Confirmatory Phase Research Articles

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma

Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients. To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded. Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin. The primary outcome was progression-free survival (PFS) of 80% at 6 months. For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.

Olaratumab plus anthracyline in advanced/metastatic soft tissue sarcoma : Data of real-world utilization in Austria.

Olaratumab is ahumanized monoclonal antiplatelet-derived growth factor receptor alpha antibody that has been approved in combination with doxorubicin for the treatment of patients with metastatic soft tissue sarcoma (STS). The purpose of this retrospective study was to assess the clinical efficacy in STS patients treated with olaratumab in areal-world setting in Austria. Retrospectively collected longitudinal data from patients treated between November 2016 and September 2018 at 9Austrian centers were obtained from the respective medical charts. All patients who received at least one dose of olaratumab were eligible. Parameters of most interest were response rates, progression-free survival (PFS) and overall survival (OS). Altogether 55patients were included in the analysis. The median age was 58years. In total, 65.5% (n = 36), 21.8% (n = 12) and 12.7% (n = 7) received olaratumab as first, second or ≥third line treatment, respectively. Olaratumab was administered either in combination with doxorubicin (81.8%, n = 45) or liposomal doxorubicin (16.4%, n = 9); one patient received olaratumab as upfront monotherapy. The median PFS and OS were 2.6 and 11.4months, respectively. The objective response rate was 11.4% and the disease control rate was 40.9%. In this real-world analysis the outcome was less pronounced compared to the results of both the phase Ib/II approval trial and the confirmatory phase IIItrial. The latter failed to show an improvement in OS and PFS for the doxorubicin/olaratumab combination. As such, olaratumab should not be used anymore in patients with STS.

MS07.04 Stage I (Resectable) NSCLC: Surgery

MS07.04 Stage I (Resectable) NSCLC: Surgery

665TiP - SOLSTICE, a phase III, randomized, open label study of trifluridine/tipiracil+bevacizumab (bev) versus capecitabine+bev for the 1L treatment of patients with unresectable metastatic colorectal cancer (mCRC) who are not candidates for intensive therapy

BackgroundA phase 2 study in first-line mCRC patients non-eligible for intensive therapy (TASCO1, NCT02743221) treated with trifluridine/tipiracil-bev (TT-B, n=77) or capecitabine-bev (C-B, n=76), reported a longer median PFS with TT-B (9.2 months) than with C-B (7.8 months). The hazard ratio (HR) for progression between TT-B and C-B was 0.71 (95% CI, 0.48 to 1.06). Preliminary median OS was 18 months with TT-B and 16.2 months with C-B (HR, 0.56; 95% CI 0.32 to 0.98). The safety of TT-B was found to be acceptable with, for all-grade toxicities, more gastrointestinal and hematologic toxicities but a much lower rate of hand-foot syndrome than C-B (serious febrile neutropenia 3.9% with TT-B or C-B and diarrhoea grade 3-4: 1.3% with TT-B vs. 7.9% with C-B). Following this phase 2 trial, a global confirmatory phase 3 trial (SOLSTICE) has been initiated. Trial designThis phase 3, international, open-label, randomized study will include 854 first-line mCRC-patients, not candidate for intensive oxaliplatin- or irinotecan-based chemotherapy and non-eligible for curative resection, according to investigator’s judgment and in relation with age, performance status (PS), low tumour burden, comorbidities or non-clinical reasons. The stratification factors are ECOG PS (0 vs 1 vs 2), tumour localization (right vs left) and reason for non-eligibility to intensive therapy. Patients will be randomly allocated to trifluridine/tipiracil (35mg/m2 given orally bid on days 1–5 and 8–12 in a 28-day cycle) plus bev (5mg/kg on days 1 and 15 of a 28-day treatment cycle) or capecitabine (1250 or 1000mg/m²/dose bid on days 1-14 in a 21-day) plus bev (7.5mg/kg on day 1 in a 21-day treatment cycle). The primary endpoint is PFS and the key secondary endpoint is OS. Other secondary endpoints include safety and quality of life assessed by EORTC QLQ-C30 and EQ-5D questionnaires. Patients will also undergo comprehensive geriatric assessment using G8 questionnaire and Charlson Comorbidity Index at baseline. Inclusion of the first patient was done in March 2019. It is planned to open approximately 200 centers in 25 countries. Clinical trial identificationNCT03869892; March 11, 2019. Legal entity responsible for the studyInstitut de Recherches Internationales Servier. FundingInstitut de Recherches Internationales Servier. DisclosureT. Andre: Advisory / Consultancy, Travel / Accommodation / Expenses: Roche/Genentech, Amgen, Bristol-Myers Squibb, MSD Oncology and Servier, and honoraria from Roche/Genentech, Sanofi, Baxter, Bayer, Bristol-Myers Squibb, Amgen, MSD Oncology, Servier, XBiotech, and Novartis. M.P. Saunders: Advisory / Consultancy: Roche, Merck, Servier, Amgen, Sanofi, and Eisai. A. Kanehisa: Full / Part-time employment: IRIS. E. Gandossi: Full / Part-time employment: IRIS. R. Fougeray: Full / Part-time employment: IRIS. N. Causse-Amellal: Full / Part-time employment: IRIS. A. Falcone: Advisory / Consultancy, Research grant / Funding (institution): Amgen, Bayer, Merck, MSD, Roche, Lilly, Servier, Bristol.

Oncology phase II proof-of-concept studies with multiple targets: Randomized controlled trial or single arm?

For oncology drug development, phase II proof-of-concept studies have played a key role in determining whether or not to advance to a confirmatory phase III trial. With the increasing number of immunotherapies, efficient design strategies are crucial in moving successful drugs quickly to market. Our research examines drug development decision making under the framework of maximizing resource investment, characterized by benefit cost ratios (BCRs). In general, benefit represents the likelihood that a drug is successful, and cost is characterized by the risk adjusted total sample size of the phases II and III studies. Phase III studies often include a futility interim analysis; this sequential component can also be incorporated into BCRs. Under this framework, multiple scenarios can be considered. For example, for a given drug and cancer indication, BCRs can yield insights into whether to use a randomized control trial or a single-arm study. Importantly, any uncertainty in historical control estimates that are used to benchmark single-arm studies can be explicitly incorporated into BCRs. More complex scenarios, such as restricted resources or multiple potential cancer indications, can also be examined. Overall, BCR analyses indicate that single-arm trials are favored for proof-of-concept trials when there is low uncertainty in historical control data and smaller phase III sample sizes. Otherwise, especially if the most likely to succeed tumor indication can be identified, randomized controlled trials may be a better option. While the findings are consistent with intuition, we provide a more objective approach.

N-Acetylcysteine Rinse for Thick Secretion and Mucositis of Head and Neck Chemoradiotherapy (Alliance MC13C2): A Double-Blind Randomized Clinical Trial

ObjectiveTo determine whether N-acetylcysteine rinse was safe and could improve thickened secretions and dry mouth during and after radiotherapy. Patients and MethodsWe designed a prospective pilot double-blind, placebo-controlled randomized clinical trial (Alliance MC13C2). Adult patients (age ≥18 years) were enrolled if they underwent chemoradiotherapy (≥60 Gy). Patients initiated testing rinse within 3 days of starting radiotherapy. With swish-and-spit, they received 10% N-acetylcysteine (2500 mg daily) or placebo rinse solution 5 times daily during radiotherapy and 2 weeks postradiotherapy. The primary aim was to evaluate N-acetylcysteine in improvement of saliva viscosity with the Groningen Radiotherapy-Induced Xerostomia questionnaire. Secondary aims included evaluating xerostomia improvement by the same questionnaire and with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Head and Neck-35 Questions survey and adverse-event profiles. The type I error rate was 20%. ResultsThirty-two patients undergoing chemoradiotherapy were enrolled. Baseline characteristics were balanced for placebo (n=17) and N-acetylcysteine (n=15). N-acetylcysteine was better for improving sticky saliva (area under curve, P=.12). Scores of multiple secondary end points favored N-acetylcysteine, including sticky saliva daytime (P=.04), daytime and total xerostomia (both P=.02), pain (P=.18), and trouble with social eating (P=.15). Repeated measures models confirmed the findings. Taste was a major dissatisifer for N-acetylcysteine rinse; however, both testing rinses were safe and well tolerated overall. ConclusionOur pilot data showed that N-acetylcysteine rinse was safe and provided strong evidence of potential efficacy for improving thickened saliva and xerostomia by patient-reported outcome. A confirmatory phase 3 trial is required. Trial Registrationclinicaltrials.gov Identifier: NCT02123511

Sacituzumab govitecan: breakthrough targeted therapy for triple-negative breast cancer

ABSTRACTIntroduction: Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with an increased risk of recurrence and cancer-related death. Unlike hormone receptor-positive or HER2-positive breast cancers, there are limited targeted therapies available to treat TNBC and cytotoxic chemotherapy remains the mainstay of treatment. Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate targeting Trop-2 expressing cells and selectively delivering SN-38, an active metabolite of irinotecan.Areas covered: This review covers the mechanism of action, safety and efficacy of sacituzumab govitecan in patients with previously treated, metastatic TNBC. Additionally, efficacy data in other epithelial malignancies is included based on a PubMed search for ‘sacituzumab govitecan’ and ‘clinical trial’.Expert opinion: Sacituzumab govitecan has promising anti-cancer activity in patients with metastatic TNBC previously treated with at least two prior lines of systemic therapy based on a single arm Phase I/II clinical trial. A confirmatory Phase III randomized clinical trial is ongoing. Sacituzumab govitecan has a manageable side effect profile, with the most common adverse events being nausea, neutropenia, and diarrhea. The activity of sacituzumab govitecan likely extends beyond TNBC with promising early efficacy data in many other epithelial cancers, including hormone receptor-positive breast cancer.

Pharmacokinetic/Pharmacodynamic Modeling to Support the Re-approval of Gemtuzumab Ozogamicin.

Gemtuzumab ozogamicin (Mylotarg; Pfizer, New York, NY) was the first antibody–drug conjugate to be approved for CD33‐positive acute myeloid leukemia (AML). However, it was voluntarily withdrawn from the US market due to lack of clinical benefit in the confirmatory phase III trial. In 2012, several investigator cooperative studies using a different dosing regimen showed efficacy, but pharmacokinetic (PK) data were not collected in these trials. Through simulation of expected concentrations for new dosing regimens, PK/pharmacodynamic modeling was able to support the safety and efficacy of these regimens. Significant exposure–response relationships were found for the attainment of complete remission with and without platelet recovery, attainment of blast‐free status, the time course of myelosuppression, several grade ≥ 3 hepatic adverse events, and veno‐occlusive disease. Gemtuzumab ozogamicin received full approval by the US Food and Drug Administration (FDA) in September 2017 for newly diagnosed and relapsed AML in adult patients and relapsed AML in pediatric patients aged 2–17 years.

Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomized clinical trial

Objective: To assess masitinib in the treatment of ALS. Methods: Double-blind study, randomly assigning 394 patients (1:1:1) to receive riluzole (100 mg/d) plus placebo or masitinib at 4.5 or 3.0 mg/kg/d. Following a blinded transition from phase 2 to phase 2/3, a prospectively defined two-tiered design was implemented based on ALSFRS-R progression rate from disease-onset to baseline (ΔFS). This approach selects a more homogeneous primary efficacy population (“Normal Progressors”, ΔFS < 1.1 points/month) while concurrently permitting secondary assessment of the broader population. Primary endpoint was decline in ALSFRS-R at week-48 (ΔALSFRS-R), with the high-dose “Normal Progressor” cohort being the prospectively declared primary efficacy population. Missing data were imputed via last observation carried forward (LOCF) methodology with sensitivity analyses performed to test robustness. Results: For the primary efficacy population, masitinib (n = 99) showed significant benefit over placebo (n = 102) with a ΔALSFRS-R between-group difference (ΔLSM) of 3.4 (95% CI 0.65–6.13; p = 0.016), corresponding to a 27% slowing in rate of functional decline (LOCF methodology). Sensitivity analyses were all convergent, including the conservative multiple imputation technique of FCS-REGPMM with a ΔLSM of 3.4 (95% CI 0.53–6.33; p = 0.020). Secondary endpoints (ALSAQ-40, FVC, and time-to-event analysis) were also significant. Conversely, no significant treatment-effect according to ΔALSFRS-R was seen for the broader “Normal and Fast Progressor” masitinib 4.5 mg/kg/d cohort, or either of the low-dose (masitinib 3.0 mg/kg/d) cohorts. Rates of treatment-emergent adverse events (AEs) (regardless of causality or post-onset ΔFS) were 88% with masitinib 4.5 mg/kg/d, 85% with 3.0 mg/kg/d, and 79% with placebo. Likewise, rates of serious AE were 31, 23, and 18%, respectively. No distinct event contributed to the higher rate observed for masitinib and no deaths were related to masitinib. Conclusions: Results show that masitinib at 4.5 mg/kg/d can benefit patients with ALS. A confirmatory phase 3 study will be initiated to substantiate these data.

P-098 - TRYbeCA-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441)

Introduction: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs), is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study in patients with advanced pancreatic cancer whose disease progressed following first-line treatment (NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression-free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is an international, randomized, open-label, phase 3 trial (N= ∼500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the phase 2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals and to review efficacy data at the planned interim and final analyses. Results: N/A - TiP abstract Conclusion: N/A - TiP abstract

Commentary on “Applying CHW method to 2-in-1 design: gain or lose”

ABSTRACTWhile 2-in-1 designs give a flexibility to make a clinical trial either an information generation Phase 2 trial or a full scale confirmatory Phase 3 trial, flexible sample size designs can naturally fit into the 2-in-1 design framework. This study is to show that the CHW design can be blended into a 2-in-1 design to improve the adaptive performance of the design. Commenting on the usual 2-in-1 design, we demonstrated that the CHW design can achieve the goal of a 2-in-1 design with satisfactory statistical power and efficient average sample size for a targeted range of the treatment effect.

Applying CHW method to 2-in-1 design: gain or lose?

ABSTRACTThe 2-in-1 design allows the possibility of seamlessly expanding a phase II study to confirmatory phase III study and controls type I error without multiplicity adjustment. In this paper, we applied the CHW method to the 2-in-1 design strategy, and compared it with the unweighted conventional test statistics. It shows that when the interim decision threshold is high enough, the CHW method is slightly more powerful. Otherwise, results based on the CHW method can be difficult to interpret when the estimated treatment effects differ notably between interim and final analysis, which may be avoided by using the conventional test statistic.

PF723 TEN YEARS OF CLINICAL EXPERIENCE WITH BIOSIMILAR FILGRASTIM IN ONCOLOGY AND HAEMATOLOGY

Background:Sandoz biosimilar filgrastim was approved in the EU in 2009 and in 2015 was the first biosimilar approved in the US. These authorisations were based on ‘totality of evidence’, considering data from the state of the art analytical characterization and comparability exercises, the PK/PD studies, and confirmatory phase III clinical study in the most sensitive patient population: breast cancer patients undergoing myelosuppressive chemotherapy. In both the EU and US, approval was granted for the same indications as the reference biologic (including stem cell mobilisation [SCM] and severe chronic neutropenia [SCN]), on the basis of extrapolation, with no clinical trials conducted at the time of approval.Aims:This review aims to discuss clinical evidence for Sandoz biosimilar filgrastim in all approved indications, including the Phase III confirmatory studies in CIN, post‐approval clinical studies in SCM and real‐world experience.Methods:A narrative review was undertaken to provide an evidence‐based summary of the available clinical studies and real‐world evidence on the efficacy and safety of Sandoz biosimilar filgrastim in CIN prophylaxis for different tumour types, autologous and allogeneic SCM, and SCN.Results:CIN: The registration trials, confirmatory to the totality of evidence, supported the approval of Sandoz biosimilar filgrastim in the EU and US. Post‐approval studies have provided further evidence of the efficacy and safety of Sandoz biosimilar filgrastim. MONITOR‐GCSF, a multicentre, prospective, observational study in cancer patients (n = 1447) receiving Sandoz biosimilar filgrastim for CIN prophylaxis, reported a total of 4271 events in 777 patients (53.7%) with bone pain the most common (24.7%).1 There were no neutropenia‐ or biosimilar filgrastim‐related deaths. MONITOR‐GCSF sub‐analyses have provided evidence for the efficacy and safety profile of Sandoz biosimilar filgrastim in different tumour types, such as DLBCL and NSCLC.2,3 SCM: Overall, data from studies of autologous SCM show that the efficacy and safety of biosimilar filgrastim matches the known profile of reference filgrastim, and results are similar when reference filgrastim is included as a comparator. A retrospective analysis in 51 healthy sibling donors showed effective mobilization without notable AEs after 2 years’ follow‐up.4 Evidence is also emerging in allogeneic SCM, such as a study with the largest donor cohort (n = 244) reported to date.5 After a mean follow‐up of 433 days, efficacy and safety of biosimilar filgrastim were consistent with previous reports, and no haematological or solid malignancies occurred.SCN: The European Branch of the SCN International Registry has followed patients with SCN since 1994. While final analysis is ongoing, no serious AEs have been reported in patients receiving Sandoz biosimilar filgrastim.Summary/Conclusion:There is now a decade of clinical experience with Sandoz biosimilar filgrastim, including over 21 million patient‐days of exposure. This experience is reassuring regarding the safety and efficacy of Sandoz biosimilar filgrastim in patients with DLBCL, and in allogeneic SCM, and shows that extrapolation for biosimilars is based on strong scientific evidence and principles.

Olaparib monotherapy versus (vs) chemotherapy for germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSR OC) patients (pts): Phase III SOLO3 trial.

5506 Background: Data from a randomized Phase II trial (NCT00628251) of olaparib (capsules, 200 or 400 mg bid, n=32 per arm) vs pegylated liposomal doxorubicin (PLD, n=33) in gBRCAm OC pts with recurrence ≤12 months after prior platinum therapy indicated efficacy for olaparib (Kaye et al. JCO 2012). However, the efficacy of PLD was higher than previously reported in this setting. We led a confirmatory Phase III, open-label study of olaparib vs non-platinum chemotherapy in gBRCAm PSR OC pts (NCT02282020). Methods: Pts were randomized (2:1) to olaparib tablets (300 mg bid) or chemotherapy treatment of physician’s choice (TPC) (paclitaxel [P; 80 mg/m2 on day 1 (D1), D8, D15, D22 every 4 weeks (q4w)], topotecan [T; 4 mg/m2 D1, D8, D15 q4w], gemcitabine [G; 1000 mg/m2 D1, D8, D15 q4w] or PLD [50 mg/m2 D1 q4w]) until progression, stratified by: TPC, prior lines of chemotherapy (2–3 vs ≥4) and platinum-free interval (6–12 vs &gt;12 months). Primary endpoint: ORR (blinded independent central review [BICR]). Secondary endpoints included PFS and safety. Results: 266 gBRCAm PSR OC pts were randomized (olaparib, n=178; TPC, n=88 [ PLD, n=47; P, n=20; G, n=13; T, n=8]); 12 in the TPC arm withdrew before receiving study treatment. 223 pts (84%) had baseline BICR measurable disease (olaparib, n=151; TPC, n=72). ORR was 72% with olaparib vs 51% with TPC (OR 2.53, 95% CI 1.40–4.58; P=0.002). HR for PFS by BICR was 0.62 (95% CI 0.43–0.91; P=0.013; median 13.4 vs 9.2 months [olaparib vs TPC]) and by investigator assessment was 0.49 (95% CI 0.35–0.70; P&lt;0.001; median 13.2 vs 8.5 months, respectively). Most common adverse events (AEs) with olaparib were nausea (65% vs 34% [TPC]) and anemia (50% vs 25%) and with TPC were palmar-plantar erythrodysesthesia (PPE; 36% vs 1% [olaparib]) and nausea. Most common grade ≥3 AEs in either arm were anemia (21% [olaparib] vs 0 [TPC]), PPE (0 vs 12%) and neutropenia (6% vs 11%). For olaparib vs TPC, serious AEs were reported by 24% vs 18% and AEs led to treatment discontinuation in 7% vs 20%. Conclusions: Pts with gBRCAm PSR OC receiving olaparib monotherapy had a significant, clinically relevant improvement in ORR and PFS vs TPC, with no new safety signals. Clinical trial information: NCT02282020.

New FDA Approved Therapies for AML &amp; Impact on the Older Population

New FDA Approved Therapies for AML &amp; Impact on the Older Population

From Bench to Bedside: Evaluation of AHCC Supplementation to Modulate the Host Immunity to Clear High-Risk Human Papillomavirus Infections.

Objective: There is currently no effective medicine or supplement for clearance of high risk- human papillomavirus (HR-HPV) infections. We have taken a systematic approach evaluating the potential use of AHCC supplementation to support clearance of HR-HPV infections. The primary objective of this research was to evaluate AHCC supplementation to modulation of the host immune system to clear HR-HPV infections from bench to bedside.Methods: Cervical cancer cells, CaSki (HPV16+), HeLa(HPV18+), SiHa(HPV16/18+), and C-33A(HPV−), were treated in vitro with AHCC 0.42 mg/mL daily x7 days then observed x7 days with daily sample collection. A confirmatory study in cervical cancer mouse models, SiHa(HPV16/18+) and C-33A(HPV−), was conducted: mice were divided into three groups per cell line then dosed with AHCC 50 mg/kg/d (N = 10), or vehicle alone (N = 10), or no supplementation (N = 10) for a total of 90 days followed by 30 days of observation. Tumors were measured 3x/week and blood samples collected bi-weekly to evaluate interferon (IFN) alpha(α), beta(β), and gamma(γ) and immunoglobulin G(IgG) by immunoassays. Tumors were evaluated for HR-HPV expression by PCR. Two pilot studies of 10 patients each were conducted in women with confirmed persistent HR-HPV+ infections. The 1st study evaluated AHCC 3g from 5 weeks up to 6 months and 2nd study evaluated AHCC 1g < 8 months. HR-HPV DNA status and the immune panel were monitored at each visit.Results: HR-HPV clearance was observed in vitro and confirmed in the animal studies as a durable response. Four of six (66.7%) patients had confirmed HR-HPV clearance after 3–6 months of AHCC 3g. Similarly, 4 of 9 (44%) patients had confirmed HR-HPV clearance after 7 months of AHCC 1g. Suppression of IFNβ <25 pg/mL was observed in those clearing the HR-HPV infection.Conclusion: Pre-clinical in vitro and in vivo studies demonstrated durable clearance of HR-HPV infections. The preliminary data from the two pilot studies suggested that AHCC supplementation supports the host immune system for successful clearance of HR-HPV infections. A confirmatory phase II randomized, double-blinded, placebo-controlled study is ongoing.

CLO19-037: Reducing the Duration, Incidence and Severity of Mucosal Injury Due to Cancer Radiation therapy (RT); Positive Randomized Phase 2b Trial Results With GC4419 (Avasopasem Manganese), a Small Molecule Superoxide (SO) Dismutase (SOD) Mimetic

Introduction: RT-induced SO contributes to initiation of mucosal injury; eg, oral mucositis (OM) and esophagitis. GC4419 specifically mimics SOD’s dismutation of SO to hydrogen peroxide (H2O2), interdicting OM initiation. GC4419 reduced RT-severe OM (SOM) in a hamster cheek pouch model, and protected mucosa and other normal tissues from radiation-induced injury in other animal models. In a published phase 1b/2a open-label trial (Anderson et al, IJROBP, 1 Feb 2018), GC4419 attenuated SOM in patients (Pts) receiving intensity-modulated RT (IMRT) plus concurrent cisplatin (CDDP) for locally advanced head &amp; neck cancer (HNC). Objectives: Determine whether GC4419 reduces duration, incidence, &amp; severity of SOM. Methods: Pts with locally advanced oral cavity or oropharyngeal cancer; definitive or postoperative intensity-modulated (IM)RT (approximately 70 Gy [&gt;50 Gy to &gt; 2 oral sites]) plus CDDP (weekly or q3wk) were randomized (stratification: tumor HPV status, CDDP schedule) to 30 or 90 mg of GC4419, or placebo (PBO), 60-minute IV infusion, M–F, ending &lt;60 minutes before IMRT delivered in 35 fractions over 7 weeks. WHO grade OM was assessed by trained evaluators biw during IMRT &amp; qwk for up to 8 wks after IMRT. Primary endpoint: duration of SOM. Efficacy was tested for each active dose vs PBO (ITT population) by a sequential, conditional approach (2-sided alpha, 0.05). Results: 223 pts (44 sites): 90 mg (n=76), 30 mg (n=73), or PBO (n=74). Baseline patient and tumor characteristics and treatment delivery were balanced. Efficacy: At 90 mg GC4419 vs PBO, duration of SOM was significantly reduced (median, 1.5 vs 19 d; P=.024). SOM incidence (43% vs 65%; P=.009), and grade 4 incidence (16% vs 30%; P=.045) also improved. There were intermediate improvements with 30 mg. Safety was comparable across arms; no significant GC4419-specific toxicity; other known toxicities of IMRT/CDDP were not increased. Conclusions: GC4419 demonstrated a significant, clinically meaningful reduction of SOM duration, and dose-dependent improvements in other SOM parameters, with acceptable safety. A confirmatory phase 3 trial (NCT03689712) is in progress. Clinical trials to reduce RT-related esophagitis are also planned.

Reasons for Premature Conclusion of Late Phase Clinical Trials: An Analysis of ClinicalTrials.gov Registered Phase III Trials

Confirmatory phase III trials aim to provide decisive evidence about a medical product's safety and efficacy. Although these trials are planned and conducted based on accumulated knowledge, they are not without risk or uncertainty. A trial prematurely concluding contributes to great loss in both financial and human research resources. We categorized and evaluated trials concluded prematurely after recruitment had begun, as registered in Clinical Trials.gov between January 2013 and August 2017. We found 9828 registered interventional phase III trials; of those, 320 were concluded prematurely. Many clinical trials were concluded prematurely for reasons related to reducing participant risk, such as interim stopping for safety, efficacy, or futility. Yet, 70% trials were halted for other reasons, such as insufficient recruitment (the most often cited reason) or unspecified business decisions. Of all prematurely concluded trials, 102 trials evaluated 72 different novel therapeutics; in 66.7% of these trials, the clinical development program was stopped entirely. Most of the prematurely concluded trials (78%) had not provided results to ClinicalTrials.gov at the time of this analysis. Evaluation of the factors that influence premature conclusion could inform solutions for improving research participation and help ensure trial completion. Registering and reporting results acknowledges the voluntary contribution and consent expectations of research participants.

Trybeca-1: A randomized, phase 3 study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441).

TPS471 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment(NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is an international, randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. An HR in OS of 0.725 is being targeted representing a conservative estimate based on the P2b data and is viewed as being highly clinically relevant. An IDMC will be established to review safety at regular intervals and to review efficacy data at the planned interim and final analyses. Clinical trial information: NCT03665441.

The Impact of Early-Phase Trial Design in the Drug Development Process.

Many of the therapeutic agents that are being used currently were developed using the 3+3 decision rule for dose finding. Over the past 30 years, several dose-finding designs have been proposed and evaluated, including the "continual reassessment method" (CRM) and the "Bayesian optimal interval design" (BOIN). This research investigates the role of the choice of an early-phase design on the likelihood that drugs entering the drug development pipeline will have 2 successful phase III trials.Experimental Design: Using simulation, each agent in a population of hypothetical agents was tracked through the drug development process, from initial dose finding to 2 confirmatory phase III trials. Varying the designs of the phase I, II, and III trials allows for an assessment of the effect of the choice of designs on the proportion of agents with successful phase III trials. The results indicate that using the CRM or BOIN, rather than the 3+3, substantially enhances the proportion of effective agents that have successful phase III trials, with the CRM having a greater effect than BOIN. A larger phase II trial magnifies the effect of the phase I design. The results underscore the importance of the choice of the early-phase designs. Use of the 3+3 results in fewer agents with successful phase III trials compared with the CRM or BOIN. The difference is more pronounced among highly effective agents. In addition, the results show the importance of a sufficiently powered phase II trial.