tbuckley/cabot-search huggingface dataset:
Concurrent bevacizumab (BEV) with biochemotherapy (BC) followed by ipilimumab for advanced melanoma: A phase I-II trial.
Authors: David R. Minor, Wei Wang, Mohammed Kashani-Sabet
Journal: Journal of Clinical Oncology (2013)

e20001 Background: Decrescendo biochemotherapy (BC) has become a common regimen for advanced melanoma; however only a minority of patients are long term survivors, and 6 cycles of BC may be complicated by severe neuropathy, asthenia, and other toxicities. The BEAM trial (JCO 30: 34-41, 2012) suggested that BEV added to chemotherapy improved response rate and survival. We felt BEV might improve the efficacy of biochemotherapy, and wanted to explore the feasibility of sequential ipilimumab to improve duration of response. Methods: 24 patients with advanced metastatic melanoma (79% stage M1C) were treated with temozolomide 150mg/m2,cisplatin 20mg/m2, vinblastine1.2mg/m2 all days1-4, IL-2 36miu day1, 18miu day2, 9miu days 3-4, and interferon 5miu/m2 d1-5 with BEV 15mg/kg q21d patients1-6 and BEV 7.5mg/kg patients 7-24 After 4 cycles of BC patients received ipilimumab at 3mg/kg. Results: 6 patients received BEV at 15mg/kg. Two had dose-limiting toxicities: one with brain metastases had CNS hemorrhage and one (thrombocytopenic) had gastrointestinal hemorrhage. Per protocol the next 18 patients received BEV at 7.5 mg/kg q 21d. One patient had posterior reversible encephalopathy syndrome but no other unusual toxicities were seen either with the BEV-biochemotherapy or the ipilimumab phase. Responses (3CR, 6 PR) were seen in 45% of 20 evaluable patients with cutaneous melanoma. Median PFS was 7 months and overall survival 12 months; these results are similar to BC alone. (Oncologist, Oct. 14 (10) 995-1002, 2009). Conclusions: Bevacizumab at 7.5mg/kg q 21days can be safely added to 4 cycles of decrescendo biochemotherapy. Further study of this combination is justified. Clinical trial information: NCT01743157.
Phase I study of midostaurin and azacitidine in relapsed and elderly AML.
Authors: Brenda W. Cooper, Tamila L. Kindwall-Keller, Hillard M. Lazarus, Mehdi Hamadani, William W. Tse, Soumit K. Basu, Michael Craig
Journal: Journal of Clinical Oncology (2013)

7058 Background: The Fms-like tyrosine kinase 3 (FLT3) receptor is expressed in 80% of AML and activating mutations are associated with an adverse prognosis. Midostaurin (mdn), an orally available agent, has been shown to inhibit FLT3 receptor signaling and induces cell cycle arrest and apoptosis of leukemic cells expressing both mutant and wild type FLT3 receptors. Preliminary data has shown modest single agent activity as well as safety and tolerablility of mdn in combination with standard induction chemotherapy. Methods: We conducted a phase I study of azacitidine (75 mg/m2 iv X 7days) with escalating doses of oral mdn (25 mg bid, 50 mg bid, and 75 mg bid) days 8-21 of a 28 day cycle in untreated elderly and relapsed AML. The protocol was IRB approved at participating institutions and all patients gave written informed consent. Dose limiting toxicities (DLTs) were defined as &gt; grade 3 non-heme toxicity during cycle 1 excluding grade 3 hepatotoxicity &lt; 7 days, grade 3/4 stomatitis or diarrhea that resolved by day 28, infections, and electrolyte abnormalities of any grade. Pharmacokinetics (pK) were obtained on day 8,15, and 21 before mdn dosing. Results: 17 pts (11 females and 6 males) ages 57-83 ( median 73) were enrolled of whom 5 patients had prior intensive treatment for AML. All pts were FLT3 negative; 5 had normal cytogenetics and 12 had high risk cytogenetics. ECOG PS: 0 (4pts), 1 (11pts), 2 (2pts). No DLT were observed during escalation or in the expansion cohort of 75 mg bid. Responses were evaluable in 14/17 pts and included 2 CR, 1 PR, and 2 HI (clearing of peripheral blasts, platelet tx independence). Median survival from enrollment was 3.5 months (range 1-12 months). 4 pts remain on treatment (2- 9+ cycles). 3 pts died within 60 days (2 PD, 1 treatment-related). Non-infectious, non hematologic SAE’s are listed on the table below. Plasma concentrations of mdn accumulated in the first week of treatment and declined thereafter despite continued dosing. Conclusions: The combination of azacitidine and midostaurin in safe and tolerable in elderly AML and should be further studied in FLT3 positive leukemia. Clinical trial information: NCT01093573. [Table: see text]
Activity of Hsp90-inhibitor drug conjugate (HDC) STA-12-8666 in preclinical models of pediatric sarcoma.
Authors: Christine Heske, Arnulfo Mendoza, Choh Yeung, David A. Proia, Len Neckers, Lee J. Helman
Journal: Journal of Clinical Oncology (2015)

10025 Background: Long-term survival in patients with metastatic relapsed or recurrent Ewing sarcoma (ES) and rhabdomyosarcoma (RMS) is poor. Early phase studies have shown encouraging responses in these patients using irinotecan. However, limitations of irinotecan, including a low conversion rate to its active metabolite (SN38) and a high excretion rate of the inactive form, diminish delivery of this drug to tumors and hinder efficacy. In addition, systemic toxicity limits dose escalation in the clinical setting, especially in drug combinations. Hsp90 is widely expressed in cancer cells, and Hsp90 inhibitors display favorable pharmacokinetics for anticancer use as they remain in tumors for a prolonged period of time and at higher levels, compared to normal tissue. This property makes them ideal intracellular delivery vehicles for chemotherapeutic drugs, allowing for high tumor exposure and low systemic toxicity. STA-12-8666 (Synta Pharmaceuticals) is an HDC conjugated to SN38. The purpose of this study was to test this HDC in xenograft models of pediatric sarcoma. Methods: To test therapeutic efficacy of this HDC, female SCID mice underwent orthotopic injection of ES or RMS cells. When tumors reached between 100 and 500 mm3 (ES) or 50 and 90 mm3 (RMS), mice were randomized and then treated weekly with STA-12-8666, vehicle, irinotecan or ganetespib (an Hsp90 inhibitor). Tumors were measured twice per week with calipers, and mice were weighed weekly to determine drug tolerability. Tumors were harvested at midpoints and at study endpoint for biology studies. Results: In xenograft models of both ES and RMS, treatment with STA-12-8666 produced superior antitumor efficacy compared to controls. All tumors underwent complete regression with tumor eradication persisting for greater than 11 weeks. Additional early data has shown regression of larger tumors up to 1000 mm3. Studies are ongoing and will be reported. Tolerability was excellent with no toxicity-related deaths or significant weight loss in treated mice. Dose titration arms and pharmacodynamic studies of tumors are ongoing. Conclusions: Preclinical data suggest that STA-12-8666 may be a promising anticancer agent for ES and RMS patients.
Development of a public knowledgebase to facilitate decision support for clinical cancer genomics reporting and clinical trial enrollment.
Authors: Kenna Rael Shaw, Jia Zeng, Ann Marie Bailey, Amber Johnson, Beate Litzenburger, Vijaykumar Holla, Elmer Victor Bernstam, Gordon B. Mills, John Mendelsohn, Mark Routbort, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2015)

e22163 Background: Public efforts characterizing thousands of human tumors and germline information have confirmed that any number and combination of alterations may drive tumorigenesis. At MD Anderson we have identified over 5,950 unique alterations in more than 12,000 patients. Thus, it is impractical for any individual to maintain a comprehensive understanding of clinically-actionable alterations. This may be one reason that fewer than 10% of patients with potentially actionable alterations receive targeted treatment. Thus, a resource that distills therapeutic opportunities is needed. Methods: Molecular alterations, therapeutic agents and corresponding clinical trials were annotated. Each variant was annotated with the level of evidence that associated specific alterations in a potentially actionable gene with a therapeutic agent/trial and appropriate references. Specific mutations, copy number variants and fusions were linked to targeted agents, clinical trials, and functional data. Since different alterations in the same gene may have distinct effects and therapeutic liabilities, the functional significance of each variant was noted. These data are used to generate reports, proactive clinical trial alerts and are publically available at www.personalizedcancertherapy.org. Results: At the time of submission, annotation is complete on 23 actionable genes, 458 functionally significant SNVs, 1,200 pharmaceutical agents and 2,927 clinical trials. Locally, clinical trial alerts and proactive reports with decision support annotations are designed to improve clinician recognition of molecular data in the patient record, increase patient accrual onto targeted trials and the development of novel trials at the institution. Conclusions: Proactive notification of therapeutic opportunities and detailed functional annotations of tumor molecular data can improve patient assignment to genomically-driven and –informed clinical trials. Sharing of the underlying data with the broader community is supported in hopes of synergizing with others and developing this as a robust public resource available to patients and physicians around the world.
Characterizing Immunophenotypic and Functional Pseudo-Exhaustion in T Cells From CLL Patients: The Impact of Lenalidomide
Authors: John C. Riches, Jeff K. Davies, Fabienne McClanahan, Rewas Fatah, Sameena Iqbal, Samir Agrawal, Alan G. Ramsay, John G Gribben
Journal: Blood (2012)
Phase II trial of cetuximab (Cmab) plus irinotecan (CPT-11) for chemorefractory Japanese patients with advanced and/or metastatic colorectal cancer (mCRC), to evaluate the efficacy and safety based on <i>KRAS</i>, <i>BRAF</i>, <i>PIK3CA</i>, <i>NRAS</i>, and <i>AKT1</i> mutation status (T-CORE0801).
Authors: Hideki Shimodaira, Hiroshi Soeda, Hisatsugu Ohori, Shoko Akiyama, Mariko Kambe, Yasuko Murakawa, Takao Suzuki, Satoshi Kato, Jugoh Itoh, Mika Watanabe, Takuhiro Yamaguchi, Shunsuke Kato, Chikashi Ishioka
Journal: Journal of Clinical Oncology (2013)

e14597 Background: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) antibody (mAb) therapy among patients with mCRC based on Caucasian studies. To date, few studies have examined the relationship between KRAS status and response to Cmab therapy in Asian populations. Therefore, this prospective study investigated the relationship between the mutation status of KRAS and other EGFR-related genes along with clinical outcomes in response to Cmab + CPT-11 therapy in Japanese patients with mCRC. Methods: Samples that had been collected from 43 chemo-refractory patients with mCRC, who had undergone Cmab + CPT-11 therapy at 11 medical centers in Japan, were subjected to direct DNA sequencing to determine their KRAS, BRAF, PIK3CA, NRAS, and AKT1 status. The response rate (RR) was the primary endpoint along with safety, median progression free survival (mPFS), and median overall survival (mOS) as secondary endpoints. Results: The clinical outcomes in response to Cmab + CPT-11 therapy was observed to be better in the wild-type (WT) KRAS subgroup than in the mutant (MT) KRAS subgroup (RR: 17.9% vs. 0%; mPFS: 3.7 vs. 1.6 months (M) ; mOS: 10.3 vs. 7.5 M). The differences in clinical outcomes were more remarkable between patients with both WT KRAS and BRAFand those with MT of either of these genes (RR: 19.2% vs. 0%; mPFS: 5.2 vs. 1.6 M; mOS: 11.8 vs. 7.4 M), as well as between patients with all 5 WT genes and those with MT of either of these genes (RR: 26.3% vs. 0%; mPFS: 5.2 vs. 1.8 M; mOS: 11.8 vs. 7.4 M). Conclusions: Despite identification of a lower than expected RR to treatment among the WT KRAS subgroup, KRAS mutation status appeared to be a useful predictive marker of response to Cmab + CPT-11 therapy in Japanese patients with mCRC . Combined analysis of KRAS and BRAF improved both the sensitivity and specificity of the predictive biomarker. However, the combined analysis of all 5 genes did not result in any considerable improvement compared with that achieved with the KRAS and BRAF analysis alone. Clinical trial information: UMIN000001668.
Management of high-risk prostate cancer with 5-treatment stereotactic body radiotherapy: Long-term results.
Authors: Josephine Kang, Alan J. Katz
Journal: Journal of Clinical Oncology (2017)

94 Background: Stereotactic Body Radiotherapy (SBRT) is an emerging treatment modality with excellent control rates for low- and intermediate-risk prostate cancer. The role of SBRT for high-risk disease, however, is less studied. The standard treatment (RT) for high-risk prostate cancer entails 8-9 weeks of daily RT with long-term androgen deprivation therapy (ADT). In comparison to this, SBRT is completed in 5 sessions, and offers convenience, low toxicity, and equivalent biochemical disease control rates as standard RT in the low- and intermediate-risk setting. We now present long-term results for SBRT in a cohort of patients with high-risk disease. Methods: We evaluated patients treated from 2006-2010 with SBRT alone (n = 52) to dose of 35-36.25 Gy in 5 fractions, or pelvic radiation to 45 Gy followed by SBRT boost of 19-21 Gy in 3 fractions (n = 46). Androgen deprivation therapy was administered to 55% of patients. Quality of life and bladder/bowel toxicity was assessed using the Expanded Prostate Index Composite (EPIC) and RTOG toxicity scale at regular time intervals. Results: Median followup was 84 months. 8-year biochemical disease-free survival (bDFS) was 61.3%. On univariate analyses,PSA was significant for bDFS (p = 0.001), whereas pelvic radiation (p = 0.97), T-stage (p = 0.79), ADT (p = 0.77), Gleason score (p = 0.78) were not. On multivariate analysis, only PSA remained significant (p = 0.003) for bDFS. Overall toxicity was mild, with 5.1% Grade 2 urinary, 3% Grade 3 urinary and 7.1% Grade 2 bowel toxicity. Use of pelvic radiotherapy was associated with significantly higher bowel toxicity (p = .001). EPIC bowel and bladder scores declined for the first six months and then returned towards baseline. Conclusions: Five-treatment SBRT appears to be a safe and effective treatment for high-risk prostate carcinoma now with median 84 month follow up. The addition of pelvic radiation or ADT does not confer any bDFS benefit with this modality. Our data suggests that SBRT alone may be the optimal approach. SBRT may be a good treatment alternative to discuss particularly for patients unable to undergo ADT or unwilling to receive standard 8-9 week RT. Prospective studies are required to corroborate our results.
Clinical implementation of anchored multiplex PCR with targeted next-generation sequencing for detection of ALK, ROS1, RET and NTRK1 fusions in non-small cell lung carcinoma.
Authors: Anna F. Farago, Zongli Zheng, Alona Muzikansky, Justin F. Gainor, A. John Iafrate, Jeffrey A. Engelman, Long P. Le, Alice Tsang Shaw
Journal: Journal of Clinical Oncology (2015)

8095 Background: Chromosomal rearrangements resulting in expression of oncogenic receptor tyrosine kinase fusions occur in a subset of epithelial malignancies and can underlie sensitivity to tyrosine kinase inhibitors. In non-small cell lung cancer (NSCLC), rearrangements involving anaplastic lymphoid kinase (ALK), ROS proto-oncogene 1 (ROS1), and RET proto-oncogene (RET) occur at frequencies of approximately 4%, 1% and 1%, respectively. Rearrangements involving neurotrophic tyrosine kinase receptor type 1 (NTRK1) have been described, though the frequency is not well characterized. Methods: We implemented a multiplex polymerase chain reaction (PCR) technology, Anchored Multiplex PCR (AMP), for detection of fusion transcripts using targeted next-generation sequencing of cDNA generated from clinical samples (Zheng et al., 2014). The sequencing library targets known fusion exons in ALK, ROS1, RET and NTRK1. We retrospectively reviewed the NSCLC cases assessed by this method. Results: Between July 2013 and January 2015, 663 clinical NSCLC cases from our institution were assessed, providing > 99% power to detect at least one fusion event at an underlying frequency as low as 1%. 584 cases were adenocarcinoma histology. We detected fusions involving ALK, ROS1, RET and NTRK1 at frequencies of 2.6%, 0.9%, 2.0% and 0.0% (17, 6, 13 and 0 cases), respectively. All were mutually exclusive. The histologic subtype was adenocarcinoma in all fusion cases except one. The average age at diagnosis was 57.0, 55.9 and 58.3 years, and average pack years were 8.5, 5.8 and 7.7 for patients with ALK, ROS1 and RET fusions, respectively. The ALK fusion partner in all cases was EML4; ROS1 fusion partners were SDC4, CD74, and EZR; and RET fusion partners were KIF5B, CCDC6, RUFY2 and TRIM24. Although no NTRK1 fusion was detected in NSCLC, we detected a PPL-NTRK1 fusion in a thyroid carcinoma. Conclusions: With this method, we identified ALK, ROS1 and RET fusions at frequencies and with patient characteristics consistent with previous studies. NTRK1 fusions appear to be rare in NSCLC, though it is possible that this assay may not detect all fusions.
Low oncotype recurrence score (RS) and poor clinical outcomes: An irish multicentre experience.
Authors: Emily Harrold, Niamh Keegan, Ciara Marie Kelly, Susie Conlon, Connor Gerard O'Leary, Rachel Collins, Janice Maria Walshe, M. John Kennedy, Seamus O'Reilly
Journal: Journal of Clinical Oncology (2015)

e11586 Background: Oncotype RS is used to assess recurrence risk and predict chemotherapy benefit for hormone positive, node negative, early stage breast cancer. There is a predicted recurrence rate of 6.8% at 10 years with an RS of less than 18, considered low, with the use of hormonal treatment alone. We sought to identify patients with a low RS who subsequently relapsed and to identify any clinicopathologic factors that might allow for futher optimisation of risk stratification. Methods: Using prospectively maintained institutional databases in seven tertiary level Irish cancer centres we identified all patients in these centres with node negative hormone positive breast cancers suitable for chemotherapy, referred for Oncotype Dx testing. We retrospectively examined baseline clinical characteristics, mode of detection of breast cancer and histopathological features of the surgical resection specimens. RS were identified and Recurrence Score-Pathological Criteria (RSPC) was also calculated for each patient. Time to progression, site of progression and subsequent treatment lines were noted and survival at time of study was documented. Results: In seven tertiary level cancer centres 8 patients with low RS relapsed while on hormone therapy. Time to recurrence varied from 7 to 37 months; median of 20 months. Most common site of recurrence was bone (3) followed by liver (2), local skin recurrence (2) and then lung (1). Use of the RSPC score led to the re-classification of two patients; one patient was reclassified as intermediate risk and the other was reclassified as high risk. Conclusions: This is the most up to date Irish experience of the clinical validity of the low Oncotype Recurrence score. Evidently the majority of patients stratified according to the Oncotype Recurrence score have received appropriate and effective treatment. The investigators acknowledge that the number of patients who relapsed is small and the mechanism for relapse and early indicators of poorer outcomes in this sample cannot yet be identified. As international experience evolves identifying additional prognostic features will allow us to continue to refine our strategy of treatment allocation.
Clinical activity of Crenolanib in patients with D835 mutant FLT3-positive relapsed/refractory acute myeloid leukemia (AML).
Authors: Robert Collins, Hagop M. Kantarjian, Mark J. Levis, Alexander E. Perl, Abhijit Ramachandran, Farhad Ravandi, Nora Ku, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2014)

7027 Background: Development of D835 is a common mechanism of resistance to most FLT3 inhibitors. Crenolanib, a type I FLT3 tyrosine kinase inhibitor, has in vitro activity against FLT3 ITD and FLT3 D835. Crenolanib trials in relapsed/refractory FLT3 mutant AML (FLT3 ITD, FLT3 D835, FLT3 ITD/D835) are ongoing (NCT01522469, NCT01657682). Methods: Clinical data on the first 19 patients (7M, 12F) with a median age of 47 years (21-81) are currently available. 6 patients were refractory and 7 had relapsed within 6 months of induction therapy. 4 had undergone prior allogeneic transplants. 11/19 had progressed after exposure to ≥1 prior FLT3 TKI (8 Sorafenib, 7 AC220, 2 PLX3397, 1 PKC412,). 3 had received 2 or more prior FLT3 TKIs. Initially, crenolanib was given at a fixed dose of 100 mg PO TID but the dose was subsequently individualized to 200 mg/m2/d given in 3 divided doses. Results: Crenolanib had a Tmax of 1.5-2 hours and a T1/2 of 8-9 hours. Median day 15 trough levels (from 11 patients) ranged from 136 -785 nM (median 473nM). Commonly observed side effects included nausea and vomiting and transaminase elevations (primarily grade 1, 2). No patient had to go off study due to toxicity. One patient each required crenolanib dose reduction to 80mg TID due to grade 3 nausea or transaminitis, respectively. No QT prolongations on EKG were observed in any patient. 18 patients are currently evaluable for response. 1 patient achieved a rapid molecular and clinical CR with full count recovery. 2 patients achieved a CR with incomplete count recovery (CRi). An additional 4 patients had a partial response. 4 patients were bridged to transplant. Conclusions: Crenolanib is a FLT3 TKI that is showing preliminary clinical activity in a heavily pretreated population with both FLT3 D835 and compound FLT3 ITD/D835 mutant AML. Importantly, crenolanib is also the first agent to demonstrate clinical activity in patients refractory to other FLT3 TKIs via the major clinical resistance mechanism. Trials of crenolanib in newly diagnosed as well as first relapsed AML patients, are being initiated. Clinical trial information: NCT 01522469, NCT01657682. Patient No. N=18 CR/CRi 3 (17%) Partial Response 4 (22%) Blast Response 2 (11%) Overall Response 9 (50%) Patients bridged to transplant 4 (22%)
Comparison of different prognostic scores versus physician’s subjective prognosis in patients with advanced/metastatic renal cell carcinoma treated with temsirolimus in regular clinical setting: An analysis of the STAR-TOR registry.
Authors: Martin Boegemann, Michael Woike, Johanna Gillhaus, Andres Jan Schrader
Journal: Journal of Clinical Oncology (2017)

441 Background: In treatment of metastatic renal cell carcinoma (mRCC) patients several prognostic scores are used: the MSKCC-, IMDC-, and for pts treated with Temsirolimus (TEMS) the Hudes-score. We assessed prognostic value of these scores in TEMS treated cohort and compared the results with physician’s prognosis. Methods: A German multicenter registry for pts with mRCC (NCT00700258) was established to evaluate the safety and efficacy of TEMS in clinical routine. We retrospectively analyzed the data to compare established prognostic scores with risk assessment by the treating physician and match them with survival outcomes. Results: From 02/2008-05/2015, 547 mRCC pts were treated with TEMS. Risk was calculated for 305 (MSKCC), 248 (IMDC), and 187 (Hudes) pts. Physician’s prognosis was documented for 530 pts. Multivariate survival analyses are shown in table below. Abbreviations: g (good), i (intermediate), p (poor), n-p (non-poor). Conclusions: Risk assessment by treating physician is as meaningful as objective prognostic scores. In this data set, IMDC and Hudes performed worse than the MSKCC score. Physician’s risk assessment independently discriminates better between good and intermediate risk. The MSKCC score performs better for discrimination between an intermediate and a poor prognosis. Thus, the physician seems to be able to identify a subset of patients with a good prognosis while the MSKCC score can identify pts which are falsely placed in poor risk group by the physician. [Table: see text]