bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical importance of including new and nontarget lesion assessment of disease progression (PD) to predict overall survival (OS): Implications for randomized phase II study design.
Authors: Mietlowski William Leonard , Bao Weichao , Wood Patricia Ann , Williams Denise E , El-Hashimy Mona , Sarr Celine , Stein Andrew Marc , Shi Michael , Weber Dirk , Habr Dany , Porro Maria Grazia 
Published: March 2020

2543 Background: Fridlyand (2011) retrospectively compared PFS vs. change in tumor burden as a primary endpoint in phase II non-small cell lung cancer (NSCLC) trials to inform phase III decision making and found the use of PFS was superior. Since the classic tumor burden model only uses measurements of target lesions, we investigated whether the model could be strengthened by incorporating new and non-target lesion progression. The ability to use a strong tumor burden model has the benefit of potentially earlier decision making and considerable timeline savings. Methods: We analyzed five phase III trials of combination chemotherapy ± targeted therapies with an OS primary endpoint: 1st, 2nd line NSCLC (ATTRACT-1, -2), 1st, 2nd line colorectal carcinoma (CONFIRM-1, -2), and 2nd line ovarian cancer (EPO906A2303). We applied Cox’s proportional hazards model to OS using the covariates of baseline tumor burden, 1st tumor assessment percentage change from baseline, new lesions, and non-target PD. Results: See table. Conclusions: We show that predictive models for OS should consider new and non-target lesions for PD, as well as target lesion tumor burden, findings independently corroborated by Suzuki (2011). We propose a longitudinal rank-based randomized phase II design, ranking a patient’s risk of death, differentially weighting PDs by type and time of PD, and percentage change in tumor burden. This may be more informative for phase II decision making for phase III trials based on OS, than PFS which only uses time of PD. Further studies with other tumor types and treatment modalities are warranted. [Table: see text]
Predictive model for survival and toxicity in early-phase trials in hematology.
Authors: Jamal Rahima , Chen Bingshu E , Hristova Gergana , Seymour Lesley , Assouline Sarit E. 
Published: March 2020

2547 Background: Strict criteria are used to limit toxicity for patients (pts) enrolled in phase I/II clinical trials, but the ability to survive beyond 12 weeks, a common inclusion criterion, is subjective and error-prone. A prognostic score with 3 variables was designed and validated as an independent predictor of OS in pts with solid tumors included in phase I trials (Arkenau, JCO 2009). We examined the ability of objective measures to predict OS and risk of grade ≥3 toxicity in pts with hematologic malignancies enrolled in early-phase trials. Methods: A retrospective analysis was conducted on 290 pts in Phase I (79 pts) and II (211 pts) trials from the NCIC - Clinical Trials Group and our institution from 1995 to 2009. Only pts with survival data up to 90 days were included. Univariate model (UVA) was used to identify factors significantly associated with OS. A Cox proportional hazards model (MVA) included all factors identified from the UVA. Six prognostic factors were identified in the MVA, and each assigned a score of 0 or 1. Pts were categorized as high or low risk based on the total scores that they received, ≥3 were assigned to the high risk group, and a ≤2 to the low risk group. Kaplan-Meier method was used to generate the survival distribution for the high and low risk groups. Multivariate logistic regression was used to identify the risk factors for grade ≥3 toxicity. Results: The overall median survival was 238 days (95% CI 237 to 331), and 27% of pts had grade ≥ 3 toxicity. In the MVA, albumin (alb), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lymphocytes, platelets (plts) and diagnosis were significantly associated with OS. Pts in the low risk group had a median survival of 10.6 months, relative to 2.4 months among pts in the high risk group. Survival at 90 days was 80% in lower risk vs. 36% in the high risk group. In addition, the MVA for toxicity showed that alb, ALP, LDH, plts and performance status were significantly associated with grade ≥3 toxicity. Conclusions: Our model predicts OS, 90 day survival and risk of grade ≥ 3 toxicity among pts with hematologic malignancies entered in Phase I/II trials. Future work will include a linear predictor score based on MVA to refine the prediction model. The model will also be validated using another dataset.
Difference between duration of treatment (DOT) and progression-free survival (PFS) as a marker of unbalanced censoring.
Authors: Amiri-Kordestani Laleh , Wilkerson Julia , Balasubramaniam Sanjeeve , Bates Susan Elaine , Fojo Antonio Tito 
Published: March 2020

2548 Background: In the conduct of randomized trials Kaplan and Meier envisioned rates of censoring as similar between arms, providing accurate assessment of clinical trial results. Censoring is used when patients withdraw consent, leave study due to toxicity, or reach data cut-off without disease progression or death. Censoring can lead to erroneous conclusions as it can be either beneficial or detrimental to the arm under study. Such censoring can also explain how a statistically valid difference in PFS “disappears” when overall survival (OS) is examined. We hypothesized that censoring, especially that due to toxicity, would lead to a discrepancy between DOT and PFS since two different patient populations would be scored. Methods: We reviewed all phase III randomized studies of drugs approved by FDA since 2005 for pts with metastatic solid tumors, looking for DOT and PFS. We used standard statistical analyses using SAS. Results: We identified 55 Phase III studies conducted with abiraterone, axitinib, bevacizumab, cabazitaxel, cetuximab, eribulin, erlotinib, everolimus, ipilimumab, ixabepilone, lapatinib, panitumumab, pazopanib, sorafenib, sunitinib, temsirolimus and vandetinib. DOT was not provided in 27%. Forty-four comparisons (88 arms) were included in the analysis. The median PFS, DOT, delta PFS (difference in PFS between experimental and control arms) and delta DOT were: 161, 126, 51 and 36 days, respectively. The slopes of PFS vs DOT and delta PFS vs delta DOT were 1.16 and 1.03, respectively close to the ideal of 1.0. Five trials fell above the 90% CI boundary with delta PFS/delta DOT of 3 to 36, including two everolimus studies (PNET and breast cancer) two sunitinb studies (RCC and PNET) and one bevacizumab study (E2100, breast cancer). Conclusions: PFS and DOT as well as delta PFS and delta DOT should be concordant. The most likely explanation for a discordance between these values is toxicity-driven censoring and its occurrence raises concerns regarding the degree of efficacy. A greater utilization of “Time to Treatment Failure”, an endpoint that includes toxicity in its definition would be valuable in oncology trials, particularly those with high levels of toxicities.
Recommendation of dose banding of cytotoxics according to pharmacokinetic criteria.
Authors: Chatelut Etienne , White-Koning Melanie , Mathijssen Ron H.J. , Baker Sharyn D. , Sparreboom Alex 
Published: March 2020

2549 Background: Dose-banding has been recently suggested in order to optimize chemotherapy preparation. Ranges (or bands) of body surface area (BSA) are predefined. The individual dose of a particular patient is calculated according to a single BSA value per band, usually the mid-point of the BSA band in which the actual BSA of the patient lies. Thanks to this simple procedure, chemotherapy provision can be rationalized and chemotherapies can be prepared in advance for drugs with sufficient long-term drug stability. The primary purpose of dose-banding is to reduce patient waiting time and improve capacity planning of the pharmacy production, but additional benefits can also be found, such as reduced potential for medication errors, reduced drug wastage, and prospective quality control of preparations. The objective of this analysis was to compare dose-banding to individual BSA-dosing (current practice) according to pharmacokinetic (PK) criteria. Methods: Dose-banding was defined according to three bands of BSA: BSA<1.7m², 1.7m²≤BSA<1.9m², and BSA≥1.9m² for which the values of 1.55m², 1.80m², and 2.05m² were allocated, respectively. By using individual actual values of clearance of six drugs (cisplatin, docetaxel, paclitaxel, doxorubicin, topotecan, and irinotecan) from a total of 1,206 adult cancer patients, the AUCs corresponding to the two dosing methods were compared to a target value of AUC for each drug. Results: Over all 6 drugs, by using dose-banding the percent change of individual dose in comparison with BSA dosing ranged between -14% and +22%. In terms of capacity to attain the target AUC, there was no significant difference in precision when using dose-banding as compared to BSA-dosing for all drugs except paclitaxel (precision of 23.2% versus 21.8%, respectively). For all drugs including paclitaxel, distributions of AUC values were very similar with both dosing methods. Conclusions: For these 6 drugs and maybe others, dose-banding may be implemented without any risk of increasing interindividual plasma exposure. Dose-banding would make it possible to anticipate chemotherapy preparation and analytical control without any delay for the patients.
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of intravenous dimethane sulfonate (DMS612, NSC 281612) in advanced malignancies.
Authors: Bates Susan Elaine , Balasubramaniam Sanjeeve , Parise Robert A , Bryla Christina , Bonner William , Redon Christophe E. , Nakamura Asako , Wright John Joseph , Piekarz Richard , Jiang Yixing , Eiseman Julie , Chu Edward , Belani Chandra Prakash , Beumer Jan Hendrik , Appleman Leonard Joseph 
Published: March 2020

2553 Background: DMS612 is a dimethane sulfonate compound that was identified as preferentially cytotoxic to renal cell carcinoma (RCC) cell lines in a chemical screen of the NCI-60 panel. DMS612 has bifunctional alkylating activity in vitro. Objectives of this first-in-human phase I study included determining the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), PK and PD of DMS612 administered by 10 minute intravenous infusion on day 1, 8 and 15 of a 28 day cycle. Methods: Eligibility criteria included adults with advanced solid malignancies or lymphoma with ECOG performance status 0-2, life expectancy > 3 months and adequate organ and marrow function. Patients were enrolled using a standard “3+3” dose escalation scheme. Plasma PK of DMS612 and metabolites was assessed by LC-MS/MS. DNA damage PD was assessed by γ-H2AX immunofluorescence. Results: 35 subjects were enrolled (22 male, 13 female) with median age 59 years (41-75). Tumor types included colorectal (8), RCC (4), cervix (2), and urothelial (2). Doses administered were 1.5, 3, 5, 7, 9 and 12 mg/m2. The MTD was determined to be 9 mg/m2, with only one DLT of grade 4 thrombocytopenia in 12 subjects enrolled. The maximum administered dose of 12 mg/m2 was considered to be intolerable after 1 of 3 subjects had grade 4 neutropenia and 1 had prolonged grade 3 thrombocytopenia. Prolonged thrombocytopenia in later cycles was observed in other subjects, including one patient naïve to prior cytotoxic chemotherapy. One subject with RCC had a confirmed partial response at 7 mg/m2. DMS612 was rapidly converted into carboxy, chloroethyl and hydroxyethyl analogues and their glucuronides, some of which retained alkylating activity in vitro. Dose-dependent pharmacodynamic evidence of DNA damage induced by DMS612 in vivo was observed by γ-H2AX immunofluorescance in both peripheral blood lymphocytes and plucked scalp hairs. Conclusions: The MTD of DMS12 administered by intravenous infusion on day 1, 8 and 15 of a 28-day cycle was 9 mg/m2. Pre-clinical and clinical observations suggest that further study of DMS612 in RCC is warranted.
Where to look for sentinel node in breast cancer?
Authors: Scharl Anton J. , Düran Andreas ,   Breast Cancer Center Klinikum Bayreuth GmbH
Published: March 2020

2560 Background: It has been observed, that the caudal Axilla on the border to pectoralis muscle is predicive for the sentinel node. The sono-morphology of lymph nodes has been the subject of multiple publications, usually dealing with malignant melanoma. In the context of sentinel lymph node biopsy (SLNB) in breast cancer patients, the following study examines the feasibility of the sonographic differentiation of the Sentinel lymph node (SLN) from neighboring non-SLNs and whether sentinel-ultrasound-needle localization (SUN) is a useful addition or alternative to current methods of “lymphatic mapping”. Methods: During a prospective study performed from 1/2003 to 9/2005 including 404 breast cancer patients (Tis-T4), the SLNB was performed using patent blue+/- 99Tc-Nanocoll. In addition to and independent of this method, the axilla was sonographically examined for “reactive” lymph nodes n=180 pt. (Siemens Elegra 7.5 MHz). The “reactivity” of the nodes was quantified using an index , which allowed the comparison of adjacent nodes. The most “reactive” lymph node in the caudal axilla was identified as the “Ultrasound-Sentinel-Node”(US-SLN) and has been marked with a wire. Results: In 180 patients the SLN was localized using the standard methods as well as (SUN). The was no difference in detection rates of US-SLN and the standard methods in tumor-free nodes(SLN-). However, for patients with axillary metastases (SLN+) SUN provided superior detection rate (99,1%). The false-negative-rate was reduced from 10,7 % to 1,3%. This was attributed to the embolization of lymph vessels afferent to the metastasized (SLN+) node causing a bypass of the “lymphatic mapping” and inhibiting detection. Conclusions: The SUN–Method is comparable to “lymphatic mapping” in tumor free nodes (SLN -). If SLN is metastasized (SLN+) - SUN is superior to the standard methods in sensitivity and specificity (80%) and the false-negative-rate can be reduced. Systematic axilla sonography is an effective method for the SLN-Localisation, and offers an excellent method for quality control during SLNB.
A phase I study of the safety and pharmacodynamic effects of everolimus in combination with lenalidomide in patients with advanced solid malignancies.
Authors: Owonikoko Taofeek Kunle , Harvey R Donald , Kauh John S , Lewis Colleen Margaret , Hossain Mohammed S , Akintayo Adebowale O , Merriewether A. Rene , Chen Zhengjia , Hawk Natalyn Nicole , Saba Nabil F. , Harris Wayne , Shin Dong Moon , El-Rayes Bassel F , Huang Chunzi , Lonial Sagar , Lawson David H. , Khuri Fadlo Raja , Waller Edmund K. , Ramalingam Suresh S. 
Published: March 2020

2576 Background: Everolimus (E), an mTOR inhibitor, and Lenalidomide (L) are both potent anti cancer agents with immunomodulatory effects. Preclinical evidence of enhanced cytotoxicity of the combination of an mTOR inhibitor and lenalidomide provided the rationale for this phase I study. Methods: Patients with advanced solid malignancies, ECOG performance status (PS) 0-2 and adequate organ function were eligible. Using standard 3+3 dose escalation schema, patients were treated in cohorts of three with increasing doses of E (5mg, 10mg) and L (10, 15, 20, 25mg) on day 1-28 of a 28-day cycle. Treatment cycles were repeated until disease progression by RECIST criteria or intolerable toxicity. Pharmacodynamic (PD) effects of treatment on circulating B and T lymphocytes subsets were assessed by multiparameter flow cytometry at baseline and after 2 cycles. Results: We enrolled 21 patients (thyroid-5, salivary gland-5, colon-4, sarcoma-2, and others-5); median age-58 (29-74); male-13; ECOG PS of 0, 1, 2 (3/17/1). Salient grade 3/4 toxicities included rash (67%), anemia (19%) and vomiting (5%) without dose limiting toxicities. The median number of completed cycles was 3 (1 - ≥15) and best response in 14 of 18 evaluable patients was stable disease (range 2- ≥14 months); median PFS was 116 days (14- ≥498). The RP2D of E and L was defined as 10mg and 25mg once daily, respectively. PD endpoint analysis after 2 cycles of treatment showed a significant increase in activated cytotoxic T cell subset (CD8+ICOS1+) in patients with salivary or thyroid cancers compared to other tumor types (+2051.0 vs. +394 vs. -1687.4 respectively; p=0.0303) and a trend for an increase in patients with non-progressing tumors (+661.7 vs. -384.1; p=0.0988). Other significant correlations were: Changes in total B-cells (CD3-CD19+) with PFS; NK cells with age (p=0.0211) and activated T cells (CD3+CD69+; CD3+CD62L-; p=0.01) with gender. Conclusions: The combination of E and L is well tolerated at the recommended single agent doses and showed promising efficacy in neuroendocrine and salivary adenoidcystic carcinoma. Modulation of activated T cell subsets (CD8+ICOS1+) correlates with efficacy of these agents.
Vaccine therapy with tumor-specific mutated ras peptides and IL-2, GM-CSF, or both in adult patients with solid tumors.
Authors: Rahma Osama E. , Hamilton Michael , Dakheel Omar , Steinberg Seth M. , Bernstein Sarah , Schlom Jeffrey , Khleif Samir 
Published: March 2020

2577 Background: We have shown in previous trials that vaccination with mutant ras peptides corresponding to the tumor mutation is feasible and can induce specific immune responses against the mutant proteins. Immune adjuvants are used to enhance the effect of antigen vaccines. Here, we tested the ras vaccine in combination with Interleukin-2 (IL-2), GM-CSF, or the combination of both in patients with advanced malignancies. Methods: We treated 53 patients with advanced cancers (38 CRC, 11 pancreatic, 3 NSCLC and 1 cholangiocarcinoma) with 5000µg of the corresponding mutant ras peptide given SQ along with IL-2 (Arm A), GM-CSF (Arm B) or both (Arm C). IL-2 was given SQ at 6.0 million IU/m2/day starting day 5, 5 days/week for 2 weeks. GM-CSF was given SQ in a dose of 100 µg/day one day prior to each vaccination for 4 days. Vaccines were repeated every 4 weeks for a maximum of 15 cycles or until disease progression. Results: The median PFS and OS for the full cohort was 3.6, and 16.9, respectively. Median PFS was 3.9, 3.2 and 3.6 months for arm A, B, C, respectively. Median OS was 17.3, 20.8 and 9.1 months, respectively. There was no difference in PFS or OS between the three arms (p= 0.74 and 0.99, respectively). In a subgroup analysis, patients with advanced CRC had a median PFS and OS of 3.5 and 14.2 months, respectively. Most adverse events were grade I-II toxicities and resolved spontaneously. Conclusions: Two important conclusions came out of this trial: 1) no difference was found in clinical response between the three arms; and 2) although patients with CRC in the subgroup analysis progressed earlier compared to historical control (3.5 vs. 7.3 months), the time from progression to death “post progression survival, PPS” was notably longer (10.3 vs. 5.6 months). This provides further evidence to the emerging understanding of the difference in clinical trial monitoring between immunotherapy and other types of therapy. Accordingly, removing patients with standard CTEP definition of progressive disease may adversely affect the clinical outcome of vaccine therapy. We believe that future clinical trial design strategies in cancer vaccine should be modified to allow patients to continue therapy despite of disease progression.
Effect of the vaccine Ad5 [E1-, E2b-]-CEA(6D) on CEA-directed CMI responses in patients with advanced CEA-expressing malignancies in a phase I/II clinical trial.
Authors: Morse Michael , Hobeika Amy , Chaudhry Arvind , Amalfitano Andrea , Niedzwiecki Donna , Clay Timothy M. , Osada Takuya , Devi Gayathri , Burnett Bruce K. , Weinhold Kent , Hsu Shiaowen David , Blobe Gerard C. , Xu Younong , Nguyen Susan , Dua Rajesh , Balcaitis Stephanie , Gabitzsch Elizabeth , Balint Joseph , Jones Frank , Lyerly H. Kim 
Published: March 2020

2585 Background: Adenovirus (Ad) vectors are promising platforms for use as cancer vaccines because of their substantial immunogenicity; however, Ad-specific neutralizing antibodies, present due to natural infection, limit their use. We created a new vector containing additional deletions of the E2b gene and observed that this Ad5 [E1-, E2b-] vector, engineered to express carcinoembryonic antigen (CEA(6D)), could induce antitumor immune responses in mice despite pre-existing Ad5 immunity. The purpose of the current translational study was to evaluate the immunologic effect of increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice and then to extended these pre-clinical observations into a phase I/II study. Methods: Ad5 naïve female C57Bl/6 mice, 4-6 weeks old, were immunized subcutaneously 3 times at 2 week intervals with doses of 1.4X107 viral particles (vp) up to1.4X109 vp of Ad5 [E1-, E2b-]-CEA(6D). Two weeks after the last immunization, splenocytes were harvested for immune determinations. Cohorts of patients (n=25 total) with advanced colorectal cancer, refractory to prior therapies, received escalating doses of Ad5 [E1-, E2B-]-CEA(6D) (109 to 1011 vp) subcutaneously every 3 weeks for 3 immunizations.CEA-specific cell mediated immunity was measured by ELISPOT. Results: Increasing doses of Ad5 [E1-, E2b-]-CEA(6D) in mice induced increasing CEA-specifc CMI responses. Similarly, patients who received the highest dose of Ad5 [E1-, E2b-]-CEA(6D) exhibited the highest levels of CEA-specific CMI responses. The induction of CEA-specific CMI responses increased over the course of the 3 injections despite the presence of pre-existing Ad5 immunity in the majority (75%) of patients. There were no drug related grade 3/4 toxicities.Two patients with stable disease remained so during the study. All other patients experienced progressive disease; however, 1-year survival was 54%. Conclusions: Multiple homologous doses of Ad5 [E1-, E2b-]-CEA(6D) could break tolerance and generate CEA-specific CMI responses in the setting of Ad specific immunity in colorectal cancer patients.