Empowering the Next Generation of Nephrologists: Trainee Opportunities in Glomerular Disease Study and Trial Consortium's Educational Ecosystem.

Heat shock protein 90 (Hsp90) has been studied as a therapeutic target in many cancers. In preclinical trials, the Hsp90 ATPase inhibitor ganetespib demonstrated potent inhibition of solid tumor growth, with superior potency than prior Hsp90 inhibitors. Given the promising preclinical outcome and favorable pharmacologic properties of ganetespib, we conducted a phase II trial of single-agent ganetespib in patients with metastatic, castrate-resistant prostate cancer (mCRPC). The primary objective of the study was to determine the 6-month progression-free survival (PFS) rate. Patients with mCRPC who had been previously treated with docetaxel were enrolled after meeting eligibility criteria. All patients received ganetespib at 200 mg/m(2) on days 1, 8, and 15 of every 28 days (one cycle). Subjects who tolerated therapy were continued on ganetespib until disease progression. Considering that Hsp90 acetylation may confer insensitivity to Hsp90 inhibitors and maspin inhibits protein deacetylation, maspin-associated molecular markers were evaluated. Eighteen patients were recruited into the trial; most were Caucasian, had performance status 1, had received prior docetaxel, and were heavily pretreated. Of the 17 patients who were treated, none attained 6-month PFS. Only 2 patients achieved PFS > 4 months. The median PFS was 1.9 months. As per the study design, the trial was terminated after the interim analysis. The most frequent types of Grade 3 toxicity were dehydration, diarrhea, and fatigue. Molecular markers provided little additional insight regarding drug activity. Ganetespib demonstrated minimal clinical activity in men with mCRPC. The true 6-month PFS rate was, at most, 0.20. Possible reasons for this include selection of a heavily pretreated patient population and lack of agent potency in patients with mCRPC.

Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study.

156 Background: Platinum based therapies have demonstrated efficacy in DP mCRPC. EVE demonstrated preclinical efficacy in chemotherapy resistant prostate cancer models. Clinical synergy was noted between C and EVE, hence a phase II trial of the combination was conducted. Methods: Primary endpoint was time to progression (TTP). Progression was defined per RECIST criteria for measurable disease (MD), or skeletal event, or > 2 new areas of bone metastases. DP mCRPC patients with adequate renal and liver function, and performance status of 0 or 1 were eligible. Intravenous C at target AUC of 5 on day 1, and oral EVE 5mg once daily and P 5mg twice daily were administered in 21 day cycles. PSA was assessed every 21 days and radiologic response was assessed every 3 cycles. Secondary endpoints included overall survival (OS), correlation of TTP and PSA response, with markers such as phopho mTOR, pAKT, p70S6 and circulating tumor cells (CTC). Results: 26 patients (pts) enrolled, including 8 African Americans, and accrual is complete. Median age was 69 years (range 54-86). Median pretherapy PSA was 190 ng/ml (range 13 - 2174). 18 pts (69%) had bone pain. Gleason score was > 8 in 18 pts. 19 pts had measurable disease of which 15 had MD progression, 18 had bone scan progression, and 2 had PSA-only progression. 124 cycles have been administered; median 3 cycles (range 1 - 16). The predominant grade 3 or 4 toxicities were thrombocytopenia in 8 pts, pulmonary embolism in 2 and neutropenia in 3. No treatment related deaths occurred. Of 26 pts who are response evaluable, 4 (15%) had a > 30% PSA decline and 1 had a >90% PSA decline. Of 19 pts with MD, 8 had stable disease and no objective responses were observed. The median TTP and OS were 2.5 months (90% CI: 1.8 - 4.3), and 12.5 months (90% CI: 6.7 - 16.1), respectively. Correlative studies including pharmacokinetic and pharmacodynamic evaluations are ongoing, and will be reported. Conclusions: The combination was tolerable but revealed modest clinical efficacy. Biomarker evaluation may help identify a subset likely to benefit from mTOR inhibition strategy in mCRPC. Clinical trial information: NCT01051570.

Readily identified markers of tuberculosis relapse risk are needed, particularly in resource-limited settings. The association between weight gain or loss during antituberculosis therapy and relapse has not been well studied. Subjects in the Tuberculosis Trials Consortium Study 22 were studied. Underweight was defined as 10% or more below ideal body weight at diagnosis. Weight change was assessed between (1) diagnosis and completion of induction phase therapy, (2) diagnosis and end of continuation phase therapy, and (3) completion of induction to completion of continuation phase therapy. A total of 857 subjects were monitored for 2 yr, and 61 of 857 (7.1%) relapsed. Relapse risk was high among persons who were underweight at diagnosis (19.1 vs. 4.8%; p < 0.001) or who had a body mass index of less than 18.5 kg/m(2) (19.5 vs. 5.8%; p < 0.001). Among persons who were underweight at diagnosis, weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy was moderately associated with an increased relapse risk (18.4 vs. 10.3%; relative risk, 1.79, 95% confidence interval, 0.96-3.32; p = 0.06). In a multivariate logistic regression model that was adjusted for other risk factors, a weight gain of 5% or less between diagnosis and completion of 2-mo intensive phase therapy among persons underweight at diagnosis was significantly associated with relapse risk (odds ratio, 2.4; p = 0.03). Among persons underweight at diagnosis, weight gain of 5% or less during the first 2 mo of treatment is associated with an increased relapse risk. Such high-risk patients can be easily identified, even in resource-poor settings. Additional studies are warranted to identify interventions to decrease risk of relapse in such patients.

The Xpert MTB/RIF assay is both sensitive and specific as a diagnostic test. Xpert also reports quantitative output in cycle threshold (CT) values, which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert CT trajectory and drug exposure during tuberculosis (TB) treatment to assess the potential utility of Xpert CT for treatment monitoring. We obtained serial sputum samples from patients with smear-positive pulmonary TB who were consecutively enrolled at 10 international clinical trial sites participating in study 29X, a CDC-sponsored Tuberculosis Trials Consortium study evaluating the tolerability, safety, and antimicrobial activity of rifapentine at daily doses of up to 20 mg/kg of body weight. Xpert was performed at weeks 0, 2, 4, 6, 8, and 12. Longitudinal CT data were modeled using a nonlinear mixed effects model in relation to rifapentine exposure (area under the concentration-time curve [AUC]). The rate of change of CT was higher in subjects receiving rifapentine than in subjects receiving standard-dose rifampin. Moreover, rifapentine exposure, but not assigned dose, was significantly associated with rate of change in CT (P = 0.02). The estimated increase in CT slope for every additional 100 μg · h/ml of rifapentine drug exposure (as measured by AUC) was 0.11 CT/week (95% confidence interval [CI], 0.05 to 0.17). Increasing rifapentine exposure is associated with a higher rate of change of Xpert CT, indicating faster clearance of Mycobacterium tuberculosis DNA. These data suggest that the quantitative outputs of the Xpert MTB/RIF assay may be useful as a dynamic measure of TB treatment response.

Activation of the mammalian target of rapamycin (mTOR) pathway is observed in neurofibromatosis type 1 (NF1) associated low-grade gliomas (LGGs), but agents that inhibit this pathway, including mTOR inhibitors, have not been studied in this population. We evaluate the efficacy of the orally administered mTOR inhibitor everolimus for radiographically progressive NF1-associated pediatric LGGs. Children with radiologic-progressive, NF1-associated LGG and prior treatment with a carboplatin-containing chemotherapy were prospectively enrolled on this phase II clinical trial to receive daily everolimus. Whole blood was analyzed for everolimus and markers of phosphatidylinositol-3 kinase (PI3K)/mTOR pathway inhibition. Serial MRIs were obtained during treatment. The primary endpoint was progression-free survival at 48 weeks. Twenty-three participants (median age, 9.4 y; range, 3.2-21.6 y) were enrolled. All participants were initially evaluable for response; 1 patient was removed from study after development of a malignant peripheral nerve sheath tumor. Fifteen of 22 participants (68%) demonstrated a response, defined as either shrinkage (1 complete response, 2 partial response) or arrest of tumor growth (12 stable disease). Of these, 10/15 remained free of progression (median follow-up, 33 mo). All remaining 22 participants were alive at completion of therapy. Treatment was well tolerated; no patient discontinued therapy due to toxicity. Pharmacokinetic parameters and pre-dose concentrations showed substantial between-subject variability. PI3K/mTOR pathway inhibition markers demonstrating blood mononuclear cell mTOR pathway inactivation was achieved in most participants. Individuals with recurrent/progressive NF1-associated LGG demonstrate significant disease stability/shrinkage during treatment with oral everolimus with a well-tolerated toxicity profile. Everolimus is well suited for future consideration as upfront or combination therapy in this patient population.