Pretherapy Ferumoxytol-enhanced MRI to Predict Response to Liposomal Irinotecan in Metastatic Breast Cancer.

Purpose To investigate ferumoxytol (FMX)-enhanced MRI as a pretreatment predictor of response to liposomal irinotecan (nal-IRI) for thoracoabdominal and brain metastases in women with metastatic breast cancer (mBC). Materials and Methods In this phase 1 expansion trial (ClinicalTrials.gov identifier, NCT01770353; 27 participants), 49 thoracoabdominal (19 participants; mean age, 48 years ± 11 [SD]) and 19 brain (seven participants; mean age, 54 years ± 8) metastases were analyzed on MR images acquired before, 1-4 hours after, and 16-24 hours after FMX administration. In thoracoabdominal metastases, tumor transverse relaxation rate (R*2) was normalized to the mean R*2 in the spleen (rR*2), and the tumor histogram metric rR*2,N, representing the average of rR*2 in voxels above the nth percentile, was computed. In brain metastases, a novel compartmentation index was derived by applying the MRI signal equation to phantom-calibrated coregistered FMX-enhanced MRI brain scans acquired before, 1-4 hours after, and 16-24 hours after FMX administration. The fraction of voxels with an FMX compartmentation index greater than 1 was computed over the whole tumor (FCIGT1) and from voxels above the 90th percentile R*2 (FCIGT1 R*2,90). Results rR*2,90 computed from pretherapy MRI performed 16-24 hours after FMX administration, without reference to calibration phantoms, predicted response to nal-IRI in thoracoabdominal metastases (accuracy, 74%). rR*2,90 performance was robust to the inclusion of some peritumoral tissue within the tumor region of interest. FCIGT1 R*2,90 provided 79% accuracy on cross-validation in prediction of response in brain metastases. Conclusion This first in-human study focused on mBC suggests that FMX-enhanced MRI biologic markers can be useful for pretherapy prediction of response to nal-IRI in patients with mBC. Keywords: MRI Contrast Agent, MRI, Breast, Head/Neck, Tumor Response, Experimental Investigations, Brain/Brain Stem Clinical trial registration no. NCT01770353 Supplemental material is available for this article. © RSNA, 2023 See also commentary by Daldrup-Link in this issue.

Overcoming Taxane Resistance: Preclinical and Phase 1 Studies of Relacorilant, a Selective Glucocorticoid Receptor Modulator, with Nab-Paclitaxel in Solid Tumors.

PURPOSE: Chemotherapy resistance remains a major problem in many solid tumors, including breast, ovarian, and pancreatic cancer. Glucocorticoids are one potential driver of chemotherapy resistance as they can mediate tumor progression via induction of cell-survival pathways. We investigated whether combining the selective glucocorticoid receptor (GR) modulator relacorilant with taxanes can enhance antitumor activity. PATIENTS AND METHODS: The effect of relacorilant on paclitaxel efficacy was assessed in OVCAR5 cells in vitro and in the MIA PaCa-2 xenograft. A phase 1 study of patients with advanced solid tumors was conducted to determine the recommended phase 2 dose of relacorilant + nab-paclitaxel. RESULTS: In OVCAR5 cells, relacorilant reversed the deleterious effects of glucocorticoids on paclitaxel efficacy (P < 0.001). Compared with paclitaxel alone, relacorilant + paclitaxel reduced tumor growth and slowed time to progression in xenograft models (both P < 0.0001). In the heavily pretreated phase 1 population [median (range) of prior regimens: 3 (1-8), prior taxane in 75.3% (55/73)], 33% (19/57) of response-evaluable patients achieved durable disease control (≥16 weeks) with relacorilant + nab-paclitaxel and 28.6% (12/42) experienced longer duration of benefit than on prior taxane (up to 6.4×). The most common dose-limiting toxicity of the combination was neutropenia, which was manageable with prophylactic G-CSF. Clinical benefit with relacorilant + nab-paclitaxel was also associated with GR-regulated transcript-level changes in a panel of GR-controlled genes. CONCLUSIONS: The observed preclinical, clinical, and GR-specific pharmacodynamic responses demonstrate that selective GR modulation with relacorilant combined with nab-paclitaxel may promote chemotherapy response and is tolerable. Further evaluation of this combination in tumor types responsive to taxanes is ongoing.

Safety, antitumor activity, and pharmacokinetics of dostarlimab, an anti-PD-1, in patients with advanced solid tumors: a dose-escalation phase 1 trial.

PURPOSE: New immuno-oncology therapies targeting programmed cell death receptor 1 (PD-1) have improved patient outcomes in a broad range of cancers. The objective of this analysis was to evaluate the PK, pharmacodynamics (PDy), and safety of dostarlimab monotherapy in adult patients with previously-treated advanced solid tumors who participated in parts 1 and 2A of the phase 1 GARNET study. METHODS: Part 1 featured a 3 + 3 weight-based dose-escalation study, in which 21 patients received dostarlimab 1, 3, or 10 mg/kg intravenously every 2 weeks. The 2 fixed-dose nonweight-based dosing regimens of dostarlimab 500 mg every 3 weeks (Q3W) and 1000 mg every 6 weeks (Q6W) were evaluated using a modified 6 + 6 design in part 2A (n = 13). In parts 1 and 2A, treatment with dostarlimab could continue for up to 2 years or until progression, unacceptable toxicity, patient withdrawal, investigator's decision, or death. RESULTS: The dostarlimab PK profile was dose proportional, and maximal achievable receptor occupancy (RO) was observed at all dose levels in the weight-based and fixed-dose cohorts. Trough dostarlimab concentration after administration of dostarlimab 500 mg Q3W was similar to that after dostarlimab 1000 mg Q6W, the values of which (≈40 µg/mL) projected well above the lowest dostarlimab concentration required for full peripheral RO. No dose-limiting toxicities were observed. CONCLUSIONS: Dostarlimab demonstrated consistent and predictable PK and associated PDy. The observed safety profile was acceptable and characteristic of the anti-PD-1 drug class. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02715284. Registration date: March 9, 2016.

First-in-Human Study of PF-06647020 (Cofetuzumab Pelidotin), an Antibody-Drug Conjugate Targeting Protein Tyrosine Kinase 7, in Advanced Solid Tumors.

PURPOSE: We investigated safety, tolerability, pharmacokinetics, and antitumor activity of the protein tyrosine kinase 7 (PTK7)-targeted, auristatin-based antibody-drug conjugate (ADC) PF-06647020/cofetuzumab pelidotin (NCT02222922). PATIENTS AND METHODS: Patients received PF-06647020 intravenously every 3 weeks at 0.2-3.7 mg/kg or every 2 weeks at 2.1-3.2 mg/kg, in sequential dose escalation, following a modified toxicity probability interval method. In dose expansion, pretreated patients with advanced, platinum-resistant ovarian cancer, non-small cell lung cancer (NSCLC), or triple-negative breast cancer (TNBC) received PF-06647020 2.8 mg/kg every 3 weeks. RESULTS: The most common, treatment-related adverse events for PF-06647020 administered every 3 weeks were nausea, alopecia, fatigue, headache, neutropenia, and vomiting (45%-25%); 25% of patients had grade ≥ 3 neutropenia. Two patients experienced dose-limiting toxicities (grade 3 headache and fatigue) at the highest every 3 weeks dose evaluated. The recommended phase II dose was 2.8 mg/kg every 3 weeks. The overall safety profile observed with PF-06647020 administered every 2 weeks was similar to that of the every 3 weeks regimen. Systemic exposure for the ADC and total antibody generally increased in a dose-proportional manner. Antitumor activity was observed in treated patients with overall objective response rates of 27% in ovarian cancer (n = 63), 19% in NSCLC (n = 31), and 21% in TNBC (n = 29). Responders tended to have moderate or high PTK7 tumor expression by IHC. CONCLUSIONS: This PTK7-targeted ADC demonstrated therapeutic activity in previously treated patients with ovarian cancer, NSCLC, and TNBC at a dose range of 2.1-3.2 mg/kg, supporting further clinical evaluation to refine dose, schedule, and predictive tissue biomarker testing in patients with advanced malignancies.

Phase I study of liposomal irinotecan in patients with metastatic breast cancer: findings from the expansion phase.

PURPOSE: Metastatic breast cancer (mBC) remains incurable and is associated with low survival rates. This study assessed the efficacy and safety of liposomal irinotecan in heavily pretreated patients with mBC, with or without active brain metastases (BM). METHODS: Following the dose escalation phase and determination of recommended phase 2 dose, the expansion phase of this phase I, open-label, non-randomized study, assigned adult women to cohorts based on mBC subtype: cohort 1, hormone receptor +/human epidermal growth factor receptor 2-; cohort 2, triple-negative breast cancer; or cohort 3, any mBC subtype with active BM. Patients received liposomal irinotecan 50 or 70 mg/m2 free base every 2 weeks. Here, we report secondary outcomes including best overall response (BOR), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). RESULTS: For non-central nervous system (non-CNS) disease across all cohorts (intent-to-treat population, N = 29), the ORR was 34.5% (95% confidence interval: 17.94-54.33), with a BOR of partial response in 10 patients (34.5%), stable disease in five (17.2%), progressive disease in 10 (34.5%); four patients were unevaluable (13.8%). The ORR for the CNS cohort was 30.0% (95% confidence interval: 6.67-65.25) using modified Response Evaluation Criteria in Solid Tumors. Common grade 3 or higher TEAEs were diarrhea (27.6%), nausea (17.2%), fatigue (13.8%), asthenia (10.3%), and hypokalemia (10.3%). Serious treatment-related TEAEs were reported in six patients (20.7%). No treatment-related TEAEs resulted in death. CONCLUSIONS: Liposomal irinotecan monotherapy demonstrated antitumor activity in heavily pretreated patients with mBC, with or without BM. The observed safety profile was consistent with that in previous studies. CLINICAL TRIAL REGISTRATION: Trial registration ID NCT01770353.

Effect of Capivasertib in Patients With an AKT1 E17K-Mutated Tumor: NCI-MATCH Subprotocol EAY131-Y Nonrandomized Trial.

Importance: In the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial, agents targeting genetic tumor abnormalities are administered to patients. In the NCI-MATCH subprotocol EAY131-Y trial, patients with an AKT1 E17K-mutated metastatic tumor received the pan-AKT inhibitor capivasertib. Objective: To assess the objective response rate (ORR) of capivasertib in patients with an AKT1 E17K-mutated tumor. Design, Setting, and Participants: Between July 13, 2016, and August 10, 2017, patients in the NCI-MATCH trial were enrolled and assigned to the subprotocol EAY131-Y nonrandomized trial. Patients included adults with an AKT1 E17K-mutated metastatic tumor that had progressed with standard treatment, and these patients were assigned to receive capivasertib. Tumor assessments were repeated every 2 cycles. Data analysis of this evaluable population was performed from November 8, 2019, to March 12, 2020. Interventions: The study treatment was capivasertib, 480 mg, orally twice daily for 4 days on and 3 days off weekly in 28-day cycles until disease progression or unacceptable toxic effect. If patients continued hormone therapy for metastatic breast cancer, the capivasertib dose was 400 mg. Main Outcomes and Measures: The primary end point was the ORR (ie, complete response [CR] and partial response) according to the Response Evaluation Criteria in Solid Tumors criteria, version 1.1. Secondary end points included progression-free survival (PFS), 6-month PFS, overall survival, and safety. Results: In total, 35 evaluable and analyzable patients were included, of whom 30 were women (86%), and the median (range) age was 61 (32-73) years. The most prevalent cancers were breast (18 [51%]), including 15 patients with hormone receptor (HR)-positive/ERBB2-negative and 3 with triple-negative disease, and gynecologic (11 [31%]) cancers. The ORR rate was 28.6% (95% CI, 15%-46%). One patient with endometrioid endometrial adenocarcinoma achieved a CR and remained on therapy at 35.6 months. Patients with confirmed partial response had the following tumor types: 7 had HR-positive/ERBB2-negative breast cancer, 1 had uterine leiomyosarcoma, and 1 had oncocytic parotid gland carcinoma and continued receiving treatment at 28.8 months. Sixteen patients (46%) had stable disease as the best response, 2 (6%) had progressive disease, and 7 (20%) were not evaluable. With a median follow-up of 28.4 months, the overall 6-month PFS rate was 50% (95% CI, 35%-71%). Capivasertib was discontinued because of adverse events in 11 of 35 patients (31%). Grade 3 treatment-related adverse events included hyperglycemia (8 [23%]) and rash (4 [11%]). One grade 4 hyperglycemic adverse event was reported. Conclusions and Relevance: This nonrandomized trial found that, in patients with an AKT1 E17K-mutated tumor treated with capivasertib, a clinically significant ORR was achieved, including 1 CR. Clinically meaningful activity with single-agent capivasertib was demonstrated in refractory malignant neoplasms, including rare cancers. Trial Registration: ClinicalTrials.gov Identifier: NCT00700882.

Phase I Basket Study of Taselisib, an Isoform-Selective PI3K Inhibitor, in Patients with PIK3CA-Mutant Cancers.

PURPOSE: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib. PATIENTS AND METHODS: Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed. RESULTS: A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. CONCLUSIONS: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.

Phase 1 study of TTC-352 in patients with metastatic breast cancer progressing on endocrine and CDK4/6 inhibitor therapy.

PURPOSE: TTC-352 is a selective human estrogen receptor (ER) partial agonist developed for treatment of hormone-refractory ER + breast cancer. METHODS: This was an accelerated dose escalation study with the primary endpoint of maximum tolerated dose that evaluated five dose levels of TTC-352 in breast cancer progressing after at least two lines of hormonal therapy including one in combination with a CDK4/6 inhibitor. The secondary objectives were to determine treatment tolerability, pharmacokinetics of TTC-352, best response, progression-free survival (PFS), and PKCα expression in tumors. RESULTS: The study enrolled 15 patients. No dose-limiting toxicity was observed. Patients experienced the following grade 3 toxicities: asymptomatic pulmonary embolism, diarrhea, aspartate transaminase elevation, and myalgia, and one grade 4 toxicity of gamma glutamyltransferase elevation. Pharmacokinetic half-life was 7.6-14.3 h. The intra- and inter-individual variability for AUC0-∞ hampered assessment of the relationship between dose and AUC0-∞. Median PFS was 58 days (95% CI = 28,112). Higher PKCα expression in tumor stroma was associated with a trend toward longer PFS. CONCLUSIONS: TTC-352 demonstrates safety and early clinical evidence of antitumor activity against heavily pretreated hormone-refractory breast cancer. Based upon TTC-352 plasma concentrations and tolerability, the 180 mg twice a day is recommended for further testing. (ClinicalTrials.gov Identifier: NCT03201913).

Phase I study of imalumab (BAX69), a fully human recombinant antioxidized macrophage migration inhibitory factor antibody in advanced solid tumours.

AIM: Preclinical evidence suggests that oxidized macrophage migration inhibitory factor (oxMIF) may be involved in carcinogenesis. This phase 1 study (NCT01765790) assessed the safety, tolerability, pharmacokinetics and antitumour activity of imalumab, an oxMIF inhibitor, in patients with advanced cancer using '3 + 3' dose escalation. METHODS: In Schedule 1, patients with solid tumours received doses from 1 to 50 mg/kg IV every 2 weeks. In Schedule 2, patients with metastatic colorectal adenocarcinoma, non-small-cell lung, or ovarian cancer received weekly doses of 10 or 25 mg/kg IV (1 cycle = 28 days). Treatment continued until disease progression, unacceptable toxicity, dose-limiting toxicity, or withdrawal of consent. RESULTS: Fifty of 68 enrolled patients received imalumab. The most common treatment-related adverse events (TRAEs) included fatigue (10%) and vomiting (6%); four grade 3 serious TRAEs (two patients) occurred. The dose-limiting toxicity was allergic alveolitis (one patient, 50 mg/kg every 2 weeks). The maximum tolerated and biologically active doses were 37.5 mg/kg every 2 weeks and 10 mg/kg weekly, respectively. Of 39 assessed patients, 13 had stable disease (≥4 months in 8 patients). CONCLUSIONS: Imalumab had a maximum tolerated dose of 37.5 mg/kg every 2 weeks in patients with advanced solid tumours, with a biologically active dose of 10 mg/kg weekly. Further investigation will help define the role of oxMIF as a cancer treatment target.

First-in-Human Study of Mivebresib (ABBV-075), an Oral Pan-Inhibitor of Bromodomain and Extra Terminal Proteins, in Patients with Relapsed/Refractory Solid Tumors.

PURPOSE: Bromodomain and extraterminal (BET) proteins play important roles in transcriptional regulation relevant to cancer pathogenesis, and therapeutic targeting/inhibition of BET causes apoptosis of cancer cells in vitro. In this first-in-human study of the pan-BET inhibitor mivebresib (ABBV-075), the safety profile, MTD, and recommended phase II dose (RP2D) were determined in patients with advanced solid tumors. PATIENTS AND METHODS: A 3 + 3 dose escalation for different mivebresib dosing schedules [daily, Monday/Wednesday/Friday (M-W-F), 4 days on/3 off (4/7)] was followed by dose expansion in patients with prostate cancer. Endpoints were safety, tolerability, pharmacokinetics, and preliminary antitumor activity. RESULTS: Seventy-two patients with solid tumors (14% uveal melanoma; 11% colorectal; 11% breast; 8% pancreatic; 7% head/neck; 49% others) were treated with mivebresib during dose escalation, and 12 additional patients with prostate cancer in expansion cohort. Most common treatment-emergent adverse events (TEAE) related to mivebresib were dysgeusia (49%), thrombocytopenia (48%), fatigue (26%), and nausea (25%). Most common grade 3/4 TEAEs related to mivebresib were thrombocytopenia (35%) and anemia (6%). Dose-limiting toxicities included thrombocytopenia (2 mg daily; 4.5 mg M-W-F), gastrointestinal bleed (2 mg daily), hypertension (2-3 mg 4/7), fatigue, decreased appetite, and aspartate aminotransferase elevation (4 mg M-W-F). Of 61 evaluable patients from dose escalation, 26 (43%) had stable disease and 35 (57%) had progressive disease. Median progression-free survival was 1.8 months (95% confidence interval, 1.8-1.9). CONCLUSIONS: On the basis of safety and tolerability, mivebresib RP2D is 1.5 mg for the daily schedule, 2.5 mg for 4/7, and 3 mg for M-W-F. Mivebresib has a tolerable safety profile, and stable disease was observed in some patients with malignant solid tumors.

Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma.

IMPORTANCE: Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. OBJECTIVE: To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. DESIGN, SETTING, AND PARTICIPANTS: The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. INTERVENTIONS: The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. RESULTS: Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. CONCLUSIONS AND RELEVANCE: Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02657889.

Update on Precision Medicine in Breast Cancer.

Precision medicine approaches have found applications in the treatment of several tumor types and have led to rapid advancement in the number of available therapies for some difficult-to-treat diseases. In comparison to tumors like EGFR-mutated lung cancer, and BRAF-mutated melanoma for example, precision medicine in breast cancer is still in its infancy despite the much earlier identification of targets like ER and HER2. Though significant progress has been made in new therapies for hormone-receptor-positive and HER2-positive breast cancers, identification of molecular heterogeneity and lack of other valid reproducible targets in triple-negative breast cancer remain a challenge. In this chapter, we outline the recent advances in technology and targeted treatments for breast cancer, the remaining challenges and ongoing efforts to address these to make precision medicine a reality for all breast cancer patients.

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study.

Purpose: To determine whether deposition characteristics of ferumoxytol (FMX) iron nanoparticles in tumors, identified by quantitative MRI, may predict tumor lesion response to nanoliposomal irinotecan (nal-IRI).Experimental Design: Eligible patients with previously treated solid tumors had FMX-MRI scans before and following (1, 24, and 72 hours) FMX injection. After MRI acquisition, R2* signal was used to calculate FMX levels in plasma, reference tissue, and tumor lesions by comparison with a phantom-based standard curve. Patients then received nal-IRI (70 mg/m2 free base strength) biweekly until progression. Two percutaneous core biopsies were collected from selected tumor lesions 72 hours after FMX or nal-IRI.Results: Iron particle levels were quantified by FMX-MRI in plasma, reference tissues, and tumor lesions in 13 of 15 eligible patients. On the basis of a mechanistic pharmacokinetic model, tissue permeability to FMX correlated with early FMX-MRI signals at 1 and 24 hours, while FMX tissue binding contributed at 72 hours. Higher FMX levels (ranked relative to median value of multiple evaluable lesions from 9 patients) were significantly associated with reduction in lesion size by RECIST v1.1 at early time points (P < 0.001 at 1 hour and P < 0.003 at 24 hours FMX-MRI, one-way ANOVA). No association was observed with post-FMX levels at 72 hours. Irinotecan drug levels in lesions correlated with patient's time on treatment (Spearman ρ = 0.7824; P = 0.0016).Conclusions: Correlation between FMX levels in tumor lesions and nal-IRI activity suggests that lesion permeability to FMX and subsequent tumor uptake may be a useful noninvasive and predictive biomarker for nal-IRI response in patients with solid tumors. Clin Cancer Res; 23(14); 3638-48. ©2017 AACR.

Phase I Study of PSMA-Targeted Docetaxel-Containing Nanoparticle BIND-014 in Patients with Advanced Solid Tumors.

PURPOSE: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)-targeted nanoparticle, containing docetaxel. EXPERIMENTAL DESIGN: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m(2) and 15 to 45 mg/m(2), respectively. RESULTS: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non-small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors. CONCLUSIONS: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m(2) every three weeks or 40 mg/m(2) weekly. Clin Cancer Res; 22(13); 3157-63. ©2016 AACR.

Use of Cytotoxic Chemotherapy in Metastatic Breast Cancer: Putting Taxanes in Perspective.

Agents that target microtubule (MT) dynamics have been used extensively for the treatment of metastatic breast cancer (MBC). Among these agents are taxanes (solvent-based paclitaxel [sb-paclitaxel], docetaxel, and nab-paclitaxel) and non-taxanes, such as eribulin and ixabepilone. Although these agents have been approved for the treatment of MBC, questions regarding the ideal agent, regimen (single agent vs. combination vs. sequential), and schedule still remain. This systematic review examined pivotal trials for taxanes, eribulin, and ixabepilone as well as first-line taxane trials in MBC. Only randomized trials that enrolled ≥ 100 patients were included. Publications on combination regimens with targeted agents were excluded unless they also included a comparison between nontargeted regimens. The studies were grouped into taxane versus taxane, sb-paclitaxel versus non-taxane, and docetaxel versus non-taxane regimens. In taxane versus taxane comparisons, the efficacy of sb-paclitaxel and docetaxel appeared similar, nab-paclitaxel every 3 weeks (q3w) appeared superior to sb-paclitaxel q3w, and weekly nab-paclitaxel appeared superior to docetaxel. In general, taxane regimens demonstrated higher overall response rates (ORRs) versus non-taxane regimens; however, only 2 trials demonstrated longer overall survival (OS) for taxane regimens. Taxanes will likely continue to be used in earlier lines of therapy, whereas eribulin and ixabepilone may be more appropriate for later lines of treatment. Ongoing research may identify biomarkers that could help in selecting the appropriate MT-targeted agent for a given patient.

Safety, Pharmacokinetics, and Pharmacodynamics of a Humanized Anti-Semaphorin 4D Antibody, in a First-In-Human Study of Patients with Advanced Solid Tumors.

PURPOSE: Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VX15/2503 in advanced solid tumor patients. EXPERIMENTAL DESIGN: Weekly i.v. doses were administered on a 28-day cycle. Safety, immunogenicity, PK, efficacy, T-cell membrane-associated SEMA4D (cSEMA4D) expression and saturation, soluble SEMA4D (sSEMA4D) serum levels, and serum biomarker levels were evaluated. RESULTS: Forty-two patients were enrolled into seven sequential cohorts and an expansion cohort (20 mg/kg). VX15/2503 was well tolerated. Treatment-related adverse events were primarily grade 1 or 2 and included nausea (14.3%) and fatigue (11.9%); arthralgia, decreased appetite, infusion-related reaction, and pyrexia were each 7.3%. One pancreatic cancer patient (15 mg/kg) experienced a Grade 3 dose-limiting toxicity; elevated γ-glutamyl transferase. Complete cSEMA4D saturation was generally observed at serum antibody concentrations ≥ 0.3 µg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusion number. Neutralizing anti-VX15/2503 antibodies led to treatment discontinuation for 1 patient. VX15/2503 Cmax and AUC generally increased with dose and dose number. One patient (20 mg/kg) experienced a partial response, 19 patients (45.2%) exhibited SD for ≥ 8 weeks, and 8 (19%) had SD for ≥ 16 weeks. Subjects with elevated B/T lymphocytes exhibited longer progression-free survival. CONCLUSIONS: VX15/2503 was well tolerated and produced expected PD effects. The correlation between immune cell levels at baseline and progression-free survival is consistent with an immune-mediated mechanism of action. Future investigations will be in combination with immunomodulatory agents.

Dantrolene sodium for the treatment of aldesleukin-induced rigors in a melanoma patient.

OBJECTIVE: To report the case of a 58-year-old male with melanoma who developed aldesleukin-induced rigors and was successfully treated with intravenous dantrolene sodium 20 mg and provide a review of the literature discussing other agents that have been used to treat drug-induced rigors. CASE SUMMARY: A 58-year-old male was treated with 720,000 IU/kg of aldesleukin every 8 hours as part of his antimelanoma therapy. The patient developed rigors after aldesleukin administration and was successfully treated with 25 mg of meperidine. Later, he experienced renal dysfunction that was also linked to aldesleukin therapy and developed normeperidine-induced neurotoxicity requiring discontinuation of meperidine therapy. The rigors were treated with intravenous dantrolene sodium 20 mg every 4 hours, with complete resolution of symptoms. DISCUSSION: Several antineoplastic agents can cause rigors; many of these agents can also lead to renal failure. Several agents have been investigated for their use in the management of rigors but can cause adverse effects or are unsuitable in the setting of renal insufficiency or failure. Although meperidine remains the mainstay for the treatment and prevention of rigors, it can be associated with neurotoxicity in some patients, particularly those with impaired renal function. Given that dantrolene has been shown to be effective against rigors, it may be a useful alternative for patients who can not tolerate meperidine. Drugs with a more favorable adverse effect profile that are not eliminated through the kidneys are needed. CONCLUSIONS: In the oncology setting, severe rigors can result in the interruption of a patient's cancer therapy, which can increase the risk of treatment failure. Dantrolene may be a useful alternative for patients experiencing rigors who can not tolerate meperidine.

Blockade of the HER family of receptors in the treatment of HER2-positive metastatic breast cancer.

Breast cancer is the most common type of cancer among women and the second leading cause of cancer death in the United States. Metastatic breast cancer is considered incurable, and treatment is aimed at palliating symptoms, achieving remission, and prolonging survival. Treatment options for metastatic disease vary based on tumor surface markers and clinical factors in an individual patient and include cytotoxic chemotherapy, hormonal therapy, biological therapy, or some combination of these. An important molecular determinant of therapy is the human epidermal growth factor receptor 2 (HER2) positivity of the tumor, which affects response to HER2-targeted treatment. HER2 is a member of the human epidermal growth factor receptor family of receptor tyrosine kinases, also known as the HER family, which activates signaling that promotes tumorigenic cellular processes such as proliferation and evasion of apoptosis. Several targeted agents, including monoclonal antibodies and tyrosine kinase inhibitors that inhibit one or more HER family receptors have been developed that affect signaling through this pathway. Some of these, such as trastuzumab and lapatinib, have been approved for breast cancer treatment. Resistance to therapy is a challenge that limits the duration of benefit achieved with these agents. Therefore, combinations of HER family-targeted agents with other therapies such as cytotoxic agents, hormonal therapy, or inhibitors of other cellular pathways, are being developed to exploit synergy and overcome resistance mechanisms. Here we review the HER family-targeted agents currently approved or in development for HER2-positive metastatic breast cancer with a focus on strategies to overcome tumor resistance.

Does race affect outcomes in triple negative breast cancer?

BACKGROUND: There is discordance among studies assessing the impact of race on outcome of patients with Triple Negative Breast Cancer (TNBC). We assessed survival outcomes for African American (AA) versus Caucasian (CA) women with TNBC treated at an urban cancer center in Memphis, TN with a predominant AA patient population. METHODS: Patients with Stage I-III TNBC were identified from our breast database. Event free survival (EFS) and Breast cancer specific survival (BCSS) were the primary outcome measures. Cox proportional hazards models were fitted for EFS and BCSS. RESULTS: Of the 124 patients, 71% were AA. No significant association between race and stage (P = 0.21) or menopausal status (P = 0.15) was observed. Median age at diagnosis was significantly lower for AA versus CA women (49.5 vs. 55 years, P = 0.024). 92% of the patients received standard neo/adjuvant chemotherapy, with no significant difference in duration and type of chemotherapy between the races. With a median follow up of 23 months, 28% of AA vs. 19% of CA women had an event (P = 0.37). 3 year EFS and BCSS trended favorably towards CA race (77% vs. 64%, log rank P = 0.20 and 92% vs. 76%, P = 0.13 respectively) with a similar trend noted on multiple variable modeling (EFS: HR 0.62, P = 0.29; BCSS: HR 0.36, P = 0.18). AA women >/=50 years at diagnosis had a significantly worse BCSS than the CA women in that age group (P = 0.012). CONCLUSION: Older AA women with TNBC have a significantly worse breast cancer specific survival than their CA counterparts. Overall, there is a trend towards lower survival for AA women compared to Caucasians despite uniformity of tumor phenotype and treatment. The high early event rate, irrespective of race, underscores the need for effective therapies for women with TNBC.

Pattern of use of adjuvant chemotherapy for stage II colon cancer: a single-institution experience.

PURPOSE: American Society of Clinical Oncology (ASCO) guidelines define high-risk prognostic features (HRFs) in stage II colon cancer and recommend limiting adjuvant chemotherapy to patients with HRFs. We evaluated the extent to which HRFs influenced decisions on adjuvant chemotherapy before and after publication of the guidelines. PATIENTS AND METHODS: We reviewed data from 100 consecutive patients with stage II colon cancer resected between January 2000 and June 2007. Practice pattern in the pre-guideline era (2000 through 2004) was compared with the post-guideline era (2005-2007). RESULTS: The median age of the cohort was 65.8 years. A total of 60 patients had > or = 1 HRF. Overall, 38% of the patients with HRFs did not receive chemotherapy; 37.5% without HRFs did. Seventy-one percent of the patients given adjuvant chemotherapy had HRFs versus 48% of the patients not given chemotherapy. There was no association between the presence/absence of HRFs and chemotherapy (P = .25). The association between number of HRFs per individual and chemotherapy was significant (P = .0255). Bowel obstruction and T4 disease were the only individual HRFs significantly associated with chemotherapy (P = .0059 and .0294, respectively). A significant drop in use of chemotherapy for all patients occurred after publication of the guidelines, but this was caused mostly by a drop in treatment for patients with HRFs from 80% to 36% (P = .001). CONCLUSION: Decisions for or against adjuvant chemotherapy did not adhere completely to ASCO guidelines. Publication of the guidelines led to a significant drop in appropriate use of adjuvant chemotherapy in high-risk patients.