tbuckley/cabot-search huggingface dataset:
Safety and tolerability of veliparib, an oral PARP inhibitor, and M6620 (VX-970), an ATR inhibitor, in combination with cisplatin in patients with refractory solid tumors.
Authors: Arjun Mittra, Geraldine Helen O'Sullivan Coyne, Khanh Tu Do, Sarina Anne Piha-Paul, Shivaani Kummar, Naoko Takebe, Ashley Bruns, Lamin Juwara, Lawrence Rubinstein, Murielle Hogu, Robert J. Kinders, Ralph E. Parchment, Brandon Miller, Deborah Wilsker, M. Cecilia Monge B., Sabrina Sharmin Khan, L. Austin Doyle, James H. Doroshow, Alice P. Chen
Journal: Journal of Clinical Oncology (2019)

3067 Background: M6620 (M), a potent ATR inhibitor, has synergistic activity with cisplatin (C) in multiple preclinical models, resulting in DNA damage and antitumor activity. We hypothesize that inhibition of both homologous recombination and base excision repair through the combination of M6620 and veliparib (V, a potent inhibitor of PARP1/2) would result in accumulation of lethal double stranded breaks induced by cisplatin and increased antitumor activity and initiated a phase-1 dose escalation trial of this combination in patients (pts) with advanced solid tumors (NCT02723864). Methods: This is a standard 3+3 dose escalation design with 21-day cycles. M is given IV day 2 (D2) and D9; V orally twice daily D1-3 and D8-10; C IV D1 (and D8 from dose level 3 [DL3] onwards) at 40 mg/m 2 (with option of holding after cycle 6). Primary objectives: safety; tolerability; maximum tolerated dose (MTD). Secondary objectives: pharmacodynamic (PD) biomarkers; antitumor activity. Dose-limiting toxicity (DLT) evaluated during cycle 1, response using RECIST 1.1. Results: Thirty-seven patients enrolled, median 5 lines of prior therapy (Range 1-12). MTD: V 200 mg, M 210 mg/m 2 , C 40 mg/m 2 (DL6). DLT: grade (gr) 4 thrombocytopenia (DL4), hypophosphatemia (not resolved in 24 hrs., DL3), infusion reaction (DL7). Common gr 3/4 toxicities: anemia (41%), thrombocytopenia (30%), neutropenia (27%), hyponatremia (11%) and hypophosphatemia (8%). Of 34 pts evaluable for response: 2 partial response (PR) (6%, 1 confirmed &amp; 1 transient), 22 stable disease (SD) (65%, median 4 cycles, range 2-11). Of 24 pts with PR/SD, 22 had prior platinum chemotherapy. After July 2018, V was held for gr ≥2 anemia until improved to gr 1, followed by dose reduction. Of 5 pts treated in this period, 3 required V held. PD analysis of circulating tumor cells is underway to elucidate biomarkers of DNA damage and apoptosis. Conclusions: This combination of M6620, veliparib and cisplatin is safe, with activity seen in pts having received prior platinum. The most common toxicity was anemia, which prevented adequate delivery of veliparib. While MTD was established in a heavily pretreated population, consideration should be given to continued dose escalation in pts who have received fewer prior lines of therapy. Funded in part by NCI Contract No. HHSN261200800001E. Clinical trial information: NCT02723864.
Pathologic response and surgical outcomes in patients undergoing nephrectomy after receipt of immune checkpoint inhibitors for renal cell carcinoma.
Authors: Vitaly Margulis, Nirmish Singla, Roy Elias, Rashed Ghandour, Yuval N Freifeld, I. Alex Bowman, Solomon L. Woldu, Jeffrey Gahan, Aditya Bagrodia, James Brugarolas, Hans J. Hammers
Journal: Journal of Clinical Oncology (2019)

e16102 Background: With the approval of immune checkpoint inhibitors (ICI) for metastatic renal cell carcinoma (RCC), the role, timing, and safety of surgically excising the primary tumor remain unclear. We sought to evaluate the safety and feasibility of nephrectomy following receipt of ICI for RCC. Methods: We reviewed our experience of RCC patients who underwent nephrectomy from 2016-2018 following exposure to nivolumab or combination ipilimumab/nivolumab. Demographics, IMDC risk score, and pathology were collected. Surgical outcomes including operative time (OT), estimated blood loss (EBL), hospital length of stay (LOS), readmission rates, and 30- and 90-day complication rates were analyzed using descriptive statistics. Results: 11 nephrectomies (10 radical, 1 partial) were performed in 10 patients after ICI with median postoperative follow-up 180 days. 6 patients received 1-4 cycles of ipilimumab/nivolumab, while 5 received 2-12 infusions of nivolumab preoperatively. One patient with non-metastatic, synchronous bilateral renal masses underwent staged left radical nephrectomy and right partial nephrectomy. 5 surgeries were performed laparoscopically, and 4 patients underwent thrombectomy. IMDC score for metastatic patients was intermediate (7/9) or poor (2/9). One patient exhibited complete response (pT0) to ICI, and 3/4 patients who underwent metastasectomy for hepatic, pulmonary, or adrenal lesions exhibited no malignancy in any of the metastases resected. No patients experienced any major intraoperative complications, and all surgical margins were negative. Median OT, EBL, and LOS were 180 minutes, 100 mL, and 4 days, respectively. Four patients experienced any complication, including 3 that were addressed with a single interventional radiology procedure. One patient died of progressive disease &gt; 3 months after surgery, and one patient succumbed to pulmonary embolism complicated by sepsis. No complications or readmissions were noted in 6 patients. Conclusions: Nephrectomy following ICI for RCC is safe and technically feasible with favorable surgical outcomes and pathologic response. As multimodal management in the era of ICI continues to evolve, the utility and timing of nephrectomy combined with ICI in selected patients warrants attention.
Immunotherapy clinical trials suggest predictive immune-related biomarkers are tissue specific.
Authors: Wendell Jones, Ram N. Ganapathi, Mahrukh K Ganapathi
Journal: Journal of Clinical Oncology (2019)

e14206 Background: RNA-based immune landscape signatures (RILS) portray the breadth of immune and stromal cell activity in the tumor microenvironment (TME). Their predictive and prognostic capability for patients with solid tumors and treated with various therapies has been reported. Methods: Single and multi-variable survival analysis, multi-variable linear models, publicly available data on clinical trials NCT00796445, NCT01621490, NCT02108652. Results: Using publicly available data, RILS were compared to each other and to tumor mutational burden (TMB) to determine their relative ability to identify responders/non-responders and estimate patient survival in a series of immunotherapy clinical trials. These immunotherapy trials include patients treated with a PD1 inhibitor, PD-L1 inhibitor or MAGE-A3 tumor antigen combined with immunostimulant (MAGE-A3). Although no single RILS/TMB biomarker emerged as a clear indicator of immunotherapy response and survival for all cases, there were certain immune-related signatures that recurred as significant (p &lt; .05) or had near-significance (p &lt; .10) related to a specific cancer or therapy. Immune signatures for T cell trafficking, ratios of PD1 to PD-L1 expression, cytotoxic lymphocytes and B cells were consistently predictive and prognostic in melanoma patients treated with the PD1 inhibitor, nivolumab or MAGE-A3. However, while these same signatures were not predictive/prognostic in bladder and kidney/ureter cancer patients treated with the PD-L1 inhibitor, atezolizumab, biomarkers significantly associated with outcome included TMB, TGFB1, and the ratio of T cell trafficking to M2 tumor associated macrophage activity. Since TMB and various immune signatures generally worked better together than individually in predicting outcome, there is potential for utilization of a combination of biomarkers and immune signatures in the design of effective immunotherapy clinical trials. Conclusions: In summary, our results suggest effective immunotherapy trials may require tissue-specific biomarker development. Further, a combination of immune signatures and biomarkers such as TMB shows markedly increased utility compared to single factor such as TMB, PD-1 or PD-L1 expression alone.
Phase I/II study of depatuxizumab mafodotin (ABT-414) monotherapy or combination with temozolomide in Japanese patients with/without <i>EGFR</i>-amplified recurrent glioblastoma.
Authors: Yoshitaka Narita, Yoshihiro Muragaki, Takashi Maruyama, Naoki Kagawa, Katsunori Asai, Junichiro Kuroda, Kazuhiko Kurozumi, Motoo Nagane, Masahid Matsuda, Keisuke Ueki, Christopher Joseph Ocampo, Ikiru Matsumoto, Reiko Odagawa, Yasuko Nishimura, Kazuhiko Mishima
Journal: Journal of Clinical Oncology (2019)

2065 Background: The poor prognosis of glioblastoma (GBM; WHO grade IV) results from a high rate of disease recurrence and lack of effective treatment options. Depatuxizumab mafodotin (depatux-m, ABT-414) is comprised of an EGFR-directed antibody, depatuxizumab (depatux, ABT-806), conjugated to the microtubule toxin monomethyl auristatin F (MMAF, mafodotin). Once bounded with tumor cells, depatux-m is internalized and releases the cytotoxin, resulting in cell death. Here, we report safety, pharmacokinetic (PK) and efficacy in an ongoing phase 1/2 study of Japanese patients with/without EGFR-amplified recurrent GBM (rGBM). Methods: M13-714 (INTELLANCE-J, NCT02590263) is a non-randomized, phase 1/2 study in Japanese patients. Phase 1 assessed tolerability and PK where the dose escalation of depatux-m was from 0.5 to 1.25 mg/kg/Q2W at day 1 and 15 during 28-day cycle until progression disease (PD) or intolerable toxicity. Phase 2 assessed efficacy and safety of depatux-m in EGFR-amplified, rGBM and patients received 1.0 mg/kg of depatux-m on day 1 and 15 + 150 mg/m 2 temozolomide (TMZ) on days 1-5 during each 28-day cycle until PD or intolerable toxicity. Results: As of 10 Jan 2019, 38 patients (WHO grade ≥3) were enrolled (9 in phase 1, 29 in phase 2). There was no dose limiting toxicity in phase 1. The recommended phase 2 dose was 1.25 mg/kg where the most common adverse events (AEs) were punctate keratitis in 21 patients (72%); lymphopenia in 14 patients (45%), thrombocytopenia in 13 patients (41%). Grade 3/4 AEs included thrombocytopenia and lymphopenia in 20 patients (69%). Ocular AEs were reported in 27 patients (93%) including punctate keratitis (72%). PK results (31 patients) in both phases were similar to those of non-Japanese result. Progression Free Survival (PFS) of 27 patients in phase 2 for 12 and 6 months were 8% and 27.5% respectively. The median PFS was 4 months. The overall survival (OS) for 24, 12 and 6 months were 28%, 62.5% and 93% respectively. The median OS was 15.5 months. Conclusions: Preliminary safety, PK and efficacy in Japanese patients with/without EGFR-amplified, rGBM suggests depatux-m was tolerated and showed encouraging anti-GBM effects. Clinical trial information: NCT02590263.
Association of Ki67 expression levels and therapy outcome in low-grade serous ovarian cancer.
Authors: J.P. P. Grabowski, Clara Martinez-Vila, Rolf Richter, Eliane T Taube, Elena Ioana Braicu, Jalid Sehouli
Journal: Journal of Clinical Oncology (2019)

5577 Background: Low-grade serous ovarian cancers (LGSOC) characterize different clinical pattern and lower chemotherapy responsiveness. The expression level of Ki67 is associated with prognosis differences in this patient group. However, Ki67 has not been evaluated as prognostic marker and a predictor of therapy outcome until now. Methods: Patients with LGSOC and Ki67 expression results were identified in institutional database. Receiver-operator characteristics (ROC) curve analysis was performed to find cut off values of Ki67% to discriminate patients with residual tumor mass after surgery from maximal debulked patients, and platinum sensitive patients from platinum resistant patients. Odd ratios (OR) and 95% confidence intervals (95% CI) were calculated using univariate and multivariate logistic regression analysis. Two-sided tests p &lt; 0.05 and are considered statistically significant at a 95% confidence interval. The statistical analysis was performed with the IBM SPSS Statistics 25.0. Results: A total of 68 patients with LGSOC were included. All patients underwent surgery and 15 (22.1%) patients had residual mass ( &gt; 0 mm) after cytoreduction. Sixty-one (89.7%) patients received platinum based first-line chemotherapy. Forty-three patients revealed a recurrence ≥6 months and eleven &lt; 6 months. Patients with Ki67 &lt; 3.6% had significantly higher therapy-free interval (TFI≥6 months), (OR = 13.9, 95%CI 1.62-118.40, p = 0.016). In the multivariate analysis of TFI over 6 months including CA 125, age at diagnosis, peritoneal carcinomatosis and ascites ( &gt; 500ml) Ki67 &lt; 3.6% remained significant (OR = 17.6, 95%CI 1.56-197.52, p = 0.020). Moreover, Ki67% &gt; 3.6% were associated with higher risk of residual mass after surgery (OR = 6.75, 95%CI 1.39-32.87, p = 0.018). Conclusions: It is the first study showing association between Ki67% expression and duration of TFI to platinum-based chemotherapy as well as outcome of the surgery in LGSOC. Further prospective trials should be planned to develop predictive models in this patients.
Nanoparticle entrapped docetaxel (CPC634) enhances intratumoral docetaxel exposure compared to conventional docetaxel (Cd) in patients with solid tumors.
Authors: Florence Atrafi, Ruben A.G. van Eerden, Marte A.M. van Hylckama Vlieg, Esther Oomen De Hoop, Peter de Bruijn, Cristianne J.F. Rijcken, Rob Hanssen, Ferry Eskens, Ron H.J. Mathijssen, Stijn L.W. Koolen
Journal: Journal of Clinical Oncology (2019)

3096 Background: Failure or resistance to chemotherapy may be caused by sub‐therapeutic intratumoral drug levels. Nanomedicine aim to improve intratumoral drug exposure. CPC634 is a nanoparticle entrapping docetaxel. We hypothesized that CPC634 increases intratumoral docetaxel exposure. Methods: In this randomized cross-over study we assessed intratumoral and plasma pharmacokinetics (PK) of docetaxel after intravenous administration of CPC634 and conventional docetaxel (Cd). The study was powered to identify an 25% increase in intratumoral docetaxel exposure of CPC634 relative to Cd. Patients (≥18 years) were randomized to receive 75 mg/m 2 CPC634 in cycle 1 and Cd in cycle 2 or vice versa. After drug administration, patients underwent tumor biopsies during both cycles. Total docetaxel was determined for both drugs and released docetaxel for CPC634 in tumor tissue and in plasma with a validated LC-MS/MS method. PK data were analyzed with mixed model analysis. Results: Sixteen evaluable patients were included. Intratumoral PK revealed a 323% (95% CI: 148,621) higher total docetaxel (p &lt; 0.001) for CPC634. Released docetaxel for CPC634 was comparable to total docetaxel levels for Cd (95% CI: -35-,67) (p = 0.43). Plasma released docetaxel for CPC634 exhibited an 89% (95% CI: 86, 91) lower (p &lt; 0.001) peak plasma concentration (C max ) and 81% (95% CI: 46, 125) higher (p &lt; 0.001) area under the curve (AUC) relative to Cd. Conclusions: CPC634 resulted in higher intratumoral total docetaxel and comparable released docetaxel levels relative to total docetaxel for Cd. CPC634 had a favorable plasma PK profile with a lower C max and prolonged higher systemic exposure relative to Cd. These results indicate that CPC634 could improve intratumoral docetaxel exposure compared to Cd. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in patients with platinum resistant ovarian cancer (NCT03742713) are currently ongoing.
Phase I trial of endoxifen gel versus placebo gel in women undergoing breast surgery.
Authors: Katrina Alber, Kelly A. Benante, Yanfei Xu, Mary Beth Tull, Adrian J. Segura, Kiril Kalinichenko, Lifang Hou, Borko Jovanovic, Marjorie Perloff, Brandy M. Heckman-Stoddard, Eileen P. Dimond, Seema Ahsan Khan
Journal: Journal of Clinical Oncology (2019)

TPS1588 Background: Despite large Phase III clinical trials that have established the success of selective estrogen receptor modulators (SERMs) for breast cancer prevention and therapy of duct carcinoma in situ (DCIS), acceptance by women likely to benefit has been low, primarily because of toxicity related to systemic exposure. Local drug delivery to the breast in gel form is an attractive alternative since low systemic levels could minimize toxicity. Endoxifen (ENX) is an active metabolite of tamoxifen, that has unique activity compared with 4-hydroxytamoxifen (4-OHT). It is smaller and more polar than 4-OHT making it potentially more suitable for transdermal delivery. The NCI PREVENT program has developed ENX transdermal alcoholic gel products. Methods: We are conducting a randomized, double-blinded, placebo-controlled, Phase I trial to establish the dermal tolerability and safety of endoxifen (ENX) gel. 38 women planning unilateral or bilateral mastectomy will be enrolled across 3 institutions in 3 cohorts: (a) ENX gel 10mg (N = 8) vs. placebo gel (N = 4) daily; (b) ENX gel 20mg (N = 8) vs. placebo gel (N = 4) daily; (c) the maximum tolerated dose (N = 8) with last dose 72 hours prior to surgery. Treatment duration will be 4 ± 1 weeks. All participants will be evaluated for toxicity and skin tolerability. Secondary endpoints include TAM metabolite measurements in breast tissue and plasma; serum hormone concentrations, serum estrogenic response, changes in coagulation parameters, gene expression changes reflective of therapeutic effects, and experienced symptoms. 65 potential participants have been pre-screened for eligibility. 33 were ineligible prior to contact, most commonly due to the use of neoadjuvant chemotherapy. Of 32 potential participants who have been eligible to be contacted, 21 did not consent for screening, most commonly because they were too overwhelmed with their recent diagnosis. 7 have consented, 4 are pending consent, and 6 have started study intervention. No adverse events have been reported to date. This pre-surgical trial testing transdermal ENX for breast cancer prevention is accruing as projected. The results will establish the skin safety of this agent, provide data on skin permeability, and the duration of drug retention in the breast. Clinical trial information: NCT03317405.
Prognostic significance of blood-based cancer detection in plasma cell-free DNA (cfDNA): Evaluating risk of overdiagnosis.
Authors: Geoffrey R. Oxnard, Xiaoji Chen, Eric T. Fung, Ting Ma, Jafi Lipson, Earl Hubbell, Kathryn N. Kurtzman, Shilpen Patel, Rita Shaknovich, Zhao Dong, Hai Liu, Jacqueline D. Brooks, David R. Spigel, Michael Seiden, Alex Aravanis, Eric A. Klein, Anne-Renee Hartman, Minetta C. Liu
Journal: Journal of Clinical Oncology (2019)

1545 Background: Screening tests for early cancer detection are often criticized due to risk of overdiagnosis—detection of good prognosis cancers which may not require immediate treatment. We recently reported development of cfDNA sequencing approaches for cancer detection; longitudinal follow-up (F/U) data were utilized here to evaluate prognostic significance of cancer detection using cfDNA. Methods: Plasma cfDNA samples were subjected to whole-genome bisulfite sequencing (WGBS, 30X) as part of a previously-reported Circulating Cell-free Genome Atlas (CCGA; NCT02889978) substudy. This exploratory analysis evaluated the overall survival (OS) of training and test set participants (pts) with cancer (20 cancer types, any stage I-IV). Combining train and test set pts, univariate and multivariate analyses (Cox proportional hazards) assessed OS association with WGBS result (cancer detected vs not detected, set at 98% specificity), clinical stage (IV vs I-III), diagnostic method (symptom- vs screen-detected), sex, age, and histologic grade. Results: Of 827 pts from the training set with F/U (median 12.2 mo), 334 (40.4%) had WGBS-detected cancer. Among 127 (15.4%) pts with cancer that died during F/U, cancer was detected in 104 (81.9%). Results were similar in the test set. In univariate analyses all variables were associated with prognosis, including WGBS result (HR 7.7 p&lt;0.001). In multivariate analyses accounting for other covariates, the three variables that most significantly remained prognostic were WGBS (HR 3.0, p&lt;0.001), clinical stage (HR 3.3, p&lt;0.001), and diagnostic method (HR 3.0, p&lt;0.001). Validation of these findings is ongoing in an independent cohort of ~5,000 cancer pts from CCGA using an optimized assay; updated performance results will be reported. Conclusions: Cancers detected using WGBS of cfDNA had a worse prognosis than cancers not detected. WGBS cancer detection carried comparable prognostic significance as clinical stage. By preferentially detecting higher risk cancers, cancer detection using plasma cfDNA may avoid some of the overdiagnosis that has been seen with some existing cancer screening methods. Clinical trial information: NCT02889978.
A novel mutation panel for predicting etoposide in small cell lung cancer.
Authors: Peng Luo, Zhengang Qiu, Anqi Lin, Kun Li, Weiyin Lin, Qiongyao Wang, Ting Wei, Weiliang Zhu, Jian Zhang
Journal: Journal of Clinical Oncology (2019)

e20090 Background: Platinum-based chemotherapy, consisting of etoposide and cisplatin (EP), has been the cornerstone of therapy for extensive-stage small cell lung cancer (ES-SCLC) for decades. Despite the marked initial sensitivity of SCLC to chemotherapy, EP regimens cannot avoid the emergence of drug resistance in clinical practice. With the rise of new chemotherapy regimens in recent years and the primary resistance or insensitivity of ES-SCLC to EP regimens, it is desirable to be able to identify patients with resistant or insensitive ES-SCLC. Methods: The sequencing and drug sensitivity data of SCLC cell lines were provided by The Genomics of Drug Sensitivity in Cancer Project (GDSC); the data regarding of sensitivity to etoposide of 54 SCLC cell lines were analyzed, and etoposide-sensitive cell lines and etoposide-resistant cell lines were differentiated according to the IC50 values defined by the GDSC. ROC curve analysis was performed on all mutations and combinations of mutations to select the optimal panel to predict resistance to etoposide. Results: Receiver Operating Characteristic(ROC) analysis of etoposide resistance revealed that the most significant single gene mutation indicating resistance to etoposide was CSMD3, and the accuracy of predicting resistance to etoposide proved to be the highest when there was any mutation in CSMD3/PCLO/RYR1/EPB41L3, area under the curve (AUC) = 0.804 (95% confidence interval (CI): 0.679-0.930, p &lt; 0.001). Conclusions: This study found that a panel with four genes (CSMD3, EPB41L3, PCLO, and RYR1) can accurately predict sensitivity to etoposide. These findings provide new insights into the overall treatment for patients with ES-SCLC that is resistant or insensitive to etoposide.