Phase I Study of CC-486 Alone and in Combination with Carboplatin or nab-Paclitaxel in Patients with Relapsed or Refractory Solid Tumors.

Purpose: This large two-part, three-arm phase I study examined the safety and tolerability of CC-486 (an oral formulation of azacitidine, a hypomethylating agent) alone or in combination with the cytotoxic agents, carboplatin or nab-paclitaxel, in patients with advanced unresectable solid tumors.Patients and Methods: Part 1 (n = 57) was a dose escalation of CC-486 alone (arm C) or with carboplatin (arm A) or nab-paclitaxel (arm B). The primary endpoint was safety, MTD, and recommended part 2 dose (RP2D) of CC-486. In part 2 (n = 112), the primary endpoint was the safety and tolerability of CC-486 administered at the RP2D for each treatment arm, in tumor-specific expansion cohorts. Secondary endpoints included pharmacokinetics, pharmacodynamics, and antitumor activity of CC-486.Results: At pharmacologically active doses CC-486 in combination with carboplatin or nab-paclitaxel had a tolerable safety profile and no drug-drug interactions. The CC-486 RP2D was determined as 300 mg (every day, days 1-14/21) in combination with carboplatin (arm A) or as monotherapy (arm C); and 200 mg in the same dosing regimen in combination with nab-paclitaxel (arm B). Albeit limited by the small sample size, CC-486 monotherapy resulted in partial responses (three/eight) and stable disease (four/eight) in patients with nasopharyngeal cancer. Three of the stable disease responses lasted more than 150 days.Conclusions: CC-486 is well tolerated alone or in combination with carboplatin or nab-paclitaxel. Exploratory analyses suggest clinical activity of CC-486 monotherapy in nasopharyngeal cancer and provided the basis for an ongoing phase II clinical trial (ClinicalTrials.gov identifier: NCT02269943). Clin Cancer Res; 24(17); 4072-80. ©2018 AACR.

Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial.

BACKGROUND: Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC). METHODS: In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing. FINDINGS: Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2-11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression. INTERPRETATION: Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting. FUNDING: Merck KGaA and Pfizer.

Metaplastic Breast Cancer: Molecular Typing and Identification of Potential Targeted Therapies at a Single Institution.

INTRODUCTION: Metaplastic breast carcinoma (MBC) is a rare and aggressive histologic subtype of breast cancer comprising approximately 0.5% to 5.0% of all invasive breast cancers with a poor prognosis and limited therapeutic options. PATIENTS AND METHODS: We investigated MBC at our institution to evaluate outcomes and investigate the molecular profile of our cohort to determine the presence of mutations for which there are targeted therapies. RESULTS: We found our cohort to consist mainly of the matrix-producing variant (72%) with 48% having the stereotypical estrogen receptor-negative/progesterone receptor-negative/human epidermal growth factor receptor-2-negative phenotype. While the overall survival of our cohort was an average of 1679 days (4.6 years), we had a surprising number of patients with second primaries (40%) and distant metastases (40%), yet few recurrences (12%). Molecular analysis of the tumors indicated that one gene mutation, CSFIR, was significantly associated with outcome (P = .021); however, the cohort was defined by frequent mutations in ERBB4 (36%), PIK3CA (48%), and FLT3 (60%), for which there are now targeted therapies. CONCLUSION: While surgery is the appropriate first step in the management of this aggressive malignancy, the collection of data pertaining to the use of targeted agents, although anecdotal, may provide clues to better treatment for these patients.