A Phase 1 Trial of Durvalumab in Combination with Bacillus Calmette-Guerin (BCG) or External Beam Radiation Therapy in Patients with BCG-unresponsive Non-muscle-Invasive Bladder Cancer: The Hoosier Cancer Research Network GU16-243 ADAPT-BLADDER Study.

BACKGROUND: Novel treatments and trial designs remain a high priority for bacillus Calmette-Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC) patients. OBJECTIVE: To evaluate the safety and preliminary efficacy of anti-PD-L1 directed therapy with durvalumab (D), durvalumab plus BCG (D + BCG), and durvalumab plus external beam radiation therapy (D + EBRT). DESIGN, SETTING, AND PARTICIPANTS: A multicenter phase 1 trial was conducted at community and academic sites. INTERVENTION: Patients received 1120 mg of D intravenously every 3 wk for eight cycles. D + BCG patients also received full-dose intravesical BCG weekly for 6 wk with BCG maintenance recommended. D + EBRT patients received concurrent EBRT (6 Gy × 3 in cycle 1 only). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Post-treatment cystoscopy and urine cytology were performed at 3 and 6 -mo, with bladder biopsies required at the 6-mo evaluation. The recommended phase 2 dose (RP2D) for each regimen was the primary endpoint. Secondary endpoints included toxicity profiles and complete response (CR) rates. RESULTS AND LIMITATIONS: Twenty-eight patients were treated in the D (n = 3), D + BCG (n = 13), and D + EBRT (n = 12) cohorts. Full-dose D, full-dose BCG, and 6 Gy fractions × 3 were determined as the RP2Ds. One patient (4%) experienced a grade 3 dose limiting toxicity event of autoimmune hepatitis. The 3-mo CR occurred in 64% of all patients and in 33%, 85%, and 50% within the D, D + BCG, and D + EBRT cohorts, respectively. Twelve-month CRs were achieved in 46% of all patients and in 73% of D + BCG and 33% of D + EBRT patients. CONCLUSIONS: D combined with intravesical BCG or EBRT proved feasible and safe in BCG-unresponsive NMIBC patients. Encouraging preliminary efficacy justifies further study of combination therapy approaches. PATIENT SUMMARY: Durvalumab combination therapy can be safely administered to non-muscle-invasive bladder cancer patients with the goal of increasing durable response rates.

T-Cell Infiltration and Adaptive Treg Resistance in Response to Androgen Deprivation With or Without Vaccination in Localized Prostate Cancer.

PURPOSE: Previous studies suggest that androgen deprivation therapy (ADT) promotes antitumor immunity in prostate cancer. Whether a vaccine-based approach can augment this effect remains unknown. PATIENTS AND METHODS: We conducted a neoadjuvant, randomized study to quantify the immunologic effects of a GM-CSF-secreting allogeneic cellular vaccine in combination with low-dose cyclophosphamide (Cy/GVAX) followed by degarelix versus degarelix alone in patients with high-risk localized prostate adenocarcinoma who were planned for radical prostatectomy. RESULTS: Both Cy/GVAX plus degarelix and degarelix alone led to significant increases in intratumoral CD8+ T-cell infiltration and PD-L1 expression as compared with a cohort of untreated, matched controls. However, the CD8+ T-cell infiltrate was accompanied by a proportional increase in regulatory T cells (Treg), suggesting that adaptive Treg resistance may dampen the immunogenicity of ADT. Although Cy/GVAX followed by degarelix was associated with a modest improvement in time-to-PSA progression and time-to-next treatment, as well as an increase in PD-L1, there was no difference in the CD8+ T-cell infiltrate as compared with degarelix alone. Gene expression profiling demonstrated that CHIT1, a macrophage marker, was differentially upregulated with Cy/GVAX plus degarelix compared with degarelix alone. CONCLUSIONS: Our results highlight that ADT with or without Cy/GVAX induces a complex immune response within the prostate tumor microenvironment. These data have important implications for combining ADT with immunotherapy. In particular, our finding that ADT increases both CD8+ T cells and Tregs supports the development of regimens combining ADT with Treg-depleting agents in the treatment of prostate cancer.

Pharmacodynamic and pharmacokinetic neoadjuvant study of hedgehog pathway inhibitor Sonidegib (LDE-225) in men with high-risk localized prostate cancer undergoing prostatectomy.

PURPOSE: To determine the pharmacodynamic effects of Sonidegib (LDE-225) in prostate tumor tissue from men with high-risk localized prostate cancer, by comparing pre-surgical core-biopsy specimens to tumor tissue harvested post-treatment at prostatectomy. METHODS: We conducted a prospective randomized (Sonidegib vs. observation) open-label translational clinical trial in men with high-risk localized prostate cancer undergoing radical prostatectomy. The primary endpoint was the proportion of patients in each arm who achieved at least a two-fold reduction in GLI1 mRNA expression in post-treatment versus pre-treatment tumor tissue. Secondary endpoints included the effect of pre-surgical treatment with Sonidegib on disease progression following radical prostatectomy, and safety. RESULTS: Fourteen men were equally randomized (7 per arm) to either neoadjuvant Sonidegib or observation for 4 weeks prior to prostatectomy. Six of seven men (86%) in the Sonidegib arm (and none in the control group) achieved a GLI1 suppression of at least two-fold. In the Sonidegib arm, drug was detectable in plasma and in prostatic tissue; and median intra-patient GLI1 expression decreased by 63-fold, indicating potent suppression of Hedgehog signaling. Sonidegib was well tolerated, without any Grade 3-4 adverse events observed. Disease-free survival was comparable among the two arms (HR = 1.50, 95% CI 0.26-8.69, P = 0.65). CONCLUSIONS: Hedgehog pathway activity (as measured by GLI1 expression) was detectable at baseline in men with localized high-risk prostate cancer. Sonidegib penetrated into prostatic tissue and induced a >60-fold suppression of the Hedgehog pathway. The oncological benefit of Hedgehog pathway inhibition in prostate cancer remains unclear.

A Multicenter, Randomized, Observer-blinded, Active-controlled Study to Evaluate the Safety and Efficacy of Ceftaroline Versus Comparator in Pediatric Patients With Acute Bacterial Skin and Skin Structure Infection.

BACKGROUND: Ceftaroline has in vitro activity against bacterial isolates, including methicillin-resistant Staphylococcus aureus. This is the first study to investigate ceftaroline fosamil in pediatric patients with acute bacterial skin and skin structure infections (ABSSSIs). METHODS: A multicenter, observer-blinded study (NCT01400867) in pediatric patients (2 months-17 years of age) with ABSSSIs. Patients were randomized 2:1 to receive intravenous (IV) ceftaroline fosamil or IV comparator (vancomycin or cefazolin, plus optional aztreonam) with optional switch to oral antibacterials from Day 4. Safety and clinical outcomes were assessed. RESULTS: Of 163 enrolled patients, 159 received treatment. Treatment groups were comparable for baseline characteristics. Rates of study drug-related treatment-emergent adverse events were similar for ceftaroline fosamil [22% (23/106)] and comparator [23% (12/53)]. One serious adverse event, considered to be related to IV study drug, occurred in the ceftaroline fosamil group (hypersensitivity). In both the treatment groups, 85% (ceftaroline fosamil, 91/107 and comparator, 44/52) of the modified intent-to-treat population achieved early clinical response (≥20% reduction in infection area from baseline). Clinical cure rates at test-of-cure were high [ceftaroline fosamil, 94% (101/107) and comparator, 87% (45/52)]. For patients evaluated 8 to 15 days after the last dose of any antibiotic (IV or oral), from whom methicillin-resistant Staphylococcus aureus was initially isolated, a favorable microbiologic response (reflecting the efficacy of oral/IV therapy and capturing a relapse or reinfection) was achieved with ceftaroline fosamil [89% (16/18)] and comparator [57% (4/7)]. CONCLUSIONS: Ceftaroline fosamil, with optional oral switch, was as well-tolerated and effective in pediatric patients with ABSSSIs as comparator therapy.

A Multicenter, Randomized, Observer-blinded, Active-controlled Study Evaluating the Safety and Effectiveness of Ceftaroline Compared With Ceftriaxone Plus Vancomycin in Pediatric Patients With Complicated Community-acquired Bacterial Pneumonia.

BACKGROUND: The broad-spectrum cephalosporin ceftaroline, a metabolite of the prodrug ceftaroline fosamil, has shown in vitro activity against clinical isolates from pediatric patients. METHODS: This multicenter, randomized, observer-blinded, active-controlled study (NCT01669980) assessed the safety and effectiveness of ceftaroline fosamil compared with ceftriaxone plus vancomycin in patients between 2 months and 17 years of age with complicated community-acquired bacterial pneumonia. Patients were randomized 3:1 (stratified by age cohort) to receive either ceftaroline fosamil or ceftriaxone plus vancomycin (comparator) as intravenous therapy for ≥3 days. Patients who met specific study criteria on or after Study Day 4 were permitted to switch to an oral study drug. Safety assessments were treatment-emergent adverse events, and the effectiveness of treatment was assessed by clinical and microbiologic outcomes. RESULTS: The median duration of intravenous treatment was 9.0 (range, 3.0-19.0) days in the ceftaroline fosamil group (N=30) and 7.5 (5.0-13.0) days in the comparator group (N=10). At least one treatment-emergent adverse event was experienced by 12/30 patients (40%) in the ceftaroline fosamil group and 8/10 (80%) in the comparator group; most treatment-emergent adverse events in both groups were mild to moderate in intensity. Clinical response rates in the modified intent-to-treat population were 52% (15/29 patients) in the ceftaroline fosamil group and 67% in the comparator group (6/9); clinical stability at Study Day 4 was 21% (6/29) and 22% (2/9), respectively. CONCLUSIONS: Ceftaroline fosamil was well tolerated and showed similar clinical response rates to ceftriaxone plus vancomycin in pediatric patients with complicated community-acquired bacterial pneumonia.

A Randomized, Prospective Study of Pediatric Patients With Community-acquired Pneumonia Treated With Ceftaroline Versus Ceftriaxone.

BACKGROUND: Community-acquired bacterial pneumonia (CABP) remains a major infection among children, despite the use of pneumococcal vaccination. Ceftaroline fosamil is a broad-spectrum cephalosporin antibiotic with activity against many bacteria, including Streptococcus pneumoniae (both penicillin-nonsusceptible and multidrug-resistant strains) and Staphylococcus aureus (including methicillin-resistant S. aureus). This article describes the safety, tolerability, and effectiveness of ceftaroline fosamil in the treatment of pediatric patients hospitalized with CABP, from a randomized, active-controlled, observer-blinded clinical study (registration number NCT01530763). METHODS: Pediatric patients were stratified into 4 age cohorts and randomized (3:1) to receive either intravenous ceftaroline fosamil or ceftriaxone, with optional oral switch for a total treatment duration of 5-14 days. Enrollment was planned for 160 patients. Data collected included demographics, infection characteristics and pathogens. Treatment-emergent adverse events, clinical outcomes, and microbiologic responses were assessed. RESULTS: Ceftaroline fosamil was well tolerated. Similar percentages of patients in the ceftaroline fosamil (55/121; 45%) and ceftriaxone (18/39; 46%) groups reported treatment-emergent adverse events. Coombs seroconversion was observed in 17% of patients in the ceftaroline fosamil group; however, no evidence of hemolytic anemia or hemolysis was found. No deaths were reported during the study. Ceftaroline fosamil had similar effectiveness to ceftriaxone, with high clinical cure rates at test-of-cure in the modified intent-to-treat population (94/107; 88% and 32/36; 89%, respectively). Three documented S. aureus infections were successfully treated in the ceftaroline group, including one caused by methicillin-resistant S. aureus. CONCLUSIONS: The results of this study suggest that ceftaroline fosamil may be an important treatment option for pediatric patients hospitalized with CABP.

Prospective study of the Wilson severity-of-illness scoring system for complicated skin and skin structure infections.

Wilson et al. (Am. J. Surg. 185:369-375, 2003) developed a disease severity classification system for use in complicated skin and skin structure infections (cSSSI). Two phase 3 trials of ceftaroline fosamil in cSSSI provided the opportunity to evaluate the association between Wilson Severity Risk Class and clinical cure rates. Our analyses did not confirm that an association exists between Wilson Severity Risk Class and clinical cure rate and, thus, did not validate its predictive utility.

CANVAS 1 and 2: analysis of clinical response at day 3 in two phase 3 trials of ceftaroline fosamil versus vancomycin plus aztreonam in treatment of acute bacterial skin and skin structure infections.

Scientific and regulatory interest in assessing clinical endpoints after 48 to 72 h of treatment for acute bacterial skin and skin structure infections (ABSSSI) has increased. Historical, pre-antibiotic-era data suggest that a treatment effect relative to untreated controls can be discerned in this time interval. Ceftaroline fosamil, a broad-spectrum bactericidal cephalosporin with activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA), and Gram-negative organisms was efficacious in two phase 3 trials of complicated skin infections (CANVAS 1 and 2) using clinical cure rates at the test-of-cure visit. To assess an early clinical response in the CANVAS trials, a retrospective analysis using a day 3 clinical endpoint was conducted. Adults with ABSSSI received intravenous ceftaroline fosamil at 600 mg every 12 h (q12h) or vancomycin at 1 g plus aztreonam at 1 g (V/A) q12h for 5 to 14 days. Clinical response at day 3, defined as cessation of infection spread and absence of fever, was analyzed in patients with a lesion size of ≥ 75 cm(2) and either deep and/or extensive cellulitis, major abscess, or an infected wound. Day 3 integrated CANVAS clinical response rates were 74.0% (296/400) for ceftaroline and 66.2% (263/397) for V/A (difference, 7.8%; 95% confidence interval [CI], 1.3% to 14.0%). In the individual studies, absolute treatment differences of 9.4% (CANVAS 1) and 5.9% (CANVAS 2) favoring ceftaroline were observed. For ABSSSI due to MRSA, response rates were 81.7% and 77.4% in the ceftaroline and V/A groups, respectively. In this retrospective analysis, ceftaroline fosamil monotherapy had a numerically higher clinical response than V/A at day 3 in the treatment of ABSSSI.