bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study cohort evaluating an optimized administration schedule of SAR3419, an anti-CD19 DM4-loaded antibody drug conjugate (ADC), in patients (pts) with CD19 positive relapsed/refractory b-cell non-Hodgkin’s lymphoma (NCT00796731).
Authors: Coiffier Bertrand , Morschhauser Franck , Dupuis Jehan , Haioun Corinne , Laine Fabrice , Houot Roch , Tilly Herve , Brehar Oana , Lambert John M. , Fagniez Nathalie , Payrard Sandrine , Ribrag Vincent
Published: March 2020

8057

Background: The recommended dose (RD) of SAR3419 administered intravenously every 3 weeks (q3w) for 6 cycles is 160 mg/m2 and is 55 mg/m2 when administered weekly (q1w) for 8-12 doses. Reversible corneal deposits were dose limiting (DLT) in the q3w schedule. The q1w schedule was well tolerated and active. However, based on the occurrence of late/cumulative adverse events (AE) at the RD supported by pharmacokinetic (PK) analyses showing ADC plasma accumulation after 4 weekly doses, an optimized schedule consisting of 4 weekly doses followed by 4 bi-weekly doses at the RD was tested. Methods: The q1w study was extended to treat 25 pts with the optimized schedule for 8 to 12 doses. Results: Twenty-one pts were evaluable. Main histologies were diffuse large B-cell (DLBCL) (9; 43%) and follicular (6; 29%). Median number of prior regimens was 2 [1-8], 6 pts received prior autologous transplantation and 95% of pts were Ann Arbor stage III-IV at study entry. Median number of doses received was 8 as planned with a median relative dose intensity of 1.0 [0.8-1.0]. Most frequent AEs were asthenia (1 pt with grade 3) and gastrointestinal disorders in 7 pts each. No AE fulfilled the defined DLT criteria. Reversible grade 1 blurred vision/corneal event occurred in 1 pt. Grade 3-4 haematological toxicities were minor consisting of non complicated neutropenia in 4 pts, thrombocytopenia in 2 pts and anemia in 1 pt with no transfusion support. Six (29%) pts, among them 3 with DLBCL, achieved an objective response including 3 CRu (1 in a pt refractory to last regimen). In addition, 9 (43%) pts had stable disease. Response duration was [8-35+] weeks, 5 pts still responding at the cut-off date. Conclusions: The optimized administration schedule shows an improved safety profile compared to prior tested schedules. The clinical efficacy is preserved essentially in aggressive lymphoma. The optimized schedule is being assessed in 2 phase II studies evaluating SAR3419 either as a single agent or in combination with rituximab in pts with DLBCL histology.
Hodgkin’s disease and HIV infection (HD-HIV): Prognostic factors in 596 patients (pts) within the group of European Cooperation on AIDS and Tumors (GECAT).
Authors: Spina Michele , Ribera Josep-Maria , Gabarre Jean , Wyen Christoph , Montoto Silvia , Jaeger Ulrich , Talamini Renato , Re Alessandro , Ferreri Andres J. , Tirelli Umberto
Published: March 2020

8058

Background: Hodgkin’s disease (HD) is the most common non-AIDS defining tumour diagnosed in HIV setting. The introduction of highly active antiretroviral therapy (HAART) has opened a new prospective in the treatment of pts with HD-HIV as the better control of the underlying HIV infection allows the use of more aggressive chemotherapy regimens, including high dose chemotherapy. However, up to now prognostic factors on overall survival (OS) or time to treatment failure (TTF) have not yet been identified. Methods: In order to identify prognostic factors, we analyzed data on 596 pts with HD-HIV diagnosed and treated in 90 different Institution of 6 European countries from October 1983 to March 2010. All factors were analyzed for OS and TTF. Results: 86% of pts were male and the median CD4 cell count was 224/dl (range 3-1274); 52% of pts had mixed cellularity subtype, stages III-IV were diagnosed in 72% of cases and 55% of pts had extranodal involvement (bone marrow 35%, spleen 21%, liver 14%). The table summarizes the results of multivariate analysis. Conclusions: We identified a new “European Score” for HD-HIV able to predict different outcomes in these patients. This score should be considered for future prospective studies. [Table: see text]
High affinity CD3 RECRUIT TandAb for T cell-mediated lysis of CD19+ tumor B cells.
Authors: Zhukovsky Eugene , Reusch Uwe , Burkhardt Carmen , Knackmuss Stefan , Fucek Ivica , Eser Markus , McAleese Fionnuala , Ellwanger Kristina , Little Melvyn
Published: March 2020

8059

Background: CD19 is expressed from early B cell development to the differentiation into plasma cells and is an attractive target for B cell malignancies either lacking CD20 expression or refractory to anti-CD20 antibody therapies. T cells are potent tumor killing effector cells that are not recruited by native antibodies. The CD3 RECRUIT-TandAb AFM11, a human bispecific tetravalent antibody with two binding sites for both CD3 and CD19, is a novel therapeutic for the treatment of NHL that harnesses the cytotoxic nature of T cells. Methods: A bispecific anti-CD19/anti-CD3 tetravalent TandAb with humanized and affinity matured variable domains was constructed. The TandAb’s binding, T-cell mediated cytotoxic activity, and cytokine release were characterized in a panel of in vitro assays. In vivo efficacy was evaluated in a murine NOD/scid xenograft model reconstituted with human PBMC. Results: AFM11 mediates highly potent target tumor cell lysis in cytotoxicity assays: EC50 values are low to sub-picomolar range in a panel of CD19+ cell lines and primary B-CLL tumor cells. The cytotoxic activity of tetravalent AFM11 is superior to that of alternative bivalent antibody formats possessing only a single binding site for both CD19 and CD3. High affinity binding of AFM11 to CD19, and more so to CD3 (low to sub-nanomolar Kd), is essential for efficacious T cell recruitment. The high affinity bivalent binding of AFM11 to CD3 does not trigger T cell activation in the absence of CD19+ target cells in functional in vitro assays. AFM11 activates T cells only in the presence of its targets and mediates lysis while sparing antigen-negative bystanders. AFM11 induces down-modulation of the CD3/TCR complex in the absence of target cells and at high concentrations. Also, AFM11-treated T cells can be re-engaged for target cell lysis. These features of AFM11-induced T cell activation may contribute additional safety with no compromise of efficacy. Finally, AFM11 demonstrates a robust dose-dependent inhibition of subcutaneous Raji tumors in mice. Conclusions: AFM11 is a novel highly efficacious drug candidate for the treatment of B cell malignancies with an advantageous safety profile.
Central nervous system involvement in T-cell lymphomas: A single center experience.
Authors: Gurion Ronit , Maragulia Jocelyn , Zelenetz Andrew David , Horwitz Steven M.
Published: March 2020

8069

Background: Large experiences have reviewed the risk of central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL), but there are limited data on CNS involvement by peripheral T cell lymphomas (PTCL). We characterized the incidence of CNS involvement, risk factors and outcome in a large single institution dataset of PTCL. Methods: Retrospective review of the T-cell lymphoma database at Memorial Sloan Kettering Cancer Center. We identified 232 patients with any subtype of PTCL between 1994-2011 with a minimum 6 months of follow-up or an event defined as relapse or death. We excluded indolent forms of cutaneous T cell lymphoma. Results: Histologies included PTCL-NOS (31%), angioimmunoblastic (16.8%), anaplastic (ALCL), ALK negative (12%), ALCL, ALK positive (6%), extranodal NK/T cell lymphoma (7.3%), adult T cell leukemia/lymphoma (ATLL) (7.3%), and transformed MF (8.6%). Median age was 58 years with 59.9% men. CNS disease was found in 17 patients (7.32%). 8 (47%) had pathologic confirmation and 7 (41.2%) were clinically diagnosed. Two had other diagnoses at biopsy: DLBCL and glioblastoma. Median time to CNS involvement was 2.33 months (range, 0.16 to 103.1). CNS prophylaxis was given to 24 (10.34%), primarily intrathecal methotrexate. There was no difference in CNS involvement in patients who received prophylaxis vs. those who did not: 3/24 (12.5%) vs. 12/208 (5.77%) (p=0.192) respectively. Univariate analysis identified: stage III-IV (p=0.03), bone marrow involvement (p=0.018), >1 extranodal site (p<0.001), and ATLL vs. all other subtypes, 23.5% vs. 6.4% (p=0.003) as risk factors for CNS disease. On multivariate analysis, >1 extranodal site (p=0.004) and high intermediate (H-I) and high (H) IPI (IPI 3-5 & 4-5) were predictive for CNS involvement (p<0.05). The median survival of patients with CNS involvement was 2.628 months. Conclusions: Despite high relapse rates, PTCL carries a low risk of CNS involvement other than the ATLL subtype. As with other aggressive lymphomas, survival of patients with CNS involvement is poor and risk factors include: >1 extra nodal site and H-I-H IPI. In this dataset, prophylactic intrathecal chemotherapy does not appear to reduce the risk of CNS disease.
Phase I trial of temsirolimus and lenalidomide in pts with rel/ref lymphomas.
Authors: Smith Sonali M. , Cohen Kenneth Stuart , Kline Justin Paul , Zavala Jose D , Conner Kathy , Thomas Sachdev P , Lesho Patricia , Doyle Laurence A. , Stadler Walter Michael , Karrison Theodore , Kimball Amy Sarah
Published: March 2020

8075

Background: The PI3K/Akt/mTOR axis is deregulated in lymphomas and is an emerging therapeutic target. We previously reported activity of temsirolimus (TEM) in DLBCL and FL (JCO 2010 28(31); however, the response duration was short. Lenalidomide (LEN) is an immunomodulatory agent with multiple anti-tumoral and microenvironmental effects, with activity across lymphoma subtypes. We are thus conducting a phase I/II study of TEM plus escalating doses of LEN. The phase I portion is completed. Methods: Patients (pts) had rel/ref lymphoma after >1 cytotoxic regimen. Other criteria: ANC > 1000/mL, platelets > 75,000/mL, nl renal and hepatic function, no VTE within 3 months, non-pregnant. A standard “3 + 3” design was used with dose levels (DL) listed (Table). TEM was given IV weekly and LEN was dosed orally on D1-D21, q28 days. Dose-limiting toxicity (DLT) was defined as cycle 1 grade 3 or 4 non-hematologic toxicity not responsive to standard supportive care, grade 4 thrombocytopenia > 7 days (or associated with bleeding or requiring more than 1 platelet transfusion), ANC < 500/mL > 7 days despite growth factors, or any thromboembolic event. Results: 18 pts (13M, 5F), med age 64 y (range, 42-80 y) were enrolled. 3 pts are ineval for DLT evaluation: one withdrew consent before starting treatment, 1 withdrew consent after a single dose, and 1 died of rapid disease progression after 1 dose. There was 1 DLT at DL1 and 2 DLTs at DL3 (Table). Adverse effects that did not meet DLT criteria: hypokalemia, hypertriglyceridemia, vomiting, urinary tract infection, skin infection, nausea, hypoxia, hyponatremia, diarrhea, and hyperglycemia (each occurring in one pt). There are 5 partial responses, 4 stable disease, 3 progressive disease, 2 not adequately assessed, and 4 still on active treatment. Conclusions: The combination of weekly intravenous TEM plus oral LEN is well-tolerated in a heavily pretreated group of pts with rel/ref lymphomas. The recommended phase II doses are TEM 25mg weekly plus LEN 20mg (D1-D21, q28d). [Table: see text]
Association of tumor-associated macrophages of M2 subtype with outcome in follicular lymphoma.
Authors: Chua Clarinda Wei Ling , Tay Kevin , Tan Iain B. , Tang Tiffany , Pan Summer , Kalaw Emarene , Khoo Lay Poh , Ha Jeslin , Quek Richard Hong Hui , Tao Miriam , Tan Leonard , Teh Bin Tean , Lim Soon Thye , Tan Soo Yong
Published: March 2020

8078

Background: Current methods used to prognosticate patients with follicular lymphoma (FL) include the Follicular Lymphoma International Prognostic Index (FLIPI) and tumor grade. However, they do not provide information on the biological and molecular features of FL. Recent data suggest that high tumor-associated macrophages (TAM) content may be an adverse prognostic factor in FL. However, TAM consists of two main subtypes, M1 and M2, with the former related to pro-inflammatory properties while the latter, anti-inflammatory functions. Currently, the prognostic impact of each individual subtype has not been elucidated and this may be more important than looking at TAM alone. Methods: Tumor specimens of 98 patients with FL diagnosed between 2005 and 2009 were investigated using immunohistochemistry and fluorescence in-situ hybridization (FISH) using break-apart FISH probes targeting BCL2, BCL6, MYC and IgH genes. Tumor specimens expressing a higher proportion of CD68+/CD163- in one high power field were defined as M1 subtype and those that expressed a greater proportion of CD68+/CD163+ were denoted as M2 subtype. Results: Amongst the 98 patients, 60 (61%) were of the M2 subtype, 59% presented with advanced disease, 47% were grade 3 and the median age was 59 years (21 – 88 years). Baseline characteristics including grade, stage and recurrent translocations did not significantly differ between the M1 and M2 groups. Similarly, there was also no difference in terms of treatment received (both Rituximab and chemotherapy) between the two groups. Despite these similarities, with a median follow-up of 3.2 years, the 3-year overall survival (OS) was significantly different (M1, 100% vs M2, 85%; p < 0.01). All 11 patients who died were of the M2 subtype (p=0.009). Conclusions: Our findings show that despite similar patient characteristics and treatment, there was, however, a statistically significant difference in OS, with the M2 subtype demonstrating an inferior outcome. The M2 TAM subtype rather than TAM alone may be a more important prognostic marker in FL, which could possibly be explained by its known biological anti-inflammatory function.
An update on gemcitabine, rituximab, and oxaliplatin in combination for relapsed/refractory non-Hodgkin lymphomas.
Authors: Crescentini Robert M. , Sweet Kendra Lynn , Liu Jijun , Liboy Idalia , Dalia Samir , Chavez Julio C. , Bello Celeste M. , Sokol Lubomir , Sotomayor Eduardo M. , Cabanillas Fernando , Cultrera Jennifer L.
Published: March 2020

8084

Background: Relapsed/refractory non-Hodgkin lymphomas (NHL) have no standard of care. A variety of salvage chemotherapy options are available. We previously reported results of our phase II trial using gemcitabine, rituximab and oxaliplatin (GROC) in the salvage setting for relapsed/refractory NHL in which we observed an overall response rate of 58% with an incidence of grade 3-4 thrombocytopenia of 9% and neutropenic fever of 3.5%, but no grade 3-4 non-hematologic toxicities. Here we update progression free survival (PFS) and overall survival (OS) data. Methods: This phase II, single-arm, multicenter study evaluated safety and efficacy of GROC in patients with relapsed/refractory NHL. Patients were treated on a 14 day cycle. On day 1, patients with CD20+ NHL received rituximab (375 mg/m2). On day 2, patients received gemcitabine (1000 mg/m2) and oxaliplatin (100 mg/m2). Granulocyte colony stimulating factor was given. Stem cell transplant (SCT) was considered after a minimum of 6 cycles. Results: A total of 58 patients were enrolled from the H. Lee Moffitt and the Auxilio Mutuo Cancer Centers. Ages ranged from 24 to 88 years (median 72 years). The majority of patients had an ECOG performance status of 0-1 (89%). Lymphoid neoplasms included large B-cell (79%), follicular (7%), lymphoblastic (1.8%), Burkitt (1.8%), primary mediastinal large B-cell (3.5%), and peripheral T-cell lymphoma (7%). Eighty-one percent of patients had stage III-IV disease, median IPI was 3, 40% had B-symptoms, 43% had bulky disease and 74% had an elevated LDH. Anthracycline-based therapy had been used in 91% of patients and 66% had received rituximab. Median PFS was 134 days (95% CI 115-153) and median OS was 296 days (95% CI 164-428). No difference in response was observed based on age >60, IPI, LDH or albumin levels. Prior therapy with rituximab (p=0.02) and initial response to front-line therapy (p=0.04) appear to correlate with improved outcomes. Nine patients went on for SCT. Conclusions: GROC is a useful salvage regimen for relapsed/refractory NHL with minimal toxicities and good clinical efficacy. Several patients were able to be successfully mobilized, collected and transplanted post GROC therapy.
Natural killer (NK) cell activation, cytokine production, and cytotoxicity in human PBMC/myeloma cell co-culture exposed to elotuzumab (Elo) alone or in combination with lenalidomide (Len).
Authors: Balasa Balaji , Yun Rui , Belmar Nicole , Starling Gary , Rice Audie
Published: March 2020

8087

Background: Elo is a monoclonal IgG1 antibody targeting CS1, a cell surface glycoprotein highly expressed on >95% of myeloma cells. In preclinical models Elo exerts anti-myeloma activity via NK cell-mediated antibody-dependent cellular cytotoxicity. Len is an immunomodulatory agent that may activate NK cells. The combination of Elo + Len synergistically enhanced anti-tumor activity in myeloma xenograft models. We investigated the mechanism of enhancing NK cell activation and myeloma cell killing with Elo + Len. Methods: Human PBMC/OPM-2 co-cultures were treated for 24-72h with Elo, Len, or Elo + Len. Activation markers and adhesion receptors were evaluated by flow cytometry. Cytokines were measured by Luminex and ELISpot assays. Cytotoxicity was assessed by cell counting. Results: Elo + Len increased IFN-γ secretion significantly more than Elo or Len alone. IFN-γ elevates ICAM-1 expression, and ICAM-1 surface expression on OPM-2 target cells increased synergistically with Elo + Len. Elo, Elo + Len but not Len increased expression of CD25 (IL-2Rα) on NK cells. Len increased the levels of IL-2, but those were decreased in the presence of Elo due to increased consumption by CD25 expressing NK cells. Blocking uptake of IL-2 with anti-CD25 resulted in higher IL-2 levels than with Len. ELISpot assays confirmed that Elo + Len significantly increased the number of IL-2-producing cell colonies compared with Elo or Len. Elo induced NK dependent myeloma cell killing, and the effect was significantly higher with Elo + Len. Conclusions: Elo alone activated NK cells and mediated the killing of myeloma cells in PBMC/OPM-2 co-cultures. Elo + Len synergistically enhanced myeloma cell killing and increased expression/production of IFN-γ, ICAM-1, IL-2, and CD25. [Table: see text]
Second autologous stem cell transplantation as a strategy for management of relapsed multiple myeloma.
Authors: Gonsalves Wilson I. , Kumar Shaji , Lacy Martha , Dispenzieri Angela , Hayman Suzanne R. , Buadi Francis , Dingli David , Hogan William J. , Gertz Morie A.
Published: March 2020

8092

Background: High dose therapy and autologous stem cell transplant (SCT) remain an integral part of the treatment of multiple myeloma (MM). Despite the introduction of several new drugs, disease relapse remains inevitable and a second SCT often allows continued disease control. Methods: We examined the outcomes in 105 patients (pts) undergoing a second SCT (SCT2) for relapsed MM, from among 1033 pts receiving initial transplant between 1994 and 2009. Patients receiving an allogeneic SCT post SCT2 were not included in the survival analysis. Results: Median (range) age at SCT2 was 60 yrs (35-74) and the time between SCTs was 46 mos (10-130). The median follow-up was 5 yrs from SCT2. The median (range) number of regimens between the two SCTs and from diagnosis was 2 (0-7) and 3 (1-11), respectively. Conditioning regimen was Mel 200 in 85 (81%) pts. Median (range) CD34 cells infused was 4.6 (2.5-25 million/kg). Hospitalization was required for 53 pts (50%), median hospital stay was 7 days.. Median time to ANC of 500 and platelets of 50,000 were 13 and 16 days, respectively. Treatment related mortality was seen in 5 (5%) pts. A partial response or better was seen in 95 (90%) pts, including a stringent CR in 10%, CR in 19%, and VGPR in 21%. Stable disease or progression was seen in 7 pts and 3 pts died prior to disease assessment. The median (95% CI) PFS and OS after SCT2 were 10.4 (8, 14) and 33 (28, 51) mos, respectively. The median OS was not reached and 33 mos respectively, for those obtained a CR and those with <CR, P=0.03. FISH pre-SCT2 was available for 73 pts; the PFS and OS were not affected by the presence of high-risk MM. In multivariate analyses, shorter duration of response to SCT1, higher plasma cell (PC) labeling index at SCT2, more regimens used prior to SCT2 all predicted shorter PFS and OS post SCT2. Lack of CR to SCT2 was also significantly associated with shorter PFS. Conclusions: Second SCT is an effective therapy for eligible pts relapsing after other treatments. It provides a meaningful duration of response and appears to be well tolerated. Pts with longer duration of response to first transplant and those achieving a CR appear to have maximum benefit.
BREAK-MB: A phase II study assessing overall intracranial response rate (OIRR) to dabrafenib (GSK2118436) in patients (pts) with BRAF V600E/k mutation-positive melanoma with brain metastases (mets).
Authors: Kirkwood John M. , Long Georgina V. , Trefzer Uwe , Davies Michael A. , Ascierto Paolo Antonio , Chapman Paul B. , Puzanov Igor , Hauschild Axel , Robert Caroline , Kefford Richard , Goodman Vicki L. , Switzky Julie C. , Swann R. Suzanne , Martin Anne-Marie , Guckert Mary E. , Streit Michael R. W. , Schadendorf Dirk
Published: March 2020

8501

Background: Melanoma brain mets carry a poor prognosis (median survival ≤4 months), for which more effective therapies are needed. Dabrafenib is a potent, selective oral inhibitor of mutated BRAF that has demonstrated clinical efficacy in pts with BRAF V600E/K mutant melanoma and previously untreated brain mets in a phase I study. Therefore, a phase II study (BREAK-MB) was initiated. Methods: Stage IV pts with ≥ 1 intracranial met (0.5 cm–4 cm assessed by MRI) without prior brain therapy (Cohort A) or with progression following prior brain therapy (Cohort B) were eligible with V600E/K mutation. Pts received dabrafenib 150 mg BID. The primary endpoint was investigator-assessed OIRR among V600E mutation-positive pts. Results: Overall, 172 pts were recruited. At interim analysis, of 127 pts enrolled (safety population), 41 (Cohort A n=24; Cohort B n=17) had reached 8-week disease assessment. Unconfirmed OIRR in Cohort A was 10/19, (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed OIRR was 8/15 (53%; 95% CI: 26.6%–78.7%) for V600E and 1/2 (50%; 95% CI: 1.3–98.7%) for V600K pts. Unconfirmed overall response rate (ORR) in Cohort A was 10/19 (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed ORR was 6/15 (40%; 95% CI: 16.3–67.7%) for V600E and 1/2 (50%; 95% CI: 1.3–98.7%) for V600K pts. In the safety population, 12/63 pts (19%) in Cohort A reported an SAE; 1 (2%) was fatal (cerebral hemorrhage). In Cohort B 15/64 pts (25%) reported an SAE; 1 (2%) was fatal (seizure). In Cohort A, 47 pts (75%) experienced AEs: 9 grade 3 (14%) and 3 grade 4 (5%). The most common AEs were headache (21%), hyperkeratosis and rash (17% each). In Cohort B, 47 pts (73%) experienced AEs: 12 grade 3 (19%) and 3 grade 4 (5%). The most common AEs were fatigue or nausea (22% each) and pyrexia (17%). Conclusions: Dabrafenib shows high clinical activity both in pts with intra- and extracranial mets with acceptable toxicity. Final data will be presented.
Intermittent high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III malignant melanoma: Final analysis of a randomized phase III DeCOG-trial (NCT00226408).
Authors: Mohr Peter , Hauschild Axel , Trefzer Uwe , Enk Alexander , Tilgen Wolfgang , Loquai Carmen , Gogas Helen , Haalck Thomas , Koller Josef , Schadendorf Dirk , Dummer Reinhard , Gutzmer Ralf , Brockmeyer Norbert , Hölzle Erhard , Sunderkötter Cord , Mauch Cornelia , Stein Anette , Schneider Lars , Podda Maurizio , Weichenthal Michael
Published: March 2020

8505

Background: Adjuvant high-dose interferon (HDI) treatment of patients (pts) with malignant melanoma (MM) usually consists of 4 weeks initial intravenous (iv) infusion of 20 MU/m² IFNa2b followed by 11 months of 10 MU/m² subcutaneously (sc). It is still unclear, whether both components are necessary for the efficacy of HDI in high-risk MM pts. The adjuvant phase III DeCOG MM-ADJ-5 trial evaluates efficacy, safety, tolerability and quality of life (QoL) of an intermittent (pulsed) high-dose iv IFNa2b regimen as compared to standard HDI. Methods: Patients with stage III (AJCC 2002) resected intransit or lymph node metastasis from cutaneous malignant melanoma were randomly assigned to receive either standard HDI regimen (Arm A), or 3 courses of IFNa2b 20 MU/m² iv on 5 days a week for 4 weeks repeated every 4 months (Arm B). Distant metastasis free survival (DMFS) was the primary endpoint for efficacy analysis. The EORTC QLQ C30 questionnaire was used before and during the study in a standardized way (weeks 0, 4, 16, 24, 40). In addition, patients completed a diary containing global QoL measures every week. Results: Out of 649 patients who were enrolled, 22 patients had to be excluded from the intent-to-treat analysis. The remaining 627 patients were well balanced between both arms according to sex, age, and stage. Median follow-up was similar in both groups (55.4 vs. 55.3 months). Distant metastasis occurred in 138 (Arm A; 44%) vs. 145 (Arm B; 47%) patients without statistical significance (p=0.46). Survival was not significantly different for DMFS (HR 1.1; p=0.39) or OS (HR=1.0; p=0.85). Termination of treatment due to adverse events or QoL related reasons occurred significantly more often in arm A than in arm B (26.0% vs. 14.8%; p<0.001). The pulsed schedule resulted in less cumulative toxicity as compared to the standard regimen, in particular regarding fatigue and neuropsychiatric side effects. Conclusions: The final analysis of pulsed adjuvant HDI treatment showed no significant DMFS or OS differences in comparison to conventional HDI. There is a clearly favorable safety and QoL profile of the pulsed regimen.
Hypersensitivity skin reactions in melanoma patients treated with vemurafenib after ipilimumab therapy.
Authors: Harding James J. , Lacouture Mario E. , Pulitzer Melissa , Callahan Margaret , Postow Michael Andrew , Carvajal Richard D. , Wolchok Jedd D. , Chapman Paul B.
Published: March 2020

8515

Background: Ipilimumab (IPI) and vemurafenib (VEM) each improve overall survival for patients (pts) with metastatic melanoma. Both are FDA-approved and are being used in pts with BRAFV600E-mutated metastatic melanoma. We previously described cases of prominent skin eruptions associated with VEM in pts who had previously received IPI. Methods: We have updated our experience of BRAFV600E-mutated melanoma pts treated with VEM who had previously received IPI. Pts were treated at our center from January 2007 to January 2012. Data were collected under an approved IRB waiver. Results: Sixteen melanoma pts were treated with VEM after having received IPI. The most common drug-related adverse event (AE) associated with VEM was rash, occurring in 13/16 patients (81.3%, 95% CI 56.5-93.2). Four pts developed a severe, Grade 3, maculopapular rash within 8 days of starting VEM. Biopsies in 2 pts revealed spongiotic and perivascular dermatitis with eosinophils consistent with a drug hypersensitivity reaction. Hypersensitivity reactions did not progress to life-threatening reactions such as anaphylaxis or Stevens-Johnson syndrome, nor did they result in VEM dose discontinuation. Reactions were managed with corticosteroids and dose modifications. Grade 3 rash strongly correlated with initiating VEM within one month of IPI (Fisher’s exact test, p = 0.007) and was not associated with the dose of prior IPI, the number of prior doses, or immune-related AEs. The incidence of Grade 3 rash in this pt cohort was significantly higher than in pts treated on the phase III trial of VEM (4/16, 25% versus 28/336, 8%; χ2 = 5.13, Df = 1, p = 0.02). The objective overall response for VEM was 50% (95% CI 26.5-73.4), which is similar to response rates seen on the phase II and III trials. Conclusions: In pts receiving VEM who have previously received IPI, dermatologic AEs appear to be more common. This effect seemed most pronounced if VEM was given within one month of completing IPI. Although more data are necessary to confirm this apparent association, we speculate that the release of immune checkpoint inhibition by IPI may predispose pts to hypersensitivity skin reactions to VEM.
Predicting early relapse in patients with BRAFV600E melanoma with a highly sensitive blood BRAF assay.
Authors: Sullivan Ryan J. , Lawrence Donald P. , Flaherty Keith T. , McDermott David F. , Aldridge Julie , Cho Daniel C. , Simonson Rachel , Seery Virginia Jean , Hodi F. Stephen , Atkins Michael B. , Mier James Walter , Panka David J
Published: March 2020

8516

Background: Many patients (pts) with metastatic melanoma (MM) who progress on BRAF inhibitors (BRAFi) develop rapidly progressive disease (PD) which is difficult to manage. Identification of an early marker of PD may allow for therapeutic intervention prior to clinical deterioration. We have developed a highly sensitive and inexpensive assay in our laboratory which can detect as little as 1 BRAFV600E mutant melanoma cell in 400,000 peripheral blood lymphocytes (PBL). We aimed to determine the utility of our assay as a tool to follow pts with BRAF mutant MM who are being treated with a BRAFi. Methods: Every pt had a BRAFV600E mutation detected from a tumor sample in a CLIA-approved laboratory prior to commencing BRAFi therapy. 20 pts with stage IV BRAFV600E MM underwent serial venopunctures before and every 4 weeks during treatment with a BRAFi. BRAFV600E level was quantified using our proprietary assay (Panka et al Melanoma Research 2010). Serial BRAFV600E levels were generated for every pt and normalized to the pre-treatment value. BRAFV600E level was then correlated with response to therapy and PD. Results: BRAFV600E was detected in the PBL of each pt. To date, 10 pts have had BRAFV600E levels quantified at 3 or more time points (data for all 20 pts will be available at time of presentation). Relative BRAFV600E levels reduced by half following the first and second cycles of treatment in 7 pts, which correlated with disease regression in each pt. Following the third cycle of treatment, the relative BRAFV600E levels varied greatly with a subset of pts having continued suppression while others having a rise in their BRAFV600E levels. In each pt with PD, the BRAF assay showed an increase > 4 wks in advance of clinically or radiographically defined PD. Conclusions: Our assay is able to quantify changes in BRAFV600E levels in the blood of pts with BRAF mutant MM receiving BRAFi therapy. In these pts, the BRAFV600E levels are reduced in the setting of initial disease regression and increase well in advance of clinical or radiographic PD. While further development is necessary, such a test could be used to identify pts who may be selected to receive alternative therapy prior to clinical or radiographic PD.
A phase II trial of dasatinib in patients with unresectable locally advanced or stage IV mucosal, acral, and solar melanomas: An Eastern Cooperative Oncology Group study (E2607).
Authors: Kalinsky Kevin , Lee Sandra J. , Lawrence Donald P. , Iafrate A. John , Borger Darrell R. , Averbook Bruce Jeffrey , Tarhini Ahmad A. , Kirkwood John M.
Published: March 2020

8522

Background: Pre-clinical studies report a critical role of c-KIT mutations in mucosal, acral, and solar melanomas. Clinical trials of KIT-directed therapy with imatinib and sunitinib demonstrate activity in these subtypes. Unlike other TKIs, dasatinib inhibitory activity is seen in melanoma cell lines with the most common KIT mutation at exon 11L576P. E2607 tests the efficacy of dasatinib in treatment-naïve or previously treated patients (pts) with these unresectable subtypes. Methods: Pts receive dasatinib 70 mg PO twice daily for this two-stage phase II trial. The primary objective is response rate (RR: RECIST). Stage I was open to KIT mutated (KIT+) and wild-type (KIT-) tumors with these subtypes (n=56). Depending upon the interim analysis, stage II would pre-select for KIT+. If the overall response rate were < 5%, the study would be terminated. Secondary objectives include progression-free survival (PFS), overall survival (OS), safety, and KIT mutation status. Results: Between May 2009-Dec 2010, 57 pts have been accrued to stage I. Of 54 (2 no therapy, 1 ineligible), 26 have mucosal (48%), 13 acral (24%), and 15 solar melanomas (28%). As of Jan 2012, the median f/u is 15 months (mo, range: 4-24 mo). Best responses (n=52) are 1 complete (CR: 2%), 3 partial (PR: 6%), 13 stable disease (25%), 29 progression (56%), and 6 unevaluable (11%). 51/52 have progressed (median PFS: 1.9 mo, 95% CI: 1.5-2.8) and 40/54 died (median OS: 7.4 mo, 5.7-10.8). KIT status has been assessed in 42 pts: 39 KIT- (93%) and 3 KIT+ (7%). PR is seen in 1/39 KIT-. All KIT- have died: median PFS (1.8 mo, 95% CI: 1.4-2.9) and OS (6.8 mo, 95% CI: 5.2-10.8). Of the 3 KIT+ (1 acral, 2 mucosal), 2 have died (PFS 1.4-2.5 mo, OS: 1.4-10.5 mo), and 1 refused f/u (OS: 13.3+ mo). The pt with a CR is alive at 14.4+ mo (unknown KIT status). Toxicities include 1 grade IV (elevated lipase) and grade III dyspnea (n=7), nausea (n=6), and vomiting (n=3). Conclusions: Further evaluation of dasatinib should be pursued in pts selected for KIT+ and subtype, given the lack of promising results in Kit-(<5% RR). The current trial is revised to enroll only KIT+ acral, mucosal, and vulvovaginal melanomas and available via CTSU.
Phase II trial of RO4929097 Notch gamma-secretase inhibitor in metastatic melanoma: SWOG S0933.
Authors: Margolin Kim Allyson , Moon James , Redman Bruce G. , Chidiac Tarek , Othus Megan , Ribas Antoni , Flaherty Lawrence E. , Sondak Vernon K. , Gajewski Thomas
Published: March 2020

8525

Background: The Notch pathway regulates expression of genes for cell cycle, tissue-specific differentiation, and vasculogenesis. Notch target genes affect melanomagenesis, and Notch levels can influence stemlike versus differentiated tumor cells. Gamma-secretase, which activates intracellular Notch, can be inhibited to kill melanoma cells. We designed this trial to test RO4929097 in pts with melanoma and its effects on T lymphocytes and tumor gene expression. Methods: To assess 6-month progression-free survival (PFS) and 1-year overall survival (OS) in advanced, untreated melanoma patients (pts), a 2-stage accrual design was used. Correlative studies: markers of Notch pathway activation in archived or fresh tumor and T cell functional assays pre-treatment (Rx) and at week 3. Rx dose was 20 mg orally on 3 consecutive days, weekly. Results: 33 pts were Rx’d in stage 1 (median age 61 [range 32-85]; 70% male; 42% elevated LDH; 30% unknown primary; 24% bone mets; 36% liver; 55% lung; 55% lymph node, skin or soft tissue). The clinical outcomes did not meet criteria for stage 2 accrual. One pt had a confirmed PR of 7 months’ (mo) duration. The median PFS was 1.4 mo, [95% confidence interval, c.i. 1.3-2.7], the 6-mo PFS was 11% [95% c.i 3%-33%], and the 1-year OS was 45% [95% c.i. 23%-90%]. Treatment was well-tolerated with no grade (gr) 4-5 tox. The most common gr 2 drug tox were fatigue and nausea in 4 patients (12%) each, and only 4 of 7 gr 3 tox were considered drug-related (1 increased ALT, 1 QTc prolongation, 1 bradycardia, 1 lymphopenia). Pre- and week 3 on-Rx peripheral T cell samples assayed for IL-2 (23 pts) and IFN-γ (22 pts) secretion to Staphylococcal enterotoxin A showed no significant change, in contrast to in vitro gamma-secretase inhibitors which blocked T cell activation. Pre- and on-Rx tumor biopsies in one pt showed no decrease in the Notch target Hey1. Conclusions: RO4929097 at this dose and schedule has limited activity in molecularly-unselected pts with melanoma. Lack of effect on T cell function and tumor Hey1 expression suggests that sustained target inhibition might not have been achieved. Supported in part by PHS Cooperative Agreements, NCI, DHHS CA32102 and CA38926. ClinicalTrials.gov identifier: NCT01120275.
Association of high T-cell immune infiltrate and low hemorrhage in melanoma brain metastases (MBMs) with prolonged survival.
Authors: Krauze Michal Tadeusz , Hamilton Ronald H. , Romkes Marjorie , Bortoluzzi Stephanie , Harasymczuk Malgorzata , Reinhard Todd , Junecko Beth Fallert , Nukui Tomoko , Konstantinopoulos Panagiotis , Becker Dorothea , Kondziolka Douglas , Tarhini Ahmad A. , Whiteside Theresa , Mintz Arlan H. , Tawbi Hussein , Ferrone Soldano , Kirkwood John M. , Moschos Stergios J
Published: March 2020

8528

Background: Despite the poor prognosis of patients (pts) with MBM several pts have prolonged survival. We hypothesized that the heterogeneity of BrMM is determined by differences in melanoma biology and its brain microenvironment. Methods: We identified pts who have undergone craniotomy for MBMs. Evaluation entailed complete clinical information, acquisition of archived melanoma brain metastases, histopathologic analysis of hematoxylin and eosin-stained sections (n=101), whole genome expression profiling (WGEP, Illumina DASL) in 29 archived tissues. Results were validated by immunohistochemistry (IHC) or in situ hybridization (ISH). Results: In univariate analysis (log-rank) factors significantly associated with prolonged survival were high immune infiltrate (HII) plus low hemorrhage (hazard ratio, HR, 2.71, p<0.001), present melanin (1.67, p=0.03), and recursive partitioning analysis (RPA) class 1 (0.37, p<0.0001). No association between HII and use of immunotherapy prior to craniotomy was noted. Only RPA class 1 (p=0.029) and HII plus low hemorrhage (p=0.002) remained significant in Cox proportional hazards model analysis. Gene set analysis of WGEP data confirmed that Encarta pathways related with T-cell activation and differentiation were significantly associated with prolonged survival whereas Y branching of actin filaments, presenilin action in Notch and Wnt signaling, G-protein signaling through tubby protein, lissencephaly gene in neuronal migration and development are among the gene categories associated with worse survival. IHC and ISH analysis of tumor sections for various markers (n=40) showed that high peritumoral CD3+ (3.31, p=0.009), high peritumoral CD4+ (4.41, p=0.014), and high peritumoral CD8+ (3.02, p=0.030) are associated with prolonged survival whereas neither CD14+ nor FoxP3+ infiltrate, nor high melanoma expression of antigen presentation molecules are associated with survival. Conclusions: Our study is the first to document that high peritumoral T-cell infiltrates are associated with prolonged survival. High tumor hemorrhage, an adverse prognostic sign, reflects aggressive melanoma cells that migrate and invade in the brain.
Long-term cure after complete resection and adjuvant immunotherapy for distant melanoma metastases.
Authors: Morton Donald L. , Mozzillo Nicola , Kashani-Sabet Mohammed , Thompson John F , Kelley Mark C. , De Conti Ronald C. , Lee Jeffrey Edwin , Huth James F. , Faries Mark B. , Dalgleish Angus George , Wagner Jeffrey D. , Hersh Evan , Schneebaum Schlomo , Anderson Clay M. , Smithers Mark , Schuchter Lynn Mara , McMasters Kelly M. , Testori Alessandro , Karakousis C. P. , Elashoff Robert ,   MMAIT-IV Clinical Trial Group
Published: March 2020

8534

Background: In phase II trials, postoperative therapy with Canvaxin allogeneic melanoma cell vaccine plus Bacillus Calmette-Guerin (BCG) improved the survival of patients with stage IV melanoma. A multicenter, phase III placebo-controlled study was undertaken to investigate the vaccine’s efficacy. Methods: After complete resection of melanoma involving up to 5 distant sites, patients were randomized to treatment with BCG plus Canvaxin (BCG-Canvaxin) or BCG plus placebo (BCG-placebo). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS) and skin test responsiveness to the study agent. Results: Between May 1998 and April 2005, 496 patients were randomized. In April 2005, entry to the study was terminated due to low probability of demonstrating treatment differences. However, 256 patients from sites enrolled in a follow-up study were monitored until March 2010. Median OS and 5-year and 10-year rates of OS were 39.1 months, 43.3% and 33.3%, respectively, in the BCG-placebo group, versus 34.9 months, 42.5% and 36.4%, respectively, in the BCG-Canvaxin group (hazard ratio, 1.053; 95% confidence interval, 0.81 to 1.36; p=0.6964). Median DFS, 5-year DFS, and 10-year DFS were 7.6 months, 23.8% and 21.7%, respectively, for the BCG-placebo group, versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG-Canvaxin group (hazard ratio, 0.882; 95% confidence interval, 0.708 to 1.097; p=0.2595). Positive skin test results correlated with improved survival. Conclusions: BCG-Canvaxin was not superior to BCG-placebo, but the highly favorable long-term survival for combined groups indicates that complete metastasectomy should be considered as initial therapy for patients with resectable stage IV melanoma (ClinicalTrials.gov identifier: NCT00052156).
Impact of comorbidities on overall survival of high-risk and advanced melanoma.
Authors: Peddi Prashanth , Oh Jeong Hoon , Kim Kevin B. , Gershenwald Jeffrey E. , Palla Shana L. , Schacherer Christopher W , Jakkoju Rakesh , Suarez-Almazor Maria
Published: March 2020

8536

Background: Comorbidities have been shown to adversely affect survival among patients with cancer. Currently, the most important prognostic factor in patients with melanoma is AJCC stage. However, little is known regarding the impact of comorbidities on melanoma prognosis. The aim of our study was to determine the impact of the severity of concurrent comorbidities on the overall survival of patients with high-risk and advanced melanoma (defined as AJCC stages IIc, III and IV). Methods: We conducted a retrospective cohort study of eligible adult melanoma patients available in the MelCore prospective database at MD Anderson Cancer Center (MDACC) from 01-2003 to 12-2006 who were diagnosed and completed staging within 3 months of presentation to MDACC. Patients with ocular melanoma were excluded. Demographic, AJCC staging, and survival data were collected. The Adult Comorbidity Evaluation-27 (ACE-27) was utilized to collect comorbidity information and grade its severity. A Cox proportional hazards model was used. Results: Of 444 patients that met enrollment criteria, 176 (39.6%) had grade 0 (no comorbidities), 222 (50%) had grade 1 or 2 (mild or moderate comorbidities) and 46 (10.4%) had grade 3 (severe comorbidities). The median age of the entire cohort was 56.4 years (19.7-98.9), 141 (32%) were female, and 406 (91.4%) were white. The median overall survival after presentation to MDACC was 5.0 years for the entire cohort. Adjusted hazard ratios are shown in the table. Comorbidity and AJCC Stage were significantly associated with survival. Age, gender and race did not have a significant impact on overall survival. Conclusions: In our study, the presence of comorbidities at presentation were independent predictors of decreased survival, even when adjusted for AJCC stage. Our findings suggest that comorbidity should be incorporated into prognostic models and therapeutic decision-making for patients with high-risk or advanced melanoma. [Table: see text]
Prognostic value of BRAFV600 mutations in melanoma patients after resection of metastatic lymph nodes.
Authors: Saiag Philippe , Moreau Stephanie , Aegerter Philippe , Bosset Daphne , Longvert Christine , Helias-Rodzewicz Zofia , Marin Cristi , Peschaud Frederique , Chagnon Sophie , Zimmermann Ute , Clerici Thierry , Emile Jean-François
Published: March 2020

8540

Background: Prognosis of AJCC stage III melanoma is heterogeneous. BRAFV600 mutations are frequent in melanomas. BRAFV600-targeted therapy has dramatic, but often transitory, efficacy in stage IV patients (pts). We aimed to determine for the first time the prognostic value of BRAFV600 mutations and other known prognostic criteria in stage III pts with sufficient nodal invasion. Methods: We searched all pts with cutaneous melanoma who had radical lymphadenectomy in our institution between 1/1/00 and 15/6/10 and included those with a nodal deposit >2 mm. BRAFV600 mutations were detected by DNA sequencing and pyrosequencing in formalin-fixed nodal samples containing >60% melanoma cells. Samples were considered mutated when >15% of DNA was positive. Endpoints were overall survival (OS) and distant metastasis free survival (DMFS). 92 patients had to be included to demonstrate a doubling of OS in patients without (40 months (m)) and with BRAFV600 mutation (20 m). Log-rank test and multivariate Cox proportional hazards regression model were used. Results: 105 consecutive pts were included, with 72% prospectively followed-up pts. BRAFV600 mutations (E: 83%; K: 14% of pts) were detected in 40% of pts. Median follow-up was 19 m (range: 3-139). Death occurred in 83% and 60% of pts with and without BRAF mutations, respectively, with median OS of 1.4 and 2.8 years. Pts’ age, primary melanoma ulceration, number of invaded nodes, AJCC staging, and BRAF status influenced OS and DMFS in the univariate analysis. The multivariate analysis showed the major prognostic role of BRAF status and of the number of invaded nodes (table). Conclusions: Provided our findings are independently replicated, BRAFV600 status should be used to stage melanoma pts with nodal metastasis. Our results also help to plan adjuvant trials with BRAFV600-targeted therapy in such patients, for whom the low tumor load may induce longer efficacy of BRAF-targeted therapies. [Table: see text]
BEVATEM: Phase II single-center study of bevacizumab in combination with temozolomide in patients (pts) with first-line metastatic uveal melanoma (MUM): First-step results.
Authors: Piperno-Neumann Sophie , Servois Vincent , Bidard Francois-Clement , Mariani Pascale , Plancher Corine , Asselain Bernard , Vago-Ady Nora , Desjardins Laurence
Published: March 2020

8546

Background: Overall survival (OS) of MUM pts remains poor. In our retrospective series of 470 MUM pts, median OS was 13 months, ranging from 3 to 12 and 21 months for best supportive care, systemic treatment and surgery groups respectively, stressing the lack of effective therapies in this rare cancer. Targeting angiogenesis seems to be promising in uveal melanoma. Intravitreal application of antiangiogenic agents is used to treat neovascular ocular diseases such as age-related macular degeneration or proliferative diabetic retinopathy. Bevacizumab suppressed in vitro growth and in vivo hepatic establishment of micrometastases in experimental uveal melanoma. Preclinical data suggest a potential clinical benefit of the combination of dacarbazine and bevacizumab. Methods: Phase II study, modified 2-step Fleming plan; with expected 6-month progression-free survival (PFS) rates of 15% with chemotherapy and 40% with BEVATEM, 35 pts are to be recruited for a power of 94% (α and β risk 3 and 6%). After the first 17 pts, the study will be continued and another 18 pts will be enrolled in the second step if ≥3 evaluable pts show stable disease or response. Primary endpoint: 6-month PFS according to RECIST. Secondary objectives: response and survival rates, safety; liver perfusion CT for functional imaging of response; impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. Treatment schedule: Temozolomide 150mg/m2 d1-d7 and d15-d21 oral route, Bevacizumab 10 mg/kg d8 d22 IV infusion, 6 cycles (d1=d28) then Bevacizumab maintenance until toxicity or progression. Results: From May 2010 to January 2011, 17 pts were enrolled according to the first step of the study: 3/17 achieved disease control at 6 months, second step is on going with 26/35 pts already recruited. One patient with minor response in liver and lung metastases is under Bevacizumab maintenance for 12 months. Safety of BEVATEM is as good as expected. Liver perfusion CT study showed decrease in blood flow and blood volume before lesion size decrease in one stable patient. Conclusions: BEVATEM study in first line MUM pts is on going, showing promising results in the first step of 17 pts.