Background The SMILE study is a multi-institutional phase II clinical trial to determine the efficacy and safety of an antiprogestin, onapristone, in combination with fulvestrant as second-line therapy for patients with ER+, PgR+/-, HER2- metastatic breast cancer. This study was terminated early and herein, we report patient characteristics, and outcomes. Methods Eligibility criteria included disease progression on >= 2 lines of prior therapy, ECOG performance status <= 2, measurable disease per RECIST 1.1 criteria, and optional F-18-fluorofuranylnorprogesterone (F-18-FFNP) PET/CT imaging. Results Consented subjects received standard-dose fulvestrant plus onapristone 50 mg orally, twice daily, until disease progression, or unacceptable toxicity. The study enrolled 11 women from 2 sites within the Wisconsin Oncology Network from November 2021 through March 2023. Mean age of the subjects was 58.5 years. Other than grade 1 toxicities, the treatment was well tolerated. None of the 11 subjects met RECIST 1.1 definition of response. The median time to progression was 63 days. A total of 4 of 11 patients had stable disease as best response and 2 of them were on treatment for 5.5 and 7.7 months. Two of the 11 subjects underwent functional imaging with F-18-FFNP PET/CT before and 10 or 14 days after starting treatment. For both subjects, tumor uptake of F-18-FFNP was stable or increased in all target lesions while F-18-FFNP uptake in the uterus, a normal PgR-rich internal control organ, was decreased. Conclusion The study regimen was well-tolerated with no significant toxicities. Future studies may evaluate antiprogestins with various combinations such as targeted therapies. (c) 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Estrogen receptor beta (ER beta) is a potential therapeutic target in triple-negative breast cancer (TNBC). This 2-stage phase 2 study investigated estradiol in advanced TNBC. The study was closed after 17 patients completed the first stage. One patient with an ER beta-positive tumor experienced a prolonged confirmed partial response. Future study of ER beta agonists in selected TNBC may be warranted.Background: Estrogen receptor beta (ER beta) is expressed by 50% to 80% of triple-negative breast cancers (TNBC). Agonism of ER beta has antiproliferative effects in TNBC cells expressing ER beta. This phase 2 study evaluated single-agent high-dose estradiol in patients with advanced TNBC. Patients and Methods: Adult women with measurable advanced TNBC were treated with estradiol 10 mg oral 3 times daily provided continuously for 28-day cycles. A Simon optimal 2-stage design was used. The primary end point was objective response (OR). Secondary end points included progression-free survival (PFS), clinical benefit (CB), and safety. OR, CB, and PFS by ER beta status were also examined. Results: Seventeen evaluable women were enrolled. Median age was 58 years (range, 34-90 years); the median number of prior systemic therapies was 2 (range, 0-6). One patient had a confirmed partial response (OR rate, 5.9%) and remained on the study for > 24 weeks. Three patients had stable disease, with one lasting more than 16 weeks. ER beta expression was detected in 77% (13 patients). The CB rate at 16 weeks was 15% (2 of 13) in ER beta-positive patients and 0% (0 of 4) in ER beta-negative patients (P = 1). PFS was poor (median, 1.9 months) and not statistically significantly different between ER beta-positive versus -negative patients. No new adverse events from estradiol were identified. The study closed after the first stage as a result of limited responses in these unselected patients. Conclusion: In unselected TNBC, high-dose estradiol has limited efficacy. However, further evaluation of ER beta selective agonists in TNBC selected by ER beta expression may be warranted. (C) 2016 Elsevier Inc. All rights reserved.

PURPOSE:Retreatment with bortezomib (B) is often considered for patients with relapsed multiple myeloma (MM), but this strategy is hindered by uncertainty of response and emergence of B-induced peripheral neuropathy (PN). We incorporated acetyl-L-carnitine (ALCAR) to prevent PN and allow for adequate dosing. We also investigated the correlation between B-inducible NF-κB activation and response to therapy.METHODS:Nineteen patients with relapsed/refractory MM received up to 8 cycles of intravenous bortezomib, doxorubicin and oral low-dose dexamethasone (BDD) to evaluate response and toxicity. Thirteen additional patients received prophylactic ALCAR (BDD-A). Patients receiving BDD-A were evaluated by FACT-GOG-TX, FACIT-Fatigue, Neuropathic Pain index (NPI) and Grooved Pegboard (GP) testing. Primary MM cells from 11 patients were tested for B-inducible NF-κB activation.RESULTS:Seventy-six percent of subjects were refractory to previous treatment, 39% refractory to bortezomib. Median cycles received were 5. CR + PR for the entire group were 53% and did not differ between groups. Incidence of ≥3 PN was 32% in the BDD group versus 15 % in the BDD-A group (p = ns). Patient-reported fatigue and PN measured by FACT-GOG-TX increased throughout the treatment period in the BDD-A group, although time to complete GP testing declined. In a sub-study examining constitutive bortezomib-inducible NF-κB activity in primary subject-specific MM cells, the presence of NF-κB activation correlated with lower likelihood of response.CONCLUSIONS:Addition of ALCAR to BDD did not alter the incidence or severity of PN in relapsed MM patients receiving a B-based regimen. Bortezomib-inducible NF-κB activation in patient-derived primary MM cells may be associated with poorer response.

INTRODUCTION:Dose-dense therapies have had a major effect on reducing toxicity and improving outcomes in breast cancer. A combination of TC every 3 weeks has emerged as a common chemotherapy regimen used for treatment of node-negative or lower-risk node-positive breast cancer. We tested whether it is feasible to deliver TC on a dose-dense schedule, with therapy completed within 10 weeks.PATIENTS AND METHODS:We enrolled women with early stage breast cancer on a single-arm phase II study of adjuvant dose-dense TC through a regional oncology network. All women completed primary surgery before accrual, and subsequent therapy with TC was deemed appropriate by the treating physician. Planned treatment was docetaxel 75 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 2 weeks for 4 cycles with subcutaneous pegfilgrastim 6 mg administered 24 to 48 hours after the administration of each chemotherapy cycle.RESULTS:Of 42 women enrolled, 41 were evaluable using prespecified criteria. Of these, 37 (90.2%) completed therapy within 10 weeks and 34 (83%) completed therapy at 8 weeks without dose modification. Rates of neuropathy were similar to that reported previously. The rate of neutropenic fever was low (2.5%). Rash and plantar-palmar erythrodythesia were common and reached grade 3 in 4 subjects (9.8%).CONCLUSION:Dose-dense TC is feasible with tolerability profiles similar to standard TC and a low likelihood of neutropenic fever. This study supports further clinical development of this 8-week adjuvant chemotherapy regimen.