bluuebunny/crossref_metadata_2025 huggingface dataset:
Pertuzumab in combination with trastuzumab plus an aromatase inhibitor in patients with hormone receptor-positive, HER2-positive metastatic breast cancer: A randomized phase II study (PERTAIN).
Authors: Rimawi Mothaffar F. , Poole Christopher John , Ferrero Jean-Marc , De la Haba Rodriguez Juan R. , Mitchell Lada , Pelizon Christina H. , Arpino Grazia
Published: March 2020

TPS654^

Background: Resistance to endocrine therapy in patients (pts) with breast cancer remains a major clinical concern. Preclinical studies suggest that complete blockade of the hormone receptor (HR) combined with the inhibition of HER family members may be necessary to overcome resistance and improve clinical outcome in HR-positive and HER2-positive breast cancer (BC). The combination of pertuzumab (P) and trastuzumab (H) with docetaxel significantly improves patient outcome by blocking, more efficiently and completely, the HER signalling pathway. This benefit, however, may be smaller in HR-positive patients. PERTAIN is the first clinical trial to study whether a more potent blockade of the HER pathway with P and H in combination with endocrine therapy may restore or enhance endocrine sensitivity of HER2-positive BC and provide an effective treatment option in pts with HER2-positive and HR-positive MBC. Methods: PERTAIN is a multicenter, open-label, Phase II trial for post-menopausal women with HER2- and HR-positive BC, studying the efficacy of the combination of P plus H with an aromatase inhibitor (AI) as first-line therapy for MBC. Pts will be randomized 1:1 to Arm 1 (P: 840 mg loading dose, 420 mg q3w IV; H: 8 mg/kg loading dose, 6 mg/kg q3w IV; AI [anastrozole 1 mg or letrozole 2.5 mg qd po]) or Arm 2 (H + AI at same dose as Arm 1). Pts in either arm may also receive induction chemotherapy (docetaxel or paclitaxel) for up to 18 weeks at the investigator’s discretion. Study medication will be administered until disease progression or unacceptable toxicity. Pts must not have previously been treated with anti-HER2 agents except H and/or lapatinib in the (neo)adjuvant setting, and must have no CNS involvement or clinically significant cardiovascular disease. The primary endpoint is PFS, and secondary endpoints include overall survival, overall response rate, clinical benefit rate, duration of response, time to response, safety and tolerability, and quality of life. The study opened in January 2012 and will recruit 250 pts. Analysis of the primary endpoint will be performed after 165 PFS events using the Kaplan-Meier approach.
A phase I study of MM-302, a HER2-targeted liposomal doxorubicin, in patients with advanced, HER2-positive (HER2+) breast cancer.
Authors: Munster Pamela N. , Miller Kathy , Krop Ian E. , Dhindsa Navreet , Reynolds Joe , Geretti Elena , Niyikiza Clet , Nielsen Ulrik , Hendriks Bart , Wickham Thomas J. , Moyo Victor M. , LoRusso Patricia
Published: March 2020

TPS663

Background: Anthracyclines have been an effective backbone of breast cancer therapies for decades. However, cardiotoxicity issues associated with free anthracyclines have limited their effective use in the clinic and led to the exploration of anthracycline-free regimens, particularly with HER2-positive cancers that require treatment with another cardiotoxic agent, trastuzumab. While liposomal doxorubicin formulations have succeeded in reducing cardiotoxicity, they have failed to demonstrate clear-cut efficacy advantages and can involve other toxicities. To address the safety and efficacy limitations of currently available anthracyclines, we have designed a new liposomal formulation, MM-302, that targets doxorubicin to HER2-overexpressing tumor cells. Antibody fragments that bind to HER2 without blocking HER2-mediated signaling are coupled to the outer surface of pegylated liposomal doxorubicin. MM-302 specifically binds and enters tumor cells overexpressing HER2 with minimal uptake into normal cells such as cardiomyocytes which express low levels of HER2. This first-in-human phase I study evaluates the safety of MM-302 in patients and provides preliminary efficacy data in HER-2+ advanced breast cancer (ABC). Methods: Patients aged > 18 years with histologically confirmed HER-2+ advanced breast cancer that have progressed or recurred on standard therapy or for which no standard therapy exists who have adequate performance status, bone marrow reserve, and organ function, are eligible for the study. Following a standard 3 + 3 dose escalation design, the maximum tolerated dose (MTD) or maximum feasible dose (MFD) is determined and up to 25 additional patients with HER-2+ ABC will be enrolled for a planned total of 40-49 patients. The primary endpoint is determination of the MTD/MFD. Secondary endpoints include determination of dose-limiting toxicity, adverse event(s), and pharmacokinetic and immunogenicity profiles of MM-302, as well as overall response and clinical benefit rates of MM-302. MM-302 is administered intravenously weekly in 4-week cycles. At the time of this submission, 8 patients have been enrolled in the dose escalation portion.
JAKARTA: A phase III, multicenter, randomized, double-blind, placebo-controlled, three-arm study of SAR302503 in patients with intermediate-2 or high-risk primary myelofibrosis (MF), post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF with splenomegaly.
Authors: Pardanani Animesh Dev , Cortes Jorge E. , Cervantes Francisco , Harrison Claire N , Passamonti Francesco , Lebedinsky Claudia , Neumann Frank , Cohen Pamela , Tefferi Ayalew
Published: March 2020

TPS6639

Background: SAR302503 is an orally administered selective JAK-2 inhibitor being evaluated for the treatment of MF. In a phase 1 study, SAR302503 reduced spleen size and disease-related symptoms and provided clinical benefit, including a reduction in the JAK2V617F allele burden, with an acceptable safety profile in patients with primary MF, post-PV MF, or post-ET MF (J Clin Oncol 2011;29:789). An ongoing open-label extension of this trial confirmed the durability of those results and found that doses between 400–500 mg/day of SAR302503 represented the optimal balance between safety and efficacy (Pardanani, ASH 2011;Abs 3838). These results led us to initiate a Phase 3 trial in December 2011 to evaluate SAR302503 at doses of 400 mg/day and 500 mg/day, compared with placebo, for the treatment of patients with MF (NCT01437787; EFC12153). Methods: Eligibility criteria include age of at least 18 years, platelets >50,000/µl, ECOG PS 0–2, and a diagnosis of high- or intermediate-risk 2 primary MF, post-PV MF, or post-ET MF according to IPSS criteria (Blood 2009;113:2895). Patients are being randomized (1:1:1) to receive 400 mg or 500 mg of SAR302503 or placebo orally once a day for at least 6 consecutive 28-day cycles. Assigned treatment will continue as long as patients are deriving benefit or until progression or unacceptable toxicity. Cross-over is allowed after 6 cycles or in case of progression before completion of 6 cycles according to predefined criteria. The primary endpoint is spleen response (≥35% reduction in spleen volume by MRI/CT at the end of cycle 6). Key secondary objectives are symptom response rate and durability of spleen response. Additional secondary endpoints include assessment of allele burden and bone marrow fibrosis reduction. It is planned to randomize 75 patients per treatment group at approximately 130 sites worldwide.
A phase I study of BKM120, a novel oral selective phosphatidylinositol-3-kinase (PI3K) inhibitor, in combination with fulvestrant in postmenopausal women with estrogen receptor positive metastatic breast cancer.
Authors: Nagaraj Gayathri , Ma Cynthia X. , Luo Jingqin , Ellis Matthew J.
Published: March 2020

TPS664

Background: PI3K pathway activation plays a crucial role in mediating endocrine therapy resistance in estrogen receptor positive (ER+) breast cancer. We have shown previously that BKM120 in combination with fulvestrant induced synergistic apoptotic cell death in long-term estrogen deprived ER+ breast cancer (LTED) cell line models, supporting the clinical investigation of this combination in ER+ breast cancer. Methods: The study is composed of the dose escalation cohort (phase IA) and the expansion cohort (phase IB). In phase IA, a standard 3+3 phase I design is employed to determine the maximum tolerated dose (MTD) of the combination of BKM120 and fulvestrant in patients (pts) with ER+ metastatic breast cancer (MBC). In phase IB, an additional 10 pts will be enrolled at the MTD to further examine the toxicity profile and preliminary efficacy of this combination. Steady state concentrations of BKM120 will be analyzed. Postmenopausal women with ER+ MBC and measurable disease per RECIST are eligible. Pts who are currently taking fulvestrant without disease progression are eligible. There is no restriction on the number of prior lines of systemic therapy for metastatic disease in phase IA but < 3 lines is required in phase IB. Treatment consists of fulvestrant 500 mg IM administered monthly on day (d) 1 of each 28-d cycle, following the loading dose of 500 mg on d1 and d15, and BKM120 orally daily on d1-28 of each cycle. The starting dose level (DL) is DL1 (Table). Correlative studies include assessing PI3K pathway abnormalities (loss of PTEN and PIK3CA mutation) on archival tumor specimen, and treatment induced inhibition of PI3K pathway activity (pAKT, pS6, Cyclin D1, subcellular localization of FOXO3a, phosphoproteomics), tumor cell proliferation (Ki67) and apoptosis (cleaved caspase 3 or TUNEL staining) on tumor biopsies collected at baseline and cycle 2 day 1 in consented patients. Enrollment to DL1 is complete and the study is currently enrolling pts to DL2. [Table: see text]
ASTER 70s: Benefit of adjuvant chemotherapy for estrogen receptor-positive HER2-negative breast cancer in women over 70 according to genomic grade—A French GERICO/UCBG UNICANCER multicenter phase III trial.
Authors: Brain Etienne , Girre Veronique , Rollot Florence , Bonnetain Franck , Debled Marc , Lacroix Magali , Baffert Sandrine , Latouche Aurelien , Falandry Claire , Peyro Saint Paul Helene P. , Orsini Christine , Andre Fabrice , Bonnefoi Herve R. ,   UNICANCER GERICO and UCBG groups
Published: March 2020

TPS667

Background: The benefit of adjuvant chemotherapy (CT) is highly controversial for elderly breast cancer (BC) women presenting with an oestrogen receptor-positive (ER+) HER2-negative (HER2-) phenotype. Conversely to hormonal treatment (HT) that remains the cornerstone of adjuvant treatment for such luminal tumours, CT may severely decompensate comorbidities and alter quality of life in elderly patients. As disappointing as it is in drug development, elderly have been constantly excluded from trials evaluating new modern prognosis classifiers. This prospective multicentre trial funded by a French national grant (PHRC 2011) is the first phase III trial to investigate the impact on overall survival (OS) of adjuvant CT in elderly ER+ HER2- BC patients selected with a modern prognosis classifier and taking into account competing risks for mortality (EudraCT 2011-004744-22). Methods: Following surgery, 2,000 women 70+ with ER+ HER2- BC (any pT/pN), will have a genomic grade (GG, derived from frozen MapQuantDx™, Ipsogen) centrally assessed on formalin-fixed paraffin-embedded samples. Only those with a high GG (estimation~700) will be randomized between HT alone vs CT followed by HT. CT regimen is left to the choice of investigators amongst 3 regimen of same duration [4 q3w cycles, docetaxel+cyclophosphamide, doxorubicin or non pegylated liposomal doxorubicin (Myocet)+cyclophosphamide, all with G-CSF], as well as HT (aromatase inhibitor±tamoxifen). Those with low GG or not included for other reasons (estimation~1,300) will be followed as an observational parallel cohort with HT alone. Sample size is based on 4-year OS as primary endpoint (87.5 vs 80%), bilateral α=0.05, β=0.20 and HR= 0.60. Secondary endpoints include assessment of competing risks for mortality, cost-effectiveness and Q-TWiST analysis, geriatric items (e.g. Lee’s 4-year mortality score and G8 screening tool), acceptability, quality of life (QLQ-C30 and specific elderly scale ELD15), and translational research on ageing/prognostic biomarkers and pharmacogenetic. The trial has been just opened to inclusion in February 2012.
IFCT-GFPC-0701 MAPS trial, a multicenter randomized phase III trial of pemetrexed-cisplatin with or without bevacizumab in patients with malignant pleural mesothelioma (MPM).
Authors: Zalcman Gerard , Mazieres Julien , Scherpereel Arnaud , Margery Jacques , Moro-Sibilot Denis , Parienti Jean-Jacques , Gounant Valérie , Riviere Alain , Monnet Isabelle , Molinier Oliver , Lena Hervé , Friard Sylvie , Duhamel Jean-Paul , Audigier-Valette Clarisse , Robinet Gilles , Creveuil Christian , Ligeza-poisson Catherine , Morin Franck
Published: March 2020

TPS7112

Background: MPM median OS does not exceed 13 months with pem/CDDP doublet. U.S. Intergroup phase II trial of gemcitabine/CDDP, with or without bevacizumab, gave an appealing 15.6 months median OS in the bevacizumab arm. French Intergroup aimed to test pem/CDDP with bevacizumab (PCB), in a randomized phase III trial. Methods: Eligible patients had unresectable histologically proved MPM, no prior chemo, PS 0-2, no thrombosis, nor bleeding. Primary endpoint: The primary outcome will be survival. The secondary endpoint will be Progression-Free Survival. Patients received pem 500 mg/m2, CDDP 75 mg/m2 (PC),at D1, and vitamin B12 +B9 substitution, with (arm B) or without bevacizumab (arm A), 15 mg/kg Q21D, for 6 cycles. Arm B nonprogressive patients received bevacizumab maintenance therapy until progression or toxicity. 445 patients to be recruited during a period 48 months, with at least 24 months of follow-up, and 385 events (deaths), will be needed to assure a power of 80% and detect at least a 4.3 months of median survival increase. This hypothesis leads to a Hazard Ratio (HR) of 1.33 and a 3-years survival of 14.7% in control arm and 23.6 % in experimental arm, with an absolute difference of 8.9% in survival rates. Accrual status: The first patient was included in February 2008. On January 31, 2012, 257 patients from 85 French centers had been enrolled. The end of accrual can be expected for September 2013. Ancillary studies: For molecular biomarker analyses, thoracoscopic tissue specimens (TS, ERCC1, MSH2, TUBB3, NF2, p16, RASSF1A methylation,15 microRNAs ) and blood samples (micro-RNAS, VEGF, osteopontin, SRMP) at diagnosis are centrally collected. Finally, a prospective study comparing PET-CT to standard CT with central blinded analysis, is currently on-going for evaluation of response, and accuracy of modified RECIST criteria for mesothelioma.
Pilot trial of molecular profiling and targeted therapies in advanced thoracic malignancies: Non-small cell lung cancer, small cell lung cancer and thymic malignancies (CUSTOM).
Authors: Lopez-Chavez Ariel , Rajan Arun , Thomas Anish , Raffeld Mark , Xi Liqiang , Meltzer Paul S. , Duffy Regan M. , Pack Svetlana , Sandler Alan , Corless Christopher L. , Killian Keith , Oberholtzer Carl , Abdullaev Zied , Giaccone Giuseppe
Published: March 2020

TPS7609

Background: For decades, clinical trial design strategies have relied upon the broad classification of tumors into tumor site and histopathology. Several lines of evidence have shown that a molecular approach to patient selection may be better in its capacity to improve patient outcomes. CUSTOM is an innovative clinical trial that allows for the parallel evaluation of multiple targeted therapies in molecularly selected patients with multiple cancer histological subtypes and the prospective evaluation of multiple molecular biomarkers. Methods: All patients with advanced lung cancer and thymic malignancies and a good performance status are eligible independently of previous lines of treatment. The trial begins with tumor biopsy and molecular profiling using a multi-platform approach to identify oncogenic alterations in more than 34 genes for treatment allocation (12 genes) and exploratory purposes. Depending upon the specific biomarker identified, patients are then triaged into 5 experimental arms. Erlotinib for sensitizing EGFR mutations; AZD6244 for KRAS, NRAS, HRAS and BRAF mutations; MK2206 for PIK3CA, AKT and PTEN mutations and PIK3CA amplification; Lapatinib for ERBB2 mutations or amplification; Sunitnib for KIT mutations and PDGFRA mutations and amplification. Patients not eligible for the experimental treatment arms are enrolled into a standard treatment arm. Upon disease progression patients are eligible for repeat biopsy and molecular profiling in order to identify molecular changes and mechanisms of resistance. All patients are followed until death. The primary endpoint is response rate and secondary endpoints include progression-free survival, duration of response and overall survival. With three disease types and five experimental drugs, there are 15 possible treatment arms which will be under active consideration. For each of these, the study will be conducted as an optimal two-stage phase II trial in order to rule out an unacceptably low 10% clinical response rate in favor of a modestly high response rate of 40%. As of January 11, 2012, two hundred and sixteen patients have been enrolled.
CA184-104: Randomized, multicenter, double-blind, phase III trial comparing the efficacy of ipilimumab (Ipi) with paclitaxel/carboplatin (PC) versus placebo with PC in patients (pts) with stage IV/recurrent non-small cell lung cancer (NSCLC) of squamous histology.
Authors: Reck Martin , Lu Haolan , Gribkoff Greta , Maier Sabine , McGovern Rachel , Cuillerot Jean-Marie , Lynch Thomas James
Published: March 2020

TPS7611

Background: Years of research in advanced NSCLC have not improved outcomes for the squamous subtype beyond those of standard platinum doublets. Evidence of responses to immune therapies in NSCLC of squamous cell histology supports investigation in this subtype. Ipi, a fully human monoclonal antibody which blocks CTLA-4, augments antitumor immune responses. Ipi improved overall survival (OS) in advanced melanoma, with side effects managed using product-specific treatment guidelines; immune-related response criteria (irRC) were derived from WHO criteria to better capture response patterns observed with Ipi. A randomized Phase 2 study of Ipi/PC in Stage IV NSCLC pts showed significant improvement in progression-free survival (PFS), as measured by mWHO or irRC, with a trend toward improved OS, over chemotherapy alone in pts receiving phased Ipi/PC (Ipi started after 2 cycles of PC). Phased Ipi/PC appeared to show efficacy in tumors of squamous histology. Addition of Ipi did not exacerbate PC toxicity, and immune-related adverse events were managed using protocol-specific guidelines. A Phase 3 trial (ClinicalTrials.gov identifier NCT01285609) is examining whether phased Ipi/PC will prolong OS in chemotherapy-naïve pts with squamous NSCLC. Methods: Stage IV/recurrent squamous NSCLC with ECOG 0-1 will be included; pts with CNS metastases or history of autoimmune disease will be excluded. Pts are randomized to receive 2 cycles of PC (175 mg/m2 and AUC=6, respectively; IV), followed by 4 cycles of study drug (Ipi in Arm A, placebo in Arm B; IV) with 4 additional cycles of PC (total 6 cycles). Pts without progressive disease (PD) after induction receive maintenance therapy with blinded study drug Q12W until PD per mWHO. The study will randomize 920 pts 1:1 between arms. The primary endpoint of this study is OS; secondary endpoints include OS among pts who receive blinded therapy, PFS and best overall response rate.
Phase III study of investigational MLN8237 (alisertib) versus investigator’s choice in patients (pts) with relapsed/refractory (rel/ref) peripheral T-cell lymphoma (PTCL).
Authors: O'Connor Owen , Leonard E. Jane , Benaim Ely
Published: March 2020

TPS8110

Background: PTCL is a rare form of aggressive non-Hodgkin lymphoma (NHL), accounting for 5–20% of NHL diagnoses. Standard NHL therapies developed primarily for B-cell lymphomas are not optimal for PTCL and early relapse is common. Current treatments for rel/ref PTCL include pralatrexate, romidepsin, and gemcitabine; however, outcomes remain poor. The oral, investigational drug, MLN8237, is a selective inhibitor of Aurora A kinase (AAK) – a key mitotic regulator that is overexpressed or amplified in various human tumors. Emerging clinical data from a phase II study of single agent MLN8237 in rel/ref aggressive T-cell lymphoma (Friedberg et al, ASH 2011) support further clinical evaluation in this indication. Methods: In this open-label, randomized, phase III study, a maximum of 354 adults with rel/ref PTCL after ≥1 prior systemic cytotoxic therapies will be enrolled at approximately 140 centers worldwide. Pts will be randomized 1:1 to MLN8237 50 mg twice daily as an enteric coated tablet on days 1–7 of 21-day cycles, or to investigator’s choice of: pralatrexate 30 mg/m2 IV once weekly for 6 weeks in 7-week cycles; romidepsin 14 mg/m2 IV on days 1, 8, and 15 of 28-day cycles; or gemcitabine 1000 mg/m2 IV on days 1, 8, and 15 of 28-day cycles. Pts with disease response/stabilization will be able to continue treatment provided that clinical benefit is demonstrated and treatment is tolerable. The expected study duration is 44 months. Primary endpoints are overall response rate (complete response [CR] + partial response) and progression free survival by International Working Group criteria (Cheson et al, 2007). Secondary endpoints include CR rate, overall survival, time to progression, time to response, duration of response, safety, and quality of life. Exploratory endpoints include an evaluation of candidate biomarkers (such as AAK protein expression levels and gene amplification, and the tumor proliferative marker Ki-67) in tumor biopsies. This study is registered at ClinicalTrials.gov: #NCT01482962.
Pilot evaluation of sulforaphane in melanoma patients with multiple atypical nevi: Tissue STAT1 and STAT3 as risk markers.
Authors: Lobur David , Davar Diwakar , Singh Shivendra , Beumer Jan Hendrik , Edington Howard , Tarhini Ahmad A. , Tawbi Hussein , Zarour Hassane M. , Talalay Paul , Kirkwood John M.
Published: March 2020

TPS8606

Background: Increasing incidence and the poor prognosis of advanced melanoma argue for prevention efforts. Primary prevention and ultraviolet radiation (UVR) reduction have failed to gain traction in the population, making chemoprevention increasingly attractive. Sulforaphanes (SFN) are bioactive cruciferous compounds rich in the Brassica family, especially broccoli sprouts. Topical broccoli sprout extracts (BSE) decrease UVR erythema response in human skin, and may protect against UVR DNA damage. We have shown SFN inhibition of STAT3, which is constitutively activated in melanoma. We have therefore initiated a pilot study to evaluate BSE SFN in relation to melanoma progression biomarkers, and expression of STAT proteins of atypical melanocytic nevi. Methods: Melanoma patients with >2 atypical nevi are eligible for this trial, which aims to define the safety and clinico-pathological response to oral BSE-SFN. Secondary objectives are documentation of pharmacokinetics and pharmacodynamics of BSE-SFN, and the modulation of STAT 1/3 expression in atypical nevi and normal skin. Baseline photo-documentation and atypical nevus biopsy is performed to assess histopathological atypia and STAT 1/3 expression. Adjacent normal skin biopsies will establish baseline skin SFN levels. Six subjects per group will be accrued at daily dosages of 50, 100, and 200 μM. Subjects must abstain from dietary glucosinolates and isothiocyanates for the study duration and maintain food diaries. Following 27 days of BSE-SFN, blood samples, photography of index atypical nevi, and biopsies of selected atypical nevi and normal skin will be obtained. The three dosage groups will be analyzed for changes in atypia, SFN localization histopathology, and STAT 1/3 expression in the nevi and skin harvested at baseline and at study completion. This trial, UPCI 10-114, has received an IND and is IRB-approved. Accrual is planned to be completed during 2012-13.
CATCH: A randomized trial comparing tinzaparin versus warfarin for treatment of acute venous thromboembolism (VTE) in cancer patients.
Authors: Lee Agnes Y. , Bauersachs Rupert , Janas Mette S. , Jarner Mikala F. , Kamphuisen Pieter W , Meyer Guy , Paz-Ares Luis , Khorana Alok A. ,   on behalf of the CATCH Investigators
Published: March 2020

TPS9149^

Background: VTE is a major cause of morbidity and mortality in cancer patients. LMWHs have been shown to be superior to warfarin in one randomized study, but adequately powered confirmatory studies have not been conducted and warfarin continues to be widely used for treatment of cancer-associated VTE. Methods: We are conducting an open-label, randomized trial of tinzaparin versus warfarin in 900 patients with active cancer and symptomatic proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE). Tinzaparin is given at full treatment doses (175 IU/kg once daily) for 6 months in the experimental arm and initial tinzaparin treatment for 5-10 days followed by dose-adjusted warfarin (target INR 2.0-3.0) is given for 6 months in the control arm. The primary composite outcome is time to recurrent VTE event, including incidentally diagnosed VTE and fatal PE. Baseline characteristics will be analysed for their ability to predict the risk for recurrent VTE or bleeding. In particular, the parameters of the Khorana scale and Wells rule will be tested for their usefulness in predicting recurrent VTE. Predictive biomarkers will be tested including D-dimer and Tissue Factor. Assessment of post-thrombotic syndrome (PTS), quality of life and healthcare resource utilization will also be performed. The trial is recruiting in > 160 sites in >25 countries in 4 continents (NCT01130025). As of Jan 2012, 135 sites were activated for study enrolment and 228 patients have been enrolled. We anticipate completion of enrolment in Jan 2013. The results obtained from this study will add significantly to the knowledge on the efficacy, safety and cost-effectiveness of LMWH to prevent recurrent VTE. Important prospective data on the clinical significance of incidental VTE in patients with active cancer will be generated, and analyses of risk stratification parameters will add important information that may help to further tailor therapy. The study of PTS, which has not previously been done in this selected patient population, will add to the evidence that tinzaparin significantly reduces the incidence of PTS and leg ulcers (Hull et al, Am J Med 2009;122:762-9).
Randomized phase III trial to evaluate radiopharmaceuticals and zoledronic acid in the palliation of osteoblastic metastases from lung, breast, and prostate cancer: Report of RTOG 0517.
Authors: Seider Michael J. , Shook Stephanie , Langer Corey J. , Wyatt Gwen , Demas William F. , Rashtian Afshin , Clausen Cathy L , Derdel Jerry , Cleary Sean F , Peters Christopher A. , Ramalingam Ashok , Clarkson James E. , Tomblyn Michael B. , Rabinovitch Rachel , Kachnic Lisa A. , Berk Lawrence B. ,   RTOG
Published: March 2020

TPS9150

Background: Skeletal related events (SREs) diminish quality of life (QOL) as well as overall survival (OS) in patients with bone metastases, a common event in breast, lung and prostate cancer. SREs can be reduced or delayed by the use of bisphosphonates. It is postulated that the radiopharmaceuticals, Strontium-89 (Sr89) and Samarium-153 (Sm153), when added to a bisphosphonate can decrease the incidence of SREs. Methods: RTOG 0517 randomized patients with breast, lung and prostate cancer and blastic bone metastases to either Zoledronic acid (ZA) alone or ZA plus a single standard dose of either Sr89 or Sm153. No limitations were placed on additional therapy such as chemotherapy or hormonal treatment. The projected median time to SRE [pathological bone fracture, spinal cord compression, surgery to bone, or radiation to bone] for the ZA arm was 10.4 months requiring 257 SRE events to detect a 33% relative reduction for the radiopharmaceutical arm in the time to development of an SRE with 90% power. Other study objectives included quality of life, pain control, OS and toxicity. Results: 261 patients (median age 68; 62% male; 55% prostate, 35% breast, 10% lung) were accrued from July 2006 through February 2011 (4.6 patients/month). Due to a lower than expected rate of SREs in the control (ZA) arm, the study was closed early and therefore did not reach the targeted accrual. 28 (17.4%) patients in the ZA arm and 27 (16.8%) in the radiopharmaceutical arm experienced an SRE. Median time to development of an SRE in the ZA and radiopharmaceutical arms was 11.60 and 16.74 months, respectively (p=.47). Median OS in the ZA arm and radiopharmaceutical arm was 15.95 and 11.18 months, respectively (p=0.12). Cox proportional hazards regression model showed that baseline characteristics, including gender, race, ethnicity, primary disease site or number of bone metastases, had no significant impact on OS. There was no difference in QOL parameters or toxicities between the two arms. Conclusion: Patients receiving ZA only experienced a much lower SRE rate than was hypothesized. The addition of Sr89 or Sm153 did not result in a difference in SREs, OS, or QOL
A multi-site, fixed dose, parallel arm, double-blind, placebo controlled, block randomised trial of the addition of infusional octreotide or placebo to regular ranitidine and dexamethasone for the evaluation of vomiting associated with bowel obstruction at the end of life.
Authors: Currow David C , Clark Katherine , Cartmill John , Pather Selvin , Plummer John , Eckermann Simon , Abernethy Amy Pickar , Agar Meera , Quinn Stephen
Published: March 2020

TPS9153

Background: Bowel obstruction due to advanced cancer that is surgically inoperable is a major management problem. Studies to date have either been underpowered or have used comparators that may not draw on the best available evidence. Methods: This double-blind, block randomised, placebo controlled, set dose, parallel arm study was conducted across 12 sites in Australia. Eligibility included inoperable bowel obstruction secondary to cancer or its treatments. The intervention was the addition of infusional octreotide or placebo in addition to 200mg ranitidine per 24 hours parenterally and 4mg per 24 hours parenterally of dexamethasone. The primary outcome measure was the numbers of days free of vomiting up to 72 hours after all medications were administered the first time. Participants were also administered between 10-20mls per hour of subcutaneous isotonic fluid over the 72 hour period. Results: This study will close to recruitment in March 2012. To date 89 of 92 required participants have been randomised. Conclusions: This adequately powered study will define the additional net clinical benefit derived from octreotide over placebo in people who have an anti-secretary agent (ranitidine) and glucocorticoids (dexamethasone).
Intraperitoneal radioimmunotherapy (RIT) for desmoplastic small round cell tumor (DSRCT).
Authors: Modak Shakeel , Carrasquillo Jorge A. , La Quaglia Michael P. , Zanzonico Pat , Pandit-Taskar Neeta , Lewis Jason S. , Cheung Nai-Kong V.
Published: March 2020

TPS9595

Background: DSRCT, a rare sarcoma of adolescents and young adults arises from serosal surfaces typically the peritoneum. It is characterized by t(11;22)(p13;q12) chromosomal translocation; and is lethal in >80% of patients despite aggressive surgery and chemoradiotherapy. Disease recurrence often presents as multifocal peritoneal implants, making it uniquely suited for intraperitoneal (IP) targeting. Since DSRCT is radiosensitive, we hypothesize that improving local control with targeted radiotherapy may reduce relapse and enhance survival. IP RIT, by virtue of prolonged residence time, and slow/incomplete transfer to the circulation, may selectively target IP disease while minimizing organ toxicity. The anti-4Ig-B7H3 murine monoclonal antibody 8H9 binds to 96% of primary DSRCT with restricted reactivity to normal tissue (Med Pediatr Oncol 39:547). 131I-8H9 targets DSRCT xenografts and has proven safe at 80mCi when injected intrathecally (J Neurooncol 97:409). 124I-8H9, a novel positron-emitting radioimmunoconjugate is ideally suited for quantitative imaging and pharmacokinetic (PK) studies. Methods: We have initiated a phase I study to test the safety of IP RIT using 131I-8H9 in patients with DSRCT (clinicaltrials.gov NCT01099644). Cohorts of 3-6 patients are treated with 131I-8H9 at escalated doses from 30mCi/m2-60mCi/m2 as a single IP injection. An IP tracer dose of 2mCi124I-8H9 is given prior to 131I-8H9 to acquire high-resolution PET images and data on 8H9 tumor targeting and biodistribution. PK is also studied using serial blood draws. Patients are monitored for toxicity clinically and biochemically. Response to treatment is assessed using RECIST criteria and via a follow up 124I-8H9 PET scan if tumor targeting is noted on initial imaging. Hematopoietic stem cells are harvested a priori to reverse myelosuppression if any. Three cohorts of patients (n=9) up to 50mCi/m2 have completed therapy thus far without dose-limiting toxicity or myelosuppression. This is the first study of IP RIT in pediatrics, and the first to use PET for IP RIT. Data obtained will be critical in establishing safety of IP 131I-8H9 in children and young adults, and in designing phase II trials to study efficacy of IP RIT for DSRCT.
10-yr follow-up results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients.
Authors: Julian Thomas B. , Anderson Stewart J. , Krag David N. , Harlow Seth P. , Costantino Joseph P. , Ashikaga Takamaru , Weaver Donald L. , Mamounas Eleftherios P. , Wolmark Norman
Published: March 2020

1000

Background: NSABP B-32, the largest surgical prospective randomized phase III trial was designed to compare overall survival (OS), disease-free survival (DFS), and morbidity between SNR alone vs SNR + AD in SN negative (-) pts. We present 10 yr outcome data for primary endpoints as well as updated data on the effect of occult metastases, found later in the SN by central, detailed pathologic analysis. Methods: 5,611 women with operable, clinically N0, invasive breast cancer were randomized to SNR + AD (Group [Grp] 1) or to SNR alone with AD only if SNs were positive (Grp2). 3,989 (71.1%) of 5,611 pts were SN-. 3,986 (99.9%) of these SN- pts had follow-up information: Grp 1: 1,975, Grp 2:2,011. Median time on study was 9.4 yrs. Cox proportional hazard models adjusting for study stratification variables were used to compare OS and DFS between the two groups. Two-sided p values were used. HR values > 1 indicate a more favorable outcome in Grp 1 Results: At 10 yrs, there continues to be no significant difference in OS between the two groups (HR: 1.11, p = 0.27). 10 yr Kaplan-Meier (K-M) estimates for OS are 87.8% for SNR alone and 88.9% for SNR + AD. There continues to be no significant difference in DFS between the two groups (HR: 1.01, p=0.92). 10-yr K-M estimates for DFS were 76.9% for both groups. Occult nodal disease was originally detected in 3,884 pts (15.8%) with SN- on initial H and E analysis. Comparisons between the groups with and without occult disease yielded an adjusted HR for OS: 1.25 (p = 0.08) with an absolute difference at 10 yrs of 2.8% and a HR for DFS: 1.24 (p = 0.018) with an absolute difference of 4.1%. The cumulative incidences of local-regional events were low (10-yr values: SNR 4.0%, SNR+AD, 4.3%) and not significant (HR: 0.95, p = 0.77). Conclusions: At 10 yrs there continues to be no significant differences in OS and DFS between SNR and SNR + AD in pts with negative SN. The relative increase in risk of DFS and OS for pts with occult SN metastases remains stable. Support: PHS grants: NSABP: U10CA-12027, U10CA-37377, U10CA-69651, U10CA-69974; VT Ca Cntr: P30 CA22435; DNK: 5RO1CA074137 NCI Dpt HHS. Clinical trial information: NCT00003830.
IQ change within three years of radiation therapy in pediatric brain tumor patients treated with proton beam radiation therapy versus photon radiation therapy.
Authors: Kahalley Lisa , Okcu M. Fatih , Ris M. Douglas , Grosshans David , Paulino Arnold , Chintagumpala Murali M. , Moore Bartlett , Stancel Heather , Wickham Robert , Mehta Paras , Mahajan Anita
Published: March 2020

10009

Background: Radiation therapy (RT), an essential treatment for pediatric brain tumors, increases the risk of cognitive impairment. Advanced RT techniques reduce the volume of normal tissues receiving radiation dose. Proton beam radiation therapy (PBRT) minimizes irradiation to surrounding healthy brain tissue, with the potential to preserve cognitive function better than photon radiotherapy (XRT). We examined change in IQ over time between patients treated for pediatric brain tumors with PBRT versus XRT. Methods: IQ scores obtained in the first 3 years post-RT were abstracted for pediatric brain tumor patients treated with PBRT or XRT. Results: Baseline and follow-up IQ scores were available for 53 survivors (31 PBRT, 22 CRT). A linear regression model predicted follow-up IQ scores controlling for baseline IQ, age-at-RT, time-since-RT, and craniospinal irradiation (CSI), F(7,45)=23.4, p<.001. Follow-up IQ scores were significantly lower in the XRT group compared to the PBRT group (p<.05). The XRT group lost 10.3 IQ points on average with each additional year post-RT (p<.01), while the PBRT group remained stable, losing only 0.1 points per year on average (p<.05). CSI was associated with IQ decline in both groups (p<.05), while age-at-RT was not in either group (p=.154). Total RT dose was not associated with IQ with the above variables in the model. Conclusions: Findings suggest significant cognitive risk is associated with XRT, with IQ scores declining by more than half a standard deviation with each additional year post-RT. In contrast, IQ remained stable in the PBRT group. Preliminary findings suggest that PBRT may spare cognitive functioning in the first 3 years post-RT. Future research should replicate these findings with a larger sample and should study longer-term cognitive outcomes in patients treated with PBRT versus XRT. [Table: see text]
Pleuropulmonary blastoma: The causative role of germ-line DICER1 mutations.
Authors: Doros Leslie Ann , Yang Jiandong , Field Amanda , Rossi Christopher , Williams Gretchen M , Schultz Kris Ann Pinekenstein , Dehner Louis P , Messinger Yoav H. , Hill D Ashley
Published: March 2020

10024

Background: Pleuropulmonary blastoma (PPB) is a rare, aggressive childhood lung cancer that is often the first manifestation of the PPB-DICER1 familial tumor predisposition which includes other benign and malignant conditions. The initial genetic mutation is inherited by a germ-line loss of function of DICER1 gene which was discovered by Hill et al. It is proposed that loss of DICER1 expression alters miRNA regulation of key regulatory cellular mechanisms which promote tumor growth. PPB can progress from the purely cystic, curable Type I to a high-grade Type III having a dismal prognosis. We sought to determine the frequency of DICER1mutation in the largest cohort of PPB patients to date. Methods: We obtained germ-line DNA from saliva or blood samples from 113 PPB patients collected from 2005-2012. DNA was extracted using the Maxwell 16 Research System (Promega Corporation, Madison WI). Sample quality and quantity was checked using the Nanodrop 2000 (Thermo Scientific, Wilmington, DE). Sequencing was performed using the Sanger sequencer. For a subset of cases we used targeted sequencing services or full gene sequence analysis (Ambry Genetics, Aliso Viejo, CA). Results: Seventy-four (65.5%) PPB patients were found to have deleterious DICER1germ-line mutations. The most common mutation type found was small insertion/deletions. These 74 samples were composed of 7 (9.5%)Type Ir PPBs, 22 (29.7%)Type I PPBs, 24 (32.4%) Type II PPBs, and 21 (28.4%)Type III PPBs. The following Table shows a summary of mutation types identified. Conclusions: Our results confirm that DICER1 germline mutations are the most common genetic alterations in PPB making it critical for genetic testing to be performed at diagnosis. Additionally, this underscores the need for important correlative studies to describe the genotype-phenotype relationship in order for appropriate screening guidelines to be developed and implemented to allow for early detection. While a majority of cases are explained by germline DICER1 mutations using current sequencing methods, further investigation is warranted to elucidate other possible mechanisms in the development of PPB. [Table: see text]
Estimated long-term outcomes in children newly diagnosed with standard risk acute lymphoblastic leukemia (ALL) based on similarly treated members of the childhood cancer survivor study (CCSS) cohort.
Authors: Essig Stefan , Li Qiaozhi , Chen Yan , Hitzler Johann , Leisenring Wendy M. , Greenberg Mark L. , Sklar Charles A. , Hudson Melissa M. , Armstrong Gregory T. , Krull Kevin R. , Neglia Joseph Philip , Oeffinger Kevin C. , Robison Leslie L. , Yasui Yutaka , Nathan Paul C.
Published: March 2020

10032

Background: Therapy for ALL has evolved such that the risk for late effects in children treated in early eras is likely different from those that will occur in children treated today. In order to estimate future risks for late effects in newly diagnosed children with standard risk ALL, we examined the long-term outcomes in a cohort of patients enrolled in the CCSS who were treated in a manner analogous to contemporary ALL therapies. Methods: We assessed outcomes that occurred ≥5 years from diagnosis in survivors of ALL enrolled in the CCSS who were aged 1-9.9 years at diagnosis, treated with 0-120 mg/m2 of anthracyclines and 0-1000 mg/m2 of alkylating agents, and no radiotherapy. We compared their risks for death, second malignant neoplasms (SMN), chronic physical health conditions and decreased health status with the general population (death and SMN) and the CCSS sibling cohort (remaining outcomes). Results: 556 survivors were eligible. At last assessment, they were a median of 27.8 years old (range 9.1 to 45.7) and 23.4 years (range 5.0-38.0) from diagnosis. 29/556 (5.2%) died (standardized mortality ratio 3.6, 95% CI 2.4-5.2); 12 of these deaths were due to ALL recurrence. Compared to siblings, the rate ratio for ≥1 chronic condition was 1.4 (95% CI 1.3-1.6), and for a severe/life threatening chronic condition was 1.7 (95% CI 1.3-2.3). Four survivors (0.7%) developed a SMN (standardized incidence ratio 1.7, 95% CI 0.5-4.5), 114 were obese (odds ratio (OR) 1.2, 95% CI 1.0-1.5), and 2 (0.4%) reported a stroke. No survivors reported symptomatic congestive heart failure. The OR for reporting adverse general health was 1.2 (95% CI 0.8-1.8), poor mental health 1.3 (95% CI 1.0-1.8), decreased functional status 2.1 (95% CI 1.4-3.0), and activity limitations 1.4 (95% CI 1.1-1.8). Conclusions: Children treated for standard risk ALL on contemporary protocols are at increased risk for future chronic health conditions and decreased health status. Despite excellent survival after leukemia therapy, such survivors will likely benefit from life-long medical care focused on the long-term risks stemming from their therapy.
A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto).
Authors: Von Minckwitz Gunter , Schneeweiss Andreas , Salat Christoph , Rezai Mahdi , Zahm Dirk Michael , Klare Peter , Blohmer Jens U. , Tesch Hans , Khandan Fariba , Jud Sebastian , Jackisch Christian , Mehta Keyur , Loibl Sibylle , Untch Michael ,   German Breast Group
Published: March 2020

1004

Background: Use of carboplatin in neoadjuvant chemotherapy (NACT) has never been prospectively examined in breast cancer. Cohort studies suggest a high sensitivity to DNA-damaging agents (e.g., carboplatin in triple negative breast cancer [TNBC]), which have a high prevalence of BRCA mutations. Two trials examining carboplatin in HER2+ metastatic disease have shown conflicting results, but one was biased by different dosage of docetaxel in treatment arms. GeparSixto investigates the impact of carboplatin in addition to an identical, optimized cytotoxic-targeted regimen on pathological complete response (pCR) in these two breast cancer subtypes. Methods: In GeparSixto trial (NCT01426880) patients were treated for 18 weeks with paclitaxel 80mg/m² q1w and non-pegylated-liposomal doxorubicin (NPLD) 20mg/m² q1w. HER2+ patients received concurrently trastuzumab 6(8) mg/kg q3w and lapatinib 750mg daily. TNBC patients received concurrently Bevacizumab 15mg/kg i.v. q2w. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2 q1w vs not, stratified by subtype. Primary objective is pCR rates (ypT0 ypN0), secondary objectives are pCR rate in predefined subgroups or by other definitions, clinical response rate, compliance and tolerability of carboplatin. Carboplatin dose was reduced from AUC 2.0 to 1.5 by an amendment after 330 patients due to carboplatin-related toxicity at pre-planned safety analyses. Results: 595 patients were recruited (8/2011 - 12/2012) in 51 German centers, 299 did not receive carboplatin. Median age was 47/48 years (no carb/carb), 36.8/36.5% were postmenopausal; 14.0/13.3% had T3, 5.0/3.7% T4, 41.8/37.6% N+, 93.0/92.9% ductal invasive, 64.5/65.3% G3 tumors; 46.2/46.3% had HER2+, 53.8/53.7% TNBC. 225 patients had a SAE (149 no carb/177 carb) and 3 died (postoperative pneumonia; reduced general condition; acute myocardial infarct), all in no carb arms. Final analysis on primary endpoint will be presented. Conclusions: This is first study, evaluating efficacy and safety of the addition of carboplatin to anthracycline-taxane containing NACT in patients with primary HER2+ and TNBC. Clinical trial information: NCT 01426880.
The role of c-Met inhibition for neuroblastoma treatment.
Authors: Zage Peter , Scorsone Kathy , Zhang Linna
Published: March 2020

10041

Background: Neuroblastoma is the most common extra-cranial solid tumor of childhood. Many children present with high-risk disease characterized by rapid tumor growth, resistance to chemotherapy, and widespread metastasis, and novel therapies are needed. Previous studies have identified a role for the HGF/c-Met pathway in the pathogenesis of neuroblastoma. We hypothesized that EMD1214063 would be effective against neuroblastoma tumor cells and tumors in preclinical models via inhibition of HGF/c-Met signaling. Methods: We determined the expression of c-Met in a panel of neuroblastoma tumor cells and neuroblastoma cell viability after treatment with EMD1214063 using MTT assays. Analyses were performed for changes in cell morphology, cell cycle progression, and cell death via apoptosis after EMD1214063 treatment. To investigate the efficacy of EMD1214063 against neuroblastoma tumors in vivo, neuroblastoma cells were injected orthotopically into immunocompromised mice, and the mice in which tumors developed were treated with oral EMD1214063. Results: All neuroblastoma cell lines were sensitive to EMD1214063, and IC50 values ranged from 2.4 - 8.5 mcM. EMD1214063 treatment inhibited HGF-mediated c-Met phosphorylation in neuroblastoma cells. EMD1214063 induced cell cycle arrest in neuroblastoma tumor cells with high c-Met expression, and induced apoptosis in all tested cell lines. In mice with neuroblastoma xenograft tumors, EMD1214063 inhibited tumor growth. Conclusions: Treatment of neuroblastoma tumor cells with EMD1214063 inhibits HGF-induced c-Met phosphorylation and results in cell death. Furthermore, EMD1214063 induces cell cycle arrrest prior to cell death in neuroblastoma tumor cells with high c-Met expression. EMD1214063 treatment is effective in reducing tumor growth in vivo in mice. Inhibition of c-Met represents a potential new therapeutic strategy for neuroblastoma, and further preclinical studies of EMD1214063 are warranted.