Faculty Bibliography

OBJECTIVE:To determine if the concentration and saturation of natalizumab (NTZ) administration at extended interval dosing (EID; every 5-8 weeks) over 18 months is able to be maintained in the range considered adequate to sustain the clinical efficacy of NTZ. METHODS:-integrin receptor saturations were analyzed via cytometry, in blood samples obtained at trough timepoints. RESULTS:Trough serum concentration was above the "therapeutic" concentration of 2.0 μg/mL in 72% of EID patients. Trough saturation was above the "therapeutic" 50% threshold in 79% of EID-treated patients. Our model predicted that at least 9 NTZ infusions/year are required to maintain adequate trough saturation and concentration levels. Higher body mass index (BMI) was a predictor of suboptimal trough saturation on EID NTZ. CONCLUSIONS:Trough α4-integrin receptor saturation >50% correlated with high clinical efficacy of NTZ in previous studies. A continual treatment with EID maintains receptor saturation and concentration that are in the "therapeutic range" for most patients. This finding provides biological plausibility for the clinical efficacy of NTZ EID. Patients with higher BMI may require closer clinical and MRI follow-up.

Background: Preoperative chemoRT is a standardof- care as shown in the CROSS trial (N Engl J Med 2012;366:2074-2084), Surgery is sometimes deferred in pts with clinical CR (cCR) based on lack of overall survival benefit (J Clin Oncol 2005;23:2310-2317, J Clin Oncol2007;25:1160-1168). Nivolumab has activity in advanced ESCC (Lancet Oncol 2017;18:631-639), and adding it to chemoRT may improve outcomes.
Method(s): This phase I/II study was designed to assess the safety and tolerability and efficacy of nivolumab added to chemoRT (6 weekly carboplatin AUC 2, paclitaxel 50mg/m2, RT 50.4 Gy in 1.8 Gy fractions 5/7 days) for pts with TanyN1-3 or T3-4N0M0 ESCC. The phase I primary endpoint is 'unacceptable toxicity' at 28 days after the last dose of chemotherapy. The phase II primary endpoints are cCR (endoscopy + PET/CT) and pCR rates for pts undergoing surgery. Nivolumab is given q2W x2, then concurrent chemoRT with nivolumab q2W x3. If no cCR, pt proceeds to esophagectomy, then adjuvant nivolumab q2W x3; if cCR, pt has an option of no surgery but receives nivolumab q2W x3.
Result(s):From 7/20/17 to 12/27/18, 6 pts were enrolled. No unacceptable or grade 5 toxicities were observed. The most common grade 1/2 AEs in >1 pt were anorexia, myelosuppression, elevated AST and nausea. Grade 3/4 AEs in >1 pt were lymphopenia and leukocytopenia. 2 pts required hospitalizations (dyspnea 1, colitis 1). All pts completed therapy; 1 pt had dose delay due to grade 2 esophagitis; 2 pts progressed, 4 achieved cCR. Of 4 pts with cCR, 2 pts chose surgery and both achieved pCR. None of the 4 pts recurred.
Conclusion(s): ChemoRT with nivolumab is tolerable with manageable toxicities in locally advanced ESCC. Enrollment to the phase II portion ended because of slow accrual. Adverse Events. Grade 1 &2 in > 1 pt: 4/6: Anorexia & Anemia 3/6: Leukocytopenia Neutropenia Thrombocytopenia Nausea & Elevated AST 2/6: Hypomagnesemia Hypokalemia Grade 3 & 4 in > 1 pt: 5/6: Lymphopenia, 2/6: Leukocytopenia

BACKGROUND: There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a ?hypermutator phenotype?. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily trans- formed IDH-mutant GBMs. Safety-lead-in results will be presented.
METHOD(S): This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE.
RESULT(S): Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5-54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade >= 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade <= 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4-5.7). Median OS was 10.1 (range 6.8-21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual.
CONCLUSION(S): Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in patients with ET/PV previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC) 111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET/PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rate ORR (CR / PR) at 12 months was 69.2% (43.1% / 26.2%) in ET, and 60% (22%/38%) in PV patients. CR rates were higher in CALR mutated ET patients (56.5% vs. 28.0%, p= 0.01) as compared to subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction (VAF) was -6% (range -84%-47%) in patients achieving a CR versus +4% (range -18%-56%) in patients with PR/non-response (NR). Therapy was associated with a significant rate of adverse events (AE), most were manageable, and PEG discontinuation due to AEs occurred only in 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET/PV who were previously refractory and/or intolerant to HU. (ClinicalTrials.gov Identifier: NCT01259856).

OBJECTIVE:To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS). METHODS:This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions. RESULTS:< 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID. CONCLUSION/CONCLUSIONS:Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.

BACKGROUND:We previously reported the results of a multicentric prospective randomized trial of chemo-refractory metastatic breast cancer patients testing the efficacy of two doses of TGFβ blockade during radiotherapy. Despite a lack of objective responses to the combination, patients who received a higher dose of TGFβ blocking antibody fresolimumab had a better overall survival when compared to those assigned to lower dose (hazard ratio of 2.73, p = 0.039). They also demonstrated an improved peripheral blood mononuclear cell (PBMC) counts and increase in the CD8 central memory pool. We performed additional analysis on residual PBMC using single cell network profiling (SCNP). METHODS:The original trial randomized metastatic breast cancer patients to either 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, combined with radiotherapy to a metastatic site at week 1 and 7 (22.5 Gy given in 3 doses of 7.5 Gy). Trial immune monitoring results were previously reported. In 15 patients with available residual blood samples, additional functional studies were performed, and compared with data obtained in parallel from seven healthy female donors (HD): SCNP was applied to analyze T cell receptor (TCR) modulated signaling via CD3 and CD28 crosslinking and measurement of evoked phosphorylation of AKT and ERK in CD4 and CD8 T cell subsets defined by PD-1 expression. RESULTS:T cells from HD. CONCLUSIONS:Functional T cell analysis suggests that baseline T cell functionality is hampered in metastatic breast cancer patients, at least in part mediated by the PD-1 signaling pathway. These preliminary data support the rationale for investigating the possible beneficial effects of adding PD-1 blockade to improve responses to TGFβ blockade and radiotherapy. TRIAL REGISTRATION/BACKGROUND:NCT01401062 .

Objective: Few effective treatment options exist for women with advanced or recurrent endometrial cancer (EC). To explore a modification of the standard systemic treatment for advanced or recurrent EC, we sought to determine the feasibility of completing 6 cycles of nab-paclitaxel (Nab-P) and carboplatin. Unlike paclitaxel, Nab-P does not require any steroid or other premedication, an important consideration for patients with diabetes mellitus and in the investigation of combinations with immunotherapy. We prospectively evaluated safety and efficacy of a day 1, 8-dose schedule of Nab-P in combination with carboplatin day 1 q3weeks in patients with chemotherapy naive EC.
Method(s): Patients with early-stage and high-risk, advanced primary, or recurrent EC with no prior platinum and taxane exposure were enrolled at a single institution. Patients received 6 cycles of day 1 Nab-P 100 mg/m² IV with carboplatin AUC 6 IV and day 8 Nab-P 100 mg/m² IV q21days. We evaluated percentage completion of 6 cycles with standard dose reductions, as well as toxicity per CTCAE v.4. Measurable disease was not required, and efficacy was assessed by PFS rate at 6 months.
Result(s): From 2016 to 2018, 23 subjects were enrolled; median age was 65 (43-73) years. Nineteen (82%) completed 6 cycles of the doublet therapy. Eight subjects (35%) were dose-reduced 1 level, and 5 (22%) were reduced 2 levels; only 1 subject withdrew due to toxicity. Twelve subjects (52%) had at least 1 grade 3/4 treatment-related adverse event, the most common being anemia, 6 (26%); neutropenia, 4 (17%); and diarrhea, 2 (9%). Pre-existing neuropathy was an exclusion criteria, and 13 (57%) reported at least grade 1 neuropathy with treatment. After treatment, 3 (13%) deaths occurred with 2 due to disease progression and 1 to pulmonary embolism. At 6 months after treatment initiation, 19 (83%) had no evidence of disease or its progression; 4 (17%) had progressed. Kaplan-Meier analysis revealed a 6-month PFS rate of 80.5% (95% CI 65.1%-99.7%) (Figure 1).
Conclusion(s): The Nab-P/carboplatin day 1, 8 regimen met the prespecified criteria of feasibility with acceptable toxicity and efficacy. Use of Nab-P obviates steroid premedications, ideal for immune checkpoint inhibitors that target mismatch repair deficient advanced EC. A future phase II feasibility trial combining an anti-PD-1 agent with Nab-P and carboplatin is planned. [Figure presented]
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