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Background CXCR1 is recognized as an actionable receptor selectively expressed by breast cancer stem cells (BCSC). Reparixin is an investigational allosteric inhibitor of chemokine receptors 1 and 2 (CXCR1/2), and demonstrates activity against BCSC in human breast cancer xenografts. This Phase Ib clinical trial examined dose, safety, and pharmacokinetics of paclitaxel plus reparixin therapy, and explored effects of reparixin on BCSCs in metastatic breast cancer (MBC) patients (Trial registration ID: NCT02001974). Experimental Design Eligible patients had MBC and were candidates for paclitaxel therapy. Study treatment included a three-day run-in with reparixin oral tablets 3 times daily (t.i.d.), followed by paclitaxel 80 mg/m2/week (Days 1, 8, and 15 for 28-day cycle) + reparixin tablets t.i.d. for 21/28 days; three dose cohorts were examined in a 3+3 dose escalation schema. Additional patients were recruited into an expansion cohort at the recommended Phase II dose to further explore pharmacokinetics, safety, and biological effects of the combination therapy. Results There were neither G4-5 adverse events nor serious adverse events related to study therapy, and no interactions between reparixin and paclitaxel to influence their respective PK profiles. A 30% response rate was recorded, with durable responses > 12 months in two patients. Exploratory biomarker analysis was inconclusive for therapy effect on BCSC. Conclusions Weekly paclitaxel plus reparixin in MBC appeared to be safe and tolerable, with demonstrated responses in the enrolled population. Dose level 3, 1200 mg orally t.i.d., was selected for further study in a randomized Phase II trial. (NCT02370238)

This phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody-drug conjugate consisting of a humanized anti-folate receptor alpha (FRa) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRa-positive and platinum-resistant ovarian cancer. Patients and MethodsPatients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) once every 3 weeks. Eligibility included a minimum requirement of FRa positivity by immunohistochemistry ($ 25% of tumor cells with at least 2+ staining intensity). Adverse events, tumor response (via Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), and progression-free survival (PFS) were determined. ResultsForty-six patients were enrolled. Adverse events were generally mild (# grade 2), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4%). For all evaluable patients, the confirmed objective response rate was 26%, including one complete and 11 partial responses, and the median PFS was 4.8 months. The median duration of response was 19.1 weeks. Notably, in the subset of patients who had received three or fewer prior lines of therapy (n = 23), an objective response rate of 39%, PFS of 6.7 months, and duration of response of 19.6 weeks were observed. ConclusionIMGN853 exhibited a manageable safety profile and was active in platinum-resistant ovarian cancer, with the strongest signals of efficacy observed in less heavily pretreated individuals. On the basis of these findings, the dose, schedule, and target population were identified for a phase III trial of IMGN853 monotherapy in patients with platinum-resistant disease.

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Background. Malignancy‐related pericardial effusions may represent a terminal event in patients with therapeutically unresponsive disease. However, select patients with malignancies sensitive to available therapies may achieve significant improvement in palliation and long term survival with prompt recognition and appropriate intervention. Methods. From 1968 to 1994, 150 invasive procedures were performed for the treatment or diagnosis of pericardial effusion in 127 patients with underlying malignancies. These cases were reviewed retrospectively to best identify the clinical features, appropriate diagnostic workup, and optimal therapy for this complication of malignancy. Results. Dyspnea (81%) and an abnormal pulsus paradoxus (32%) were the most common symptoms. Echocardiography had a 96% diagnostic accuracy. Cytology and pericardial biopsy had sensitivities of 90% and 56%, respectively. Fifty‐five percent of all effusions were malignant comprising 71% of adenocarcinomas of the lung, breast, esophagus, and unknown primary site. In 57 patients, a malignant effusion could not be determined, and no definitive etiology could be established for 74% of these effusions. Radiation‐induced, infectious, and hemorrhagic pericarditis each were identified in fewer than 5% of cases. Conclusions. Subxyphoid pericardiotomy proved to be a safe and effective intervention that successfully relieved pericardial effusions in 99% of cases with recurrence and reoperation rates of 9% and 7%, respectively. Survival most closely was related to the extent of disease and its inherent chemo‐/radiosensitivity, with 72% of the patients who survived longer than 1 year having breast cancer, leukemia, or lymphoma.

IMGN853 demonstrated a manageable safety profile and encouraging preliminary clinical activity, particularly in patients with ovarian cancer. The results establish a recommended phase 2 dosing of 6.0 mg/kg (based on adjusted ideal body weight) once every 3 weeks. Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:3080-7. © 2017 American Cancer Society.

Chemotherapy for advanced ovarian cancer remains sub‐optimal. Despite the improvements in objective response rates realized with cisplatin‐based combination chemotherapeutic regimens, most patients still die of refractory cancer. Drug resistance has emerged as the single most important determinant of treatment outcome. Laboratory studies have provided substantial insights into the cellular mechanisms of resistance to the commonly used chemotherapeutic agents. Decreased drug accumulation, metabolic drug inactivation, and repair or tolerance to drug‐induced cellular injury all contribute to resistance at the cellular level. Identification of these mechanisms has facilitated the development of specific treatment strategies, many of which are in or nearing clinical trials. These strategies include dose intensification, inhibition of P‐glycoprotein function, inhibition of cellular glutathione synthesis, and inhibition of cellular DNA repair. The initial results from clinical trials that use these strategies provide reasonable grounds for optimism. In addition, efforts to identify new drugs with activity against resistant cells continue. One such drug, taxol, has significant activity in tumors refractory to conventional therapy. These approaches offer hope that intensive laboratory and clinical efforts ultimately will translate into real improvements in the efficacy of chemotherapy for ovarian cancer.

Concordance of FRα expression in biopsy versus archival tumor samples suggests that archival tissue can reliably identify patients with receptor-positive tumors and is appropriate for patient selection in mirvetuximab soravtansine clinical trials. Regardless of the tissue source analyzed, higher FRα expression was associated with greater antitumor activity.