Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium

PURPOSE 131I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate. PATIENTS AND METHODS Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m2/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected. RESULTS One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%. CONCLUSION Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.

Activity of Vincristine and Irinotecan in Diffuse Anaplastic Wilms Tumor and Therapy Outcomes of Stage II to IV Disease: Results of the Children’s Oncology Group AREN0321 Study

PURPOSE AREN0321 evaluated the activity of vincristine and irinotecan (VI) in patients with newly diagnosed diffuse anaplastic Wilms tumor (DAWT) and whether a regimen containing carboplatin (regimen UH1) in addition to regimen I agents used in the National Wilms Tumor Study 5 (NWTS-5; vincristine, doxorubicin, cyclophosphamide, and etoposide plus radiotherapy) would improve patient outcomes. PATIENTS AND METHODS Patients with stage II to IV DAWT without measurable disease received regimen UH1. Patients with stage IV measurable disease were eligible to receive VI (vincristine, 1.5 mg/m2 per day intravenously on days 1 and 8; irinotecan, 20 mg/m2 per day intravenously on days 1-5 and 8-12 of a 21-day cycle) in an upfront window; those with complete (CR) or partial response (PR) had VI incorporated into regimen UH1 (regimen UH2). The study was designed to detect improvement in outcomes of patients with stage II to IV DAWT compared with historical controls treated with regimen I. RESULTS Sixty-six eligible patients were enrolled. Of 14 patients with stage IV measurable disease who received VI, 11 (79%) achieved CR (n = 1) or PR (n = 10) after 2 cycles. Doses of doxorubicin, cyclophosphamide, and etoposide were reduced midstudy because of nonhematologic toxicity. Four patients (6%) died as a result of toxicity. Four-year event-free survival, relapse-free survival, and overall survival rates were 67.7% (95% CI, 55.9% to 79.4%), 72.9% (95% CI, 61.5% to 84.4%), and 73.7% (95% CI, 62.7% to 84.8%), respectively, compared with 57.5% (95% CI, 47.6% to 67.4%; P = .26), 57.5% (95% CI, 47.6% to 67.4%; P = .048), and 59.2% (95% CI, 49.4% to 69.0%; P = .08), respectively, in NWTS-5. CONCLUSION VI produced a high response rate in patients with metastatic DAWT. AREN0321 treatment seemed to improve outcomes for patients with stage II to IV DAWT compared with NWTS-5, but with increased toxicity. The UH2 regimen warrants further investigation with modifications to reduce toxicity.

SAT-163 Status at 10 Years: Long-Term Follow-Up for a Phase 2a Study of High-Specific-Activity (HSA) I 131 Iobenguane in Patients (Pts) with Relapsed/Refractory High-Risk Neuroblastoma

Background: Metaiodobenzylguanidine (MIBG; iobenguane), a guanethidine derivative, is a substrate for norepinephrine reuptake transporter which is highly expressed on the surface of neuroblastoma cells. AZEDRA® (HSA I-131 MIBG) has been approved by the FDA for the treatment of pheochromocytoma and paraganglioma, in pts 12 years and older with MIBG avid, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. The aim of this study was to establish the maximum tolerated dose in children with neuroblastoma, with secondary aims of assessing overall response and tumor and organ dosimetry. Here we report current long-term survival and toxicity data. Methods: Eligible pts were 1-30 years old with resistant neuroblastoma. A diagnostic dose of HSA I-131 MIBG was followed by 3 dosimetry scans to assess radiation dose to critical organs and soft-tissue tumors. To prevent prolonged myelosuppression, autologous hematopoietic stem cells were infused 14 days after therapy. Response and toxicity were evaluated on day 60. Dose-limiting toxicity (DLT) was failure to reconstitute neutrophils to greater than 500/µL within 28 days, or platelets to greater than 20,000/µL within 56 days, or grade 3 or 4 nonhematologic toxicity by Common Terminology Criteria for Adverse Events (version 3.0) except for predefined exclusions. Results: First pt was enrolled in June 2008. 15 pts total were evaluable at 12 (n=5), 15 (n=3), and 18 (n=7) mCi/kg. Mean whole-body radiation was 0.23 mGy/MBq, and mean organ doses were 0.92, 0.82, and 1.2 mGy/MBq of MIBG for the liver, lung, and kidney, respectively. Eight pts had 13 soft-tissue lesions with tumor-absorbed doses of 26-378 Gy. MYC-N amplification was present in two of 11 pts with available results. Of the 15 treated pts, 1 had a complete response, 3 had a partial response, 1 had a mixed response and 6 had stable disease. The remaining 4 had progressive disease. Twelve of the 15 evaluable pts received non-protocol therapy after HSA I-131 MIBG, the remaining 3 died due to tumor without further therapy. At 3.6 years of follow-up the overall survival was 26.7% (95% CI, 8.3%-49.6%). As of March 2018, one remaining pt is in long term follow up with an overall survival of 8.4 years. This pt was previously reported to have a secondary malignancy of myelodysplastic syndrome which has been in remission since receiving an allogenic bone marrow transplant in March 2014. Conclusions: HSA I-131 MIBG contributed to long term median survival of two years and was well tolerated. Treatment showed promising activity in the absence of significant nonhematologic toxicity.

Primary treatment of light-chain amyloidosis with bortezomib, lenalidomide, and dexamethasone

Key Points Bortezomib with dexamethasone and low-dose lenalidomide is an active therapy for previously untreated patients with AL amyloidosis. VRD can induce MRD-negative responses, but nonhematologic toxicity may be significant in patients with advanced disease.

Effective Dosing of Topotecan with Carboplatin in Relapsed Ovarian Cancer

Patients and Methods: Topotecan was given as a 30-minute infusion daily for 5 days, with carboplatin given immediately after topotecan on day 5. Treatment was repeated every 21 days. Carboplatin and then topotecan were escalated in sequential cohorts of three to six patients. Four dosage combinations of topotecan days 1 to 5 and carboplatin (day 5) were tested: 0.5 mg/m2/d and carboplatin area under the curve (AUC) of 4, topotecan 0.5 mg/m2/d and carboplatin AUC of 5, topotecan 0.75 mg/m2/d and carboplatin AUC of 5, and topotecan 1.0 mg/m2/d and carboplatin AUC of 5.Results: Grade 3 and 4 neutropenia was common at doses of 0.75 mg/m2/d and above, but dose-limiting hematologic toxicity occurred in only one patient. The most common reason for dose reduction or delay was failure of myelosuppression to resolve by day 21. Nonhematologic toxicity was generally mild. The maximum-tolerated dose as defined in the protocol was not reached, but topotecan dose escalation was stopped at 1.0 mg/m2/d, because delayed neutrophil recovery precluded re-treatment on a 21-day schedule.Conclusion: Hematologic toxicity was common but rarely serious, and the combination of topotecan with carboplatin on this schedule was safe and well tolerated. Giving carboplatin to patients after topotecan on day 5, rather than on day 1, allowed dose escalation beyond the levels reported in other studies. The recommended doses for previously treated patients are topotecan 0.75 mg/m2/d, days 1 to 5, with carboplatin at an area under the curve (AUC) of 5 following topotecan on day 5. The combination of topotecan 1 mg/m2/d, days 1 to 5, followed on day 5 by carboplatin at an AUC of 5, merits further examination in untreated patients.TAJ 2016; 29(2): 31-36

A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia

Key Points Vadastuximab talirine, a novel antibody-drug conjugate, consists of an anti-CD33 monoclonal antibody conjugated to pyrrolobenzodiazepine dimers. In a phase 1 trial, vadastuximab talirine demonstrated single-agent activity and minimal nonhematologic toxicity in patients with AML.

Randomized Phase II Study of Clofarabine-Based Consolidation for Younger Adults With Acute Myeloid Leukemia in First Remission

Purpose To evaluate the efficacy and safety of a clofarabine-based combination (CLARA) versus conventional high-dose cytarabine (HDAC) as postremission chemotherapy in younger patients with acute myeloid leukemia (AML). Patients and Methods Patients age 18 to 59 years old with intermediate- or unfavorable-risk AML in first remission and no identified donor for allogeneic stem-cell transplantation (SCT) were eligible. Two hundred twenty-one patients were randomly assigned to receive three CLARA or three HDAC consolidation cycles. The primary end point was relapse-free survival (RFS). To handle the confounding effect of SCT that could occur in patients with late donor identification, hazard ratios (HRs) of events were adjusted on the time-dependent treatment × SCT interaction term. Results At 2 years, RFS was 58.5% (95% CI, 49% to 67%) in the CLARA arm and 46.5% (95% CI, 37% to 55%) in the HDAC arm. Overall, 110 patients (55 in each arm) received SCT in first remission. On the basis of a multivariable Cox-adjusted treatment × SCT interaction, the HR of CLARA over HDAC before or in absence of SCT was 0.65 (95% CI, 0.43 to 0.98; P = .041). In a sensitivity analysis, when patients who received SCT in first remission were censored at SCT time, 2-year RFS was 53.3% (95% CI, 39% to 66%) in the CLARA arm and 31.0% (95% CI, 19% to 43%) in the HDAC arm (HR, 0.63; 95% CI, 0.41 to 0.98; P = .043). Gain in RFS could be related to the lower cumulative incidence of relapse observed in the CLARA arm versus the HDAC arm (33.9% v 46.4% at 2 years, respectively; cause-specific HR, 0.61; 95% CI, 0.40 to 0.94; P = .025). CLARA cycles were associated with higher hematologic and nonhematologic toxicity than HDAC cycles. Conclusion These results suggest that CLARA might be considered as a new chemotherapy option in younger patients with AML in first remission.

Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia

Purpose To characterize the toxicity, pharmacokinetics, and pharmacodynamics of selinexor, a selective inhibitor of nuclear export, when combined with fludarabine and cytarabine, in children with relapsed or refractory leukemia. Patients and Methods Eighteen patients with relapsed or refractory acute leukemia were enrolled in the SELHEM (Selinexor With Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome) clinical trial (NCT02212561). Selinexor, initially at 30 mg/m2 per dose, was given orally on days 1, 3, 8, 10, 22, and 24 and was escalated according to a rolling-six design. Fludarabine 30 mg/m2 and cytarabine 2 g/m2 were administered on days 15 to 19. Pharmacokinetic and pharmacodynamic studies were performed on days 1 and 22. Response evaluations were performed on day 15 and at the completion of course 1. Results Among the 17 patients who were evaluable for toxicity, three were treated at 30 mg/m2, three at 40 mg/m2, six at 55 mg/m2, and five at 70 mg/m2. The most common grade 3 nonhematologic toxicity was asymptomatic hyponatremia. Two patients who were treated at 70 mg/m2 experienced reversible cerebellar toxicity, thereby defining the dose-limiting toxicity. Pharmacokinetic parameters demonstrated that plasma exposure was dose proportional. Fifteen of 16 patients demonstrated at least a twofold increase of XPO1 mRNA, indicating inhibition of the XPO1 protein. In this group of heavily pretreated, relapsed, and refractory patients, seven of 15 evaluable patients (47%) achieved complete response or complete response with incomplete count recovery. Conclusion Selinexor, in combination with fludarabine and cytarabine, is tolerable at doses up to 55 mg/m2 in pediatric patients with relapsed or refractory leukemia. All patients who received selinexor at ≥ 40 mg/m2 demonstrated XPO1 target inhibition. Response rates are promising and will be further explored in a phase II trial.

Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance)

Purpose We compared nab-paclitaxel or ixabepilone once per week to paclitaxel with bevacizumab as first-line therapy for patients with advanced breast cancer (BC) to evaluate progression-free survival (PFS) for nab-paclitaxel or ixabepilone versus paclitaxel. Patients and Methods Eligible patients were age ≥ 18 years with chemotherapy-naive advanced BC. Patients were randomly assigned to bevacizumab with paclitaxel 90 mg/m2 (arm A), nab-paclitaxel 150 mg/m2 (arm B), or ixabepilone 16 mg/m2 (arm C), once per week for 3 of 4 weeks. Planned enrollment was 900 patients, which would give 88% power to detect a hazard ratio of 0.73. Results In all, 799 patients were enrolled, and 783 received treatment (97% received bevacizumab). Arm C was closed for futility at the first interim analysis (n = 241), and arm A (n = 267) and arm B (n = 275) were closed for futility at the second interim analysis. Median PFS for paclitaxel was 11 months, ixabepilone was inferior to paclitaxel (PFS, 7.4 months; hazard ratio, 1.59; 95% CI, 1.31 to 1.93; P < .001), and nab-paclitaxel was not superior to paclitaxel (PFS, 9.3 months; hazard ratio, 1.20; 95% CI, 1.00 to 1.45; P = .054). Results were concordant with overall survival; time to treatment failure was significantly shorter in both experimental arms v paclitaxel. Hematologic and nonhematologic toxicity, including peripheral neuropathy, was increased with nab-paclitaxel, with more frequent and earlier dose reductions. Conclusion In patients with chemotherapy-naive advanced BC, ixabepilone once per week was inferior to paclitaxel, and nab-paclitaxel was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms, particularly for nab-paclitaxel. Paclitaxel once per week remains the preferred palliative chemotherapy in this setting.