A Multicenter Phase II Trial of Ipilimumab and Nivolumab in Unresectable or Metastatic Metaplastic Breast Cancer: Cohort 36 of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART, SWOG S1609).

PURPOSE: Metaplastic breast cancer (MpBC) is a rare aggressive subtype that responds poorly to cytotoxics. Median survival is approximately 8 months for metastatic disease. We report results for advanced MpBC treated with ipilimumab + nivolumab, a cohort of S1609 for rare cancers (DART: NCT02834013). PATIENTS AND METHODS: Prospective, open-label, multicenter phase II (two-stage) trial of ipilimumab (1 mg/kg i.v. every 6 weeks) plus nivolumab (240 mg i.v. every 2 weeks) for advanced MpBC. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Overall, 17 evaluable patients enrolled. Median age was 60 years (26-85); median number of prior therapy lines was 2 (0-5). ORR was 18%; 3 of 17 patients achieved objective responses (1 complete, 2 partial responses; 2 spindle cell, 1 chondromyxoid histology), which are ongoing at 28+, 33+, and 34+ months, respectively. Median PFS and OS were 2 and 12 months, respectively. Altogether, 11 patients (65%) experienced adverse events (AE), including one grade 5 AE. Eight patients (47%) developed an immune-related AE (irAE), with adrenal insufficiency observed in all 3 responders. Responses occurred in tumors with low tumor mutational burden, low PD-L1, and absent tumor-infiltrating lymphocytes. CONCLUSIONS: The ipilimumab and nivolumab combination showed no new safety signals and met its primary endpoint with 18% ORR in advanced, chemotherapy-refractory MpBC. All responses are ongoing at >2 to almost 3 years later. The effect of ipilimumab and nivolumab was associated with exceptional responses in a subset of patients versus no activity. This combination warrants further investigation in MpBC, with special attention to understanding mechanism of action, and carefully designed to weigh against the significant risks of irAEs.

Gemcitabine/epirubicin/paclitaxel as neoadjuvant chemotherapy in locally advanced breast cancer: a phase II trial of the NSABP Foundation Research Group.

BACKGROUND: This phase II protocol of neoadjuvant chemotherapy with gemcitabine/epirubicin/paclitaxel (GET) was designed to determine the pathologic complete response (pCR) rate in the breast, clinical response rate, disease-free survival, and overall survival at 2 years as well as toxicity in patients with locally advanced breast cancer. This trial also evaluated the feasibility of tissue collection for gene-expression profiling. PATIENTS AND METHODS: Seventy-six women with stage IIB, IIIA, and IIIB breast cancer were entered into this trial. Patients received a maximum of 6 cycles of neoadjuvant GET chemotherapy every 21 days (gemcitabine 1000 mg/m2 intravenously [i.v.] on days 1 and 4, epirubicin 90 mg/m2 i.v. bolus on day 1, and paclitaxel 175 mg/m2 i.v. on day 1). After chemotherapy, patients underwent surgery and were assessed for pathologic response. RESULTS: The pCR rate among the 74 patients evaluable for efficacy was 23% (95% CI, 14%-34.2%). Adverse events among the 76 patients evaluable for toxicity included anemia requiring transfusion (14.5%), infection with grade 3/4 neutropenia (10.5%), febrile neutropenia (7.9%), and platelet transfusion (6.6%). Infectious complications occurred in 24 patients (31.6%), of whom 18.4% were in the setting of neutropenia. High-quality RNA and successful probe synthesis were obtained from all pretreatment core biopsy specimens that contained tumor cells (n=66; 88%). CONCLUSION: Neoadjuvant GET chemotherapy is an active regimen but with substantial toxicity. Tissue collection for gene-expression profiling is feasible in a multi-institutional setting.

A phase II clinical trial of ZD1839 (Iressa) in combination with docetaxel as first-line treatment in patients with advanced breast cancer.

This was a phase II multi-institutional trial to determine the efficacy and tolerability of gefitinib (Iressatrade) and docetaxel as first-line treatment in patients with metastatic breast cancer. All patients had histologically confirmed breast cancer with metastatic disease. They were permitted to have received adjuvant chemotherapy, but no prior docetaxel or prior chemotherapy for metastatic disease. Patients received gefitinib 250 mg once daily and docetaxel 75 mg/m(2) every 3 weeks, until tumor progression, toxicity or other reasons for discontinuation. Thirty-three patients were enrolled and received a median of 5 cycles of treatment. The clinical benefit rate was 51.5% (95% CI: 33.5-69.2%). There were 1 confirmed complete response and 12 confirmed partial responses, and the overall objective response rate was 39.4% (95% CI: 22.9-57.9%). Four patients had stable disease for > or =24 weeks. The median duration of clinical benefit was 10.9 months (95% CI: 6.0-17.6 months). The most common reason for study discontinuation was disease progression (16 patients), followed by toxicity (ten patients). Toxicities were mainly attributable to docetaxel, including > or =grade 3 neutropenia in 43% of patients. The combination of gefitinib and docetaxel is an active regimen in patients with previously untreated metastatic breast cancer, with a clinical benefit rate and toxicity profile in the range of that reported for docetaxel alone.

Factors affecting purification of CD34(+) peripheral blood stem cells using the Baxter Isolex 300i.

A total of 201 patients with breast cancer, ovarian cancer, or hematological malignancies underwent mobilization of peripheral blood stem cells (PBSC) using chemotherapy and granulocyte-colony stimulating factor (G-CSF). Stem cell products were collected using the Baxter CS3000 pheresis machine. The Baxter Isolex 300i was used to perform 240 CD34(+) cell separations on the apheresis products. Factors affecting yield and purity of the CD34(+) cells were analyzed. Overall yield was 55% and overall purity was 91.7%. T cell contamination was limited to 0.43% of total cells. Variables including red blood cells (RBC) concentration, platelet concentration, CD34(+) cell concentration, total WBCs selected, and time until processing had little effect on yields and purities. Installation of version 2.5 of the software in the Isolex 300i showed a modest improvement in yield and purity. Patients were reinfused with the cryopreserved CD34(+) selected cells following high-dose chemotherapy. No infusion-related side effects were noted. Analysis of engraftment data using the CD34(+)-selected cells revealed an increased risk of delayed or failed platelet engraftment when <5.0 x 10(6) CD34(+) cells per kilogram were transplanted. The Baxter Isolex 300i provides reproducible CD34(+) cell purification over a wide range of starting conditions. To provide prompt engraftment, >5.0 x 10(6) CD34(+) cells per kilogram should be infused for transplantation.

Treatment of myelodysplastic syndromes with 5-azacytidine.

Patients with myelodysplastic syndromes (MDS) who were anemic and/or thrombocytopenic were treated with 5-azacytidine (5-AZA) at a dose of 75 mg/m(2) per day SQ x 7 days. This cycle was repeated every 28 days. Forty-eight patients who received at least one cycle of 5-AZA were evaluable for response. Hematological toxicity was mild and consisted of thrombocytopenia and leukopenia. Extramedullary toxicity was uncommon and consisted of pneumonia, arthralgia, diarrhea, and injection site irritation. Eighteen of the 46 transfusion dependent patients became transfusion independent (39%). Median duration of response was 7 months with three patients continuing beyond 2 years. French Anglo British (FAB) classification and the International Scoring System (ISS) did not predict response to 5-AZA. However, a decrease in the white blood cells (WBC) during the initial cycle of 5-AZA correlated with a higher response rate.