bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase III, multicenter, randomized, double-blind, placebo-controlled trial of ganitumab or placebo in combination with gemcitabine (G) as first-line therapy for metastatic adenocarcinoma of the pancreas: The GAMMA trial.
Authors: Fuchs Charles S. , Azevedo Sergio Jobim , Carrato Alfredo , Haddad Vincent , Lipton Lara Rachel , McGreivy Jesse S. , Moore Malcolm J. , Okusaka Takuji , Riess Hanno , Szczylik Cezary , Van Laethem Jean-Luc
Published: March 2020

TPS4135

Background: Ganitumab (AMG 479) is an investigational, fully human, monoclonal antibody inhibitor of the IGF1R. In a randomized phase II study in patients with metastatic pancreatic cancer, addition of ganitumab 12 mg/kg every 2 weeks (Q2W) to G prolonged progression-free survival (PFS) and overall survival (OS) (Kindler. Ann Onc. 2010;21:741P). Exposure-efficacy analysis showed that patients with higher ganitumab exposure levels (AUCss at or above median) had longer PFS and OS (Lu. JCO. 2011;29:4049). Methods: In this phase III study, patients are randomized 2:2:1 to placebo + G, ganitumab 12 mg/kg + G, or ganitumab 20 mg/kg + G. Patients receive ganitumab or placebo IV days (D) 1 and 15 and G 1000 mg/m2 IV D 1, 8, and 15 every 28 D. Patients receiving 20 mg/kg ganitumab are expected to achieve ganitumab levels above the median in phase 2. Key eligibility criteria: untreated metastatic adenocarcinoma of the pancreas; ECOG score 0 or 1; ≥ 18 years old; adequate organ function; and fasting (or non-fasting) glucose ≤ 160 mg/dL. The primary endpoint is OS. A log-rank test stratified by ECOG, presence of liver metastases, and geographic region will compare OS independently for each ganitumab arm at an overall one-sided 2.5% significance level for declaring superiority of ganitumab + G vs placebo + G. Key secondary endpoints include PFS, objective response, safety, and patient-reported outcomes. An additional objective is to define a subpopulation with improved OS based upon baseline levels of circulating biomarkers. Enrollment began in April 2011. As of January 23, 2012, 463 of 825 patients have been enrolled. The study is overseen by an independent data monitoring committee. Status: open. Supported by Amgen Inc. in collaboration with Takeda Global Research & Development Center, Inc.; ClinicalTrials.gov: NCT01231347.
An observational study of metastatic renal cell carcinoma patients prior to initiation of initial systemic therapy.
Authors: Plimack Elizabeth R. , Nemec Cheryl , Elson Paul , Suarez Cristina , Dorff Tanya B , Larkin James M. G. , McAleer Cecilia , Nuñez Isaac , Fisher Rosalie Anne , Rini Brian I.
Published: March 2020

TPS4679

Background: The biology of metastatic RCC is extremely diverse, including a subpopulation of patients with indolent growth of metastases. Because of the acute and chronic toxicity and assumed non-curative nature of current systemic targeted therapy, a select subset of patients may be better served with initial surveillance. Such an approach may allow for deferral of systemic therapy to minimize overall treatment-related toxicity burden while maintaining treatment benefit. Methods: A prospective phase II trial is being conducted to characterize the clinical course of patients with mRCC who defer initial systemic treatment. Appropriate patients are selected by the treating physician based on an observed indolent growth pattern. As such, there is a 12 month window allowed between the first diagnosis of metastatic disease and study entry. Patients must be treatment-naïve, asymptomatic, with histologically confirmed mRCC and clinically-evident, measurable disease to be eligible. Radiographic assessment is performed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months. The primary objective is to characterize the clinical outcome of patients on observation in terms of time to RECIST defined disease progression and time to initiation of systemic treatment. Secondary endpoints include measurement of disease-related symptoms and depression/anxiety using standardized questionnaires (FKSI-DRS and HADS), as well as correlative endpoints analyzing the immune response over time for which blood is being collected for immune assays (TH1/TH2 phenotype, Tregs). Pts remain on study until initiation of systemic therapy due to radiographic disease progression, development of disease-related symptoms, withdraw of consent or clinical change that renders the patient unacceptable for further observation. Local therapy (e.g. surgery, radiation) during the observation period is permitted. Currently, 29 patients have been accrued at 5 collaborating sites. The target accrual of 50 pts provides adequate power for the primary descriptive endpoint as well as 80% power to detect changes from baseline for the correlate endpoints based on a two-sided Wilcoxon signed rank test.
Phase III trial of dovitinib (TKI258) versus sorafenib in patients with metastatic renal cell carcinoma after failure of anti-angiogenic (VEGF-targeted and mTOR inhibitor) therapies.
Authors: Motzer Robert John , Porta Camillo , Bjarnason Georg A. , Szcylik Cezary , Rha Sun Young , Esteban Emilio , De Giorgi Ugo , MacKenzie Mary J. , Mainwaring Paul N. , North Scott , Sabbatini Roberto , Bodrogi Istvan , Kabbinavar Fairooz , Carteni Giacomo , Sternberg Cora N. , Vogelzang Nicholas J. , Shi Michael , Urbanowitz Gladys , Escudier Bernard J.
Published: March 2020

TPS4683

Background: Standard first- and second-line treatments in metastatic renal cell carcinoma (mRCC) target the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signaling pathways. However, signaling through other pathways, including the fibroblast growth factor receptor (FGFR) pathway, may account for tumor resistance to these standard therapies. Dovitinib (TKI258) is an oral FGF, VEGF, and platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor, with IC50 values of ≈ 10 nM. In a phase II study of 59 RCC patients, many of whom had failed prior VEGF-targeted and mTOR inhibitor therapies, dovitinib (500 mg/day on a 5-days-on/2-days-off schedule) was well tolerated and demonstrated promising anti-tumor effects, with progression-free survival (PFS) of 5.5 months (Angevin et al, ASCO 2011). Methods: Approximately 550 patients from over 26 countries will be randomized 1:1 in this multicenter, open-label, randomized phase III trial (NCT01223027) to receive dovitinib (500 mg/day on a 5-days-on/2-days-off schedule) or sorafenib (400 mg twice daily). Eligible mRCC patients must have failed 1 VEGF-targeted therapy and 1 mTOR inhibitor (disease progression on or within 6 months of stopping the prior treatment). Patients will remain on study until disease progression, unacceptable toxicity, death, or discontinuation for any other reason. No treatment crossover is planned. The primary endpoint is PFS as determined by central radiology assessment according to RECIST v1.1, with evaluations performed every 8 weeks. Secondary endpoints include overall survival, overall response rate, safety, patient-reported outcomes, and pharmacokinetics. The pharmacodynamic effects of dovitinib on plasma/serum biomarkers will also be explored. The data monitoring committee last reviewed the trial on 20 December 2011 and recommended that the trial continue as planned. This is the first third-line randomized clinical trial in mRCC to evaluate a multitargeted inhibitor of FGFR.
CA184-043: A randomized, double-blind, phase III trial comparing ipilimumab versus placebo following a single dose of radiotherapy (RT) in patients (pts) with castration-resistant prostate cancer (CRPC) who have received prior treatment with docetaxel (D).
Authors: Drake Charles G. , Scher Howard I. , Bossi Alberto , van den Eertwegh Alfons JM , McHenry Brent , Fitzmaurice Thomas F. , Cuillerot Jean-Marie , Chin Kevin M. , Gagnier Paul , Fizazi Karim , Gerritsen Winald R.
Published: March 2020

TPS4689

Background: Ipilimumab (Ipi), a fully human monoclonal antibody which blocks CTLA-4, augments antitumor immune responses. Ipi has shown antitumor effects in prostate cancer model systems and clinical activity (via prostate-specific antigen [PSA] declines and RECIST response) in Phase 1/2 investigations in CRPC, with a side effect profile reflective of its mechanism of action. Preclinical data suggest that RT given prior to CTLA-4 blockade may increase antitumor activity. Methods: In this study, pts with CRPC who have progressed during or after D are randomized 1:1 to receive either a single dose of bone-directed RT followed by Ipi 10mg/kg, or RT followed by placebo. Within 2 days of RT administration (up to 5 lesions at 8 Gy on a single day) patients receive their initial dose of Ipi/placebo; Ipi/placebo is then given every 3 weeks for a total of 4 doses. Eligible pts may continue to receive blinded study drug every 12 weeks until they meet treatment stopping criteria, withdraw consent, are lost to follow-up, or study closure. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival, pain response, and safety. The study is designed to detect a 3.8 month difference (HR=0.76) in median OS with 90% power and 0.05 2-sided type one error. The enrollment goal is 800 randomized patients, with a single interim analysis for superiority of OS planned at 435 events at approximately 33 months from first patient first visit (ClinicalTrials.gov identifier: NCT00861614). [Table: see text] [Table: see text]
A study of autologous dendritic cell therapy targeting mucin-1 for treatment of patients with epithelial ovarian cancer in first remission.
Authors: Berek Jonathan S. , Goh Jeffrey C. , Gray Heidi J. , Fiorica James , Mason James R.
Published: March 2020

TPS5113

Background: Cvac (Cvac) is an autologous dendritic cell immune stimulant targeting mucin-1 positive tumors. A phase IIa study demonstrated potential for treating mucin-1 positive epithelial ovarian carcinoma (EOC). A phase IIb study was designed to determine on a pilot basis if Cvac could demonstrate an effect on progression free and overall survival in patients with EOC in first or second remission. The current study, CANVAS (CANcer VAccine Study) is evaluating Cvac treatment of EOC patients in first remission after surgery and standard chemotherapy, with at least three cycles of platinum and taxane therapy. Endpoints include progression free survival, overall survival, safety evaluation and quality of life scores. Methods: Patients are eligible if they have stage III or IV mucin-1 positive EOC and have had optimal cytoreductive (<1cm residual disease) surgery. Apheresis to obtain immature dendritic cells occurs prior to chemotherapy. Cvac is manufactured during chemotherapy. Patients remain eligible for the study if they have a complete response to standard chemotherapy after surgery. Cvac or placebo is dosed every four weeks for three doses, and every twelve weeks for three additional doses. 1000 patients will be randomized to Cvac or placebo in 22 countries, with 800 expected to receive vaccine or placebo. CT or MRI imaging determines progression, and is centrally read prior to inclusion and at each timepoint. Recruitment commenced January 2012. Over 100 centers are participating in the study globally, with majority in Europe. Enrollment is expected to take 18-24 months. An interim analysis is planned after 400 PFS events, and final analysis after 620 PFS events. Observation of 620 events would have approximately 90% power to detect a hazard ratio of 0.77 in PFS at a significance level of p=0.049 (approximately a 30% increase in median PFS in the Cvac group compared with the placebo group).
A phase III study of standard fractionation radiotherapy with concurrent high-dose cisplatin versus accelerated fractionation radiotherapy (RT) with panitumumab in patients with locally advanced stage III and IV squamous cell carcinoma of the head and neck (SCCHN) (NCIC Clinical Trials Group HN.6).
Authors: Waldron John N , Parulekar Wendy , O'Sullivan Brian , Chen Bingshu E , Montenegro Alexander , Nabid Abdenour , Winquist Eric , Wright Jim R. , Hay John , Ringash Jolie , Martino Rosemary , Johnson Ana , Liu Geoffrey , Breen Stephen , Gilbert Ralph William , Shenouda George , Siu Lillian L.
Published: March 2020

TPS5600

Background: Standard treatment for locally advanced SCCHN, chemoradiotherapy (CRT), leads to significant acute and long-term morbidity. The demonstration that EGFR antibody (Ab) therapy improves outcome when added to standard RT (Bonner NEJM 2006) and that altered fractionation RT improves outcome compared to standard RT that is of similar magnitude as CRT (Bourhis Lancet 2006), led to the hypothesis that the combination of the two treatment strategies will improve efficacy compared to standard CRT with good tolerability. Methods: HN.6 is a Canadian phase III randomized study comparing standard RT 70Gy/35 over 7 weeks + cisplatin 100mg/m2 d 1, 22, 43 to accelerated RT 70Gy/35 over 6 weeks + panitumumab (anti EGFR Ab)) 9mg/kg 1 week prior to RT, d15, 36. Key eligibility criteria are: SCC of oral cavity, oropharynx, larynx or hypopharynx; TanyN+M0 or T3-4N0M0; adequate organ function and PS. Primary endpoint is progression free survival (PFS). Secondary endpoints include OS, local PFS, regional PFS, distant metastases, swallowing related QOL, functional swallowing outcomes, and economic evaluation (healthcare utilization, health utilities, indirect costs). Tissue and blood collection will allow biomarker evaluation including HPV status. Real time quality review of RT plans with plan data and radiology archiving will allow future analysis of RT parameters relative to toxicity and patterns of failure. Clinical epidemiological data will be prospectively collected and correlated with biomarkers and outcome. Planned sample size is 320 patients over 3.2 years with 3 more years of follow-up and target hazard ratio = 0.7 (absolute difference in control arm 2 year PFS of 12%, power 80%, 2-tail type 1 error 0.05). If superiority is not demonstrated, noninferiority will be tested. One interim analysis is planned. Conduct to Date: Study activation: Dec 2008 and completed accrual in Nov 2011. In Oct 2011, the DSMC recommended trial continuation. Supported by CCSRI grant 021039 and Amgen Inc. ClinicalTrials.gov: NCT00820248.
LUX-breast 3: Randomized phase II study of afatinib alone or with vinorelbine versus investigator’s choice of treatment in patients (pts) with HER2-positive breast cancer (BC) with progressive brain metastases (BM) after trastuzumab or lapatinib-based therapy.
Authors: Joensuu Heikki , Ould Kaci Mahmoud
Published: March 2020

TPS647

Background: Approximately 1/3 of pts with HER2-positive, advanced BC will develop BM with a poor prognosis. Efficacy of systemic therapies is limited since few drugs can readily cross the blood-brain barrier. BC BM represents a high unmet medical need for which novel targeted therapies are needed. Afatinib is a small molecule, irreversible ErbB Family Blocker that has shown preclinical activity in trastuzumab-resistant cell lines and HER2-positive tumor xenografts. Its clinical efficacy has been demonstrated in pts with heavily pre-treated, HER2-positive metastatic BC, who progressed after trastuzumab therapy, with partial responses in 10% and clinical benefit in 46% of pts. In a Phase I afatinib trial a sustained PR was observed in a NSCLC pt with BM, and in a phase II trial in NSCLC, pts with or without BM achieved comparable outcome on afatinib. The purpose of this study (NCT01441596) is to investigate whether afatinib alone or in combination with vinorelbine has any effect on HER2-positive BC with BM after failure of prior trastuzumab or lapatinib. Methods: Key eligibility criteria: histologically confirmed HER2-positive BC; recurrent/progressive BM during/after prior trastuzumab or lapatinib therapy; ≥1 measurable BM (≥10 mm on T1-weighted, gadolinium-enhanced MRI); extra-CNS lesions allowed; prior surgery, whole brain radiotherapy or stereotactic radiosurgery allowed; ECOG 0–2. Eligible pts are stratified by: ECOG score 0–1 vs 2; No of BM ≤ 3 vs >3; prior lapatinib therapy. Pts are randomized to (n = 40/arm): Arm A: afatinib (40 mg/d oral); Arm B: afatinib (40 mg/d oral) + vinorelbine (25 mg/m2/ week); Arm C: investigator’s choice of medical treatment approved for metastatic BC. Primary endpoint: pt benefit at 12 weeks (i.e. absence of CNS/extra CNS disease progression as per RECIST 1.1) and no tumour-related worsening of neurological signs/symptoms or increase in steroid dosage. Secondary endpoints: PFS, OS, safety and afatinib concentration in plasma/cerebrospinal fluid in ≥12 pts. The study began in October 2011 and enrollment is ongoing.
Docetaxel, carboplatin, trastuzumab, and bevacizumab (TCH+B) for early-stage HER2/neu(+) breast cancer and bone marrow micrometastases.
Authors: Baar Joseph , Silverman Paula , Budd G. Thomas , Gibson Laura , Meyerson Howard , Fu Pingfu , Diorio Dawn
Published: March 2020

TPS655

Background: Bone marrow (BM) micrometastases confer a poor prognosis to early-stage breast cancer (BC) and HER-2/neu(+) BC is a high-risk phenotype. We have shown that BM-associated stromal cells support the survival of metastatic BC in microenvironmental niches and this activity is dependent on VEGF and CXCL-12. Therefore, the growth of nascent tumor cell clusters in BM might be impeded by disrupting stromal cells or their activating ligands, such as VEGF. There is also a positive association between HER-2/neu and VEGF expression in BC, thereby implicating VEGF in the aggressive phenotype of HER-2/neu overexpression. These observations support the use of combination therapies directed against both HER-2/neu and VEGF for the treatment of HER-2/neu(+) BC. We therefore hypothesize that an anti-VEGF agent (bevacizumab) given with docetaxel, carboplatin and trastuzumab (TCH) will eradicate the BM of HER-2/neu(+) BC micrometastases by disrupting stromal cell support within the micrometastatic BM niche. Methods: Subjects with AJCC Stage I-III HER2/neu(+) BC will undergo a single iliac-crest BM aspirate and biopsy. If the BM is positive for CK+ micrometastases, up to 17 patients will receive TCH+B therapy (docetaxel at 75 mg/m2 IV and carboplatin at AUC 6 IV given every 3 weeks for 6 cycles; trastuzumab at 4 mg/kg IV loading dose, then 2mg/kg IV every week; bevacizumab at 15 mg/kg IV every 3 weeks). Four weeks after the 6th cycle of therapy, a repeat BM aspiration and biopsy will be performed to score for response of BC micrometastases to therapy. Patients with a complete clinical response in BM will continue with trastuzumab every 3 weeks at 6 mg/kg to a total of 1 year. Patients with persistent micrometastases will receive both trastuzumab and bevacizumab every 3 weeks to a total of 1 year of therapy. These patients will then have a repeat BM aspirate and biopsy at the end of the 1 year to score for final response. The primary objective of this clinical trial is to determine clinical response against BC micrometastases in BM. The second objective is to investigate the specific contribution of VEGF and CXCL-12 signaling to BM support of micrometastatic BC cells.
HIT: A multicenter phase I-II study of trastuzumab administered by intrathecal injection for leptomeningeal meningitis of HER2+ metastatic breast cancer.
Authors: Gutierrez Maya , Fourme Emmanuelle , Taillibert Sophie , Le Rhun Emilie , Tredan Olivier , Gunzer Katharina , Dieras Veronique , Mefti Fawzia , Vago-Ady Nora , Tresca Patricia , Turbiez Isabelle , Paintaud Gilles , Brain Etienne
Published: March 2020

TPS662

Background: Leptomeningeal metastases (LM) are commonly associated with breast cancer (BC), announcing short term prognosis that intrathecal (IT) chemotherapy poorly modifies. Incidence is particularly marked in HER2+ tumours. With the better control of extra-cerebral disease and prolonged survival yielded by intra-venous (IV) trastuzumab (T), the main hypothesis is that intra-cerebral recurrences are not reached by this high molecular weight (148 kD) monoclonal antibody. Analyses performed in cerebrospinal fluid (CSF) following IV T have shown low T levels, suggesting that LM of HER2+ BC would remain potentially sensitive to anti-HER2 agents as long as they could by-pass the meningeal blood brain barrier. Intraventricular (via Ommaya port) or IT administration of T would allow keeping control on LM progression through high T therapeutic concentrations in CSF. This prospective trial is the first phase I-II study sponsored by Institut Curie to investigate the safety and efficacy of the IT administration of T for HER2+ LM BC. Methods: Eligible patients must be 18+, have a diagnosis of LM either on CSF with HER2+ cytology or on clinical/MRI pictures of meningitis, and normal end-organ functions. The phase I cohort investigates the maximum tolerated dose (MTD) and recommended dose of T given weekly IT (or via Ommaya port) + hemisuccinate hydrocortisone 25 mg, while aiming at yielding a T target-concentration in CSF close to the plasma one (30 µg/mL) obtained with standard IV schedule. The MTD is defined as the highest dose level (DL) tested with ≥2 dose-limiting toxicity (DLT, any grade ≥3 NCI CTCAE v4.0 attributed to T) observed in ≤6 patients (3+3 Fibonacci dose escalation design, 4 DL 30-150 mg) with a maximum of 24 patients. The phase II cohort will investigate the efficacy of the recommended dose (DLMTD-1) defined in cohort I on neurological progression-free survival at 2 months, in ≤19 patients. Secondary endpoints include CSF and MRI response, quality of life, FCGR3A influence, and comparative CSF/plasma pharmacokinetics. Since study activation in May 2011, 5 patients have been included at DL1, 3 being evaluable for DLT. DL2 is now open for accrual.
The GALAXY Trial(NCT01348126): A randomized IIB/III study of ganetespib (STA-9090) in combination with docetaxel versus docetaxel alone in subjects with stage IIIB or IV NSCLC.
Authors: Goss Glenwood D. , Manegold Christian , Rosell Rafael , Fennell Dean Anthony , Vukovic Vojislav M. , El-Hariry Iman , Teofilovici Florentina , Enke Aaron S. , Ramalingam Suresh S.
Published: March 2020

TPS7613^

Background: Hsp90 is a molecular chaperone required for proper folding and activation of many cancer-promoting proteins and is recognized as a key facilitator of cancer cell growth and survival. In pre-clinical models, Hsp90 inhibition causes degradation of multiple client proteins and leads to cancer cell death. Ganetespib is a resorcinolic Hsp90 inhibitor that has shown potent anti-tumor activity in patients with lung, breast, and other cancers that had progressed on standard treatment agents. Moreover, combination of ganetespib with docetaxel results in synergistic antiproliferative effects in several human non-small cell lung carcinoma (NSCLC) tumor xenografts. Ganetespib is well tolerated and is devoid of severe liver or common ocular toxicities that have been observed with some other Hsp90 inhibitors. Diarrhea is the most common adverse event and is manageable with appropriate supportive care. In a recent report, ganetespib administered at 200 mg/m2 weekly showed activity in pretreated patients with advanced NSCLC patients with ELM4-ALK translocation and KRAS mutations. Methods: Stage 1 (240 subjects): randomized, international open-label Phase 2B study in subjects that progressed on or after one prior systemic therapy for stage IIIB or IV NSCLC: patients are prospectively stratified for ECOG performance status, histology, total LDH, interval since diagnosis, and smoking status. Co-primary endpoints are PFS in the ITT population, and PFS in patients with KRAS mutations. Main secondary endpoints include ORR, disease control rate, OS and clinical activity in different molecular subtypes, including BRAF, HER2, EGFR, EML4-ALK. Patients on the control arm are treated with docetaxel 75 mg/m2 on day 1 of a three-week cycle. In the combination arm, ganetespib 150 mg/m2 is given on day 1 (with docetaxel) and day 15 of a three-week cycle. At the time of submission 90 subjects had been enrolled in Stage 1.
ELOQUENT-2: A phase III, randomized, open-label trial of lenalidomide/dexamethasone (Len/Dex) with or without elotuzumab (Elo) in relapsed or refractory multiple myeloma (RR MM) (CA204-004).
Authors: Lonial Sagar , Richardson Paul Gerard Guy , Moreau Philippe , Orlowski Robert Z. , San-Miguel Jesùs F. , Dimopoulos Meletios A. , Palumbo Antonio Pierangelo , Facon Thierry , Vij Ravi , White Darrell , Reece Donna Ellen , Singhal Anil , Kroog Glenn Scott , Kopit Justin , Anderson Kenneth Carl
Published: March 2020

TPS8112

Background: MM remains incurable and patients (pts) typically relapse or become refractory to current treatments. Novel regimens are needed to improve pt outcomes. Elo is a humanized monoclonal IgG1 antibody targeting the cell surface glycoprotein CS1, which is highly expressed on >95% of MM cells. Len/Dex is approved for treatment of relapsed MM and an objective response rate (ORR) of ~60% was reported in phase III trials of this combination in RR MM. In a phase II study (N=73) of Elo (10 or 20 mg/kg) in combination with Len/Dex in pts with RR MM, the 10 mg/kg group (n=36) demonstrated an ORR of 92% and median progression-free survival (PFS) that was not reached after a median follow-up of 14.1 months. Encouraging activity was seen in patients with high-risk cytogenetics and/or stage 2-3 disease. Based on these data, a randomized, open-label phase III trial has been initiated to determine if the addition of Elo to Len/Dex will improve PFS in patients with RR MM compared with Len/Dex alone. Methods: Pts (N=640) with RR MM and 1-3 prior therapies are eligible, including pts with mild or moderate renal impairment. Pts are randomized in a 1:1 ratio to receive 28-day cycles of Len 25 mg PO (days 1-21) and Dex 40 mg PO (days 1, 8, 15 and 22) with or without Elo. Elo dose and schedule is 10 mg/kg IV on days 1, 8, 15, 22 in the first 2 cycles and on days 1 and 15 in subsequent cycles. Dex 8 mg IV + 28 mg PO is used during the weeks with Elo. Treatment will continue until disease progression, death, or withdrawal of consent. Patients will be followed for tumor response every 4 weeks until progressive disease and then survival every 12 weeks. The primary endpoint is PFS (90% power for a hazard ratio [experimental to control arm] of 0.74) and the secondary endpoints are ORR and overall survival. Exploratory endpoints are safety, time to response, duration of response, time to subsequent therapy, health-related quality of life, and pharmacokinetics and immunogenicity of Elo. Potential biomarkers will also be assessed. As of January 10th, 2012, 107 pts were enrolled and 68 pts were treated. NCT01239797.
PILLAR-2: A randomized, double-blind, placebo-controlled, phase III study of adjuvant everolimus in poor-risk diffuse large B-cell lymphoma (DLBCL).
Authors: Lin Tongyu , Zhu Jun , Bouabdallah Kamal , Ogura Michinori , Hino Masayuki , Kim Jin Seok , Wu Cassandra , Corrado Claudia , Witzig Thomas E.
Published: March 2020

TPS8118

Background: Effective DLBCL adjuvant therapy after first-line chemotherapy is needed as high-risk DLBCL is associated with a poor 4-year overall survival (OS) rate (Sehn et al, Blood 2007;109:1857-61). In a phase II study of the oral mammalian target of rapamycin inhibitor everolimus in relapsed, aggressive non-Hodgkin lymphoma, DLBCL patients (n=47) had a 30% overall response rate (Witzig et al, Leukemia 2011;25:341-7). Methods: PILLAR-2 is an ongoing international, randomized, double-blind, phase 3 study designed to compare everolimus efficacy and safety with that of placebo in poor-risk DLBCL patients who achieved complete response (CR) with first-line rituximab-based chemotherapy (R-chemo) (ClinicalTrials.gov: NCT00790036; sponsor: Novartis Pharmaceuticals). Eligibility criteria include age ≥18 years; confirmed stage II bulky, III, or IV DLBCL and International Prognostic Index 3-5 at diagnosis; confirmed CR per revised International Workshop Response Criteria for malignant lymphoma (Cheson et al, J Clin Oncol 2007;25:579-86) after first-line R-chemo regimen completed 6-14 weeks before study drug start; Eastern Cooperative Oncology Group performance status ≤2; no ongoing or post–R-chemo radiation; and no myelosuppressive chemotherapy or biologic therapy within 3 weeks. Patients are randomized 1:1 to everolimus 10 mg once daily or matching placebo and treated for 12 months or until disease relapse, unacceptable toxicity, or death. Radiologic tumor assessment is performed at baseline, every 12 weeks during years 1 and 2, every 24 weeks during years 3 and 4, and annually thereafter until start of new anticancer therapy or 5 years after last patient randomization. The primary endpoint is disease-free survival (DFS). Secondary endpoints are OS, lymphoma-specific survival, and safety. Expected enrollment is 687 patients. Final analysis will be performed when 279 DFS events occur; survival follow-up will continue until 338 deaths occur and the last randomized patient has been followed for ≥5 years. Currently, 422 patients are enrolled. The data monitoring committee last reviewed the trial in July 2011 and recommended that it continue as planned.
Using cancer patient stories to “power” communication modules.
Authors: Lang Forrest , Sobol Joseph
Published: March 2020

TPS9147

Background: Caring for patients with cancer poses great challenges to doctors’ communication skills. This project, funded by NIH-NCI, represents an innovative collaboration between ETSU faculty in medical oncology, family medicine, and storytelling. The team secures patients’ and caregivers’ cooperation in recording stories of their journeys with illness. These are the focus of a set of cancer communication modules, to be offered as educational experiences for medical students, residents, and oncology fellows. The modules in development address 1) breaking bad news, 2) living through treatment, 3) transitioning from curative to palliative care, 4) communicating with family, and 5) sensitivity to issues of religion and spirituality. Methods: A collaborative inter-professional team developed an interview protocol to facilitate sharing of cancer-themed narratives. Video records are transcribed and coded using N-Vivo 8. The rating team meets to identify video clips that speak powerfully to positive, negative, or ambivalent aspects of cancer communication. Selected patients are brought together into “story circles,” where additional narratives are gathered. The module development team uses these stories to create empathic involvement in viewers, and to sensitize them to effective and ineffective communication strategies and challenges surrounding critical moments in patients’ lived experience of cancer. Modules effectiveness is tested with 1) Family Medicine and Internal Medicine residents, 2) medical oncology fellows and 3) multi-professionals health students just completing a communication courses. Assessment includes a pre-test and post-test OSCE addressing a number of the challenging cancer communication moments. Eighty-four of a projected 100 patient interviews and twelve physician//faculty interviews have been recorded, and all have agreed to the use of their interview materials. Representative examples of recorded cancer stories will be presented to demonstrate their evocative and pedagogical value. Opportunities will be discussed for further uses of these and similar stories in collaborations between medicine and the arts and humanities.
The European InCASA telecare-telehealth electronic platform (ICT-FP7) for the daily assessment of symptoms, weight, and activity in cancer patients on chronotherapy at home.
Authors: Levi Francis , Arbaud Alexandre , Dispersyn Garance , Simon Jordi Rovira , Innominato Pasquale F. , Bossevot Rachel , Mocquery Magali , Plessis Virginie , Fursse Jo , Caprino Massimo
Published: March 2020

TPS9154

Background: Self-rated symptoms contribute to the Quality of Life (QoL) of cancer patients (pts) and impact on prognosis. Behavioural functions are controlled by the circadian timing system (CTS), through a network of molecular clocks that time cellular proliferation and drug metabolism (Lévi et al. ARPT 2010). Chronotherapy aims at the reduction of treatment-related symptoms through the adjustment of chemotherapy delivery to the CTS. Cancer chronotherapy is delivered at home using programmable pumps, and avoids familial and social disruption. Telemedicine tools can provide continuous information on symptoms, behavior, QoL and CTS from non hospitalized pts. Methods: The inCASA platform enables telemonitoring of multiple functions in order to help physicians to detect early warning signals in pt condition at home, and prompt adequate and timely interventions. Our pilot site investigates the clinical relevance of daily teletransmitted self assessed symptoms, body weight and rest-activity circadian rhythm in cancer pts. This system was first well understood and accepted by 14 pts (9 male, 5 female, 43-77 years) at the outpt clinic, then used by 5 pts (4 male, 1 female, 61±13 years) at home daily for 6+ weeks, while receiving chronotherapy. The pilot phase will accrue 30 pts receiving chronotherapy at home from 03/01/2012. Pts will fill in the M.D. Anderson Symptom Inventory scale on a touch-screen device, measure their body weight using a Bluetooth scale and record their circadian rest-activity rhythm using an infrared wrist-watch accelerometer over 6-weeks. The data are transmitted to the platform, then to a web portal with secured access to be daily inspected by the oncology nursing and medical team. The modelling of these continuous records will define alert thresholds for nurse-controlled graded intervention decisions. Conclusion: The assessment criteria set forth for the inCASA solution will address the issues of pt autonomy, CTS entrainment in the pt usual environment, safety of chronotherapy delivery at home and treatment costs. Its use should induce important organisational changes and perception in healthcare professionals.
Treatment of pediatric lymphocyte predominant Hodgkin lymphoma (LPHL): A report from the Children's Oncology Group.
Authors: Appel Burton , Chen Lu , Hutchison Robert E. , Hodgson David C. , Ehrlich Peter , Constine Louis S. , Schwartz Cindy L.
Published: March 2020

10000

Background: LPHL, an uncommon subtype of HL, typically presents with low stage disease and responds to regimens used for classical HL. Recurrence is uncommon, but second malignant neoplasms (SMN) or development of non-Hodgkin lymphoma (NHL) can occur. Therefore, reducing radiation exposure may be of benefit. We report the results of a prospective trial in which a selected subset of patients had surgery alone and the remainder were treated with limited chemotherapy +/- involved-field radiation therapy (IFRT). Methods: Patients ages 0-21 years with newly diagnosed, low risk LPHL were eligible for AHOD03P1. Low risk was defined as clinical Stage IA or IIA without bulk disease (mediastinal mass > 1/3 of the thoracic diameter or nodal aggregate > 6 cm). Patients with Stage IA LPHL with an unresected node or more than a single involved node or Stage IIA were treated with 3 cycles of AV-PC (doxorubicin/vincristine/prednisone/cyclophosphamide). Patients with Stage IA LPHL in a single node that was completely resected were initially observed without further therapy; those who recurred after surgery with low risk LPHL received AV-PC x 3. Patients with < complete response (CR) to AV-PC x 3 received 2100 cGY IFRT. Results: 180 eligible patients with low risk LPHL were enrolled and completed study therapy. 52 patients underwent initial surgery alone; their 3 year EFS = 81.5%. 137 patients received AV-PC x 3; 128 were treated at diagnosis and 9 upon relapsing after surgery alone. 11 patients receiving AV-PC had < CR and received IFRT. 12 first events occurred among these 137 patients (11 relapses and 1 SMN, a NHL). One relapse occurred in a patient who received IFRT. The median follow-up among the 125 remaining patients is 39 (range 3 -76) months. Current 4-year EFS estimate is 88.1% (95% CI: 79.5%-93.3%) for these 137 patients. 4 year EFS for the entire cohort of 180 patients = 86.2%; their overall survival (OS) is 100%. Conclusions: Pediatric LPHL patients have an excellent EFS with chemotherapy that is less intensive than standard regimens; >90% of patients can avoid RT. NHL as a first event may be related to the underlying LPHL and not an effect of treatment. The salvage rate for the few relapses is high, and OS to date is excellent. Clinical trial information: NCT00107198.
Genetic variations in cytarabine pathway genes as determinants of outcome in acute myeloid leukemia.
Authors: Lamba Jatinder Kaur , Pounds Stanley , Cao Xueyuan , Crews Kristine Radomski , Raimondi Susana , Campana Dario , Baker Sharyn D. , Ribeiro Raul Correa , Rubnitz Jeffrey E.
Published: March 2020

10005

Background: Cytarabine (ara-C), a key component of AML therapy, is a prodrug that requires activation to ara-CTP, which inhibits DNA/RNA synthesis and triggers leukemic cell death. Thus, cellular pathways involved in ara-CTP metabolism and/or cell death are likely to influence treatment response. Methods: In the present study, we used a pathway-directed approach to identify the genetic predictors of ara-C response in 187 pediatric patients enrolled in the St. Jude AML02 trial. Patients were randomized to receive the first course of remission induction therapy containing either high- or low-dose ara-C, combined with daunorubicin and etoposide. SNPs in 14 key ara-C pathway genes were genotyped and screened for association with multiple endpoints, such as in vitro ara-C LC50 in diagnostic leukemic cells, minimal residual disease levels (MRD), event-free survival (EFS), overall survival (OS), and rate of relapse. Because AML is a very heterogeneous disease with multiple clinical, cytogenetic, and molecular features that are associated with response, we also evaluated SNPs in ara-C PK genes in the context of prognostic factors of proven clinical utility. Results: Ara-C pathway SNPs were significantly associated with clinical outcome. Known variables such as treatment, core-binding factor leukemia, MRD after one course of therapy, age at diagnosis, 11q23 rearrangements, megakaryoblastic leukemia without t(1;22), and FLT3-ITD accounted for 18.7% of variability in EFS. Additional variation in EFS could be explained by individual SNPs or a combination of SNPs within ara-C pathway genes. For instance, our analysis showed that incorporation of a DCTD SNP into existing model could enhance the percent total variation in EFS explained from 18.7% to 22.9%. Inclusion of all DCTD SNPs in the model increased the percent total variation in EFS explained from 18.7% to 29.7% Conclusions: Overall our results indicate that genetic variation in the ara-C pathway genes had a prognostic relevance that was similar to that of well-known factors. Understanding this variation can provide additional insights into the factors influencing treatment response and could lead to the identification of new prognostic markers.
Autologous-collected anti-CD19 chimeric antigen receptor T cells (19CARTs) for pediatric acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL): Clinical activity and cytokine release without graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).
Authors: Lee Daniel Warnell , Shah Nirali , Stetler-Stevenson Maryalice , Sabatino Marianna , Richards Kelly , Delbrook Cindy , Kochenderfer James , Rosenberg Steven A. , Stroncek Dave , Mackall Crystal , Wayne Alan S.
Published: March 2020

10008

Background: Despite intensive chemotherapy and HSCT, outcomes in relapsed/refractory pediatric B cell ALL and NHL are poor. To treat children with or without prior allogeneic-HSCT and quickly deliver therapy, we developed a Phase I trial of 19CARTs for both HSCT-naive and post-allo-HSCT patients where autologous-collected T cells are manufactured in 11 days. Methods: T cells collected on Day -11 by lymphopheresis were positively selected and activated using anti-CD3/CD28 beads then transduced with the CD19-CAR gene via retrovirus. Cells were infused after 7 additional days of expansion. Patients (Pt) received fludarabine and cyclophosphamide prior to receiving 1e6 19CARTs/kg. Results: A 59-65 fold expansion of 19CARTs with 39-65% transduction efficiency was achieved in Pt 1 and 3 (ALL, NHL). Pt 1 achieved a complete response (CR). Mild cytokine release syndrome was observed (Gr 3 fever, Gr 2 hypotension) correlating with mild elevation in IL6, GM-CSF, INFg and C reactive protein (CRP; Table). No other non-hematologic, CAR-related Gr ≥3 toxicities were observed. Pt 2 (ALL) received 2.8% of the targeted cell dose due to lack of cell expansion likely from recent prior chemotherapy but experienced a transient CR with significant 19CART expansion (15% blood, 5% marrow, 6% CSF). Importantly, 19CARTs were well tolerated without evidence of GVHD in these post-allo HSCT patients. Conclusions: Autologous-collected allogeneic derived 19CART cells can be rapidly manufactured and safely administered to children with ALL and NHL. Clinical activity can be achieved without GVHD despite inflammatory cytokine generation. 19CARTs offer a potentially effective strategy to treat post-HSCT relapse warranting further study. Clinical trial information: NCT01593696. [Table: see text]
Comprehensive profiling of cardiac dysfunction in asymptomatic childhood cancer survivors (CCS) treated with anthracyclines.
Authors: Armenian Saro , Gelehrter Sarah , Vase Tabitha , Venkatramani Rajkumar , Landier Wendy , Wilson Karla , Herrera Claudia , Reichman Leah , Menteer John David , Mascarenhas Leo , Freyer David Robert , Venkataraman Kalyanasundaram , Bhatia Smita
Published: March 2020

10020

Background: Anthracyclines are associated with left ventricular (LV) dysfunction in CCS with inevitable progression to congestive heart failure (CHF). Use of ejection fraction (EF) to identify LV dysfunction precludes intervention, because EF decline is a late event in the progression to CHF. Further, better understanding of pathogenesis at the cellular level could facilitate development of targeted interventions. Methods: Study design: Cross-sectional; Biomarkers: Echocardiographic (echo), and blood biomarkers in asymptomatic individuals exposed to anthracyclines ≥300mg/m2 (high-risk [HR]: n=100) compared with: i) CCS exposed to <300 mg/m2 (low-risk [LR]: n=50): and ii) matched healthy controls (Con: n=50). Pathogenesis: Metabolomic analyses (351 plasma metabolites; 64 pathways). Results: Time from dx to study was comparable for HR (12.0y) vs. LR (13.2y, p=0.8). All CCS had EF≥50%. Echo: HR had lower LV chamber thickness-dimension (T-D) ratio (Z-score: -0.62) compared with LR (-0.03) and Con (-0.02; P<0.01) as well as increased LV wall stress ([ESWS] HR: 66 g/cm2, LR: 58 g/cm2, Con: 55 g/cm2, p<0.01) and higher myocardial performance index ([MPI] HR: 0.51, LR: 0.46, Con: 0.46; P<0.01). Blood biomarkers: HR had higher plasma NT-pro BNP (HR: 71 pg/dL, LR: 37 pg/dL, Con: 26 pg/dL; P<0.01); there were no differences in troponins, Galectin-3 or ST-2. Metabolomics:Individuals with LV dysfunction (>2 SD ESWS) had reduced plasma carnitine levels (relative ratio [RR]: 0.88, p<0.01) contributing to altered fatty acid β-oxidation and accumulation of cardiotoxic long-chain (docosadienoate [RR=1.26], adrenate [RR=1.29]; p<0.05) and essential fatty acid intermediates (dihomo-linolenate [RR=1.27], eicosapentaenoate [RR=1.23], docosapentaenoate [RR=1.46]; p<0.05). Conclusions: Comprehensive profiling of anthracycline-exposed CCS with preserved EF revealed dose-dependent echo (LV ESWS, T-D ratio, MPI) and blood (NT-ProBNP) abnormalities 10+years from dx; metabolomic studies demonstrated the role of carnitine in the pathogenesis of LV dysfunction. Taken together, these findings may facilitate early detection and targeted interventions in CCS at highest risk for CHF.
Global fitness in adult survivors of childhood acute lymphoblastic leukemia (ALL).
Authors: Ness Kirsten K. , Huang Sujuan , Smith Webb A , Pui Ching-Hon , Lanctot Jennifer , Howell Carrie R , Karlage Robyn , Shelton Kyla C , Robison Leslie L. , Hudson Melissa M.
Published: March 2020

10022

Background: The extent to which adult survivors of childhood ALL may have impaired fitness has not been well documented. This study compared clinically assessed fitness between childhood ALL survivors and matched controls, and examined risk factors for impaired fitness among survivors. Methods: 365 survivors of childhood ALL diagnosed from 1980-2002, treated at St. Jude Children’s Research Hospital (SJCRH), 10+ years from diagnosis, and 18+ years old completed questionnaires, fitness testing and physical activity assessment (accelerometry). 365 friends/relatives of current SJCRH patients, frequency matched on age, race and sex, were recruited as controls. Data from fitness measures were combined into a composite (SJFIT) using factor analysis. Individual measures and SJFIT scores were compared between survivors and controls with two sample t-tests. Among survivors, associations between demographic, lifestyle, treatment variables and poor fitness, i.e. scoring in the lowest 10th percentile of controls on the SJFIT, were evaluated with logistic regression. Results: Survivors were 52% male (mean age 28±7 years, mean diagnosis age 6±5 years, mean survival 21±5 years), and scored lower than controls on individual fitness measures (Table) and the SJFIT composite. Female sex (OR 9.4, 95%CI 3.4-26.1) and fewer daily minutes of moderate and vigorous physical activity (OR 0.95, 95% CI 0.92-0.99) were associated with poor fitness after adjusting for diagnosis age, current age, cranial radiation, body fat and smoking. Conclusions: Childhood ALL survivors, particularly females, have fitness impairments when compared to matched controls. Poor fitness is associated with physical activity levels. Interventions to address impairments need to be tested and implemented. [Table: see text]
A phase I study of the anti-insulin like growth factor type 1 receptor (IGF-1R) antibody dalotuzumab in pediatric patients with advanced solid tumors.
Authors: Frappaz Didier , McGregor Lisa M. , Pearson Andrew DJ , Gore Lia , DuBois Steven G. , Aerts Isabelle , Iannone Robert , Geschwindt Ryan , Van Schanke Arne , Wang Ruixue , Geoerger Birgit
Published: March 2020

10026

Background: Insulin-like growth factor signaling plays an important role in several pediatric cancers. Dalotuzumab is a highly specific, humanized IgG1 monoclonal antibody against IGF-1R. This multicenter phase 1 study explored the safety and pharmacokinetics (PK) of dalotuzumab in pediatric patients with advanced solid tumors. Methods: Dalotuzumab was administered intravenously every 3 weeks. Dose-escalation was performed according to a modified Toxicity Probability Interval (mTPI) design starting at 900 mg/m2. The PK profile of dalotuzumab was evaluated with the primary goal of confirming that the Day 22 mean serum trough concentration exceeded 25 μg/mL. Results: 24 patients were enrolled and 20 treated (median age, 10.5 years; range, 3–17 years). Six patients had recurrent Ewing sarcoma. Patients received a median of 2 cycles (range, 1-10). No dose-limiting toxicity was observed in any of the three dose levels explored (900, 1200 and 1500 mg/m2). Main treatment-related toxicities were Grade 3 elevated transaminases. PK data showed dose dependent increases in AUC0-∞ (105,000, 164,000 and 281,000 hr*mg/mL, for the 900, 1200 and 1500 mg/m2 dose levels, respectively), Ctrough (65.2, 71.6, 148 mg/mL) and Cmax (559, 643, 888 mg/mL). The mean half-life was 247, 394 and 376 hours respectively. The Cmax exhibited mild variability (4.8-35% Coefficient of Variation), whereas variability was moderate to high on the Ctrough (39-200%), apparent t1/2 (28-154%), AUC0-∞ (29-106%) and clearance (52-161%). Except for one patient at the 1200 mg/m2 dose level, all patients met the PK target, a Ctrough of 25 μg/mL, suggesting 900 mg/m2as the recommended phase 2 dose (RP2D). One patient with Ewing sarcoma had a confirmed partial response; 2 patients with Ewing sarcoma and one with nephroblastoma had stable disease for at least 7, 5 and 6 months, respectively. Conclusions: Dalotuzumab is well tolerated in pediatric patients with advanced malignancies. The RP2D of 900 mg/m2 was chosen based on tolerability and PK parameters. Preliminary data confirm prior reports suggesting activity in Ewing sarcoma. Clinical trial information: NCT01431547.