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PurposeRetreatment 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.MethodsNineteen 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.ResultsSeventy-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.ConclusionsAddition 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.

Background Estrogen receptor beta (ERβ) is expressed by 50-80% of triple negative breast cancers (TNBC). Agonism of ERβ has antiproliferative effects in TNBC cells expressing ERβ. This phase II 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 three times daily given continuously for 28-day cycles. A Simon optimal two-stage design was used. The primary endpoint was objective response (OR). Secondary endpoints included progression-free survival (PFS), clinical benefit (CB), and safety. OR, CB and PFS by ERβ status were also examined. Results Seventeen evaluable women were enrolled. Median age was 58 (34-90); the median number of prior systemic therapies was 2 (0-6). One patient had a confirmed partial response (OR rate of 5.9%) and remained on study for >24 weeks. Three patients had stable disease, one lasting more than 16 weeks. ERβ expression was detected in 77% (13 patients). The CB rate at 16 weeks was 15% (2 of 13) in ERβ positive patients and 0% (0 of 4) in ERβ negative patients (p= 1). PFS was poor (median 1.9 months) and not statistically significantly different between ERβ-positive versus negative patients. No new adverse events from estradiol were identified. The study closed after the first stage due to limited responses in these unselected patients. Conclusions In unselected TNBC, high dose estradiol has limited efficacy. However, further evaluation of ERβ selective agonists in TNBC selected by ERβ expression may be warranted.

Introduction Dose-dense therapies have had a major impact on reducing toxicity and improving outcomes in breast cancer. A combination of docetaxel plus cyclophosphamide (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. Methods We enrolled women with early stage breast cancer on a single-arm phase II study of adjuvant dose-dense TC (ddTC) through a regional oncology network. All women completed primary surgery prior to accrual and subsequent therapy with TC was deemed appropriate by the treating physician. Planned treatment was docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 every 2 weeks for 4 cycles with subcutaneous pegfilgrastim 6 mg administered 24-48 hours after the administration of each chemotherapy cycle. Results Of 42 women enrolled, 41 were evaluable by 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 four 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.