previously unrecognized. PPV was 13% and NPV 100% for PET/CT. No patients were found to have occult distant metastases by either brain MRI or PET/CT. Conclusions: Patients with SLN positive stage III melanoma are unlikely to have occult metastatic disease detected by PET/CT or brain MRI and should not have further therapy delayed to obtain imaging. These findings are consistent with prior reports of body CT alone and question the utility of routine staging with current imaging modalities in patients with SLN positive melanoma. Future research should be directed toward improved imaging techniques in order to detect early micrometastatic melanoma. No significant financial relationships to disclose.
Second primary melanoma: Risk factors, histopathologic features, and survival
Authors: Schoellhammer H. F. , Torisu-Itakura H. , Huynh Y. , Sim M. , Faries M. B. , Morton D. L. 
Published: August 2020

9073 Background: Melanoma incidence in the United States is expected to be 4.3% of all cancers in 2008. Cutaneous melanoma patients are at risk for second primary melanoma development. Our goal was to characterize the histopathologic features, risk factors, and patient survival for second primary melanoma. Methods: A review of the melanoma database established in 1971 at John Wayne Cancer Institute was conducted identifying patients with American Joint Committee on Cancer (AJCC) stage I and II cutaneous melanoma who later developed a second primary melanoma. Patients were grouped by Breslow thickness, Clark level, and histopathologic subtype (superficial spreading [SSM], nodular, acral lentiginous, lentigo maligna, and in situ). Multivariate analysis involving age, gender, Breslow thickness, Clark level, and ulceration status was performed to determine an effect on development of second primary. Kaplan-Meier survival curves were plotted for single primary and second primary melanoma patients. Results: Second primary melanoma was identified in 411 (3.7%) of 10,968 patients with AJCC stage I-II melanoma. The most common first primary subtype was SSM, and 93% of these patients had in situ or SSM as the second primary. Sixty-five percent of first primaries had a Breslow thickness of ≤1 mm, and 75% of second primaries had a thickness ≤1 mm. Forty-nine percent of first primaries had Clark level I or II, but 68% of second primaries had Clark level I or II. In multivariate analysis, only increasing age was significantly associated with the likelihood of second primary melanoma (p<0.0001). With increasing follow-up time the hazard ratio of second primary melanoma was 1.31 for every decade. Overall survival for second primary melanoma patients was better than for single primary patients (p<0.0001). Conclusions: Most second primary melanoma patients will have SSM or in situ, with a decreased Clark level and Breslow thickness. Contrary to expectations, patients developing second primary melanoma did not exhibit decreased overall survival. Increased follow-up time after first primary melanoma is a significant risk factor for second primary development, thus illustrating the importance of lifelong patient follow-up. No significant financial relationships to disclose.
Effect of the farnesyl transferase inhibitor lonafarnib on sensitivity of melanoma cells to the multikinase inhibitor sorafenib and on Rheb farnesylation and mTOR signaling
Authors: Meier F. E. , Niessner H. , Flaherty K. , Schadendorf D. , Sinnberg T. , Schittek B. , Garbe C. 
Published: August 2020

9077 Background: Farnesyl transferase inhibitors (FTIs) inhibit the post-translational farnesylation of a number of target proteins, including Ras and Rheb, preventing their signaling function. Ras signals to the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways which are constitutively activated in melanoma and appear to play a major role in tumor progression and drug resistance. Rheb positively regulates mTOR signaling. Methods: Using a panel of melanoma cell lines we evaluated the effects of the FTI lonafarnib alone and in combination with chemotherapeutic agents (temozolomide, cisplatin) or pharmacological MAPK pathway inhibitors (sorafenib, U0126, PD98059) or AKT pathway inhibitors (LY294002, wortmannin, rapamycin) on proliferation, survival and invasive tumor growth of melanoma cells in monolayer and organotypic culture. Results: Lonafarnib did not significantly inhibit growth of metastatic melanoma cells. Also, lonafarnib did not sensitize melanoma cells to the chemotherapeutic agents tested. Most combinations of the FTI lonafarnib with MAPK or AKT pathway inhibitors lacked significant enhancement of growth inhibition compared to monotherapy. In contrast, lonafarnib significantly augmented the growth inhibitory effects of the multikinase inhibitor sorafenib in eight metastatic melanoma cell lines tested. These effects did not appear to depend on BRAF or NRAS mutation status. Moreover, lonafarnib combined with sorafenib induced marked apoptosis and abrogated invasive melanoma growth. Interestingly, the FTI lonafarnib did not inhibit phosphorylation of ERK or AKT but of p70S6K, a downstream target of Rheb and mTOR signaling. Conclusions: These data suggest that lonafarnib sensitizes melanoma cells to sorafenib by inhibiting mTOR signaling via inhibition of Rheb farnesylation. No significant financial relationships to disclose.
Survival of advanced melanoma patients with normal LDH treated with oblimersen, temozolomide, and nab-paclitaxel
Authors: Pavlick A. C. , Ott P. , Escalon J. , Madden K. , Yepes E. , Staha J. , Mendoza S. , Gandhi A. , Yee H. , Liebes L. 
Published: August 2020

9080 Background: Oblimersen (OBL), temozolomide (TMZ), and abraxane (ABX) act synergistically in preclinical studies with melanoma cell lines. Bcl-2 antisense therapy in combination with dacarbazine was encouraging in advanced melanoma patients(pts) with normal LDH. Methods: Chemotherapy-naïve advanced melanoma pts (ECOG PS ≤ 2, baseline LDH ≤1.1 × ULN, measurable disease per RECIST) were enrolled on a phase I/II protocol. The treatment regimen consisted of 56-day cycles of OBL (7 mg/kg/d continuous IV infusion, d 1–7 and 22–28), TMZ (75 mg/m2/d, d 1–42), and ABX (175 mg/m2 in Cohort 1, 260 mg/m2 in Cohort 2, d 7 and 28). Immunohistochemical (IHC) staining for Bcl-2, Bcl-XL, BAK and caspase 3 was performed in pre- and post-therapy tumor samples. Serum shed collagen cryptic epitope levels were monitored. Results: 18 pts were treated (Cohort 1 = 14 pts [1–6 cycles];Cohort 2 = 4 pts [2–3 cycles]). Median age was 58 years (range: 34–78). Disease sites included liver (6), other visceral sites (10), skin, subcutaneous tissue, and lymph nodes (2). The overall survival (OS) was 14.7 months and showed a trend towards superiority when compared to both arms of the prior oblimersen trial (DTIC, OS 9.7 months, p = 0.078 and DTIC-OBL, OS 11.4 months, p = 0.31) in pts with the same LDH cut-off (Bedikian et al. JCO. 2006). 50% of pts survived > 1 year. One CR lasted 25+ mo, five PR (>50% tumor reduction) lasted > 2 cycles, and 7 SD lasted > 3 cycles. Five PD after 1 cycle were seen. One ocular melanoma pt survived 15 mo despite PD. Shed cryptic epitopes correlated with clinical response versus disease progression. Alteration of the tumor biology based on phenotypic changes in Bcl-2, Bcl-xL, BAK and caspase 3 correlated with response to treatment. Conclusions: Our data suggest that the combination of OBL, TMZ, and ABX is synergistic in advanced melanoma pts with normal LDH, possibly translating into improved OS compared to prior regimens with dacarbazine ± OBL. Biomarker studies support the rationale that Bcl-2 antisense therapy specifically impacts apoptotic signaling pathways in melanoma cells from metastatic tumor. The survival data in the limited number of pts enrolled in cohort 1 and 2 of this trial are encouraging; further exploration with this combination is underway using 1-hour infusions of OBL. No significant financial relationships to disclose.
Effects of riluzole (RZ) and ionizing radiation (IR) in metabotropic glutamate receptor-1 (GRM1) positive human melanoma
Authors: Green C. , Schiff D. , Khan A. , Goyal S. , Goydos J. , Chen S. , Haffty B. 
Published: August 2020

9083 Background: Melanoma has long been known to be relatively radio-resistant. GRM1 is a metabotropic glutamate receptor that has been detected in human melanoma cell lines and biopsies. Riluzole (RZ), a glutamate release inhibitor, has been shown to arrest GRM1 positive human melanoma cells in G2/M and sub-G1 phases of the cell cycle. The purpose of this study was to determine if RZ enhances the lethal effects of IR in human melanoma. Methods: ATP luminescence assays were performed. Clonogenic assays were performed and cell survival curves generated. Cell cycle analysis was performed utilizing flow cytometry. Western blot analysis was performed utilizing cleaved PARP and caspase-3 antibodies as markers of apoptosis. Results: Luminescence assays revealed 25uM Riluzole to be the necessary concentration for clonogenic assays. At 2Gy, there was a 48% reduction (p≤0.05) in cell survival in RZ-treated cells. At 4 Gy, there was a 19% reduction (p≤0.05) in cell survival in RZ-treated cells. No differences were seen at 6 and 8 Gy. Cell cycle analysis showed that the combination of IR and RZ was superior to IR alone in increasing the number of cells in sub-G1, which represents apoptotic death. Western blot analysis showed that the combination of IR and RZ showed yielded increased cleaved PARP and caspase-3 activity when compared to IR alone. Conclusions: Riluzole is a FDA approved drug that has long been used in ALS. It is relatively non-toxic and crosses the blood brain barrier. Our data shows that Riluzole in combination with radiation eliminates the radio-resistant shoulder of the C8161 survival curve. RZ and IR, as combination therapy are more lethal than IR or RZ alone in human melanoma, as demonstrated by flow cytometry and WB analysis. This data has promising implications for melanoma patients with brain metastases. No significant financial relationships to disclose.