A phase 1 evaluation of the safety and tolerability of niraparib in combination with everolimus in advanced ovarian and breast cancers.

OBJECTIVES: Phase 1 trial to determine the safety and tolerability of everolimus and niraparib in patients with advanced ovarian and breast malignancies. RESULTS: Fourteen heavily pretreated patients were enrolled (12 high-grade serous ovarian cancer, 1 clear cell ovarian cancer, and 1 triple negative breast cancer). All patients were PARP naïve and received comprehensive genomic profiling prior to enrollment. Two DLTs were experienced in cohort 2 (niraparib 200 mg daily and everolimus 5 mg 3 days per week) with one patient experiencing prolonged thrombocytopenia and the other experiencing severe hypertension. Four additional patients were enrolled after dose de-escalation with one patient again experiencing severe hypertension leading to conclusion of the study. The most frequent grade 3 or greater adverse events were thrombocytopenia, hypertension, anemia, fatigue, neutropenia, and elevated alkaline phosphatase. Two patients had a PR and five patients had SD. ORR was 18% and the CBR was 45% in 11 evaluable patients. Median PFS was 6 months, and median OS is approximately 18 months with three patients still alive at the data cutoff. CONCLUSIONS: The combination of everolimus and niraparib demonstrated significant toxicity at lower doses and is not feasible due to rapid onset and severe hypertension. This limitation possibly blunted the efficacy of the combination as PFS was modest, but OS was surprisingly robust due to three patients with ovarian cancer remaining alive with platinum refractory disease. Further investigation of multiagent blockade of the PI3K pathway combined with PARP is warranted.

Phase I dose escalation study of dual PI3K/mTOR inhibition by Sapanisertib and Serabelisib in combination with paclitaxel in patients with advanced solid tumors.

BACKGROUND: Phase I trial to determine the safety and efficacy of paclitaxel, sapanisertib, and serabelisib. PATIENTS AND METHODS: Patients with previously treated advanced solid tumors were eligible for this open label, cohort study of sapanisertib (TAK-228) and serabelisib (TAK-117) with weekly paclitaxel. A traditional 3 + 3 dose escalation design with 5 dosing cohorts was used. Patient reported outcomes were also evaluated. RESULTS: 19 heavily pretreated patients were enrolled (10 ovarian, 3 breast, and 6 endometrial cancers). All patients received comprehensive genomic profiling prior to enrollment. RP2D is sapanisertib 3 or 4 mg, serabelisib 200 mg on days 2-4, 9-11, 16-18 and 23-25 with paclitaxel 80 mg/m2 on days 1, 8 and 15 every 28 days. All patients in Cohort 5 required dose reductions and one patient experienced a DLT. The most frequent grade 3 or 4 adverse events were decreased WBCs (20%), nonfebrile neutropenia (12%), anemia (9%), elevated liver enzymes (4%), and hyperglycemia (11%). 3 patients had a CR, 4 had a PR, and 4 patients had SD > six months. ORR was 47% and CBR was 73% in 15 evaluable patients. Including all 19 enrolled patients, the PFS was 11 months and OS is still ongoing at 17 months. CONCLUSIONS: The combination of sapanisertib, serabelisib, and paclitaxel was safe and generally well tolerated. Preliminary efficacy was remarkable in an area of unmet need, especially for patient with PI3K/AKT/mTOR pathway aberrations. Positive effects and sustained clinical benefit were even seen in patients that were refractory to platinum and had failed taxane, everolimus, or temsirolimus. CLINICAL TRIAL NUMBER: ClinicalTrials.gov, NCT03154294.

Case report: 16-yr life history and genomic evolution of an ER+ HER2- breast cancer.

Metastatic breast cancer is one of the leading causes of cancer-related death in women. Limited studies have been done on the genomic evolution between primary and metastatic breast cancer. We reconstructed the genomic evolution through the 16-yr history of an ER+ HER2- breast cancer patient to investigate molecular mechanisms of disease relapse and treatment resistance after long-term exposure to hormonal therapy. Genomic and transcriptome profiling was performed on primary breast tumor (2002), initial recurrence (2012), and liver metastasis (2015) samples. Cell-free DNA analysis was performed at 11 time points (2015-2017). Mutational analysis revealed a low mutational burden in the primary tumor that doubled at the time of progression, with driver mutations in PI3K-Akt and RAS-RAF signaling pathways. Phylogenetic analysis showed an early branching off between primary tumor and metastasis. Liquid biopsies, although initially negative, started to detect an ESR1 E380Q mutation in 2016 with increasing allele frequency until the end of 2017. Transcriptome analysis revealed 721 (193 up, 528 down) genes to be differentially expressed between primary tumor and first relapse. The most significantly down-regulated genes were TFF1 and PGR, indicating resistance to aromatase inhibitor (AI) therapy. The most up-regulated genes included PTHLH, S100P, and SOX2, promoting tumor growth and metastasis. This phylogenetic reconstruction of the life history of a single patient's cancer as well as monitoring tumor progression through liquid biopsies allowed for uncovering the molecular mechanisms leading to initial relapse, metastatic spread, and treatment resistance.

Stage IV Colorectal Cancer Patients with High Risk Mutation Profiles Survived 16 Months Longer with Individualized Therapies.

Personalized treatment vs. standard of care is much debated, especially in clinical practice. Here we investigated whether overall survival differences in metastatic colorectal cancer patients are explained by tumor mutation profiles or by treatment differences in real clinical practice. Our retrospective study of metastatic colorectal cancer patients of confirmed European ancestry comprised 54 Americans and 54 gender-matched Germans. The Americans received standard of care, and on treatment failure, 35 patients received individualized treatments. The German patients received standard of care only. Tumor mutations, tumor mutation burden and microsatellite status were identified by using the FoundationOne assay or the IDT Pan-Cancer assay. High-risk patients were identified according to the mutational classification by Schell and colleagues. Results: Kaplan-Meier estimates show the high-risk patients to survive 16 months longer under individualized treatments than those under only standard of care, in the median (p < 0.001). Tumor mutation profiles stratify patients by risk groups but not by country. Conclusions: High-risk patients appear to survive significantly longer (p < 0.001) if they receive individualized treatments after the exhaustion of standard of care treatments. Secondly, the tumor mutation landscape in Americans and Germans is congruent and thus warrants the transatlantic exchange of successful treatment protocols and the harmonization of guidelines.

Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study.

Cancer treatments have evolved from indiscriminate cytotoxic agents to selective genome- and immune-targeted drugs that have transformed the outcomes of some malignancies1. Tumor complexity and heterogeneity suggest that the 'precision medicine' paradigm of cancer therapy requires treatment to be personalized to the individual patient2-6. To date, precision oncology trials have been based on molecular matching with predetermined monotherapies7-14. Several of these trials have been hindered by very low matching rates, often in the 5-10% range15, and low response rates. Low matching rates may be due to the use of limited gene panels, restrictive molecular matching algorithms, lack of drug availability, or the deterioration and death of end-stage patients before therapy can be implemented. We hypothesized that personalized treatment with combination therapies would improve outcomes in patients with refractory malignancies. As a first test of this concept, we implemented a cross-institutional prospective study (I-PREDICT, NCT02534675 ) that used tumor DNA sequencing and timely recommendations for individualized treatment with combination therapies. We found that administration of customized multidrug regimens was feasible, with 49% of consented patients receiving personalized treatment. Targeting of a larger fraction of identified molecular alterations, yielding a higher 'matching score', was correlated with significantly improved disease control rates, as well as longer progression-free and overall survival rates, compared to targeting of fewer somatic alterations. Our findings suggest that the current clinical trial paradigm for precision oncology, which pairs one driver mutation with one drug, may be optimized by treating molecularly complex and heterogeneous cancers with combinations of customized agents.

RET rearrangements are actionable alterations in breast cancer.

Fusions involving the oncogenic gene RET have been observed in thyroid and lung cancers. Here we report RET gene alterations, including amplification, missense mutations, known fusions, novel fusions, and rearrangements in breast cancer. Their frequency, oncogenic potential, and actionability in breast cancer are described. Two out of eight RET fusions (NCOA4-RET and a novel RASGEF1A-RET fusion) and RET amplification were functionally characterized and shown to activate RET kinase and drive signaling through MAPK and PI3K pathways. These fusions and RET amplification can induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render sensitivity to RET inhibition. An index case of metastatic breast cancer progressing on HER2-targeted therapy was found to have the NCOA4-RET fusion. Subsequent treatment with the RET inhibitor cabozantinib led to a rapid clinical and radiographic response. RET alterations, identified by genomic profiling, are promising therapeutic targets and are present in a subset of breast cancers.

RNA based individualized drug selection in breast cancer patients without patient-matched normal tissue.

BACKGROUND: While standard RNA expression tests stratify patients into risk groups, RNA-Seq can guide personalized drug selection based on expressed mutations, fusion genes, and differential expression (DE) between tumor and normal tissue. However, patient-matched normal tissue may be unavailable. Additionally, biological variability in normal tissue and technological biases may confound results. Therefore, we present normal expression reference data for two sequencing methods that are suitable for breast biopsies. RESULTS: We identified breast cancer related and drug related genes that are expressed uniformly across our normal samples. Large subsets of these genes are identical for formalin fixed paraffin embedded samples and fresh frozen samples. Adipocyte signatures were detected in frozen compared to formalin samples, prepared by surgeons and pathologists, respectively. Gene expression confounded by adipocytes was identified using fat tissue samples. Finally, immune repertoire statistics were obtained for healthy breast, tumor and fat tissues. CONCLUSIONS: Our reference data can be used with patient tumor samples that are asservated and sequenced with a matching aforementioned method. Coefficients of variation are given for normal gene expression. Thus, potential drug selection can be based on confidently overexpressed genes and immune repertoire statistics. MATERIALS AND METHODS: Normal expression from formalin and frozen healthy breast tissue samples using Roche Kapa RiboErase (total RNA) (19 formalin, 9 frozen) and Illumina TruSeq RNA Access (targeted RNA-Seq, aka TruSeq RNA Exome) (11 formalin, 1 frozen), and fat tissue (6 frozen Access). Tumor DE using 10 formalin total RNA tumor samples and 1 frozen targeted RNA tumor sample.

A metastatic colon adenocarcinoma harboring BRAF V600E has a durable major response to dabrafenib/trametinib and chemotherapy.

The subset of metastatic colorectal adenocarcinomas that harbor BRAF V600E mutations are aggressive tumors with significantly shortened survival and limited treatment options. Here we present a colorectal cancer patient whose disease progressed through standard chemotherapy and who developed liver metastasis. Comprehensive genomic profiling (FoundationOne(®)) identified a BRAF V600E mutation in the liver lesion, as well as other genomic alterations consistent with colorectal cancers. Combination therapy of dabrafenib and trametinib with standard cytotoxic chemotherapy resulted in a durable major ongoing response for the patient. This report illustrates the utility of comprehensive genomic profiling with personalized targeted therapy for aggressive metastatic colorectal adenocarcinomas.

Preclinical and phase I results of decitabine in combination with midostaurin (PKC412) for newly diagnosed elderly or relapsed/refractory adult patients with acute myeloid leukemia.

PURPOSE: To determine the preclinical activity, clinical maximum tolerated dose (MTD), and recommended phase II dose of midostaurin (MS) combined either sequentially or concurrently with intravenous decitabine (DAC) in newly diagnosed patients 60 years or older or relapsed/refractory adult patients (18 years or older) with acute myeloid leukemia (AML). PATIENTS AND METHODS: Cultured and primary AML cells were treated with DAC and/or MS and analyzed by flow cytometry and immunoblot analyses. In the phase I study, 16 patients were enrolled; 8 were newly diagnosed patients 60 years or older and 8 were 18 years or older with relapsed AML. Only 2 of 16 patients (13%) had FLT3-internal tandem duplication (ITD) mutations, and no patient had KIT mutations. RESULTS: Compared with treatment with either agent alone, sequential treatment with DAC and MS exerted superior anti-AML activity in cultured and primary FLT3-ITD-expressing AML cells. In the subsequent phase I study, the MTD and schedule of administration of the combination was identified as DAC followed by MS. Three patients developed dose-limiting toxicities: two patients developed pulmonary edema requiring mechanical ventilation and one patient developed a prolonged QTc greater than 500 msec. Based on an intent-to-treat analysis, 57% of the patients achieved stable disease or better while enrolled in the trial; 25% had a complete hematologic response. Pharmacokinetic analysis revealed results similar to those previously reported for MS. CONCLUSION: The in vitro combination of DAC and MS is synergistically active against FLT3-ITD mutations expressing AML cells. In a clinical setting, the combination of sequentially administered DAC followed by MS is possible without significant unexpected toxicity, but the concurrent administration of DAC and MS led to pulmonary toxicity after only a few doses. On the basis of these results, additional studies exploring the sequential combination of untreated AML in elderly patients are warranted to further evaluate this combination at the MTD.

Leveraging drug-utilization and external benchmarking data to drive change in prescribing behaviors.

PURPOSE: Improved outcomes and cost savings achieved at a large hospital through a drug utilization benchmarking and reporting initiative are described. SUMMARY: Using the University HealthSystem Consortium (UHC) Clinical Resource Manager (CRM) database, the University of Kansas Hospital identified nine target areas (based on Medicare Severity Diagnosis-Related Group) in which the hospital's drug-utilization practices were deemed suboptimal relative to those of other UHC member facilities with similar caseloads. The pharmacy department developed a CRM template for generating customized reports comparing the hospital's performance on various drug-utilization metrics with that of top-performing peers (i.e., institutions achieving the best patient care outcomes in terms of mortality and length of stay) in the nine target areas. A pre-post comparison of drug-utilization data collected before and after implementation of the reporting initiative indicated improved outcomes in all nine initially selected target areas, with estimated cumulative annualized cost savings of about $900,000. The CRM-generated reports are now distributed semiannually to attending physicians and other hospital leaders via electronic and hard-copy means, focusing on variances from UHC top-performer and overall UHC averages in the use of higher-cost drugs. The reporting initiative has generally fostered enhanced physician-pharmacist collaboration in the investigation of identified drug-utilization variances and implementation of practice changes. CONCLUSION: By evaluating service-specific trends of internal drug utilization against external benchmarks and emulating prescribing practices at top-performing institutions, an academic medical center has achieved improved patient care outcomes and cost savings.

Effectiveness of exogenous albumin administration for the prevention of ifosfamide-induced encephalopathy.

STUDY OBJECTIVES: To assess the effectiveness of prophylactic albumin for the prevention of ifosfamide-induced encephalopathy (IIE), and to describe risk factors for IIE and investigate the predictive potential of a novel risk-stratification model for IIE. DESIGN: Retrospective analysis. SETTING: Single academic medical center. PATIENTS: Forty-one adults who received 93 chemotherapy cycles of regimens that included ifosfamide for the treatment of hematologic or solid tumor malignancy between November 2007 and November 2008. Patients were divided into two groups based on the use of albumin for IIE prophylaxis: albumin group (32 cycles) and no albumin group (61 cycles). MEASUREMENTS AND MAIN RESULTS: Overall occurrence of neurotoxicity during therapy served as the primary outcome measure. Proposed risk factors for IIE were assessed by conducting a subgroup analysis of patients who did and those who did not experience IIE. A novel risk-stratification model was developed in an attempt to predict patients at risk for IIE. The validity of the scheme was assessed by comparing the occurrence of IIE among high- and low-risk patients as identified by the model. Overall, among the 93 cycles, six cases of IIE (6.5%) were identified. The occurrence of IIE was more common in the albumin group compared with the no albumin group (15.6% [5/32] vs 1.6% [1/61], p=0.01). Baseline albumin level was significantly lower, and serum creatinine and aspartate and alanine aminotransferase concentrations were significantly higher among patients experiencing IIE. All cases of IIE occurred among patients identified as high risk according to the risk-stratification model (p=0.01). CONCLUSION: Prophylactic therapy with exogenous albumin is not an effective strategy for the prevention of IIE. The novel risk-stratification model appears to be an effective method for predicting patients with the greatest potential for developing this adverse effect.

Initial therapy in multiple myeloma: investigating the new treatment paradigm.

The development of three novel chemotherapeutic agents - thalidomide, lenalidomide, and bortezomib - has resulted in a fundamental shift in the management of multiple myeloma. Despite this tremendous advancement, the selection of initial treatment must still be made with a degree of uncertainty as a true standard therapy has yet to be established. Although challenging, the relative abundance of therapeutic options, when taken into consideration with unique patient characteristics, creates the potential for individualization of care.For patients eligible for autologous stem cell transplantation, various combinations of novel agents with dexamethasone or traditional chemotherapy have supplanted the previous standard regimen consisting of vincristine, doxorubicin, and dexamethasone. In elderly patients or others that are deemed ineligible for the transplant procedure, the addition of a novel agent to melphalan-prednisone has demonstrated significant improvements in response rates. Due to the immaturity of the available data, it is perhaps best to regard the era of novel agents with a degree of rational enthusiasm, as the ultimate impact on patient care remains undetermined. Although further research is clearly implicated, recent advancements have resulted in significant progress toward obtaining optimum outcomes in a historically challenging disease.

Dose modification protocol using intravenous busulfan (Busulfex) and cyclophosphamide followed by autologous or allogeneic peripheral blood stem cell transplantation in patients with hematologic malignancies.

We evaluated the safety and toxicity through a 5-cohort dose-modification model of once-daily administration of IV busulfan (Bu) in combination with high-dose cyclophosphamide (Cy) as preparative therapy for stem cell transplantation. Twenty-one adult patients with hematologic malignancies were evaluated. Eleven patients underwent autologous and 10 patients underwent HLA-matched sibling allogeneic transplantation. Patients were sequentially enrolled into 5 cohorts. Cohort 1 received intravenous (IV) Bu 1.6 mg/kg every 12 hours for 2 doses and then 0.8 mg/kg every 6 hours for 12 doses; cohort 2 received IV Bu 1.6 mg/kg every 12 hours for 4 doses and then 0.8 mg/kg every 6 hours for 8 doses; cohort 3 received IV Bu 3.2 mg/kg for 1 dose and then 1.6 mg/kg every 12 hours for 2 doses and 0.8 mg/kg every 6 hours for 8 doses; cohort 4 received IV Bu 3.2 mg/kg every 24 hours for 2 doses and then 0.8 mg/kg every 6 hours for 8 doses; and cohort 5 received IV Bu 3.2 mg/kg every 24 hours for 4 doses. In all groups, Bu was administered on day -7 through day -4 and was followed at least 6 hours after the last Bu dose by Cy 60 mg/kg daily for 2 doses on days -3 and -2. Blood samples were collected for pharmacokinetic analysis on the first and last day of IV Bu administration. All patients were alive and had engrafted at day 30. Five patients developed grade 3 or 4 toxicities. Four patients developed hepatic abnormalities, and 3 exhibited evidence of veno-occlusive disease. Two of 3 patients in cohort 5 with a Bu area under the curve >6000 micromol/min developed autopsy-confirmed veno-occlusive disease. Interpatient variability in AUCs was observed in patients within and between cohorts, but no statistically significant interpatient differences were observed in Bu half-life, volume of distribution, clearance, or dose-adjusted area under the curve. Further, minimal variability in Bu pharmacokinetics was observed between the 2 evaluations performed in each patient, thus reflecting the stability of Bu disposition within individual patients. On the basis of the dosing guidelines and schedule outlined in this study, our data suggest that administration of IV Bu 3.2 mg/kg IV every 24 hours for 4 doses in combination with Cy may result in excessive toxicity.

Comparative effects of TCDD, endrin, naphthalene and chromium (VI) on oxidative stress and tissue damage in the liver and brain tissues of mice.

The mechanism of toxicity of structurally diverse environmental toxicants including heavy metals and polyhalogenated and polycyclic hydrocarbons may involve a common cascade of events which entails an oxidative stress and production of reactive oxygen species. We have determined the comparative effects of single 0.01, 0.10 and 0.50 LD(50) doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), endrin, naphthalene and sodium dichromate (chromium VI) on lipid peroxidation, DNA fragmentation and enhanced production of superoxide anion (cytochrome c reduction) in liver and brain tissues of C57BL/6NTac mice. The effects of a single acute oral 0.50 LD(50) dose of these xenobiotics on hepatic and brain lipid peroxidation were investigated at 0, 12, 24, 48, and 96 h after treatment, while the effects of 0.10 LD(50) and 0.01 LD(50) doses of these xenobiotics were at 0, 24, 48, 72, and 96 h after treatment. Dose- and time-dependent effects were observed with all four xenobiotics. At a 0.50 LD(50) dose of TCDD, endrin, naphthalene and chromium VI, maximum increases in cytochrome c reduction (superoxide anion production) of approximately 5.7-, 5.4-, 5.3- and 4.1-fold, respectively, were observed in hepatic tissues. TCDD showed an increasing effect through 96 h. Endrin and naphthalene demonstrated a maximum effect at 12-24 h, while chromium VI exhibited a maximum effect at 48 h. With respect to lipid peroxidation, at a 0.50 LD(50) dose both endrin and chromium VI induced the maximum effect at 48 h of treatment, while naphthalene demonstrated the maximum effect after 24 h of treatment. TCDD demonstrated a continued effect through 96 h of treatment. At a 0.50 LD(50) dose TCDD, endrin, naphthalene and chromium VI produced maximum increases in hepatic lipid peroxidation of approximately 3.5-, 3.1-, 3.7- and 3.3-fold in hepatic tissues, respectively. Similar results were obtained in hepatic and brain DNA fragmentation at 0.50 LD(50) doses. Lesser effects were observed with 0.10 and 0.01 LD(50) doses of these xenobiotics as compared to the 0.50 LD(50) dose. The results clearly demonstrate that these diverse xenobiotics induce dose- and time-dependent oxidative stress and tissue damage in the liver and brain tissues of mice.