bluuebunny/crossref_metadata_2025 huggingface dataset:
Vorinostat (suberoylanilide hydroxamic acid, SAHA) is clinically active in advanced cutaneous T-cell lymphoma (CTCL): Results of a phase IIb trial
Authors: Olsen E. , Kim Y. H. , Kuzel T. , Pacheco T. R. , Foss F. , Parker S. , Wang J. G. , Frankel S. R. , Lis J. , Duvic M.
Published: March 2020

7500

Background: Vorinostat is a histone deacetylase inhibitor that has demonstrated clinical activity at tolerable dose levels in patients (pts) with advanced CTCL in phase I and IIa trials. Methods: Open-label, single-arm, nonrandomized phase IIb trial of oral vorinostat 400 mg daily until disease progression or intolerable toxicity. Eligibility: advanced CTCL; ≥ 2 prior systemic therapies which must have included bexarotene unless unable to tolerate; adequate hematologic, hepatic and renal function. Planned sample size: ≥ 50 evaluable pts with clinical stage ≥ IIB. Primary endpoint: objective response rate (OR = CR + PR) as measured by a modified skin severity weighted assessment tool. The study would be positive if OR in ≥ stage IIB pts was ≥ 20%. Secondary endpoints: assessment of response duration (DOR), time to progression (TTP), time to response (TTR), pruritus relief and safety. Results: Seventy-four pts (median age, 60 y [range, 39–83]; median 3 prior systemic therapies) were enrolled (61 pts ≥ stage IIB) from 9/04 to 5/05 at 18 centers. Data cut-off was 11/05 with a median follow-up of 4 months. Efficacy data are shown in Table 1 . The OR was 29.5% (18 PR including 1 with later CR) in ≥ stage IIB pts. Median TTP was 148 d for all pts and 203.5+ d for responders. The most common drug-related adverse experiences (AE) were diarrhea (49%), fatigue (46%), nausea (43%) and anorexia (26%), and were mostly ≤ Grade 2. Drug-related ECG changes were Grade 1 in 5 pts (7%) and Grade 2 in 1 pt (1%), but not associated with cardiac symptoms. Seven pts discontinued and 10 had dose modification due to drug-related AE. Drug-related AE ≥ Grade 3 included fatigue (5%), pulmonary embolism (5%), nausea (4%) and thrombocytopenia (4%). Twenty-five pts discontinued due to progressive disease. Causes of the 3 deaths on study were: unknown (d 2), ischemic stroke (d 227) and disease progression (d 52). Conclusion: Oral vorinostat is effective in the treatment of advanced CTCL with an acceptable safety profile.

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Mantle cell lymphoma (MCL): Induction therapy with HyperCVAD/High-dose methotrexate and cytarabine (M-C) (±rituximab) improves results of autologous stem cell transplant in first remission
Authors: Vose J. , Loberiza F. , Bierman P. , Bociek G. , Armitage J.
Published: March 2020

7511

Background: Although patients (pts) with MCL have a high response rate to standard chemotherapy, they continue to relapse with no plateau in long term disease-free survival. The use of dose intense induction therapy such as HyperCVAD (M-C) ±Rituximab(R) and high-dose therapy and stem cell may improve these results. In this analysis the outcomes of pts receiving a standard anthracycline induction therapy or HyperCVAD(M-C)(±R) then followed by a stem cell transplant in first complete (CR1) or partial remission (PR1) were compared. Methods: Between 6/91 and 11/05, 124 pts with MCL received high-dose chemotherapy and a stem cell transplant. Of these pts, 80 received an autologous stem cell transplant in CR1 (N = 47) or PR1 (N = 33). A standard anthracycline based CHOP-like (±R) induction therapy was given to 48 pts compared with 32 pts who received HyperCVAD(M-C)(±R) prior to transplant. Results: The median age of pts was 56 years (range 33–70). The male:female ratio was 33:57. Bone marrow involvement prior to conditioning was present in 52% of pts. An elevated lactic dehydrogenase (LDH) was present in 58% of pts. 65% of patients received one prior chemotherapy before coming to stem cell transplant. The median follow up of pts is 38 months (range 3–143). Progression-free survival (PFS) and overall survival (OS) are outlined in table 1 . Characteristics associated with an improved OS by multivariate analysis included receiving HyperCVAD induction (p = 0.04), transplant in CR1 (p = 0.009), ≤ 3 prior chemotherapy regimens (p = 0.02) and no B symptoms at transplant (p = 0.05). Conclusions: To improve the long term disease free survival for pts with MCL, Hyper-CVAD(M-C)(±R) induction should be given to eligible patients with autolgous stem cell transplantation in CR1.

[Table: see text]

No significant financial relationships to disclose.
A multicenter, randomized, double-blind, placebo-controlled trial of thalidomide plus dexamethasone versus dexamethasone alone as initial therapy for newly diagnosed multiple myeloma
Authors: Rajkumar S. V. , Hussein M. , Catalano J. , Jedrzejcak W. , Sirkovich S. , Olesnyckyj M. , Yu Z. , Knight R. , Zeldis J. B. , Blade J.
Published: March 2020

7517

Background: Thalidomide plus dexamethasone (Thal/Dex) yields superior response rates versus dexamethasone (Dex) but its impact as primary therapy for multiple myeloma (MM) is unknown. Methods: Patients (pts) with previously untreated, symptomatic MM were eligible and were randomized in this double-blind trial to Thal/Dex (Arm A) or placebo plus Dex (Arm B). Pts in Arm A received Thal 50 mg PO daily, escalated to 100 mg on day 15, and to 200 mg from day 1 of cycle 2; Dex 40 mg PO was given on days 1–4, 9–12, and 17–20. Pts in Arm B received placebo instead of Thal, and Dex as in Arm A. Cycles were 28 days long, repeated until progression or undue toxicity. The primary endpoint was time to progression (TTP) defined using EBMT criteria. All analyses were intent to treat. Planned sample size was 218 eligible pts in each arm. Full information for one-sided log rank test with significance level of 0.025 (allowing for 1interim analysis) to have 80% power to detect a 40% improvement in TTP (16.8 mo in Arm A vs. 12 mo in Arm B) would be achieved when 282 pts have progressed. A pre-planned interim analysis of the primary endpoint and safety was performed by an independent Data Monitoring Committee (DMC). P value < 0.0015 at this interim analysis would indicate that Arm A is superior to Arm B based on an alpha-spending function of the O’Brien-Fleming type. The DMC recommended release of results. Results: 470 pts were enrolled: 235 randomized to Thal/Dex and 235 to placebo/Dex. Median follow-up was 25 months. Median age was 65 yrs. TTP was significantly superior with Thal/Dex vs placebo/Dex, median TTP 17.4 months (95% CI: 8.1 months-NE) vs 6.4 months (95% CI: 5.6–7.4 months), respectively, P < 0.000065, crossing the upper boundary for superiority. DVT was higher with Thal/Dex vs placebo/Dex, 15.4% vs 4.3%, respectively. Median survival was not reached in either arm. Conclusions: Thal/Dex is significantly superior to Dex alone as first-line therapy for multiple myeloma.

[Table: see text]

[Table: see text]
Oral lenalidomide plus melphalan and prednisone (R-MP) for newly diagnosed multiple myeloma
Authors: Palumbo A. , Falco P. , Benevolo G. , Canepa L. , D’Ardia S. , Gozzetti A. , Nozza A. , Zeldis J. , Boccadoro M. , Petrucci M. T.
Published: March 2020

7518

Background: Lenalidomide (Revlimid) is a novel oral immunomodulatory drug active in refractory multiple myeloma (MM). In this multicenter trial, we evaluate the effect of the combination lenalidomide, melphalan and prednisone (R-MP). Methods: Patients (pts) with newly diagnosed symptomatic MM ≥ 65 years received 9 courses of lenalidomide (21 days every 4–6 weeks) plus MP (4 days every 4–6 weeks). The trial was designed to asses toxicity and efficacy of R-MP combination. Four dose levels were tested (table 1). Each cohort included 6 pts, with additional 15 pts in level 3 and 4. Dose limiting toxicity (DLT) was defined as: grade ≥ 3 non-hematologic toxicity; grade 4 hematologic toxicity (with neutropenia lasting >7 days); treatment delay due to toxicity during the first cycle. All pts received ciprofloxacin and aspirin as prophylaxis. Results: At present, 50 pts (median age 71) received at least one R-MP course. No DLTs were observed in levels 1 and 2. In level 3, 1 pt experienced DLT (grade 4 neutropenia > 7 days). In level 4, 3 pts showed DLTs (neutropenic fever, grade 3 cutaneous toxicity, pulmonary embolism and cycle 2 delay due to neutropenia). After 1 cycle, no one was in complete remission (CR) (according to the EBMT/IBMTR criteria), 51% of pts showed a response of 50–99% (PR) and 49% a response <50%, no progressive disease (PD) occurred. After 3 cycles, CR was observed in 10% of pts, PR in 60% and response <50% in 30%, no PD occured. Major grade 3–4 adverse events were hematological toxicities: neutropenia (58%) and thrombocytopenia (21%). Major grade 3–4 non-hematological toxicities were cutaneous eruption (11%), infections (5%) and febrile neutropenia (3%). Neuropathy was not observed and only one thromboembolism was recorded. Conclusions: R-MP was well tolerated with a manageable toxicity. Significant response rate was observed. It represents a feasible and promising approach for elderly newly diagnosed pts. An update of these data will be presented.

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Preliminary immune response (IR) results of a phase 2 study with idiotype (Id) immunotherapy after treatment with CVP and rituximab for follicular non-Hodgkin’s lymphoma (FL)
Authors: Leonard J. P. , Mason K. , Theriault T. , Milner K. , Sornasse T. , Ingolia D. , Mayo M. , Denney D. W.
Published: March 2020

7529

Background: Idiotype (Id) is a collection of unique immunogenic epitopes present on the surface of malignant B cells. Keyhole limpet hemocyanin (KLH) is a carrier protein used to increase antigen immunogenicity. MyVax Personalized Immunotherapy consists of the patient- and tumor-specific Id protein, produced using molecular techniques, conjugated to KLH and administered in a series of subcutaneous immunizations with the adjuvant GM-CSF. Idiotype vaccines were first studied in combination with various chemotherapeutic agents as part of initial treatment for FL. Given the widespread usage of rituximab in treating FL, the nature of IRs in patients immunized with MyVax Personalized Immunotherapy following rituximab treatment are of interest. CD19+ B cell counts following treatment with rituximab were analyzed for correlation with patient-specific Id-KLH induced humoral IR data. Methods: In a Phase 2 study, MyVax Personalized Immunotherapy following rituximab is being evaluated for patients who failed to achieve at least a PR and maintain the response over a 6 month rest period after 8 cycles of CVP chemotherapy. Eligible patients received 4 weekly doses of rituximab followed by a 13 or 26 week rest period. Patients who achieved and maintained a PR or better then received 8 immunizations with MyVax Personalized Immunotherapy over 14 weeks. CD19+ B cells and humoral IRs against Id and KLH were monitored during and 2, 8, 20, 32, 44 and 56 weeks post-immunizations. Results: 87 pts received rituximab. 52 pts went on to immunization. Median CD19 counts for all arms of the study were lower post-rituximab treatment (pre-treatment median = 76 cells/ul (N = 57) vs. post-treatment = 13 cells/ul (N = 51 evaluable); p < 0.0001). Positive results are defined as a titer >0.1 mcg/ml. 49/52 (94%) evaluable pts were able to mount anti-KLH humoral IRs post rituximab. The magnitude of the anti-KLH response was generally greater in pts with higher B cell counts when beginning immunizations. Anti-Id IRs were also observed. Conclusions: Humoral IRs to KLH occur in pts receiving MyVax Personalized Immunotherapy and correlate with regeneration of B cells post-rituximab but appear less robust than in rituximab-naïve pts.

[Table: see text]
Efficacy of radioimmunotherapy with (90Y) ibritumomab tiuxetan is superior as consolidation in relapsed or refractory mantle cell lymphoma: Results of two phase II trials of the European MCL Network and the PLRG
Authors: Weigert O. , Jurczak W. , Von Schilling C. , Giza A. , Rummel M. , Hubalewska A. , Pezzutto A. , Unterhalt M. , Hiddemann W. , Skotnicki A. , Dreyling M.
Published: March 2020

7533

Background: Radioimmunotherapy (RIT) has demonstrated high clinical efficacy in follicular lymphoma but varying results in mantle cell lymphoma (MCL). Methods: We performed a comparative analysis of two phase II studies with similar inclusion criteria to identify potential predictors of response. 32 patients with relapsed or refractory MCL, WHO performance status ≤2, appropriate hematopoesis (ANC > 1,500/mm3, platelets > 100,000/mm3) and adequate function of liver and kidneys were treated with RIT upfront (Arm A, n = 16) or as consolidation after initial cytoreduction (Arm B, n = 16). 28 patients (88%) had been previously treated with rituximab. Patients with >25% bone marrow involvement, known CNS lymphoma, HIV infection or other severe concurrent disease were excluded. Ibritumomab tiuxetan (Zevalin) was applied at a dose of 15 MBq 90Y/kg, whereas patients with reduced platelet counts (<150,000/mm3) received 11 MBq 90Y/kg. Results: The median age was 66.9 years (range 58–72) in Arm A and 63.1 years (range 45–79) in Arm B. The median number of prior regimens was 4 (range 2–6) in Arm A and 1 (1–5) in Arm B. RIT treatment was generally well tolerated with the most common toxicities being hematologic. Thrombocytopenia grade 3 and 4 was observed in 69% of patients, one patient died of hemorrhagic stroke. Granulocytopenia grade 4 occurred in 34% of patients, one patient developed a grade 4 infectious complication. Currently 22 patients are evaluable for response rate and duration of remission (DR). In Arm A a partial response (PR) was observed in 2 of 6 evaluable patients (33.3%) with a median DR of 3.9 months only. In Arm B chemoinduction achieved 2 complete responses (CR) and 14 PR. Following RIT seven of 14 PR patients (50%) converted to CR. Currently, 13 of 16 patients (81%) are still in remission. As expected the most important adverse risk factor was bulky disease before RIT with no responses seen in this patient population. Patients with less prior therapeutic lines (< 2) had significantly higher response rates. Conclusions: In future trials, RIT should be applied earlier in the treatment algorithm of MCL after a debulking strategy with combined immuno-chemotherapy.

[Table: see text]
Allogeneic hematopoietic stem cell transplantation for cutaneous T-cell lymphoma (CTCL)
Authors: Hosing C. , Donato M. , Khouri I. F. , Chu D. T. , Bethancourt D. L. , Acholonu S. , Giralt S. , Duvic M. , Champlin R. E.
Published: March 2020

7540

Background: Patients (pts.) with advanced CTCL have a poor prognosis. There has been limited experience with the use of allogeneic hematopoietic stem cell transplantation (HSCT) in these pts. We report the results of 11 pts. with advanced CTCL/Sezary syndrome who underwent allogeneic HSCT at our institution. Patients and Methods: All pts. signed informed consent. Median age at the time of HSCT was 50.5 years (range, 22–63). There were 8 F/3M. All were diagnosed with stage IV disease. The median number of prior treatment regimens was 5.5 (range, 3–11). Treatment regimens included PUVA, TSEB, ECP, topical therapy, retinoids, bexarotene, denileukin diftitox, and multiagent chemotherapy. Seven pts. had a PR to treatment administered prior to transplantation, 2 pts. were in CRu and 2 pts. had SD. The conditioning regimen was fludarabine (125 mg/m2), melphalan 140 mg/m2 in 8 pts., fludarabine (125 mg/m2), cyclophosphamide (3 g/m2) ± rituximab in 2 pts., and fludarabine (120 mg/m2), busulfan (11.2 mg/m2) in 1 pt. Patients who received unrelated or mismatched related stem cells also received ATG. GVHD prophylaxis was with tacrolimus/methotrexate in all patients. Results: Ten of 11 pts. engrafted with a median time to ANC >500 mm3 of 12 days (range, 8–14). One pt. died at 17 days post transplant without engraftment due to sepsis. One pt. developed autologous reconstitution and underwent a 2nd allogeneic HSCT procedure and remains in CR at 3 years post transplant. Of the remaining 9 pts., 7 achieved full donor chimerism and 2 pts. were mixed chimera. At the time of this report 4 of 11 pts. have died. Cause of death was sepsis in 2, fungal pneumonia in 1, and PD in 1 pt. Three pts. relapsed post transplant, all 3 were induced back in to a CR by tapering of immunosuppression (2) or DLI (1). Overall 7 pts. continue to be alive and remission with a median follow up of 2.9 years (range, 3 months to 4.4 years). Four of 7 pts. have cGVHD requiring treatment (Table). Conclusions: Allogeneic HSCT is an effective therapy for refractory CTCL/SS and merits further evaluation.

[Table: see text]

No significant financial relationships to disclose.
Phase II trial of temsirolimus (CCI-779) in patients with relapsed or refractory multiple myeloma (MM): Preliminary results
Authors: Farag S. S. , Zhang S. , Miller M. , Buckner M. , Kraut E. , Chan K. , Eng C. , Byrd J. C. , Dancey J. E. , Grever M. R.
Published: March 2020

7616

Background: Temsirolimus (TEM) is a novel inhibitor of mTOR, a critical molecule in the PI3K/Akt pathway, which is known to play an important role in transducing mitogenic signals induced by the action of cytokines on MM cells. Methods: We performed a phase II trial to investigate the clinical activity and toxicity of TEM in relapsed/refractory MM patients. Patients had Salmon-Durie stage I-IIIA, failed at least one prior therapy, were ≥18 years, had ANC ≥1.2x109/l, platelets ≥75x109/l, serum Cr ≤1.5 mg/dl, fasting cholesterol ≤350 mg/dl, triglycerides ≤400 mg/dl, and ECOG performance status 0–2. TEM was dosed at 25 mg IV on days 1, 8, 15 and 22 of each 28-day cycle. Treatment was continued until progression. Results: 14 patients are evaluable for response and toxicity. Median age was 62.5 (range, 41–75) years; 8 patients were male. 12 patients had stage IIIA and 1 patient had stage IIA and IA each, respectively. Median β2-mg was 3.3 (range, 2.5–7.9) and CRP was 2.2 (range, 0.5–139). Patients had failed a median of 2 (range, 1–5) prior regimens, and 6 had failed autologous stem cell transplant. Overall, 6 (43%) of 14 patients responded, with 5 achieving minor (26–49% decrease in M-protein) responses, and 1 a partial (>50% decrease in M-protein) response using Bladé criteria. 11 patients progressed on treatment. Overall, median time-to-progression was 4.6 months from start of treatment. Grade 3/4 toxicity included neutropenia (n=2), thrombocytopenia (n=2), interstitial pneumonitis (n=1), nausea (n=1), stomatitis (n=1) and diarrhea (n=1). Response was associated with a maximal reduction in phosphorylated p70S6K (p-p70S6K) and 4EBP1 (p-4EBP1) in peripheral blood mononuclear cells at 48 hours after TEM dosing. The median proportion of p-p70S6K relative to baseline following treatment was 0.38 (range, 0.26–0.84) in responding patients versus 1.65 (range, 0.74–1.66) in non-responders (P=0.0001). Similarly, the median proportion of p-4EBP1 following treatment in responders was 0.49 (range, 0.12–1.25) versus 1.12 (range, 0.73–2.09) in non-responders (P=0.025). Correlation with blood levels of TEM is ongoing. Conclusions: TEM has anti-myeloma activity, and further investigation of TEM as a single agent and in combination therapy is warranted.

No significant financial relationships to disclose.
Reduction of murine osteosarcoma lung metastases using the dipeptidyl peptidase inhibitor talabostat
Authors: Kim S. Y. , Cohen S. A. , Epps J. , Smedley J. , Mendoza A. , Khanna C. , Jones B. , Aziz N. , Helman L. J.
Published: March 2020

9009

Background: Dipeptidyl peptidases comprise a family of serine proteases that includes the genes dipeptidyl peptidase IV (DPP-IV) and fibroblast activation protein (FAP). FAP is expressed in stromal fibroblasts that surround sites of metastatic carcinomas, but not in the tumor cells themselves. Talabostat (valine-proline-boronic acid) is a potent and long-acting inhibitor of dipeptidyl peptidases. It has previously been shown to have anti-tumor activity in preclinical studies. We utilized this compound to determine whether inhibition of dipeptidyl peptidases leads to a decrease in lung metastases using a murine model of osteosarcoma metastasis. Methods: 1×106 K7M3-luciferase murine osteosarcoma cells were injected by tail vein into female Balb/C mice. Mice were then treated by gavage with talabostat (20 ug/dose) twice daily, talabostat once daily, or normal saline twice daily, 5 days on and 2 days off. Half of the mice were analyzed once a week using luminescent imaging. All animals were euthanized on day 24 and the number of lung metastases counted. Results: For the control mice, the average number of surface lung nodules was 75.6 (SD 45.4). Mice treated with talabostat had a ten-fold reduction in the number of nodules (twice daily - average 7.0, SD 6.1, p-value <0.01, once daily - average 3.4, SD 2.4, p-value <0.01). The number of resulting metastatic nodules correlated with luminescent intensity. Conclusions: Mice treated with the dipeptidyl peptidase inhibitor, talabostat, had a ten-fold decrease in the number of visible metastatic lung nodules. Experiments to elucidate the mechanism that links treatment with talabostat and inhibition of metastases are currently being performed.

[Table: see text]
A phase I study of 17-AAG in relapsed/refractory pediatric patients with solid tumors: A Children’s Oncology Groups study
Authors: Weigel B. , Blaney S. , Kersey J. , Bagatell R. , Ivy S. P. , Whitesell L. , Krailo M. , Reid J. , Ames M. , Adamson P.
Published: March 2020

9018

Background: A pediatric phase I study of 17-allylaminogeldanamycin (17-AAG), an Hsp90 inhibitor, was conducted to determine the dose limiting toxicities (DLTs), the recommended phase II dose, the pharmacokinetics (PK), and to evaluate a surrogate marker for Hsp90 inhibition in peripheral blood mononuclear cells (PBMCs). Methods: Cohorts of 3–6 pts were enrolled at dose levels of 150, 200, 270 and 360 mg/m2/dose, administered as a 60 min infusion, on days 1, 4, 8 and 11 of a 21-day cycle. PK and PBMC evaluations were done during the first course of therapy. Results: 17 pts (7 male), median 7 yrs of age (range 1–19), were enrolled. 5 pts who developed PD prior to completing a full cycle of therapy were not considered evaluable for toxicity. No DLTs occurred. Non-DLTs included elevated transaminases (n=6), anemia (n=3), and vomiting (n=3). Based on the adult recommended dose and challenges posed by infusing the large volumes of DMSO, dose escalation was stopped at dose level 4. No CRs or PRs were observed; 3 patients remain on therapy at 6, 7 and 9 months with SD. One patient with hepatoblastoma had a reduction in AFP and SD over 3 cycles. PK data is available from the initial 3 dose levels. Drug exposure increases in proportion to dose for both17-AAG and its metabolite 17-AG. At 270 mg/m2/dose the Cmax and AUC of 17-AAG were 5,303 ± 1,591 ng/ml and 13,150 ± 5,086 ng/ml*hr, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.0 ± 0.5 hrs. Induction of Hsp72, a surrogate marker for inhibition of Hsp90 was detected at all dose levels. Conclusions: The recommended phase II dose of 17AAG is 360mg/m2/day. Non-DMSO formulations may allow for further dose escalation in children and should be studied.

No significant financial relationships to disclose.
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of 17-Allylamino-17-demethoxygeldanamycin (17AAG) in children with solid tumors
Authors: Bagatell R. , Gore L. , Egorin M. , Ho R. , Boucher N. , Heller G. , Trippett T.
Published: March 2020

9022

Background: 17AAG is a benzoquinone ansamycin that binds to heat shock protein 90 (Hsp90) and alters levels of cancer-associated proteins that are regulated by Hsp90. 17AAG has been well-tolerated in adults, but has not previously been administered to children. Methods: A Phase I study of 17AAG was initiated to define the maximally tolerated dose and toxicity profile of this drug in children. PK and PD were also studied. Cohorts of 3–6 patients with recurrent or refractory solid tumors were treated every 21 days with escalating doses of 17AAG twice weekly for two weeks. Plasma PK of 17AAG and its major metabolite, 17AG, were measured on day 1 by HPLC. Changes in levels of the inducible isoform of Hsp70 were assessed by Western blot using peripheral blood mononuclear cells (PBMCs) obtained 24 h after the 17AAG infusion. Actin was measured for comparison. Because 17AAG is a substrate for CYP3A4/5 and MDR1, pharmacogenetic analyses have been undertaken to determine if genotypes including CYP3A4*1B, CYP3A5*3, and MDR1 G2677T/A and C3435T influence 17AAG disposition. Results: 12 pts (median age 11 years, range 5–18) with neuroblastoma (5), osteosarcoma (4), Ewing’s family tumors (2), and desmoplastic small round cell tumor (1) have been treated with 17AAG. An MTD has yet to be defined though one dose limiting toxicity (Grade 3 hypoxia) was observed at Dose Level 4 (360 mg/m2). The AUC of 17AAG increased with dose, with a linear relationship between end of infusion 17AAG plasma concentration and AUC. The AUC of 17AAG increased with dose, with a linear relationship between end of infusion 17AAG plasma concentration and AUC. Clearance ranged between 12.5 and 29.6 l/hr/m2 (median, 21.6 l/h/m2) and did not change with increasing doses. Post-treatment increases in Hsp70 in PBMCs have been observed in pts treated with 17AAG doses at or above 150 mg/m2. Declines in Akt and IGF1R in PBMCs have been seen in some but not all pts following treatment. Conclusions: 17AAG is well tolerated in children at dose levels studied to date. 17AAG dose escalation continues and at the time of the meeting, updated data will be reported.

No significant financial relationships to disclose.
Difference in outcome of adolescents (14–17 years) with acute lymphoblastic leukemia (ALL) enrolled in the Italian pediatric (AIEOP) and adult (GIMEMA) multicenter protocols
Authors: Testi A.
Published: March 2020

9024

Background: Progress in the treatment of acute lymphoblastic leukemia (ALL) has led to better survival rates; however, this benefit has not extended in the same proportion to adolescents who retain a lower cure rate, compared to younger patients. Based on some recent reports, adolescents treated on pediatric ALL trials seem to have a significantly better event free-survival (EFS) than those treated on adult trials. Methods: We retrospectively compared the results obtained in 242 adolescents enrolled either in the national cooperative pediatric (AIEOP; n=150) or adult (GIMEMA; n=92) ALL trials, between 4/1996 and 10/2003. Results: The characteristics of the patients at diagnosis in the two groups under examination were comparable except for age (median age: 15 in the AIEOP vs 16 in the GIMEMA trials). Adolescents in the AIEOP protocols had a better complete remission (CR) rate (97%) compared to those treated with the GIMEMA protocols (89%). Overall treatment results estimated at 2 years were significantly superior for patients treated in the pediatric trials: survival 81% vs 71% and EFS 78% vs 47%. This difference was significant also at the multivariate analysis. Conclusions: Our results support, in keeping with other studies, the concept that adolescents with ALL have a better outcome if treated in pediatric trials.

No significant financial relationships to disclose.
Factors affecting event free survival (EFS) after high dose chemotherapy with stem cell rescue (HDC/SCR) in children with brain tumors
Authors: Aguayo J. , Teplick A. , Butturini A. , Erdreich-Epstein A. , Jubran R. , Villablanca J. , Hyder D. , Britt B. , Finlay J.
Published: March 2020

9057

Background: HDC/SCR is a novel approach for treatment of children with brain tumors. Despite several studies suggesting results are better in children with primitive neural ectodermal tumors (PNET) or medulloblastoma (MB), it is controversial whether other factors can predict outcome. Methods: We retrospectively analyzed data from 53 patients who underwent HDC/SCR for brain tumors at Children Hospital Los Angeles between June 1992 and June 2005. Patients were aged 4 months to 15.8 years at diagnosis and 9 months to 18.1 years at transplant. In all cases the conditioning regimen included thiotepa and/or etoposide and/or carboplatin. The variables considered were age at diagnosis, histology, extent of disease, conditioning regimen, radiation therapy, stem cell type and timing of transplant. Results: Diagnoses included 33 PNET/MB, 8 high-grade gliomas, 5 ependymomas, 3 germinomas, 2 choroid plexus carcinomas and 2 rhabdoid tumors. Overall event free survival at 36 months was 53±9.1% in PNET/MB and 40±15.5% in tumors with other histology. Variables associated with better EFS in PNET/MB were no prior progression (p=0.00094), no spread into bone marrow (p=1.2 E-10) and age less than 3 years at diagnosis (p=0.046). There was a trend toward improved outcome if there was gross total resection of the tumor (p=0.11). Patients with PNET transplanted before progression had better EFS if they had localized disease at diagnosis (p=0.00024), and if gross total surgical resection was accomplished (p=0.11). Patients with PNET/MB transplanted after progression had better EFS if there was no spread of disease into blood or bone marrow (p=0.00023), if they were male (p=0.053), had localized disease at relapse (p=0.12) and if radiotherapy was given after transplant (p=0.053). In patients with tumors of other histology, the only variable associated with prolonged EFS was gross total resection (p=0.026). Conclusions: Children most likely to benefit from HDC/SCR for brain tumors are those less than 3 years old who are newly diagnosed with PNET that is locally confined, and those with a non-PNET diagnosis who have gross total resection of tumor.

No significant financial relationships to disclose.
Medulloblastoma incidence has not changed over time: A CBTRUS study
Authors: Fisher P. G. , Curran E. K. , Cobb K. L. , Le G. M. , Propp J. M.
Published: March 2020

9058

Background: Past studies of medulloblastoma (MB) present conflicting claims about declines and rises in MB incidence, possibly due to misclassification. By using a strict classification of the disease and a rigorous analysis of a data registry, we aimed to determine the incidence trends of MB over the last three decades. Methods: 441 MB patients diagnosed between 1985 and 2002 were identified from the Central Brain Tumor Registry of the United States (CBTRUS), a data set representing approximately 5% of the American population (6 registries). MB was strictly defined and non-cerebellar embryonal tumors (primitive neuro-ectodermal tumors [PNETs]) excluded, using histology and site codes. Multiplicative Poisson regression and joinpoint regression were performed (Joinpoint Regression Program, version 3.0, Statistical Research and Applications Branch, National Cancer Institute) to determine the estimated average annual percentage change (EAPC) and sharp (i.e., acute) changes in incidence, respectively. Results: A slight but nonsignificant (p=.18) increase in medulloblastoma was demonstrated (EAPC = 1.1), and no sharp changes in incidence were found (joinpoints = 0). The analysis was repeated with a less strict definition of MB (including non-cerebellar PNETs) and 559 patients were identified. Using this broader classification scheme, there was a statistically significant increase in incidence (p=.02, EAPC = 1.6), but no sharp changes in incidence (joinpoints = 0). Conclusions: MB incidence does not appear to have changed since the 1980s. “Medulloblastoma” incidence increased only when the diagnosis was not strictly defined and misclassified by including non-cerebellar PNETs in the analysis. The observed increase in the combined MB/PNET classification may relate to the PNET hypothesis–a proposal that all brain tumors of apparently undifferentiated neuroepithelial cells be considered a unique diagnostic group–popularized in the 1980s and early 1990s.

No significant financial relationships to disclose.
Role of amifostine as a cytoprotectant in children ≥ 3 years with average risk (AR) medulloblastoma (MB) treated with craniospinal irradiation (CSI) and 4 courses of cisplatin (CDDP)-based high dose chemotherapy
Authors: Fouladi M. , Chintagumpala M. , Ashley D. , Kellie S. , Broniscer A. , Merchant T. E. , Kun L. E. , Stewart C. , Wallace D. , Gajjar A.
Published: March 2020

9063

Background: Therapy for MB (CSI and CDDP-based chemotherapy) results in hearing loss before completion of therapy in 30%-50% of patients, who consequently require a reduced cisplatin dose. Cytoprotection against cisplatin-induced ototoxicity may be provided by amifostine, a thiol prodrug that protects many normal tissues against therapy-induced damage without diminishing antitumor effects. Method: This study was designed to detect a 20% decrease (80% power) in CDDP induced ototoxicity (defined as needing hearing aids) in AR MB patients with the use of amifostine (n=62) compared to historical controls (n=35) one year from diagnosis. An interim analysis was conducted after accrual of 32 pts on the experimental arm. A total of 67 AR MB patients received CSI (23.4 Gy) followed by 3-dimensional conformal boost to the tumor bed (total 55.8 Gy) and 4 cycles of high-dose cyclophsophamide (4,000 mg/m2 per cycle), cisplatin (75 mg/m2 per cycle), and vincristine (two 1.5 mg/m2 doses per cycle). When used, amifostine (600 mg/m2 per cycle) was given before and 3 hours into the cisplatin infusion. Results: The median age of the 40 male, 27 female patients was 8.7 (range, 3.2–20.2) yrs. The 2 groups had similar median ages (amifostine, 9.1; control, 7.8 years) and gender (male: amifostine, 66%; control, 54%). One year after the start of treatment, the objective criteria for needing a hearing aid in at least 1 ear were met by 13 (37%) of control-group patients and 6 (18.8%) of those who received amifostine. Conclusion: The interim analysis has demonstrated that the need for hearing aids in AR MB children treated with the above-described regimen is halved by using amifostine during CDDP administration.

No significant financial relationships to disclose.
Is a stable disease according to RECIST criteria a real stable disease in GIST patients treated with imatinib mesylate (IM) included in the intergroup EORTC/ISG/AGITG trial?
Authors: Le Cesne A. , Van Glabbeke M. , Verweij J. , Casali P. , Zalcberg J. , Reichardt P. , Issels R. D. , Judson I. R. , Blay J. Y.
Published: March 2020

9510

Background: From 2/2001 to 2/2002, 946 patients (pts) with advanced GIST were randomized to IM at two dose levels within a controlled EORTC/ISG/AGITG trial. This analysis investigates whether achievement of an objective response, according to the RECIST criteria, has any predictive value for time to progression (TTP) and overall survival (OS). Methods: According to the protocol, the 3 first disease measurements were foreseen at 2, 4, and 6 months (m). Results of those measurements were classified in 6 categories: PR (>30% reduction of the tumor load), MR (10–30% reduction), NC- (0–10% reduction), NC+ (0–20% increase), PD (> 20% increase or new lesions), and subjective PD (clinical PD, no measurements). Pts included the analyses were those still followed at the measurement point, who had not previously progressed. Results: A total of 906 pts had measurable disease at entry; from those, 852 were evaluable at 2 m, 681 at 4 m and 642 at 6 m. At all measurement time points, PR and MR resulted in similar TTP and OS; this was also true for NC- and NC+, and for PD and subjective PD. As an example, for the evaluation at 4 m, the median TTP was respectively 2.50, 2.55, 1.86, 1.65, 0.31 and 0.30 years in the 6 groups of pts, while the 3 years OS estimate were 71%, 72%, 57%, 56%, 32% and 0%. Pts were subsequently classified as responders (more than 10% reduction of the tumor load), no change (less than 10% reduction and less than 20% increase) and PD (> 20% increase, new lesions or clinical PD). This new response category is highly predictive of further progression or survival, for the 2 first measurements points, and in both therapeutic arms, but pts stable at 6 m had the same survival as responders at 6 m. In addition, RECIST response documented at 2, 4 and 6 m resulted in similar TTP and OS. Conclusions: The RECIST criteria are only optimal for identifying IM-resistant GISTs (PD > 20%) and not adequate for the evaluation of IM efficacy. All pts exhibiting at least a 10% reduction (until complete response) of the tumor load have to be considered as responders to IM (IM-sensitive GISTs). A real stabilisation of the disease consisting in a less than 10% tumor reduction and a less than 20% tumor increase identifies pts who have an intermediate sensitivity to IM.

[Table: see text]
Patterns of tumor response to trabectedin (ET743) in myxoid liposarcomas
Authors: Grosso F. , Demetri G. D. , Blay J. Y. , Judson I. , Le Cesne A. , Spreafico C. , Jimeno J. , Pilotti S. , D’Incalci M. , Casali P. G.
Published: March 2020

9511

Background: Trabectedin (T) is a marine-derived agent found to be active in ovarian cancer and sarcomas. Among sarcomas, activity has been notable in leiomyosarcomas and liposarcomas. Since liposarcomas are a heterogeneous group, including well/de-differentiated, pleomorphic, and myxoid/round cell subtypes, we have noted particularly interesting patterns of responsiveness to T in myxoid liposarcomas, which are associated with t(12;16)(q13;p11) or t(12;22)(q13;q12) chromosomal translocations, resulting in CHOP-TLS or CHOP-EWS fusion products. Methods: 15 cases of myxoid liposarcomas treated with T at the Istituto Nazionale Tumori, Milan, were retrospectively reviewed. In most cases, T was given as a 24-hr continuous infusion every 21 days, at dose levels from 1.0 to 1.5 mg/sqm. 108 courses were delivered, with a median of 5 courses per patient (range 2–20). Observations made in this series were shared with five other institutions having treated myxoid liposarcoma cases with T, all of which also report a significant response rate, for a total of 44 pts. A centralized radiological review of all pts is ongoing. Results: In the Milan series, early tissue alterations in tumors were observed in 14 patients, mainly with a decrease in tumor density on CT scan and/or decrease in contrast enhancement on MRI. These changes were followed by tumor shrinkage amounting to a conventional PR/CR in 8 (pending final review), while 3 others have responses which continue to evolve. Progression followed treatment interruption in one patient, with a minor response occurring at treatment restart. Treatment is continuing in 12 pts (median duration of therapy in excess of 5 months). Further results of the central radiological review from all centres will be reported. Conclusions: Tumor response to T seen in myxoid liposarcoma appears to be marked by early radiological alterations in tumor tissue, often preceding tumor shrinkage, which may be delayed. A selective mechanism of action for this chromosomal translocation-related sarcoma is suggested, and is being actively investigated at the moment.

[Table: see text]
Phase II study of erlotinib in metastatic or unresectable malignant peripheral nerve sheath tumors (MPNST)
Authors: Albritton K. H. , Rankin C. , Coffin C. M. , Ratner N. , Budd G. T. , Schuetze S. M. , Randall R. L. , Declue J. E. , Borden E. C.
Published: March 2020

9518

Background: MPNSTs are rare soft tissue tumors (STS) that are relatively resistant to chemotherapy. 26% have epidermal growth factor receptor (EGFR) amplification. In preclinical studies, NF1/p53 murine MPNSTs in vitro are stimulated by EGF and inhibited by EGFR inhibitors. We proposed to assess response rate (RR) to erlotinib in adult patients with unresectable or metastatic MPNST. Methods: Patients (pts) were required to have measurable disease, Zubrod performance status (PS) <3, adequate organ function, no prior EGFR therapy, and centrally reviewed confirmation of diagnosis. Treatment was erlotinib 150 mg by mouth daily, in continuous 28 day cycles. Disease evaluation was performed every 2 cycles. Results: 24 pts enrolled in 22 months, from 13 institutions. 20 pts were deemed eligible. Median age was 45.3 years; 50% had neurofibromatosis. At enrollment, 15 had a PS of 0–1, 18 had metastatic disease, and 19 had unresectable disease. Pts were heavily pretreated: 9 pts had ≥ 2 prior regimens, 6 pts had 1 prior regimen, and 4 pts had no prior chemotherapy (1 unknown). 19 of 20 pts were assessable for toxicity: 6 pts had grade 3 toxicities; only 1 was hematologic (anemia). Mild rash (in 15 pts) and fatigue (in 8 pts) were the most common side effects. 20 pts were evaluable for response: 1 had stable disease after first evaluation and 19 had no response. Median progression-free survival was 2 months. 14 patients have died; median overall survival was 4 months. Because no objective responses were observed in the first stage of the study, it was closed to further accrual. Conclusions: We were able to accrue pts with a rare STS to a phase II histology specific study through a single adult cooperative group. In spite of preclinical promise of EGFR inhibition, erlotinib does not appear to be active in MPNSTs. To further understand the role of EGFR in MPNST, we are assessing EGFR expression immunohistochemically and performing quantitative PCR for genes altered by EGFR stimulation/inhibition on pt tumors.

No significant financial relationships to disclose.
Evaluation of SRC-family kinases in gastrointestinal stromal tumors
Authors: Bauer S. , Demetri G. D. , Fletcher J. A.
Published: March 2020

9529

Background: Inhibition of KIT oncoproteins by imatinib mesylate (IM) induces clinical responses in most GIST patients. However, many patients develop IM-resistance and novel KIT-Inhibitors show clinical benefit in only a minority of patients. SRC-family kinases (SFK) are important participants in kinase oncoprotein signaling pathways in ALL and CML, and dual-specificity SRC/ABL-inhibitors show promising activity in IM-resistant CML in vitro. However, little is known about SFK functional roles in IM-resistant GIST. Methods: GIST were analyzed for SFK expression and activation by western blotting. Biological consequences of KIT inhibition alone (IM), SFK inhibition (SU6656) and combined KIT/SFK inhibition (PP1, PP2, SU6656+IM) were determined by immunoblotting for protein activation, and—in GIST cell lines—by luminescence assays for cell proliferation. Results: Primary GIST and GIST cell lines showed weak SFK activation compared to Jurkat (T-cell ALL) controls. Variable expression of the SFK proteins FYN, LYN and SRC (but not BLK and LCK) was shown in the cell lines and primary GIST. Expression of SFK proteins HCK and FGR was found in 2 primary GIST only. KIT and KIT signaling pathways (pAKT, pS6, pSTAT3) were affected by IM and combined KIT inhibitors but not by SU6656 at 1μM in GIST882 (IM-sensitive cell line) and GIST48 (IM-resistant cell line). SRC phosphorylation (Y418) was not affected by IM or SFK-inhibitors at 1μM. IM showed superior inhibition of proliferation compared to PP1 and PP2 (1μM) in GIST882 (IM: 67%, PP1: 1%, PP2: 0%) and comparable inhibition in GIST48 (IM:30%, PP1: 29%, PP2: 29%). No effects on proliferation were seen with SU6656 alone or in combination with IM; no antagonistic effects were observed. Conclusions: Our analysis showed expression and weak activation of several SFK in GIST. Expression of heme-associated SFKs in primary GIST may be explained by lymphocellular infiltration. Biochemical inhibition of SFK alone does not have antiproliferative effects in GIST cell lines, and no synergies or antagonisms were found in combination with IM or with combined KIT/SFK inhibitors. Therefore, targeting of SFK may be of less therapeutic value in GIST than in kinase-driven haematological cancers.

No significant financial relationships to disclose.
A phase II, open-label study of PTK787/ZK222584 in the treatment of metastatic gastrointestinal stromal tumors (GISTs) resistant to imatinib mesylate
Authors: Joensuu H. , De Braud F. , Coco P. , De Pas T. , Spreafico C. , Bono P. , Jalava T. , Laurent D. , Casali P.
Published: March 2020

9531

Background: PTK787/ZK222584 (PTK/ZK) is a novel, oral selective inhibitor of certain receptor tyrosine kinases that may be important in the molecular pathogenesis of GIST (KIT, PDGFRs, VEGFR-1 and VEGFR-2). The efficacy and safety of PTK/ZK are not known in the treatment of imatinib resistant GIST. Methods: Pts who had histologically diagnosed, metastatic GIST that had progressed after at least 4 weeks of treatment with imatinib were eligible. Prior therapy with KDR inhibitor therapy was not allowed. PTK/ZK was administered orally 1,250 mg once daily until treatment failure. No concomitant systemic cancer treatments were allowed. Treatment response was monitored at 4 to 8 wk intervals and evaluated using the RECIST criteria. Adverse events (AE) were scored using the NCI/NIH Common Toxicity Criteria v. 2.0. A total of 15 pts were planned to be accrued as a 2-stage procedure. The highest prior imatinib dose: 400 mg, n=1; 600 mg, n=2; 800 mg, n=11; 1,000 mg, n=1. Prior response to imatinib: PR, n=8; SD, n=5; PD, n=1; unknown, n=1. Results: All 15 pts (M 12, F 3) enrolled were eligible. Two (13%) pts achieved PR, 8 (53%) had SD for 3 months or longer, and 5 progressed. The clinical benefit rate (PR+SD) was 67% (95% CI, 38% to 86%). The duration of the 2 PRs was 95 + and 225+ days and 8 SDs from 93+ to 346+ days. All PRs and SDs are ongoing to date. The median time to treatment failure (TTTF) has not been reached. PTK/ZK was well tolerated. The most frequently recorded AEs were dizziness (n=6), nausea/vomiting (n=6), abdominal pain/abdominal pain upper (n=4) and asthenia (n=4). All recorded AEs were either of grade 1 or 2 except for 2 events (grade 4 hypercalcemia, n=1; grade 4 pain, n=1). Conclusions: PTK787/ZK222584 showed signs of activity in this series of GIST patients who progressed during imatinib treatment. The dose of 1,250 mg o.d. is generally well tolerated.

[Table: see text]
The criteria of aggressiveness and other prognostic factors for predicting relapses of primary tumors and imatinib (IM) treatment outcomes in advanced KIT immunopositive gastrointestinal stromal tumors (GIST): A report of the Polish Clinical GIST Registry (PCGR)
Authors: Rutkowski P. , Nowecki Z. I. , Michej W. , Debiec-Rychter M. , Limon J. , Siedlecki J. A. , Kakol M. , Gluszek S. , Osuch C. , Ruka W.
Published: March 2020

9544

Background: The development of adjuvant treatment trials with imatinib in GIST has raised the debate about the accuracy of NIH risk criteria consensus and about the significance of other prognostic factors. Methods: We analyzed the criteria of aggressiveness and other clinico-pathological and genetic factors influencing disease-free survival (DFS) in patients with primary CD117-positive tumors (group I: 274 patients; median follow-up 29 months; calculated from primary tumor resection) and progression-free survival (PFS) in metastatic/unresectable GIST patients treated with IM (group II: 179 patients; median follow-up 19 months; calculated from the start of imatinib therapy) enrolled into PCGR. Results: In group I statistically significant (p<0.05) factors negatively influencing DFS both in univariate (log-rank test) and multivariate (Cox’s model) analysis were: primary tumor size > 5 cm, mitotic index > 5/50HPF, male gender, primary tumor R1 resection or tumor rupture, non-gastric primary tumor localization and intermediate/high risk group (3-year DFS for high, intermediate and low/very low risk group was: 28%, 75% and 99%, respectively). In group II we identified 5 factors negatively affecting PFS statistically significant both in univariate and multivariate analyses (p<0.05): tumor genotype indicating other than exon 11 KIT mutation, mitotic index > 10/50HPF, age below 45 years at diagnosis, high baseline pre-IM granulocyte count and poor WHO performance status ≥ 2. Conclusions: We validated the value of criteria of risk groups for the assessment of the natural course of primary GIST, but we also identified additional independent prognostic factors. For the prediction of PFS during IM therapy for advanced GIST we detected 5 different, independent biological and pathological factors.

No significant financial relationships to disclose.