tbuckley/cabot-search huggingface dataset:
Subcutaneous daratumumab (DARA SC) plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in patients (Pts) with newly diagnosed amyloid light chain (AL) amyloidosis: Safety run-in results of andromeda.
Authors: Ray Comenzo, Efstathios Kastritis, Mathew Maurer, Jeffrey A. Zonder, Monique Minnema, Stefan Schönland, Ashutosh Wechalekar, Giovanni Palladini, Xiang Qin, Sandra Y. Vasey, Imran Khan, Jordan Mark Schecter, Giampaolo Merlini
Journal: Journal of Clinical Oncology (2018)

8011 Background: Systemic AL amyloidosis is characterized by disposition of insoluble amyloid fibrils into tissues and organs via clonal expansion of CD38+ plasma cells. The safety run-in of DARA SC + CyBorD in ANDROMEDA (NCT03201965) is presented. Methods: Eligible pts had ≥1 involved organs, ECOG score ≤2, absolute neutrophil count ≥1.0 × 109/L; hemoglobin ≥8.0 g/dL; platelet count ≥50 × 109/L; estimated glomerular filtration rate ≥20 mL/min/1.73m2, and NT-ProBNP ≤8,500 ng/L. In the safety run-in, pts received a concentrated co-formulation of DARA (1,800 mg in 15 mL) and recombinant human hyaluronidase enzyme (rHuPH20; 30,000 U) in a single, pre-mixed vial, given by manual SC injection qw in Cycles 1-2, q2w in Cycles 3-6, and q4w thereafter ≤2 y. Cy 300 mg/m2 PO or IV and Bor 1.3 mg/m2 SC were given on Days 1, 8, 15, 22 of each 28-day cycle for ≤6 cycles and D 40 mg was given qw. Dosing was staggered ≥48 hours between pts to assess infusion related reactions (IRRs). Safety was evaluated after ≥10 pts received ≥1 treatment cycle. Results: Pts (n = 15) had a median (range) age of 63 (35-77) y and a median of 58 (15-157) d from diagnosis. Pts had a median of 1 (1-3) involved organ, with kidney involvement affecting 67% of pts and 40% of pts with ≥2 organs involved. At baseline, 73% and 27% of pts were grouped into New York Heart Association class I and II, respectively, and 93% of pts had an ECOG score of ≤1. Pts received a median of 2 (1-4) treatment cycles and a median of 5 (1-10) DARA injections. Most common ( > 2 pts) treatment emergent adverse events (TEAEs) were nausea (47%), diarrhea (33%), fatigue (33%), injection site erythema (20%), anemia (20%), and rash (20%). Dyspnea and peripheral edema were reported in 1 (7%) pt each. One grade 3/4 TEAE (hypertension; unrelated to treatment) and no serious TEAEs occurred. IRRs occurred in 2 (13.3%) pts (all grade 1). Additional data will be presented. Conclusions: DARA-CyBorD is tolerable in pts with AL amyloidosis with a low IRR rate and no new safety signals. The limited incidence of dyspnea and peripheral edema indicate a low risk for volume overload. Randomization into ANDROMEDA has begun. Clinical trial information: NCT03201965.
Phase II study for the evaluation of efficacy of pembrolizumab (MK-3475) in patients with cancer of unknown primary.
Authors: Gauri R. Varadhachary, Kanwal Pratap Singh Raghav, Shubham Pant, Filip Janku, Siqing Fu, David S. Hong, Sarina Anne Piha-Paul, Rivka R. Colen, Vivek Subbiah, Jeane Painter, Apostolia Maria Tsimberidou, Bettzy Stephen, Daniel D. Karp, Lacey McQuinn, Tito R. Mendoza, Kenneth R. Hess, Funda Meric-Bernstam, Aung Naing
Journal: Journal of Clinical Oncology (2017)

TPS3103 Background: Cancer of unknown primary is a biopsy proven malignancy for which an anatomic primary remains unidentified after a focused search. It accounts for 3-4 % of all solid cancers and most investigators limit it to epithelial and undifferentiated cancers. Patients with metastatic melanoma and sarcoma are excluded. Sophisticated imaging, robust pathologic evaluation including immunostains, and genomic and proteomic characterization of these cancers have challenged the management of CUP. The paradigm has shifted from empiric platinum based combination doublets to a personalized approach. Nevertheless, without an anatomic primary, clinical trial opportunities are limited. There remains an unmet research need to evaluate the role of immunotherapy, specifically checkpoint blockade drugs in specific subsets of CUP patients. Methods: Adult Patients ≥ 18 years of age with ECOG PS 0-1, must meet the definition of a CUP cancer. Patients must be intolerant and/or refractory to at least one line of established therapy known to provide clinical benefit for their condition within the last 6 months (often, a platinum based therapy for carcinomas). Patients must have either measurable (RECIST 1.1) or evaluable disease. Although not limited to subtypes, there is a signficant interest in enrolling patients with isolated disseminated lymphadenopathy, HPV (+) CUP and those who have an IHC profile of those known cancers for which anti-PD therapy has been approved (lung, renal, others) The primary objective of this trial is to evaluate efficacy by evaluation of non-progression rate (NPR) at 27 weeks (9 cycles) as defined as the percentage of CUP patients who are alive and progression-free at 27 weeks (9 cycles) as assessed by RECIST 1.1. Secondary objectives include evaluating safety and tolerability of pembrolizumab (MK-3475); correlating efficacy, non-progression rate (NPR) at 27 weeks (9 cycles), objective response (CR or PR), progression-free survival (PFS), overall survival (OS) and duration of response (DOR) to PD-L1 status; and identifying imaging characteristics associated with immunological changes in tumor following treatment with pembrolizumab. Enrollment is ongoing. Clinical trial information: NCT02721732.
Results of a phase II multicenter study of obinutuzumab plus bendamustine in pts with previously untreated chronic lymphocytic leukemia (CLL).
Authors: Jeff Porter Sharman, Habte Aragaw Yimer, Michael Boxer, Nicholas DiBella, Sunil Babu, Jia Li, Yong Jun Mun, Sandra L. Skettino, Alexey Valeryevich Danilov
Journal: Journal of Clinical Oncology (2017)

7523 Background: Bendamustine (B) + rituximab (R; BR) is a commonly used 1L treatment for CLL. The CLL10 study reported an ORR of 96% and CR of 31% with BR. Obinutuzumab (GA101; G) is a glycoengineered, type II anti-CD20 monoclonal antibody. A randomized Phase III trial in 1L CLL pts showed that G significantly improved PFS and CR rate compared with R, when used in combination with chlorambucil (Goede 2014). B + G (BG) was evaluated in a subgroup of CLL pts in the GREEN study (Stilgenbauer 2015). We present results of a Phase II study (NCT02320487) evaluating the efficacy and safety of BG as 1L treatment for CLL pts. Methods: 102 pts with previously untreated CLL received BG, consisting of 6 cycles of G (cycle [C] 1: 100mg day (D) 1, 900mg D2, 1000mg D8 and D15; C2–6: 1000mg D1) and B (90mg/m 2 : C1, D2 and D3; C2–6, D1 and D2). Each cycle was 28 days. Primary endpoint was CR assessed using iwCLL criteria. Secondary endpoints included ORR, PFS, OS, and MRD. Median follow-up at the time of analysis was 11.0 months. Results: Median pt age was 61 yrs (range 35–90); 68.6% were male; 44.1% had Rai stage 3–4. For evaluated pts, IgVH status was 32.9% mutated and 67.1% unmutated. The incidences of trisomy 12, normal cytogenetics, and deletions of 13q, 11q, and 17p were 23.4%, 37.5%, 17.2%, 15.6%, and 6.3%, respectively. Investigator-assessed CR rate was 49.0% (95% CI 39.0–59.1) and ORR was 89.2% (95% CI 81.5–94.5) after 6 cycles. MRD negativity (MRD-) in blood, as measured by 4-color flow cytometry, was achieved in 42.7% of pts at the end of induction response assessment and in 75.5% of pts at any time following treatment. MRD- in bone marrow (BM) was 60.8% in pts with BM samples. The most common AEs (all grades [Gr]) were infusion reactions (72.5%), nausea (52.0%), pyrexia (36.3%), neutropenia (34.3%), fatigue (34.3%), constipation (26.5%), and rash (26.5%). The most common Gr 3–4 AE was neutropenia (26.5%). Incidence of Gr 3–4 infections was 11.8%. Incidence of TLS was 4.9% (all Gr 3). Three pts died; none were deemed related to study treatment or CLL by investigators. Conclusions: BG is an effective regimen for 1L treatment of CLL pts, inducing a high CR rate after 6 cycles of therapy. No unexpected safety signals were observed. Clinical trial information: NCT02320487.
A phase II trial of cabozantinib and erlotinib for patients with EGFR and c-Met co-expressing metastatic pancreatic adenocarcinoma (PDAC).
Authors: Anita Ahmed Turk, Amikar Sehdev, Safi Shahda, Bert O'Neil, Paul R. Helft, Aaron John Spittler, Janet Flynn, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (2020)

e16764 Background: Both EGFR and the c-MET receptors are overexpressed in a majority of PDACs. Inhibition of both receptors simultaneously may be required for anti-tumor activity. Erlotinib, an EGFR inhibitor, has modest activity in metastatic PDAC and is approved by the FDA in combination with gemcitabine. Cabozantinib is a tyrosine kinase inhibitor targeting AXL, FLT-3, KIT, MER, MET, RET, ROS1, TIE-2, TRKB, TYRO3, and VEGFR-1, -2, and -3. Preclinical data suggests that the addition of cabozantinib to erlotinib leads to tumor shrinkage and improvement in survival in a KPC PDAC mouse model compared to gemcitabine alone. This phase II study tests this hypothesis in patients with metastatic PDAC that co-express c-MET and EGFR. Methods: Key eligibility includes patients (pts) with metastatic PDAC with EGFR and c-MET overexpression (as determined by centrally tested IHC of 2+ or greater) that have progression on one prior chemotherapy regimen. Patients were treated with cabozantinib (40mg daily) and erlotinib (100mg daily) continuously. This dosing is based on previous combination data in NSCLC. This is a single arm two-stage phase II study with a primary endpoint of overall response rate. Secondary endpoints include of PFS, DCR and OS. Results: From October 2017 to October 2019, 43 pts were screened with 7 pts (median age 62 [range 51-76)] enrolled and treated on study. Pts had a median of 1 line of prior systemic chemotherapy. Most common reason for screen failure was due to lack of co-expression of c-MET and EGFR. EGFR IHC expression was +2 in 4 pts, +3 in 3 pts; c-MET IHC expression was +2 in 5 pts and +3 in 2 pts. Most common any-grade adverse events attributable to cabozantinib and erlotinib include: diarrhea (71%), AST increase (43%), fatigue (43%), nausea (43%), and rash (43%). Only one grade 3 event of fatigue occurred. All pts had clinical and/or radiographic progression within 1-2 months after initiating study therapy. Conclusions: The combination of cabozantinib and erlotinib was well tolerated with manageable toxicity. Due to lack of clinical responses, this study has been terminated due to futility. Clinical trial information: NCT03213626 .
Molecular Profiling of Patients with Pancreatic Cancer: Initial Results from the Know Your Tumor Initiative
Authors: Michael J. Pishvaian, Robert J. Bender, David Halverson, Lola Rahib, Andrew E. Hendifar, Sameh Mikhail, Vincent Chung, Vincent J. Picozzi, Davendra Sohal, Edik M. Blais, Kimberly Mason, Emily E. Lyons, Lynn M. Matrisian, Jonathan R. Brody, Subha Madhavan, Emanuel F. Petricoin
Journal: Clinical Cancer Research (2018)

Purpose: To broaden access to and implementation of precision medicine in the care of patients with pancreatic cancer, the Know Your Tumor (KYT) program was initiated using a turn-key precision medicine system. Patients undergo commercially available multiomic profiling to determine molecularly rationalized clinical trials and off-label therapies.Experimental Design: Tumor samples were obtained for 640 patients from 287 academic and community practices covering 44 states. College of American Pathologists/Clinical Laboratory Improvement Amendments-accredited laboratories were used for genomic, proteomic, and phosphoprotein-based molecular profiling.Results: Tumor samples were adequate for next-generation sequencing in 96% and IHC in 91% of patients. A tumor board reviewed the results for every patient and found actionable genomic alterations in 50% of patients (with 27% highly actionable) and actionable proteomic alterations (excluding chemopredictive markers) in 5%. Actionable alterations commonly found were in DNA repair genes (BRCA1/2 or ATM mutations, 8.4%) and cell-cycle genes (CCND1/2/3 or CDK4/6 alterations, 8.1%). A subset of samples was assessed for actionable phosphoprotein markers. Among patients with highly actionable biomarkers, those who received matched therapy (n = 17) had a significantly longer median progression-free survival (PFS) than those who received unmatched therapy [n = 18; PFS = 4.1 vs. 1.9 months; HR, 0.47; 95% confidence interval (CI): 0.24-0.94; Padj = 0.03].Conclusions: A comprehensive precision medicine system can be implemented in community and academic settings, with highly actionable findings observed in over 25% of pancreatic cancers. Patients whose tumors have highly actionable alterations and receive matched therapy demonstrated significantly increased PFS. Our findings support further prospective evaluation of precision oncology in pancreatic cancer. Clin Cancer Res; 24(20); 5018-27. ©2018 AACR.
Epidermal growth factor receptor (EGFR) exon 20 mutations in EGFR-tyrosine kinase inhibitors (EGFR-TKIs) naive non-small cell lung carcinoma (NSCLC) and response to erlotinib therapy.
Authors: Adnan Aydiner, Murat Sari
Journal: Journal of Clinical Oncology (2018)

e21212 Background: EGFR -TKIs are considered to be effective treatments for advanced NSCLC patients with sensitizing EGFR mutations. There are many complex and rare mutations in the EGFR gene in NSCLC other than the two classical mutations of L858R and exon 19 deletional mutation. The purpose of this study was to investigate the clinical significance of rare exon 20 mutations in EGFR-TKI naive patients, and the efficacy of erlotinib. Methods: We retrospectively analyzed 86 NSCLC patients with EGFR mutations who did not use previous EGFR-TKIs. Exons 18 to 21 of EGFR were analyzed by PCR and subjected to direct sequencing methods. Results: Of 86 patients who had EGFR mutations, 3 male patients (3.5%) had exon 20 mutations. Two patients with exon 20, Gln787Gln mutations were responsive to erlotinib therapy in the second line setting after first line chemotherapy. To the best of our knowledge, the presented two cases are the first to be reported with lung adenocarcinoma with EGFR Exon 20, c.2361G > A,p.Gln787Gln mutations that were evaluated for erlotinib response. Conclusions: We suggest that this rare mutation (Gln787Gln ) is a sensitive EGFR mutation in NSCLC. The identification of new novel EGFR-mutations provides new predictive biomarkers for TKI treatment and is essential to the successful use of targeted therapies. Case Age EGFR mutation Erlotinib usage time Response PFS Final 1 63 Exon 20, Gln787Gln 43 months CR No progression living 2 50 Exon 20, Gln787Gln 7 months PR 7 months exitus 3 73 Exon 20 S768I and Exon 18 G719X 2 months Progression No response exitus M: male; EGFR: epidermal growth factor receptor; PFS: progression free survival; PR: partial response; CR: complete response
Circulating tumor DNA as a predictor for response to treatment in BRAF V600E mutant malignant melanoma.
Authors: Jan Braune, Dagmar von Bubnoff, Marie Follo, Erika Graf, Ulrike Philipp, Laura Glaser, Dietmar Pfeifer, Felix Hahn, Justus Duyster, Frank Meiss, Nikolas Von Bubnoff
Journal: Journal of Clinical Oncology (2017)

9564 Background: Available biomarkers LDH and S100B possess limited sensitivity and specificity to predict outcome in melanoma. In this pilot study we evaluated the use of circulating tumor (ct)DNA harboring BRAF and NRAS mutations as a predictive biomarker for treatment response and progression-free survival (PFS) in patients with locally advanced or metastatic melanoma. Methods: We analyzed 89 retrospective plasma samples from 32 unselected pts, and 158 samples from 12 pts included in a prospective trial (DRKS00009507). We included stage III disease with planned resection or stage IV disease before initiation or change of medical treatment. Blood samples were taken at baseline at d +8, d +28, and thereafter at 3 months intervals for up to two years. We developed a hydrolysis probe based, Locked Nucleic Acid assay to detect BRAF V600E and wild type ctDNA by droplet digital PCR. Results were correlated with LDH, S100B and PFS. Results: Sensitivity of BRAF V600E specific assay was 0.01% with a limit of Blank of 0.28 copies/well. Of 31 stage IV pts with retrospective samples, 23 were positive for BRAF V600E ctDNA at least once (74%). Positive pts had a mean of 9 (range: 1-17) and 483 (range: 0.1-16,388) BRAF V600E copies/mL for stage III and stage IV respectively. The presence of ctDNA at baseline predicted poor PFS (hazard ratio [HR] 1.487, 95% CI 0.34-6.45). A negative slope in BRAF V600E ctDNA was a favorable prognostic factor for PFS (hazard ratio [HR] 0.230, 95% CI 0.04-1.20) with a median PFS of 3.42 vs. 2.56 months (Range 1.87-8.9 vs. 0.89-5.02). Residual ctDNA at the first time point after initiation or change of treatment was related to a shorter PFS (hazard ratio [HR] 2.02, 95% CI 0.39-10.53). Based on 144 measurement pairs, BRAF ctDNA strongly correlated with S100 (r = 0.73) and LDH (r = 0.52). Conclusions: Residual ctDNA early after change or institution of treatment predicted tumor progression at first clinical response assessment. A positive to negative conversion or a decrease indicated a more favorable course. These data support the use of ctDNA as an early predictive marker for treatment response. We will examine whether two or more detected mutations indicate clonal heterogeneity and confer adverse prognosis. Clinical trial information: DRKS00009507.
First-in-human clinical trial with intratumoral BO-112 in solid malignancies: A novel immunotherapy based in double-stranded RNA (dsRNA).
Authors: Ivan Marquez Rodas, Maria E. Rodriguez-Ruiz, Sara Lopez-Tarruella, Jose Luis Perez-Gracia, Enrique de Miguel, Aitana Calvo, Montserrat Blanco-Codesido, Salvador Martin-Algarra, Miguel Martin, Ignacio Melero
Journal: Journal of Clinical Oncology (2017)

3082 Background: BO-112 is a double stranded synthetic RNA, formulated with the cationic carrier polyethyleneimine that preclinically improves its intracellular delivery and resistance towards nuclease degradation. In melanoma mouse models, systemic administration activates MDA-5 and NOXA, leading to anti-tumoral activity connected to a sustained and extended expression of IFN-response genes. Intratumoral (IT) delivery, seeking a safer and more focused enhancement of local and systemic antitumor effects has been tested in transplanted mouse models. The potential of its IT use as an immune-modulatory treatment, as well as its toxicity profile, is being analyzed in this first in human, proof of concept, clinical trial (NCT02828098). Methods: Four patients with malignant solid tumors and palpable cutaneous/subcutaneous or lymph node metastases &gt;1 cm were treated with a single BO-112 dose of 0.6 mg/ml IT. Pre and post treatment biopsies from the injected metastatic lesion were obtained. Pharmacokinetics, serum cytokines and circulating immune cells were sequentially studied in pre and post treatment samples. Results: Patients did not experience relevant toxicity with the exception of a single episode of completely reversible grade 4 thrombocytopenia in one patient, attributed to the drug. BO-112 was not detectable in bloodstream following IT delivery. No changes in circulating cytokines were detected. Main immunobiological effects are summarized in the table. Conclusions: BO-112 has shown changes in tumoral immune cells in 1/4 patients, while in 3/4 induced both necrosis and changes in circulating immune cells. This ongoing trial will compile more safety data with repeated sequential administrations, escalated to higher doses of BO-112, and will thoroughly characterize its biological effects in humans with solid malignancies amenable to IT injection. Clinical trial information: NCT02828098. [Table: see text]
Safety, antitumor activity and biomarker of anti-PD-1 antibody in patients with advanced esophageal carcinoma.
Authors: Xiangrui Meng, Yachao Meng, Feng Wang, Qing Xia Fan
Journal: Journal of Clinical Oncology (2018)

e16083 Background: Esophageal squamous cell carcinoma (ESCC) has a poor outcome.Immunotherapy targeting the checkpoint programmed cell death protein 1 (PD1) has been shown to be effective in the management of melanoma, non-small cell lung cancer, and renal cell carcinoma. Methods: A retrospective study of 52 patients with advanced ESCC received anti-PD-1 antibody or chemotherapy, all patients has previously received first- or multi-line chemotherapy.26 patients in the observation group received continuous treatment of anti-PD-1 antibody: Q2W with initial dose of 200mg until disease progression or intolerable toxicity. 26 patients in the control group received irinotecan on d1 and d8 at a dose of 80 mg·m-2. Results: Total 52 patients were enrolled from January 2016 to June 2017 in the First Affiliated Hospital of Zhengzhou University and Henan Tumor Hospital,and all of them could be evaluated for objective efficacy and safety.In observation group,ORR and DCR were 26.9% and 46.2% respectively.In control group, ORR and DCR were 23.1% and 42.3% respectively.PFS were 3.5months (95% CI, 1.3-7.9 months) and 3.1months (95% CI, 1.9--5.4 months) in observation group and in control group respectively.The differences between the 2 groups in ORR,DCR and PFS were not statistically significant(P>0.05).In observation group,treatment-related AEs occurred in 20 patients (76.92%),most commonly reactive capillary hemangiomas(76.92%),pruritus(19.23%) and hypothyroidism(11.54%).Most events were grade 1 or 2. Two(7.69%) treatment-related grade 3 events( pneumonitis) were reported,No grade 4 or grade 5 AEs were reported.In control group,25 patients (96.15%) experienced treatment-related adverse events,19(73.08%) treatment-related grade 3 or grade 4 events were reported.509 genes panal sequencing showed that the TMB in the group with clinical benefit (CB) was much higher than that in that without clinical benefit (NCB) (P= 0.0479).An objective response was more common in patients with PD-L1 positive tumors as defined by > 5% staining than in those with PD-L1 negative tumors. Conclusions: In this population of ESCC patients, anti-PD-1 antibody had a manageable safety profile and promising antitumor activity.