bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of lenalidomide oral monotherapy in patients with relapsed or refractory mantle-cell lymphoma: Results from an international study (NHL-003)
Authors: Reeder C. B. , Witzig T. E. , Zinzani P. L. , Vose J. M. , Buckstein R. , Haioun C. , Bouabdallah R. , Polikoff J. , Pietronigro D. , Czuczman M. S.
Published: August 2020

8569

Introduction: Relapsed or refractory MCL patients demonstrated a promising overall response rate (ORR) of 53% with a median duration of response (DR) of 13.7 months to single-agent lenalidomide when analyzed as a subset in a recent a phase II study (NHL-002). A supporting international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed or refractory aggressive NHL. In this report, we analyze the current results from the MCL patients enrolled in this trial. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least 1 prior treatment regimen were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Patients continued therapy until disease progression or toxicity. The 1999 IWLRC methodology was used to assess response and progression. Results: Fifty-four MCL patients were enrolled and were evaluable for response assessment. Median age was 69 years (33–82) and 40 patients (74%) were male. Median time from diagnosis was 3.2 years (0.4–10.4), patients had received a median of 3 prior treatments (1–8), 17 of the patients (32%) had received prior bortezomib therapy (MCL-bortezomib), and 14 (26%) had received a prior stem cell transplant (MCL-stem cell). Response rates are shown in the Table. The most common grade 3 or 4 adverse events were neutropenia (43%), thrombocytopenia (22%) and anemia (11%). Conclusions: This is the second study to demonstrate that lenalidomide oral monotherapy is effective in the treatment of patients with relapsed or refractory MCL, with manageable side effects.

[Table: see text]

[Table: see text]
The prognostic significance of the number of extranodal sites in the patients with disseminated diffuse large B-cell lymphoma treated with R-CHOP
Authors: Yoo C. , Sohn B. , Kim J. , Yoon D. , Huh J. , Kim S. , Lee D. , Kim S. , Lee J. , Suh C.
Published: August 2020

8570

Background: The combination of rituximab and CHOP chemotherapy (R-CHOP) has improved survival of patients with diffuse large B-cell lymphoma (DLBCL). Recently, several reports have shown that standard International Prognostic Index (IPI) became less powerful prognostic predictor in patients with DLBCL in the era of R-CHOP. We evaluated the prognostic factors of DLBCL patients treated with R-CHOP. Detailed analysis was planned regarding the number of extranodal sites because of its higher frequency in Korea. Methods: Between January 2002 and May 2008, 126 patients with stage III/IV DLBCL treated with R-CHOP were identified. We performed the retrospective analysis of the clinicopathologic factors and verified the predictive power of standard IPI and revised IPI (R-IPI) which was reported by the study group of British Columbia. Various numbers of extranodal sites were analyzed for further stratification and we set E-IPI as the IPI when the number of extranodal sites is stratified in ≤2 vs >2. Results: In the univariate analysis, the number of extranodal sites (≤2 vs >2) was a significant prognostic factor for complete response (CR) (p=0.04), event-free survival (EFS) (p=0.01) and overall survival (OS) (p<0.001). Age was also significant for EFS (p=0.03). When the number of extranodal site was stratified differently (0 vs >0, or ≤1 vs >1), these were not associated with CR, EFS and OS. On the multivariate analysis, the number of extranodal sites (≤2 vs >2) remained significant for EFS (p<0.01, HR 2.6) and OS (p<0.01, HR 3.5). The standard IPI identified 3 risk groups with 2-year EFS; 68%, 55%, 56% (p=0.17) and 2-year OS; 85%, 68%, 58%, respectively (p=0.04). The R-IPI classified 2 risk groups with 2-year EFS; 65%, 50% (p=0.02) and 2-year OS 76%, 62%, respectively (p=0.04). The E-IPI represented 3 risk groups with 2-year EFS; 79%, 56%, 42% (p=0.01) and 2-year OS; 86%, 70%, 39%, respectively (p=0.001). The patient group with survival of less than 50% was only recognized by E-IPI. Conclusions: The number of extranodal sites (≤2 vs >2) is the most significant prognostic factor of EFS and OS. Although all three indices remain predictive, E-IPI is the best model to identify the prognostic group in this cohort with stage III/IV DLBCL treated with R-CHOP.

No significant financial relationships to disclose.
A phase I/II trial of the kinesin spindle protein (KSP) inhibitor SB-743921 dosed q14d without and with prophylactic G-CSF in non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL)
Authors: Gerecitano J. F. , O'Connor O. , Van Deventer H. , Hainsworth J. , Leonard J. , Afanasayev B. , Chen M. , Seroogy J. , Escandon R. , Wolff A. , Conlan M.
Published: August 2020

8578

Background: KSP is a mitotic kinesin essential for cell cycle progression. SB-743921 (SB-921), a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and cell death. In the first-in-humans (FIH) trial, the MTD was 4 mg/m2 q21d. Since neutropenia was the major DLT, with recovery by ∼d15, a q14d schedule without (-GCSF) and with prophylactic G-CSF (+GCSF) is being explored. Methods: In phase I of this phase I/II trial, DLT and MTD of SB-921 given on d1 and d15 q28d (-GCSF) and (+GCSF) will be determined. Eligible patients (pts) have relapsed or refractory HL or NHL, aggressive (a) or indolent (i), have had at least 1 prior chemotherapy (CT) regimen, and have relapsed after or were not candidates for stem cell transplant. This is a standard 3+3 dose escalation trial design, starting at 2 mg/m2 and escalating by 1 mg/m2. Once DLT (-GCSF) is identified, (+GCSF) dosing starts at the (-GCSF) MTD, escalating until (+GCSF) DLT is identified. Results: 39 pts were treated (-GCSF) at 6 dose levels (2–7 mg/m2). 5 pts had DLT: 1/3 at 4 (grade 3 hepatic enzymes; found retrospectively); 2/10 at 6 (both sepsis with neutropenia), and 2/7 at 7 (both grade 4 neutropenia lasting >5d) mg/m2. MTD (-GCSF) was 6 mg/m2. 12 pts were treated with SB-921 (+GCSF) at 6 (n=4), 7 (n=3), 8 (n=3) and 9 (n=2) mg/m2, with 1 DLT of neutropenia at 9 mg/m2. Expansion of the 9 mg/m2 (+GCSF) cohort to n=6 is ongoing. For all 51 pts treated to date, mean age was 52 yr; 53% were male; 39% HL, 33% aNHL, and 28% iNHL; 76% had ≥3 prior CT regimens. The most frequent grade 3/4 toxicity was neutropenia: 58% at ≥MTD (-GCSF) and 42% (+GCSF). Other grade 3/4 events were uncommon. There was no neuropathy or alopecia >grade 1. There were 2 partial responses (PR), both in elderly pts with HL with ≥2 prior CT regimens, 1 at 6 (-GCSF) and 1 at 8 (+GCSF) mg/m2, ongoing at Cycle 4+. Conclusions: The MTD of SB-921 (-GCSF) on a q14d schedule was 6 mg/m2. This dose density (0.43 mg/m2/d) is >2-fold higher than in the FIH trial with a q21d schedule (0.19 mg/m2/d). Dose escalation (+GCSF) is continuing. SB-921 is well tolerated with minimal toxicity other than hematologic. Activity has been observed in HL, with 2 PRs at doses ≥6 mg/m2.

[Table: see text]
Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma: A phase I study
Authors: Siegel D. S. , Weber D. M. , Mitsiades C. S. , Dimopoulos M. A. , Harousseau J. L. , Rizvi S. , Howe J. , Reiser D. , Anderson K. C. , Richardson P. G.
Published: August 2020

8586

Background: Novel drug combinations may improve patient outcome in relapsed/refractory multiple myeloma (MM), which remains especially challenging to treat. Preclinical studies suggest that the histone deacetylase inhibitor vorinostat may have synergistic potential when combined with lenalidomide and dexamethasone. This phase I, multicenter, open-label study evaluated vorinostat plus lenalidomide and dexamethasone in patients (pts) with relapsed or refractory MM. The primary objective was to determine the maximum tolerated dose (MTD); other endpoints included overall safety and tolerability, as well as activity of the combination. Methods: Pts aged ≥18 years with relapsed or refractory MM were enrolled sequentially into 1 of 5 dosing levels ( Table ) using a standard 3+3 design for ≤8 cycles. Barring dose-limiting toxicities (DLTs) in the first cycle, dose escalation continued until the MTD was established. Response was assessed, and adverse events (AEs) were recorded. Results: Of 12 pts accrued to date, 11 (92%) have experienced ≥1 AE, with drug-related AEs reported by 6 pts (96% ≤Grade 2). The most common drug-related AEs (each in 4 pts) were fatigue and thrombocytopenia. Serious AEs in 2 pts (17%) were not considered drug-related. No pts discontinued due to AEs, and no DLT has been observed to date. Dose escalation to dose level (DL) 4 was achieved as no DLTs were observed in DLs 1–3. The MTD has not yet been reached. Of 11 pts evaluable for efficacy, best responses include: complete response in 1 pt, partial response in 2 pts, minimal response in 2 pts, and stable disease in 3 pts; 3 pts had progressive disease (PD). Currently, 9 pts remain on treatment, with 3 pts discontinuing treatment due to PD. Conclusions: These preliminary data suggest that vorinostat with lenalidomide and dexamethasone represents a well tolerated and active novel oral combination therapy for the treatment of relapsed/refractory MM.

[Table: see text]

[Table: see text]
Dose-escalation trial of milatuzumab (humanized anti-CD74 monoclonal antibody) in multiple myeloma
Authors: Kaufman J. L. , Niesvizky R. , Stadtmauer E. A. , Chanan-Khan A. , Siegel D. , Horne H. , Teoh N. , Wegener W. A. , Goldenberg D. M.
Published: August 2020

8593

Background: CD74 (HLA-DR-associated invariant chain) is highly expressed in multiple myeloma (MM), rapidly internalized, and a promising target for immunotherapy. Methods: A multicenter dose-escalation study was initiated in patients (pts) with relapsed/refractory MM who had failed at least 2 standard therapies. Pts received milatuzumab IV twice-weekly for 4 wks, with doses escalated by a 3+3 cohort design. Pts were evaluated over 12 wks, with responding pts continuing follow-up. AEs and safety laboratories were evaluated by NCI CTC v3 grades, with any treatment-related Grade 3–4 events considered dose-limiting toxicity (DLT). Responses were classified by EBMT criteria, with PK and immunogenicity evaluated by serum milatuzumab levels and human anti-milatuzumab antibody (HAHA) titers, respectively. Results: Twenty-one pts (12M/9F, median age 63) have now received 1.5 (n=8), 4.0 (n=9) or 8.0 mg/kg (n=4) doses twice weekly. They had MM for 0.9–16.8 years (median 5.4), predominantly IgG subtype, were heavily pretreated (4 median prior treatments), and were Durie-Salmon stage II (n=13) or III (n=8). After increasing premedications and slowing administration, infusions were well tolerated (Grade 1–2). There was 1 DLT (infusion reaction) and 3 SAEs (bact. meningitis, confusion/hypercalcemia, fever post demerol) at 1.5 mg/kg, 1 DLT (unexplained anemia) and 2 SAEs (cord compression, epistaxis/thrombocytopenia), at 4.0 mg/kg, but no DLTs or SAEs at 8.0 mg/kg. There has been no pattern of other AEs nor effects on routine laboratories, including serum chemistries, CBC, serum immunoglobulins, B- or T-cells, and no cases of HAHA. At current doses, milatuzumab is rapidly cleared from serum, with little accumulation and low trough levels across infusions. There have been no objective responses so far, but 4 pts have had stable disease by EBMT criteria for at least 3 months post-treatment, occurring with a possible trend towards higher milatuzumab serum levels than pts with earlier disease progression. Conclusions: Milatuzumab doses up to 8.0 mg/kg may be given safely twice-weekly for 4 weeks. In spite of rapid clearance, several patients have had disease stabilization at 4.0 and 8.0 mg/kg doses, which is encouraging. Accrual of the next cohort receiving 16.0 mg/kg is ongoing.

[Table: see text]
Role of autologous stem cell transplant after induction therapy with bortezomib-lenolidomide or bortezomib-thalidomide in newly diagnosed multiple myeloma patients
Authors: Shah N. , Weber D. , Orlowski R. , Wang M. , Thomas S. K. , Richards T. , Giralt S. , Qazilbash M. , Alexanian R. , Shah J. J.
Published: August 2020

8596

Background: The introduction of novel therapeutic options with bortezomib and immunomodulatory agents in the up-front management of multiple myeloma (MM) has significantly improved induction response rates. However, the role of high dose chemotherapy and autologous stem cell transplant (ASCT) after induction with these highly active agents is not known, especially in patients with only a partial response to induction therapy. Methods: We conducted a retrospective review of 95 newly diagnosed MM patients treated with induction bortezomib-lenolidomide-dexamethasone (BLD) or bortezomib-thalidomide-dexamethasone (BTD) prior to ASCT. Responses were graded according to IMWG criteria. Results: 19 patients received BLD and 76 patients received BTD. All patients were conditioned with a melphalan-based regimen. Of the 19 patients who underwent induction with BLD, complete response (CR), very good partial response (VGPR) and partial response (PR) were achieved in 2 (11%), 8 (42%) and 9 (47%) respectively for an overall response rate (ORR) of 19/19 (100%). After ASCT, CR, VGPR and PR were achieved in 9 (47%), 5 (26%) and 5 (26%) respectively for a continued ORR of 21/21 (100%). Notably, 4/8 (50%) of patients with a VGPR after induction therapy with BLD improved to a CR after ASCT. 3/9 (33%) of patients with an initial PR to BLD improved to a CR and 1/9 (11%) with a PR improved to VGPR after ASCT. Of the 76 patients who underwent induction with BTD, CR, VGPR and PR were achieved in 6 (8%), 37 (49%) and 31(41%) respectively for an ORR of 74/76 (97%). 1 patient had stable disease and 1 patient had progressive disease. After ASCT, 27/76 (36%) achieved a CR, 30/76 (39%) a VGPR and 18/76 (24%) a PR for an ORR of 75/76 (99%). Of the patients who initially had a VGPR to BTD 16/37 (43%) improved to a CR while 5/32(16%)of PR patients improved to a CR and 9/32 (28%) of PR patients improved to a VGPR. Conclusions: Of the 40 patients who only achieved a PR after induction therapy with BLD or BTD, 16 (40%) had further improvement to a CR or VGPR after ASCT. Thus there is a significant benefit of ASCT in these patients who initially demonstrate relative resistance to induction therapy with highly active regimens.

[Table: see text]
A phase I MMRC clinical trial testing the combination of bortezomib and tipifarnib in relapsed/refractory multiple myeloma
Authors: Lonial S. , Francis D. , Karanes C. , Trudel S. , Dollard A. , Harvey D. , Kaufman J.
Published: August 2020

8597

Background: Preclinical work from our group has demonstrated that the combination of a farnesyl transferase inhibitor and bortezomib results in enhanced plasma cell apoptosis, and more recently, we have suggested that the mechanism for this synergy is due to inhibition of HDAC6, and inhibition of the proteasome and aggresome pathway. Methods: Patients with relapsed or refractory myeloma were treated with bortezomib at 1.0 or 1.3 mg/m2 on a standard schedule in conjunction with escalating doses of tipifarnib (100–400mg/BID) given on days 2–15 every 21 days. Dose escalation was accomplished using an adaptive phase I design (Escalation With Overdose Control). Results: 22 patients have been enrolled, of which 18 are evaluable, into respective tipifarnib dose levels 100 mg (n=6), 200mg (n=5) and 300mg (n=5) and 400mg (n=2). Median age for the enrolled patients is 59 and median time from myeloma diagnosis was 4.7 years. The average number of prior therapies was 4.5. Among these patients with advanced myeloma and refractory disease, stabilization of disease or better was seen among 8/10 patients with 2 of the 8 achieving an MR. Among the patients achieving clinical benefit, 1 patient had a stable M-protein, but experienced an 80% reduction in circulating plasma cells while on therapy, and another has had a 75% reduction in the free light chain assay. The most common drug related side effect was was Gr2 diarrhea (23.5%). Hematologic toxicities were difficult to ascertain as patients had advanced myeloma and many were entered onto study with platelet counts between 25 and 50. Additional grade 3 toxicities included renal insufficiency (related to PD), pneumonia and altered mental status which were all considered not related to study drug but to progression of disease. There were no Grade 3-5 drug related toxicities. One patient experienced grade 2 peripheral neuropathy who did not have pre existing PN at baseline. Conclusions: The combination of bortezomib and tipifarnib is supported by preclinical rationale and has produced stable disease or better among 10 of 18 patients with refractory myeloma. Optimal dose of tipifarnib and bortezomib have yet to be defined, and additional patients are being enrolled with 1.3mg/m2 of bortezomib, and escalating doses of tipifarnib.

[Table: see text]
Prognostic factor analyses of myeloma (MM) survival outcomes on intergroup trial S9321 (int 0141): Examining whether different variables govern different time segments of survival
Authors: Crowley J. , Bolejack V. , Robert K. , Anderson K. , Barlogie B.
Published: August 2020

8599

Background: MM survival varies enormously from few months to more than a decade. Baseline prognostic factors (PF) have been identified that are linked to survival outcomes, especially B2M and albumin. MM survival plots are typically characterized by 3 segments of slopes with decreasing steepness, suggesting that different PF may govern these time segments. Methods: We therefore examined, in S9321, PF that were associated with overall survival (OS) from baseline (BL) and from 3 subsequent landmarks 3, 5, and 7 years later (LM3, LM5, LM7). With a median follow-up of 9 years, OS and EFS were virtually identical in transplant and standard therapy arms so that the data were pooled. Results: Median OS and EFS for 817 eligible patients are 48 and 22 months. The BL model identified age (>60yr), hemoglobin (<10g/gL), platelet count (<130,000/uL), albumin (<3.5g/dL), B2M (>3.5g/dL), calcium (>10mg/dL), creatinine (>2mg/dL), LDH (>190U/L), performance status (PS, >1), IL-6 level (>140mg/L) and plasma cell labeling index (PCLI, >1%) as being univariately associated with short OS, while age (p=0.002), platelet count (p=0.04), calcium (p<0.001), B2M (p=0.002), LDH (p=0.010) and PCLI (p<0.001) retained significance in multivariate analysis. For the LM3 analyses, age (p=0.006) and B2M (p=0.009) were independently associated with poor OS, whereas PCLI was the only PF associated with LM5 (p=0.026) and age with LM7 (p<0.001). While associated univariately with OS from BL, CRP, platelet count, hemoglobin, albumin, calcium, creatinine, LDH, IL6 and PS all failed to affect OS from later LM times. Conclusions: Whereas the initial 3 years of OS are governed by a combination of features related to disease aggressiveness (LDH, calcium, albumin, CRP), tumor burden (hemoglobin, platelet count) and host tolerance (PS, creatinine), B2M and PCLI as reflectors of tumor burden and proliferation have sustained long-term OS implications. The age factor figures in partly due to death from other causes. In an era of ever-improving survival outcomes, such LM-based PF analysis may reveal trial-specific differences and thus provide guidance toward individualizing therapy.

[Table: see text]
A phase II study of imatinib mesylate (IM) for patients with advanced melanoma harboring somatic alterations of KIT
Authors: Carvajal R. D. , Chapman P. B. , Wolchok J. D. , Cane L. , Teitcher J. B. , Lutzky J. , Pavlick A. C. , Bastian B. C. , Antonescu C. R. , Schwartz G. K.
Published: August 2020

9001

Background: Three prior phase II studies of Imatinib mesylate (IM) in 62 pts with advanced melanoma reported only 1 response in a pt with acral melanoma. A proportion of melanomas arising from acral, mucosal, and chronic sun damaged (CSD) sites are characterized by KIT mutations (mut) or amplifications (amp) and we hypothesized that this subset of tumors would be sensitive to IM. We thus designed this phase II study of IM restricted to pts with melanoma harboring such alterations in KIT. Methods: Pts with unresectable melanoma arising from acral, mucosal, and CSD sites whose tumor harbored a 4q12 amp by FISH or mut in KIT and who had measureable disease by RECIST were eligible. Pts received IM 400 mg BID continually. Response was assessed every cycle (6 wks). A Simon 2-stage design was employed where initially 16 pts would be treated; if ≥ 2 responses were observed, a total of 25 pts would be enrolled. If ≥5 responses were seen in 25 pts, the study was to be considered positive. Results: Of 81 pt tumors screened, 17 (21%) had a KITmut or amp: 5/22 (23%) acral, 12/45 (27%) mucosal, 0/13 (0%) CSD, 0/1 (0%) unknown primary. 12 (15%) had a mut only; 4 (5%) had an amplification only; 1 (2%) had both. Thus far, 7 have been treated, with 5 currently evaluable for response. Median age: 64 yrs (range, 61–86); 2 male/5 female; median KPS: 90 (range, 80- 90); median # of prior therapies: 1 (range, 0–4). 3 pts (43%) achieved a PR (18 wks - exon 13 mut; 21 wks, ongoing - exon 11 mut; 18 wks, ongoing - exon 11 mut & amp); 2 pts (28%) achieved SD (12 wks - exon 11 mut; 11 wks - amp). 3 pts required a dose reduction to 400 mg QD for rash, GI toxicity and fatigue. 1 pt required a second dose reduction to 300 mg QD for visual changes. Conclusions: In this pt population, 21% of tumors are characterized by mut or amp of KIT. The 3 responses observed have allowed expansion to the second stage of enrollment which is currently on-going. While IM has limited activity in a non-selected melanoma pt population, a substantial proportion of melanomas harboring KIT mut or amp appear to respond. It may be possible to identify appropriate pts prospectively for treatment with IM. (Supported by R01FD003445–01, ASCO YIA, N01CM62206, and the Live4Life Foundation.)

No significant financial relationships to disclose.
Association of gene expression profile in metastatic melanoma and survival to a dendritic cell-based vaccine
Authors: Gajewski T. , Zha Y. , Thurner B. , Schuler G.
Published: August 2020

9002

Background: Emerging data suggests that features of the melanoma tumor microenvironment may determine the clinical outcome to immunotherapies. We recently have observed a gene expression signature that correlated with a favorable clinical outcome in response to an IL-12-based melanoma vaccine. Increased expression of chemokine genes and T cell transcripts, and decreased expression of genes associated with aggressive tumor biology, were observed in the favorable group. To determine whether these patterns were reproducible, gene expression profiling was performed from an independent vaccine clinical trial. Methods: Patients with advanced melanoma were treated with autologous, mature monocyte-derived dendritic cells loaded with a combination of melanoma antigen peptides. Pretreatment biopsies were cryopreserved for RNA extraction and gene expression profiling. Patients were categorized into “long survival” (> 24 months) or “short survival” outcomes. Supervised hierarchical clustering was performed to identify genes differentially expressed in the two outcome groups. Results: RNA that passed quality control was obtained from 17 stage IV patients, 5 with a short survival and 12 with a long survival. 408 genes were differentially at least 2- fold. Consistent with previous observations, tumors from favorable outcome patients expressed higher levels of several T cell-specific genes, including Thy1 and CD28; chemokines, including CCL19, CXCL12, and CXCL14; and other immune genes, including LTβ, IL-1R, IFNαR2, IL27R, CD69, and FcRs. Conversely, tumors from unfavorable outcome patients expressed higher levels of pro- angiogeneic genes, including Flt1; anti-apoptotic genes, including SerpinH1 and Serpine1; and multiple collagens. Conclusions: Our results confirm that a subset of transcripts expressed in melanoma metastases may be useful as a predictive biomarker for response to melanoma vaccines. The categories of genes identified point toward new opportunities for overcoming resistance mechanisms. Future studies should integrate gene expression profiling of pre-treatment biopsies as a stratification or enrichment factor in immunotherapy trials.

No significant financial relationships to disclose.
Clinical relevance of miRNA expression in metastatic melanoma
Authors: Segura M. F. , Zakrzewski J. , Belitskaya-Levy I. , Gaziel A. , Kushnir M. , Hoshen M. , Hanniford D. , Cohen D. , Osman I. , Hernando E.
Published: August 2020

9006

Background: We recently reported the identification of a specific miRNA cluster frequently overexpressed in melanoma which enhances the metastatic behavior (Segura et al., 2009. PNAS. In press). In this study, we aim to define the clinical relevance of miRNA expression, in particular whether miRNAs can serve as prognostic biomarkers for melanoma patients. Methods: Total RNA was extracted from formalin-fixed paraffin embedded (FFPE) tissue samples from 61 metastatic melanoma specimens (25 lymph node, 16 soft tissue/skin, 13 brain and 7 visceral) accrued by the NYU Interdisciplinary Melanoma Cooperative Group (IMCG). RNA was hybridized into miRNA arrays (miRdicatorTM, Rosetta Genomics, Inc) containing probes for more than 600 miRNA sequences, including all the human miRNAs in the 9.0 version of miRBase. The Significance Analysis of Microarrays (SAM) was used to identify miRNAs significantly associated with survival, and the False Discovery Rate (FDR) approach was used to adjust for multiple comparisons. Results: We identified a signature of 18 miRNAs, whose up-regulation significantly associates with better prognosis (increased overall survival and post-recurrence survival) using the FDR of 0%. Quantitative RT-PCR on the same tissues has verified the array results in 15 out of 15 miRNAs analyzed. Some of these miRNAs were significantly associated with stage at recurrence, while others significantly correlated with the site of metastasis (i.e. visceral, brain, soft-tissue). Using cross-validation, we selected a miRNA signature consisting of 10 of these significant miRNAs with lowest misclassification error in predicting 1.5-year post-recurrence survival. We are currently validating these findings in a separate cohort of metastatic patients. Furthermore, we are investigating whether these ‘protective' miRNAs can be detected in the corresponding primary lesions and thus, whether they already hold prognostic value at early stages of the disease. Conclusions: Our data suggest a role for miRNAs as melanoma biomarkers, and support the development of miRNA- based monitoring assays. These analyses are also expanding our understanding of the molecular alterations underlying melanoma progression, by revealing miRNAs whose down-regulation associates with a more aggressive biological behavior.

[Table: see text]
Association of baseline and on-study tumor biopsy markers with clinical activity in patients (pts) with advanced melanoma treated with ipilimumab
Authors: Hamid O. , Chasalow S. D. , Tsuchihashi Z. , Alaparthy S. , Galbraith S. , Berman D.
Published: August 2020

9008

Background: Ipilimumab is a fully human monoclonal antibody to cytotoxic T-lymphocyte antigen-4. Identifying predictive markers may help select advanced melanoma pts most likely to benefit from ipilimumab therapy. Biomarkers in the tumor microenvironment are thought to be more relevant for predicting response than those in the peripheral blood. Methods: We examined tumor biopsy markers in a Phase II study CA184004 (ipilimumab 3 and 10 mg/kg). Ipilimumab was administered every 3 weeks (Q3W) x 4; eligible pts could receive ipilimumab Q12W starting Wk 24. Pre- and post-treatment (Wk 4) tumor biopsies were performed for hematoxylin and eosin analysis of tumor-infiltrating lymphocytes (TILs); immunohistochemistry of FOXP3 and indoleamine 2,3-dioxygenase (IDO); and mRNA expression profile analysis. Response was assessed with modified World Health Organization criteria. Associations between tumor biomarkers and clinical activity (complete response, partial response, or stable disease ≥ 24 wks) were assessed. Results: Ipilimumab 3 or 10 mg/kg was administered to 40 and 42 pts, respectively. In tumor biopsies, clinical activity was associated with high expression of FOXP3 (P = 0.014) and IDO (P = 0.012) at baseline and an increase from baseline in TILs (Wk 4) (P = 0.005) ( Table ). Tumor mRNA profiling identified genes with significant changes from baseline in expression, or with baseline expression levels that may be associated with clinical activity. These included various immune response genes and known melanoma antigens. Conclusions: Biomarkers in the tumor microenvironment have been demonstrated to be associated with clinical activity in pts treated with ipilimumab.

[Table: see text]

[Table: see text]
Prediction of response to alkylator-based chemotherapy in metastatic melanoma (MM) using gene expression and promoter methylation signatures
Authors: Tawbi H. A. , Buch S. , Pancoska P. , Lin Y. , Saul M. , Romkes M. , Sobol R. , Kirkwood J. M.
Published: August 2020

9009

Background: Temozolomide and dacarbazine (TMZ and DTIC) remain the mainstay of alkylator-based chemotherapy for MM, despite response rates of 10–15% and the absence of any impact on survival. Classification of patients according to responsiveness can guide the individualization of therapy and inform approaches to abrogate mechanisms of chemotherapy resistance. Epigenetic mechanisms play an important role in regulation of genes associated with resistance and were evaluated in tandem with gene expression profiling in biological samples from MM patients (pts) to refine our understanding of the epigenomic-genomic-phenotypic interplay. Methods: We examined promoter methylation and gene expression in tumor tissues of 21 pts with MM treated with TMZ or DTIC, using high throughput technologies (Illumina Inc). The cases were divided into responder (R) and non-responder (NR) groups based on clinical response. The data were analyzed using Prediction Analysis of Microarrays (PAM) from BRB array tools. Results: Differential promoter methylation analysis revealed that 63.6% of promoter sites were hypomethylated in tumors obtained from R pts (p<0.0001). PAM analysis of gene expression data revealed that a classifier set consisting of 82 genes was able to predict NRs from Rs with 83% sensitivity and 89% specificity. Promoter methylation profiling did not independently correlate with R status. A simultaneous analysis of the promoter methylation and gene expression values first stratified into 3 data-driven categories and then combined into a 3 by 3 matrix allowed us to identify a common gene expression/methylation signature of 15 genes that classified both NR and R groups accurately 100% of the time. Conclusions: Gene expression signatures independently predict response to chemotherapy in MM, however promoter methylation profiling alone does not. Analysis of combined gene expression and promoter methylation in a well- annotated clinical data set dichotomized according to response identified a highly predictive signature. The findings from this study are qualified by the relatively small sample size and are currently being validated in an expanded sample set. Supported in part by the ECOG Paul Carbone, MD, Fellowship Award.

No significant financial relationships to disclose.
Use of gene expression profile and mitotic index of metastatic melanoma lesions as an adjunct to TNM staging in predicting patient survival
Authors: Bogunovic D. , O'Neill D. , Belitskaya-Levy I. , Vacic V. , Adams S. , Darvishian F. , Pavlick A. , Zavadil J. , Osman I. , Bhardwaj N.
Published: August 2020

9014

Background: Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling of metastatic lesions to search for a molecular basis for this observation, and to develop improved methods for predicting patient survival. Methods: We analyzed gene expression profiles of 44 metastatic melanoma specimens collected from 38 patients (median follow-up of 20 months after surgery). We used the False Discovery Rate (FDR) approach to identify genes significantly associated with post-recurrence survival. We then evaluated matching H&E stained tissue samples for the presence of tumor-infiltrating leukocytes (TILs) and mitotic index, (MI). Support vector machines and multi-variable Cox regression analysis was used to examine the relative ability of the pre-validated gene expression predictor, TILs, MI and TNM staging to predict survival. Results: We identified a group of approximately 300 genes associated with survival. Genes associated with immune response (ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1 etc.) or with cell proliferation (PDE4D, CDK2, GREF1, NUSAP1, SPC24 etc.) were highly represented .Prolonged survival was associated with the elevated expression of immune response genes and decreased expression of genes associated with proliferation. Furthermore, any of the three additional parameters (pre-validated gene expression signature, TILs or MI) improved the ability of TNM staging to predict post-recurrence survival; MI was the most significant contributor (HR = 2.65, p = 0.003) followed by the gene expression signature (HR = 2.71, p = 0.05). Conclusions: Gene expression profiling and MI of metastatic lesions can both be utilized to improve upon current staging of metastatic melanoma to predict patient survival. Gene expression signature and analysis of TILs indicate immune surveillance as a mechanism for prolonged survival in these patients.

No significant financial relationships to disclose.
PLX4032, a highly selective V600EBRAF kinase inhibitor: Clinical correlation of activity with pharmacokinetic and pharmacodynamic parameters in a phase I trial
Authors: Puzanov I. , Nathanson K. L. , Chapman P. B. , Xu X. , Sosman J. A. , McArthur G. A. , Ribas A. , Kim K. B. , Grippo J. F. , Flaherty K. T.
Published: August 2020

9021

Background: PLX4032 is an oral, highly selective inhibitor of oncogenic V600EBRAF kinase currently in phase I trial. V600EBRAF mutation activates Raf/MEK/ERK pathway in multiple tumor types. We evaluated the relationship between PK, PD (pERK, Ki67, FDG-PET), tumor histology and clinical activity following PLX4032 administration in a phase I trial. Methods: In the phase I trial, 6 melanoma pts with V600EBRAF were treated with PLX4032 daily at several dose levels and tumor biopsies (baseline vs. day 15) were assessed histologically and by semi-quantitative IHC analysis (modified H-score) for pERK and Ki67. The first 4 pts received a crystalline formulation of PLX4032; the last 2 pts received a formulation with increased bioavailability. Plasma PK parameters were collected at frequent time points on Days 1, 8 and 15. FDG-PET was performed on Days 1 and 15 on last 2 pts. Results: In the first 4 pts, no histological changes were observed with treatment and all developed disease progression. All had decreased percentage of Ki67 positive nuclei (pre-Rx, range 20–60%, median 45%; post-Rx, range 5–25%, median 12.5%) and 3 of the 4 had decreased pERK levels (pre-Rx, range 50–100, median 60; post-Rx, range 10–40, median 11). Mean PLX4032 AUC0–24h ∼ 126 μM*h was in the range for preclinical tumor stasis but below the threshold for shrinkage. In the last 2 pts, striking tumor necrosis and tumor melanosis was observed in the post-Rx samples. One pt remains on study with a confirmed PR, the other showed a clinical response before disease progression occurred in cycle 2. The percentage of Ki67 positive nuclei declined substantially (pre-Rx, 30% and 50% to post-Rx, 5% and 3%), as did the levels of pERK in the pt with PR (pre-Rx: 70 to post-Rx: 2). Mean PLX4032 AUC0–24h was well above the preclinical threshold in the range of 500 - 1000 μM*h. Both pts had decreased FDG uptake on D15. Conclusions: Clinical activity of PLX4032 treatment correlates with drug exposure levels as measured by AUC0–24h and was associated with histological changes in V600EBRAF positive melanomas on Day 15. Reduction of pERK, along with evidence of reduced proliferation and FDG uptake was observed. Further analysis of PD markers with additional pts at the MTD is planned.

[Table: see text]
Randomized phase II study of the safety and efficacy of a human anti-αv integrin monoclonal antibody (CNTO 95) alone and in combination with dacarbazine in patients with stage IV metastatic melanoma: 12-month results
Authors: Loquai C. , Pavlick A. , Lawson D. , Gutzmer R. , Richards J. , Gore M. E. , de Boer C. J. , Uhlar C. , Lang Z. , O'Day S.
Published: August 2020

9029

Objectives: Evaluate the safety and efficacy of CNTO 95, a human anti-αv integrin monoclonal antibody, when administered alone or in combination with dacarbazine (DTIC). Methods: Patients with Stage IV metastatic melanoma were randomized 1:1:1:1 to receive 5 or 10mg/kg CNTO 95 alone, or DTIC (1000mg/m2) + either 10mg/kg CNTO 95 or placebo administered intravenously once every 3 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. DTIC arms were blinded; single-agent arms were open-label. The primary endpoint was progression free survival (PFS); secondary endpoints included partial response (PR), complete response (CR), stable disease (SD) and overall survival (OS). Major safety endpoints included the incidence of adverse events (AEs) and serious AEs (SAEs). Results: Patients were randomized to receive 5mg/kg CNTO 95 (n=32), 10mg/kg CNTO 95 (n=33), CNTO 95+DTIC (n=32), or placebo+DTIC (n=32). Baseline demographics were similar across groups. The median PFS for CNTO 95+DTIC was 75 days, placebo+DTIC was 54 days and both CNTO 95 alone arms were 42 days. Six patients achieved PR (2–10mg/kg CNTO 95, 1-CNTO 95+DTIC, 3-placebo+DTIC); one patient achieved CR (CNTO 95+DTIC). A higher proportion (43.3%) of patients achieved SD ≥ 12 wks in the CNTO 95+DTIC group compared with the other 3 groups (<20.0%). The median survival was 11.0 months for the patients in the CNTO 95+DTIC arm, 9.8 months and 14.9 months for the 5mg/kg and 10mg/kg arms, and 8.0 months for those in the DTIC control arm. The most common AEs were headache, nausea, fatigue, pyrexia, vomiting and transient uveitic reactions. Three patients (1–5mg/kg, 2-CNTO 95+DTIC) discontinued treatment due to AEs. A higher proportion of patients experienced SAEs in the placebo+DTIC group (29.0%) than in the 5mg/kg (12.9%), 10mg/kg (16.2%) or CNTO 95+DTIC (18.8%) groups. Conclusions: CNTO 95 alone or combined with DTIC was generally well tolerated. In patients with Stage IV metastatic melanoma, a trend toward improvement in PFS, OS and disease control was demonstrated with CNTO 95+DTIC.

Centocor, Centocor Research and Development, Inc.

Centocor Research and Development, Inc.

Johnson & Johnson

Centocor Research and Development, Inc.

No significant financial relationships to disclose.
Evaluation of the effect of systemic corticosteroids for the treatment of immune-related adverse events (irAEs) on the development or maintenance of ipilimumab clinical activity
Authors: Amin A. , DePril V. , Hamid O. , Wolchock J. , Maio M. , Neyns B. , Chin K. , Ibrahim R. , Hoos A. , O'Day S.
Published: August 2020

9037

Background: Ipilimumab, a fully human monoclonal antibody that inhibits cytotoxic T-lymphocyte antigen-4, has clinical activity at 10 mg/kg in patients (pts) with advanced melanoma. Most grade 3/4 immune-related adverse events (irAEs) associated with ipilimumab can be managed with systemic corticosteroids following established treatment guidelines. However, little has been reported about the effects of corticosteroids used to treat irAEs on ipilimumab antitumor responses. Methods: Across 3 phase II studies with 10 mg/kg ipilimumab monotherapy in advanced melanoma (CA184008, 022, and 007; N=283), 83 pts (29.3%) achieved disease control [complete/partial responses (CR/PR), or stable disease (SD) ≥12 weeks] and 43/83 (52%) received steroids for treatment of irAEs. The pts' ability to develop and maintain disease control in the presence and absence of steroids was analyzed. Disease control was assessed by modified World Health Organization (mWHO) criteria and novel immune-related response criteria (irRC) (Hodi FS, et al. J Clin Oncol 26: 2008 [May 20 suppl; abstr 3008]). The range of follow-up was 5.7–6.3 months. Results: Of 117 pts who received steroids prior to response assessment, 26 pts achieved CR or PR, or maintained SD without disease progression by mWHO, and the remaining 91 pts had PD. Of 166 pts who either never received steroids or received them after response assessment, 31 achieved a CR, PR, or SD (by mWHO). Further, of 26 pts with CR/PR by mWHO, 14 received subsequent steroids and 11 maintained a response, while of 12 pts who received no subsequent steroids, 9 maintained a response. Similar results were obtained if irRC were used (see table ). Conclusions: Systemic corticosteroids for treatment of irAEs do not appear to impact the development or maintenance of ipilimumab clinical activity in advanced melanoma.

[Table: see text]

[Table: see text]
Effect of ipilimumab at 10 mg/kg on disease control in patients (pts) with M1c-stage melanoma in relation to baseline lactate dehydrogenase (LDH) levels
Authors: Smylie M. , Francis S. , Neyns B. , Maio M. , Minor D. , Verschraegen C. , Chin K. , Ibrahim R. , Hoos A. , Schadendorf D.
Published: August 2020

9041

Background: Ipilimumab, a fully human, anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody, enhances antitumor immunity. Ipilimumab is clinically active in advanced melanoma, with a 1-year survival rate of ∼50% in Phase II studies (Wolchok et al. CRI-CVC annual meeting 2008. Oral presentation). Serum LDH level is an independent prognostic factor for malignant melanoma, and is strongly predictive of reduced survival in stage IV disease (Bedikian et al. J Clin Oncol. 2006;24:4738–4745.). This analysis evaluated the association between baseline LDH levels and disease control (stable or reduced measurable tumor burden) in previously treated pts with M1c-stage melanoma (metastasis to vital organs other than the lungs) who received ipilimumab in 2 recently completed Phase II studies (CA184008 and 022). Methods: Ipilimumab at 10 mg/kg was given every 3 weeks (Q3W) × 4; eligible pts could continue to receive ipilimumab Q12W beginning at Week 24. In study 022, pts were randomized to receive ipilimumab induction dosing at 0.3, 3.0, or 10 mg/kg Q3W × 4; study 008 was a single- arm trial of ipilimumab at 10 mg/kg. Disease control data were pooled from the 2 Phase II studies for pts treated with ipilimumab at 10 mg/kg and stratified by normal and elevated (>1× upper normal limit [UNL]) LDH levels. Elevated LDH was not capped. Results: For 227 pts treated at 10 mg/kg, 123 had M1c-stage disease: 42 had normal LDH and 81 had LDH >1 × UNL (of which 32 had LDH 2 × UNL). Among these 123 pts, 17/81 (21.0%) [95% CI 12.7–31.5] with elevated LDH levels experienced disease control, whereas 12/42 (28.6%) [95% CI 15.7–44.6] with LDH levels at or below the UNL experienced disease control. Conclusions: Our data show that ipilimumab exerts similar disease control in pts with normal and elevated LDH levels. Ipilimumab therefore appears to have clinical activity in the form of disease control in pts with a very poor prognosis, i.e., M1c-stage melanoma and elevated LDH levels.

[Table: see text]
Ki67 as a prognostic biomarker for patients with vertical growth phase (VGP) melanomas
Authors: Gimotty P. , Guerry D. , VanBelle P. , Montone K. , Guerra M. , Hwang W. , Schuchter L. , Xu X. , Elder D.
Published: August 2020

9043

Background: In VGP melanomas proliferation is reflected in dermal mitotic figures (“mitogenic” VGP) and/or tumor cell nests larger than any epidermal nest. An alternative to mitotic rate (MR) to characterize cell proliferation is the expression of Ki67 protein. Since Ki67 is expressed in all phases of the cell cycle except G0, it is potentially a more robust biomarker for proliferation and prognosis than mitoses. Methods: To test the hypothesis that Ki67 would replace MR as a prognostic factor, we did a retrospective cohort study of 432 patients with Stage I/II primary VGP melanomas who had at least 10 years of follow up. Tissue sections were stained using the monoclonal antibody MIB-1 to Ki67 and the % of positive melanoma cells were evaluated by two readers. ROC curves for Ki67 and MR were computed. Predicted probabilities (PP) of 10-year melanoma-specific death were computed from 3 multivariate logistic regression models, one for each biomarker (Models 1 and 2) and one with both (Model 3), controlling for established melanoma prognostic factors (thickness, gender, anatomic site, ulceration, regression and tumor infiltrating lymphocytes), and compared. Cross-validation was used to assess differences between using Ki67 and using MR including the differences in PP, Brier scores and the misclassification rates. A decision curve analysis was done to assess the clinical net benefit of the two. Results: The areas under the ROC curve (AUCs) for Ki67 and MR, both continuous factors, were 0.69 and 0.79, respectively. In the multivariate analysis, Ki67 expression was significant in Model 1 (OR=1.03, 95% CI: 1.01–1.05), mitotic rate was not significant in Model 2 (1.05, 0.99–1.1), and only Ki67 was significant in Model 3 (1.03, 1.01–1.05). The AUCs for the three models were 0.84, 0.84, and 0.85, respectively. Based on cross-validation, there was no difference between the two biomarkers in PP, Brier scores, or misclassification rates. The decision cost analysis demonstrated the same net benefit for the two. Conclusions: A prospective study needs to be conducted to confirm that Ki67 and MR are equivalent.

No significant financial relationships to disclose.