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Supplementary Tables and Methods

Redacted protocol for supplementary files

Supplementary Figure 4 shows pharmacokinetic parameters for guadecitabine and decitabine in the dose escalation phase

Purpose:Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers.Patient and Methods:SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2–4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1–5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228.Results:Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1–5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred.Conclusions:The guadecitabine RP2D was 20 mg/m2, days 1–5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.

Supplementary Figure 1 shows a schematic of the treatment cycle

Supplementary Figure 2 shows CONSORT diagrams for both phases of the trial

Supplementary Figure 3 shows promotor methylation status for the indicated genes in cfDNA

The PI3K/AKT/PTEN pathway is frequently deregulated in metastatic castration-resistant prostate cancer (mCRPC). ProCAID was a phase 2 trial assessing addition of the AKT1/2/3 inhibitor capivasertib to docetaxel for patients with mCRPC. We previously reported that capivasertib did not extend a composite progression-free survival primary endpoint but did significantly improve the secondary endpoint of overall survival (OS). Here we present OS data after 66% of events had occurred in the intent-to-treat population (n = 150). Median OS was 25.3 mo for capivasertib plus docetaxel versus 20.3 mo for placebo plus docetaxel (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.47–1.05; nominal p = 0.09). Receipt of subsequent life-extending treatments was balanced between the treatment arms. The OS benefit associated with capivasertib was maintained in a subset of patients previously treated with abiraterone and/or enzalutamide (median OS 25.0 vs 17.6 mo; HR 0.57, 95% CI 0.36–0.91; nominal p = 0.02) but not in abiraterone/enzalutamide-naïve patients (median OS 31.1 mo vs not reached; HR 1.43, 95% CI 0.63–3.23). We conclude that OS may be extended by addition of capivasertib to docetaxel. Exploratory analysis revealed that the OS benefit was maintained in a subset of patients previously exposed to androgen receptor–targeted agents, which should be evaluated in prospective trials.\ud \ud Patient summary: \ud The ProCAID study examined whether adding the AKT inhibitor drug capivasertib to docetaxel chemotherapy improves outcomes for patients with advanced prostate cancer. Initial analysis of the ProCAID results suggested that capivasertib improved overall survival benefit. This follow-up analysis suggests that capivasertib addition may be particularly beneficial for patients whose cancer was previously treated with drugs that target the androgen receptor.

PURPOSE Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel. PATIENTS AND METHODS ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status. RESULTS One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash. CONCLUSION The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.

Background Neodymium-doped yttrium aluminium garnet (Nd:YAG) posterior capsulotomy is a common treatment for posterior capsular opacification. Practice varies regarding routine follow-up. In this study, we reviewed follow-up rates and treatment-related complications from a district general hospital's ophthalmology unit to assess areas for improvement and cost-effectiveness. Methodology We conducted a retrospective review of electronic patient records for all patients treated with Nd:YAG capsulotomy in 2019 at our hospital. Primary outcomes included visual acuity, complications, and follow-up data. Secondary outcomes included medication prescribing and the grade of surgeon. Results In total, 912 eyes of 744 patients were included. Overall, 536 (58.8%) eyes were discharged immediately following their laser. Complication rate was 4.3% (39 eyes). Junior training grades had a higher rate of medication prescribing (40/46 eyes; 87.0%) and follow-up (36/40 eyes; 78.3%). Conclusions Certain selected patients may be safely discharged following capsulotomy with safety-netting advice. This strategy increases the capacity to follow-up patients at higher risk of complications. Higher rates of follow-up among junior ophthalmologists offers potential for training.

Purpose: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers. Patient and Methods: SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2–4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1–5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228. Results: Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1–5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred. Conclusions: The guadecitabine RP2D was 20 mg/m2, days 1–5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.

108 Background: The AKT pathway is frequently deregulated in mCRPC. ProCAID tested addition of capivasertib, a potent selective inhibitor of all three AKT isoforms (AKT1/2/3) to docetaxel chemotherapy vs. placebo plus docetaxel for mCRPC. The primary analysis showed no difference between treatment arms for the primary endpoint of composite progression free survival (cPFS). However, OS, which was a secondary endpoint, was extended in the capivasertib plus docetaxel arm. cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway biomarker status (Crabb et al, J Clin Oncol 2021;39(3):190-201). Methods: An updated analysis of mature OS data was undertaken once events reached ≥65% by Cox proportional hazards model, adjusted for minimisation factors, within the intent to treat (ITT) population (n = 150). Patients (pts) and investigators remained blinded to treatment allocation. We also investigated OS outcomes within subsets based on prior androgen receptor targeted agent (ARTA) exposure to abiraterone and/or enzalutamide (abi/enza) and the balance of post-trial life extending treatment use by treatment arm. Funding: Cancer Research UK (C9317/A16029, CRUK/12/042) and AstraZeneca. Results: At this OS update, 99 pts (66.0%) had died, with 88 of these deaths (88.9%) due to prostate cancer. 5 pts (3.3%) remained on capivasertib or placebo. Median OS was 25.3 months for the capivasertib plus docetaxel arm vs. 20.3 months for placebo plus docetaxel (hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.47 to 1.05; nominal p = 0.09). One, or more, subsequent life extending treatment options, including abiraterone, enzalutamide, radium-223 and cabazitaxel, were received by 99 pts (66.0%) and were balanced between treatment arms (68% capivasertib, 64% placebo). 101 pts (67.3%; 51 capivasertib, 50 placebo) had received abi/enza prior to entering ProCAID. Within this subgroup, OS benefit for capivasertib plus docetaxel (median OS 31.1 months) was maintained vs. placebo plus docetaxel (median OS 19.3 months; HR 0.57, 95% CI 0.36 to 0.91), but not in the remaining 49 pts who were naive to prior abi/enza (median OS 31.1 vs. not reached respectively; HR 1.43, 95% CI 0.63 to 3.23). These updated OS results remained consistent irrespective of biomarker status for PI3K/AKT/PTEN pathway activation. No clinically significant differences from the previously reported safety outcomes were seen with extended follow up of this trial. Conclusions: OS remains longer within the ProCAID ITT population with the addition of capivasertib to docetaxel for mCRPC. This does not appear to be explained by subsequent treatment choices. Exploratory analysis found prolonged OS with capivasertib within a subset of pts previously exposed to an ARTA which should be evaluated in prospective trials. Clinical trial information: NCT02121639.

447 Background: Pre-clinical data support a hypothesis that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers including urothelial carcinoma (UC). SPIRE comprised a previously reported phase Ib dose escalation phase for incurable metastatic solid cancers which established a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin (GC) chemotherapy (Crabb et al, ESMO Congress 2018, abstract 425P). We now report the SPIRE phase IIa randomised dose expansion phase which tested neoadjuvant treatment of bladder UC. Methods: Patients had T2-4a N0 M0 bladder UC intended for radical treatment. All patients received an investigator choice of 3 or 4 planned, 21-day, GC cycles (cisplatin 70 mg/m2, IV, day 8; gemcitabine 1000 mg/m2, IV, days 8 and 15). 20 patients were randomised (1:1, open label) to whether they also received guadecitabine 20 mg/m2, SC, on days 1 to 5, and G-CSF prophylaxis 300 µg, SC, on days 15 to 21. The primary objective for the expansion phase was to confirm a safe and biologically effective dose and schedule for this combination for future investigation. Circulating cell free DNA LINE-1 promotor methylation was measured as a guadecitabine pharmacodynamic endpoint. Trial registration: ISRCTN 16332228. Funding: Cancer Research UK, Astex Pharmaceuticals. Sponsor: University Hospital Southampton NHS Foundation Trust. Results: Median age was 68 (interquartile range (IQR) 59-72). 19 (95%) patients were male and 17 (85%) had T2 stage. The commonest grade ≥3 adverse events were neutropenia and thrombocytopenia with one or both affecting 6 (60%) patients in each treatment arm (no grade 5 events). One episode of neutropenic fever occurred (guadecitabine arm). Addition of guadecitabine to GC, versus GC alone, resulted in similar cisplatin dose intensity (median total doses 408 mg (IQR 384-435 mg) and 435 mg (IQR 384-435 mg) respectively) but modestly reduced gemcitabine dose intensity (median total doses 10,450 mg (IQR 9,500-11,400) and 12,768 mg (IQR 9,500-12,768) respectively). All patients completed post-chemotherapy radical treatment (8 cystectomy, 2 radiotherapy, in each arm) with similar timing post chemotherapy and peri-operative morbidity scores. LINE-1 promotor methylation depletion occurred at cycle day 8 in guadecitabine treated patients. Conclusions: Guadecitabine in combination with GC and G-CSF is safe and tolerable in this combination compared to GC alone as neoadjuvant treatment for UC. Radical surgery or radiotherapy delivery, and cisplatin dose intensity, were not compromised. Pharmacodynamic endpoints are optimal with this treatment schedule. Addition of guadecitabine to GC warrants further investigation. Clinical trial information: 16332228.

5520 Background: DP extends survival in mCRPC, but clinical benefit is modest. PI3K/AKT/PTEN pathway activation is common in mCRPC contributing to disease progression and DP resistance. C is a pan-AKT inhibitor. Pre-clinical data indicate activity in prostate cancer and synergism with DP. This phase II trial combined C with DP in mCRPC. Methods: Key eligibility criteria: histologically or cytologically proven measurable or evaluable mCRPC, suitable for treatment with DP for PSA and/or radiographic disease progression, ECOG performance status 0-1, no prior chemotherapy for mCRPC, not requiring insulin or > 2 oral hypoglycaemic drugs for diabetes mellitus. Treatment: up to 10 cycles of DP (D: 75 mg/m2 IV, day 1; P: 5 mg bd oral, day 1 – 21) and random assignment (1:1, double blind) to oral C (320 mg twice daily, 4 days on/3 days off, from cycle 1, day 2) or matched placebo to disease progression. Primary endpoint: progression free survival (PFS; comprising PSA, radiographic or clinical progression, new cancer therapy or death; PCWG2 criteria) in the intent to treat (ITT) population. Secondary endpoints included overall survival (OS) and safety. PFS and OS were also assessed by composite biomarker (B) subgroup for PI3K/AKT/PTEN pathway activation status (NGS/IHC on archival tumour, contemporaneous ctDNA). Statistics: designed to detect a 50% increase in median PFS (6 to 9 months (mo)) between the placebo and C arms (90% power, 20% 1-sided alpha) by Cox proportional hazards model. Registration: ISRCTN 69139368. Results: 150 patients were randomised to 01/2019. Median follow up 16.77 months (IQR 12.0-26.5). PFS and OS by ITT and B status, are shown in the table (NR, not reached; CI confidence interval). Grade 3–4 adverse events (AE) were equally common between arms (62.2%). The most common AEs were diarrhoea, fatigue and nausea. Conclusions: Adding C to DP did not extend PFS. The OS secondary endpoint was significantly increased. PFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Clinical trial information: 69139368 . [Table: see text]

For the past few decades, many special collections repositories in the United States have charged licensing or use fees to those patrons who use or publish special collections materials for commercial purposes. In fact, about fifteen years ago the Rare Books and Manuscripts Section of the Association of College and Research Libraries charged an ad hoc committee, the Licensing and Reproductions of Special Collections Committee, to “create a reasoned and articulate defense of libraries’ right to charge licensing fees for commercial uses of their materials.”2 The Committee noted that, historically, libraries allowed scholars to publish freely from the content they . . .

SUMMARY The second edition of the International Standard Archival Authority Records for Corporate Bodies, Persons, and Families (ISAAR(CPF)2) focuses on describing entities as they exist in reality, rather than on establishing authorized terms. This change allows authority records to include multiple authorized terms representing an entity as it changed over time. Traditionally, an authority record has been created for a corporate body each time its name changed. This practice results in an artificial, fragmented view of the entity, concentrating on heading control rather than on providing contextual information necessary to assist with the provenance-method of retrieval and the interpretation of the records. In order to describe entities as ISAAR(CPF)2 allows and better reflect records-creating environments, the author proposes that an authority record describe a definable unit that performs a distinct function without major temporal interruption.

The authors argue that finding aids present only singular perspectives of the collections they describe and fail to represent the impact of archivists' work on records and subsequentreinterpretations of collections by archivists and researchers. The authors place these criticisms within the burgeoning postmodern discourse in archival studies and make two concrete suggestions for finding aids that would allow practicing archivists to acknowledge the inherent subjectivity of archival work and to incorporate multiple perspectives into the description of records.