Interim Efficacy Analysis Research Articles

Biomarker-directed precision oncology of pembrolizumab-based combination therapy for non-small cell lung cancer: Phase II KEYNOTE-495/KeyImPaCT study.

TPS9117 Background: Pembrolizumab-based combination immunotherapy aims to improve clinical outcomes over pembrolizumab monotherapy. A biomarker-based therapeutic approach may be associated with improved response to different combination therapies of immune checkpoint inhibitors and may improve overall outcomes in NSCLC. The randomized, multicenter, open-label, phase 2 KEYNOTE-495 trial ( NCT03516981 ) will evaluate the clinical usefulness of biomarker-informed, pembrolizumab-based combination therapy in patients with treatment-naive, advanced NSCLC. Methods: This is a group-sequential, adaptive randomization trial. Patients will have histologically or cytologically confirmed treatment-naive, advanced NSCLC, documented absence of EGFR and B-Raf mutations and ALK and ROS1 gene rearrangements, measurable disease per RECIST v1.1, and ECOG PS 0-1. Tumor tissue from patients will be initially screened for 2 validated, independent, next-generation biomarkers: T cell–inflamed gene expression profile (GEP) and tumor mutational burden (TMB). Based on results of biomarker screening, patients will be assigned to 1 of 4 groups: TMBlowGEPlow, TMBhighGEPlow, TMBlowGEPhigh, and TMBhighGEPhigh. Within each group, patients will be randomly assigned to receive pembrolizumab 200 mg Q3W intravenously (IV) combined with either MK-4280 200 mg Q3W (anti–LAG-3) IV or lenvatinib 20 mg orally once daily, with the randomization assignment adaptively modified based on interim efficacy analyses. Response will be assessed by imaging every 9 weeks for the first year and every 12 weeks thereafter using RECIST v1.1. Treatment will continue for 35 cycles (~2 years). Patients in the pembrolizumab + lenvatinib arm who complete 35 treatments may continue with lenvatinib monotherapy until disease progression or toxicity. Treatment arms may be terminated during the interim analysis due to safety, prespecified futility criteria, or both. Primary end point is investigator-assessed objective response rate (RECIST v1.1). Secondary end points are progression-free survival, overall survival, and safety. Recruitment and screening are ongoing in more than 8 countries. Clinical trial information: NCT03516981.

ARTIST 2: Interim results of a phase III trial involving adjuvant chemotherapy and/or chemoradiotherapy after D2-gastrectomy in stage II/III gastric cancer (GC).

4001 Background: Adjuvant chemotherapy and/or chemoradiotherapy have been the standard of care in GC for years, supported by randomized trials. We compared the efficacy of different chemotherapy regimens and chemoradiotherapy in patients with D2-resected, stage II/III, node-positive GC. Methods: From Feb 2013 through Nov 2018, we randomly assigned, in a 1:1:1 ratio, patients with pathologically-staged II or III, node-positive, D2-resected GC, to receive adjuvant S-1 (40-60 mg twice daily 4-weeks-on/2-weeks-off) for one year, S-1 (2-weeks-on/1-week-off) plus oxaliplatin 130 mg/m2 (SOX) for six months, or SOX plus chemoradiotherapy 45 Gy (SOXRT). Randomization was stratified according to the type of surgery (total or subtotal gastrectomy), stage (II or III), and Lauren histologic classification (diffuse or intestinal). The primary endpoint was disease-free survival (DFS). A total of 900 patients had to be enrolled to demonstrate superiority of SOX or SOXRT to S-1 (hazard ratio [HR] 0.667), with 90% power at a two-sided significance level of 5%. Results: A total of 538 patients were included for this interim efficacy analysis. Median age was 58 years, men constituted 65%, and stage II and III were 31% and 69%, respectively. Baseline tumor and patient characteristics were balanced between treatment arms. Adverse events were as anticipated in each arm, generally well-tolerated and manageable. DFS in the control arm (S-1) were significantly shorter than in SOX and SOXRT arms (stratified HR for recurrence): S-1 vs. SOX, 0.617 (P = 0.016) and S-1 vs. SOXRT, 0.686 (P = 0.057). The DFS at 3-years was found to be 65%, 78% and 73% in S-1, SOX and SOXRT arms, respectively. No difference in DFS between SOX and SOXRT was found (HR 0.910, P = 0.667). Based on the results after the observation of 145 recurrence events at the cutoff date of Dec 27, 2018, the independent data monitoring committee considered the results sufficient to meet the endpoint of the trial and recommended early stopping of the trial. Conclusions: In patients with curatively D2-resected, stage II/III, node-positive GC, adjuvant SOX or SOXRT was effective in prolonging DFS, when compared to S-1 monotherapy. Clinical trial information: NCT0176146.

Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3).

8503 Background: Small pilot studies (e.g., N Engl J Med. 2018;378:1976) have shown that preoperative immune checkpoint inhibitor therapy may be of benefit in early-stage NSCLC. This large multicenter trial assesses the benefit of neoadjuvant treatment with atezolizumab (atezo; NCT02927301). Methods: Patients (pts) with stages IB to selected IIIB resectable NSCLC receive 2 cycles of atezo 1200 mg (days 1, 22) then undergo resection (day 40 ± 10). Primary tumor +/- node biopsies and blood samples are obtained before atezo and at surgery for biomarker studies. The primary endpoint is major pathological response (MPR), defined as ≤ 10% viable tumor cells in the resection specimen. Secondary endpoints include safety and correlation of response with PD-L1 expression, tumor mutation burden (TMB) and gene expression signatures. Results: For this interim efficacy analysis (5 Sep 2018 data cut), we report on the first 101 of 180 planned pts: 47 males, median age, 64 y; all ECOG PS 0-1; 23 current and 68 former smokers; 66 non-squamous NSCLC; clinical stages IB/IIA/IIB/IIIA/IIIB n = 11/16/28/39/7. There were 2 treatment-unrelated Gr 5 AEs (cardiac death post surgical resection; death due to disease progression), 29 Gr 3-4 AEs (6 [6%] treatment related). 90 pts had surgery. Excluding 8 pts who had driver mutations (7 EGFR, 1 ALK, no MPR), MPR rate was 15/82 (18%, 95% CI 11%-28%), 4 pts had pathological complete response (pCR). By RECIST, 6/82 pts had PR, 72 had SD and 4 had PD. Two of 26 (8%) PD-L1− (TC0 and IC0, clone SP142) and 10 of 35 (29%) PD-L1+ had MPR ( P= 0.055). Five of 44 (11%) TPS < 50 (PD-L1 clone 22C3) and 7 of 20 (35%) TPS > 50 had MPR ( P= 0.040). Exome sequencing data was available for 47/101 pts. Median TMB was 10.4 (range, 1.5-46.5) mutations per Mb and was not different in those with MPR compared with those without MPR. Further analysis of TMB, mutation signatures, and gene expression profiling is ongoing. Conclusions: Atezo in the neoadjuvant setting was well tolerated, and pCR and MPR rates are encouraging in this large multicenter trial. Efficacy interim analysis passed its futility boundary, and study enrollment continues. Safety, efficacy results and ongoing correlative analyses will be presented. Clinical trial information: NCT02927301.

Efficacy and safety of bioresorbable vascular scaffold Absorb: 6-month outcomes of GABI-R: Russia registry

Aim. The paper demonstrates the interim analysis of efficacy and safety after everolimus-eluting bioresorbable vascular scaffold (BVS) Absorb implantation in “real-world patients” with coronary artery disease.Methods. A cohort of 500 consecutive patients who underwent percutaneous coronary intervention for stable chest pain or acute coronary syndrome with implantation of at least one BVS (Absorb, Abbott Vascular) and followed up by telephone interview and review of medical charts were included in a singlecenter, prospective, all-comers, first in Russia registry. The primary endpoint, target vessel failure, defined as the combination of cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization and secondary endpoints, MACCE (composite of cardiovascular death, myocardial infarction, coronary artery bypass surgery, target vessel revascularization, stroke) and stent thrombosis, were assessed during 6-month follow-up.Results. A total of 500 patients with coronary artery disease (CAD) (stable CAD 54.4%, acute coronary syndrome 45.6%) and different amount of affected vessels (1 vessel CAD 40.8%, n = 204; 2-vessel CAD 32.8%, n = 164; 3-vessel CAD 26.4%, n = 132) received 664 scaffolds and 55 stents in 603 stenoses. Procedure success, defined as a residual stenosis less than 30% and TIMI 3 flow in target vessel at the end of procedure, was observed in 98.51% (n = 594). At the moment of 6-month follow-up 4.2% (n = 24) of patients were lost to contact. After 6 months, incidence of target vessel failure and MACCE was 4.2% (n = 21) and 5% (n = 25). The cumulative rate of definite/probable scaffold thrombosis was 1.6% (n = 8).Conclusion. The interim analysis of Gabi-R: Russia registry, the largest trial of BVS Absorb implantation in routine clinical practice, showed high procedural success and low incidence of adverse events during follow-up. However, a tendency to high incidence of scaffold thrombosis compared to drug-eluting stents can be observed. Considering the long-term results of randomized trials retrospective registries, safety in terms of BVS routine use is of big concern. Longterm 24-month data regarding safety endpoints are required to test the afore-mentioned suggestion. Received 5 January 2019. Revised 28 March 2019. Accepted 29 March 2019.Funding: The study did not have sponsorship.Conflict of interest: Authors declare no conflict of interest.

Cisplatin and 5-Fluorouracil with or Without Epidermal Growth Factor Receptor Inhibition Panitumumab for Patients with Non-Resectable, Advanced or Metastatic Esophageal Squamous Cell Cancer: A Prospective, Open-Label, Randomised Phase 3 AIO/EORTC Trial (Power)

Background: Advanced unresectable esophageal squamous cell cancer (ESCC) is treated with palliative chemotherapy of cisplatin and 5-fluorouracil (CF). Targeting epidermal growth factor receptor (EGFR) with antibodies panitumumab (P) or cetuximab with chemotherapy enhanced overall survival (OS) in metastatic colorectal cancer or squamous cell cancer of head and neck. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in confirmed advanced ESCC. Methods: 146 patients, not curatively resectable and not qualified for definitive radio-chemotherapy were randomised 1:1 to CF (cisplatin [100 mg/m² i.v., day 1] and 5-fluorouracil [1000 mg/m²/day i.v., days 1-4]), versus CF plus P [9 mg/kg, i.v., day 1], each q3-week cycle) until progressive disease or inacceptable toxicity. Safety was reviewed by a pre-planned Monitoring Board after 40, 70 and 100 patients completing at least one cycle. After 53 patients enrolled, cisplatin was amended from 100 to 80 mg/m². Findings: The academic phase 3 trial was terminated early for futility on an interim efficacy analysis: median OS favoured CF over CFP, regardless of cisplatin dose (HR 1·77, 95%CI 1·06-2·98; p=0·028). In the final analysis, median OS was 10·2 vs 9·4 months for CF vs CFP, respectively (HR 1·17, 95%CI 0·79-1·75; p=0·43). Most deaths were related to disease progression, 44 (56·4%) in CF and 34 (43·6%) in CFP. Objective responses (27/73 [37·0%]) were identical in both arms. Most common severe adverse events were kidney injury (3 [4·3%] vs 7 [9·7%]), general deterioration (5 [7·1%] vs 5 [6·9%]), and dysphagia (4 [5·7%] vs 4 [5·6%]) in CF vs CFP, respectively. High levels of soluble (s)EGFR were associated with worse PFS. sEGFR was induced under CFP. Interpretation: Cisplatin/5-fluorouracil is an established palliative regimen in unselected advanced or metastatic ESCC patients. EGFR inhibition added to CF did not improve survival. Biomarker results support further liquid biomarker studies. Trial Registration Number: The study is registered with ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15). Funding: The trial was funded by AIO-Studien-gGmbH. Partial financial support and panitumumab were provided by Amgen Inc. Declaration of Interest: MM has travel support and advisory role for Amgen. FL reports personal fees from Amgen. All other authors declare that they have no conflicts of interest during the conduct of the study. Ethical Approval: The clinical study protocol was reviewed and approved by the responsible ethics committees of all participating sites. The trial was conducted in accordance with the principles of the International Conference on Harmonisation on Good Clinical Practice. All patients gave written informed consent before enrolment and any trial-specific procedures.

PS-193-Phase 2 open-label study with a placebo-controlled drug withdrawal period of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with Alagille Syndrome: 48-week interim efficacy analysis

PS-193-Phase 2 open-label study with a placebo-controlled drug withdrawal period of the apical sodium-dependent bile acid transporter inhibitor maralixibat in children with Alagille Syndrome: 48-week interim efficacy analysis

Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results

BackgroundSince 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice. We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016. MethodsChildren and adults with LGS/DS taking stable doses of antiepileptic drugs (AEDs) at baseline were included from 25 EAP sites across the United States. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received a pharmaceutical formulation of highly purified CBD (Epidiolex®; 100 mg/mL) in oral solution at 2–10 mg/kg/day, titrated until tolerability limit or a maximum dose of 25–50 mg/kg/day. Patient visits were every 2–4 weeks. The percentage change from baseline in median monthly convulsive (ie, major motor) and total seizures was evaluated at 12-week intervals through 96 weeks. The percentages of patients who had ≥50%, ≥75%, and 100% reduction in monthly seizures relative to the baseline period were also evaluated. Adverse events (AEs) were monitored and summarized for the safety analysis set (SAS) through 144 weeks. ResultsOf the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0–10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1–146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with ≥50%, ≥75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile; the most common AEs were somnolence (30%) and diarrhea (24%). ConclusionsResults from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.

CheckMate 384: Phase IIIb/IV trial of nivolumab (nivo) 480 mg Q4W versus 240 mg Q2W after ≤ 12 months of nivo in previously treated advanced NSCLC.

100 Background: Nivo is approved as 240 mg Q2W in the EU and Japan and 240 mg Q2W or 480 mg Q4W in the US and Canada for second-line treatment (tx) of advanced NSCLC. Pharmacokinetic modeling in various tumors predicts that exposure, efficacy and safety can be maintained with less frequent Q4W dosing, which may provide a more convenient tx option. We present an interim analysis of efficacy and safety from CheckMate 384 (NCT02713867), an international, open-label, randomized phase 3b/4 trial evaluating less frequent nivo dosing (480 mg Q4W vs 240 mg Q2W) in patients (pts) with advanced NSCLC and prior Q2W nivo tx. Methods: Pts (N = 329) with previously treated histologically confirmed stage IIIB/IV or recurrent NSCLC, ECOG performance status 0–2, and prior tx with nivo 3 mg/kg or 240 mg Q2W for ≤12 mo, with ≥2 consecutive assessments of complete / partial response or stable disease, were randomized 1:1 to nivo 480 mg Q4W or 240 mg Q2W over a 30-min infusion. Co-primary endpoints: post-randomization (RND) progression-free survival rates (PFS) at 6 mo and 1 y. Secondary endpoints included safety. Due to tx landscape changes in NSCLC, statistical analyses were amended for a reduced sample size. One-sided 95% CIs were generated to compare PFS rates; presented data analyses are descriptive. Results: Of 166 and 163 pts randomized to 480 mg Q4W and 240 mg Q2W, 164 and 161 pts were treated, respectively. Median follow-up was 9.5 mo (480 mg Q4W) and 10.2 mo (240 mg Q2W). Baseline characteristics were balanced between tx arms. Stratified PFS rates post-RND were comparable between tx arms at 6 mo and 1 y (Table). Safety profiles were similar; any grade tx-related adverse events (TRAEs) and TRAEs leading to discontinuation were reported in 48% vs 61% and 6% vs 9% of pts with 480 mg Q4W vs 240 mg Q2W. No tx-related deaths were reported. Conclusions: Nivo 480 mg Q4W showed similar efficacy and safety to 240 mg Q2W in pts with disease control on nivo, supporting the potential use of 480 mg Q4W as a more convenient dosing option for second-line NSCLC tx. Clinical trial information: NCT02713867. [Table: see text]

TALAPRO-1: An open-label, response rate phase II study of talazoparib (TALA) in men with DNA damage repair (DDR) defects and metastatic castration-resistant prostate cancer (mCRPC) who previously received taxane-based chemotherapy (CT) and progressed on greater than or equal to one novel hormonal therapy (NHT).

TPS342 Background: There are no approved therapies for mCRPC that has progressed on taxane and NHT. Preclinical studies showed that DDR-positive prostate tumors may be sensitized to PARP inhibition. TALA inhibits PARP, causing cell death in BRCA1/2-mutated cells. Methods: This study (NCT03148795) is enrolling patients (pts) (N ≈ 100) with measurable soft tissue disease per RECIST v1.1, progressive mCRPC, DDR likely to sensitize to PARP inhibition, ECOG performance status ≤ 2, and no brain metastases, who received 1-2 CT regimens (including ≥ 1 taxane-based CT) and progressed on ≥ 1 NHT (enzalutamide/abiraterone acetate). Prior use of PARP inhibitors, cyclophosphamide, mitoxantrone, or platinum-based CT ≤ 6 mos before study or progression on a platinum-based CT at any time are excluded. Pts will receive TALA 1 mg/d orally (pts with moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or withdrawal of consent. TALA should not be discontinued based on increased prostate specific antigen (PSA) or circulating tumor cell (CTC) count alone. Primary endpoint is best objective response (OR) rate (complete/partial soft tissue response; exact 2-sided 95% confidence interval). Responses must be confirmed ≥ 4 wks later by computed tomography/magnetic resonance imaging with no evidence of bone progression ≥ 6 wks later per PCWG3 criteria. Secondary endpoints include time to OR, duration of response, PSA decrease ≥ 50%, CTC count conversion (to CTC = 0 and < 5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival, overall survival, safety, pt-reported outcomes, and pharmacokinetics of TALA. Efficacy will be assessed every 8 wks for the first 24 wks, then every 12 wks thereafter. An initial safety and efficacy analysis will be performed on 20 pts after ≥ 8 wks of treatment. An interim efficacy analysis is planned when 60 pts have completed ≥ 6 mos of treatment. This study was sponsored by Pfizer Inc. Previously presented at ESMO 2018, FPN 859TiP, De Bono JS et al. Reused with permission. Clinical trial information: NCT03148795.

Abstract P1-11-10: Efficacy of NEPA as antiemetic prophylaxis in breast cancer patients receiving highly or moderately emetogenic chemotherapy – Interim results of a German prospective, non-interventional study

Abstract Background The oral fixed dose combination of netupitant and palonosetron NEPA has been approved for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) in cancer patients receiving cisplatin-based highly emetogenic (HEC) or moderately emetogenic chemotherapy (MEC). The primary objective of the prospective, non-interventional study (NIS) AkyPRO is the evaluation of quality of life in adults receiving MEC or HEC and NEPA for CINV prevention. Secondary endpoints are efficacy and safety of NEPA. Here we present an interim analysis of NEPA efficacy in the subgroup of breast cancer patients, who represent the largest subgroup (66%) of enrolled patients. Since September 2015, 2427 patients have been enrolled, of whom 986 are breast cancer patients. Methods The NIS has been designed to evaluate NEPA in 2,500 cancer patients receiving single day or two day MEC or HEC. QoL is recorded by FLIE questionnaires. Efficacy (complete response (CR, no vomiting, no rescue medication)), additional medication, and adverse events are recorded in patient diaries over three consecutive chemotherapy cycles. Additionally, physicians report their efficacy assessments of NEPA online, using an eCRF. Results At the cut-off date November 11, 2017, 2427 patients had been enrolled in the study. For the interim analysis 986 breast cancer patients were evaluated who had been fully documented in the eCRF at the cut-off date. 95% had an ECOG performance status of 0 or 1. 51% received adjuvant, 44% neoadjuvant, and 5% palliative chemotherapy. 80% of patients received HEC, mostly (79%) anthracycline/cyclophosphamide (AC) combinations. Of the women receiving MEC, the majority were treated with carboplatin-based regimens (9%). 7% of patients received other MEC regimens. 81.4-82.8 % of patients reported CR in cycles 1-3 and more than 93% of patients reported no emesis during the 3 treatment cycles covered in the patient diaries. No significant nausea was reported by 62.7-64.2% of patients. Physicians rated the efficacy of the antiemetic prophylaxis with NEPA using the 4 categories very good, good, satisfactory, and poor. In cycles 1 and 2, more than 89% of physicians rated the efficacy of NEPA very good or good. In cycle 3, 90.6% rated it very good or good. In addition to reporting CR, nausea and emesis episodes in their patient diaries, patients used the same 4 categories to assess the efficacy of NEPA at the end of each treatment cycle. Efficacy assessments of physicians and patients were very similar, with 87% of patients choosing very good or good in cycle 1 compared to 89% of physicians. NEPA was well tolerated. Low-grade constipation (14.9%) and insomnia (8.3%) were the most frequent treatment-related adverse event. Conclusion In this real life study, NEPA was effective in the prevention of CINV in the subgroup of breast cancer patients receiving HEC or MEC. The efficacy assessments by patients and physicians were comparable, with approximately 90% good or very good efficacy for 3 consecutive cycles. More than 93% of patients reported no emesis and more than 81% reported CR during the 5 days post-chemotherapy during all 3 cycles. The study is ongoing. Citation Format: Schilling J, Hielscher C, Hanusch C, Kurbacher C, Busch S, Karthaus M. Efficacy of NEPA as antiemetic prophylaxis in breast cancer patients receiving highly or moderately emetogenic chemotherapy – Interim results of a German prospective, non-interventional study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-11-10.

Abstract P6-17-06: Characterization, monitoring and management of interstitial lung disease in patients with metastatic breast cancer: Analysis of data available from multiple studies of DS-8201a, a HER2-targeted antibody drug conjugate with a topoisomerase I inhibitor payload

Abstract Background: Several classes of anti-cancer agents including certain immunotherapies, systemic chemotherapies, and targeted therapies including trastuzumab and T-DM1 increase the risk of interstitial lung disease (ILD) and fatal cases have been reported. For DS-8201a, interim efficacy and safety analyses of available data established a final recommended dose of 5.4 mg/kg IV q3wk in advanced HER2-positive breast cancer (BC). Based on preliminary clinical results, ILD was identified as an important risk for DS-8201a. A robust monitoring and management plan was established across all studies and an international, independent ILD adjudication committee (AC) reviews the cases reported as ILD on an ongoing basis. Methods: All subjects (sbj) who received ≥1 dose of DS-8201a across 7 ongoing studies were included in this analysis. Reported ILD (standardized MedDRA Query terms) included the terms ILD, pneumonitis, and organizing pneumonia. ILD frequencies were calculated based on investigator's assessment and after adjudication. The analysis of potential risk factors associated with ILD is ongoing. Results: As of 21 June 2018, 448 sbj received ≥1 dose of DS-8201a across multiple tumor types, including BC. Of the 321 sbj with BC, 173 (53.9%) were from Japan, 103 (32.1%) from the US, and 45 (14.0%) from 6 other countries (Spain, South Korea, Taiwan, Belgium, France, and Italy). These sbj received 1 of 7 doses of DS-8201a (0.8 mg/kg: 3 sbjs, 1.6 mg/kg: 1 sbj, 3.2 mg/kg: 3 sbjs, 5.4 mg/kg: 111 sbjs, 6.4 mg/kg: 178 sbj, 7.4 mg/kg: 20 sbj, 8.0 mg/kg: 5 sbj). Overall, 44 cases of potential ILD were reported by the investigators across all tumor types (44/448, 9.8%; Grade ≥3 10/448, 2.2%). In sbj with BC who received 5.4 mg/kg, any grade and Grade ≥3 investigator-reported ILD were 7.2% (8/111) and 0.9% (1/111), respectively. The ILD AC assessed 30 of 44 cases; 22 were considered drug-related ILD, 4 were ILD but not drug-related, and 4 were found not to be ILD. For adjudicated drug-related ILD cases, the median time to onset was 159 (range; 46-591) days from the time of first dose. Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 All Grades All tumors, All doses (N=448) Investigator-reported20 (4.5)14 (3.1)4 (0.9)1 (0.2)5 (1.1)44 (9.8)Cases adjudicated13840530Adjudicated as drug-related ILD9 (2.0)6 (1.3)3 (0.7)04 (0.9)22 (4.9) BC, All doses (N=321) Investigator-reported17 (5.3)11 (3.4)3 (0.9)1 (0.3)4 (1.2)36 (11.2)Cases adjudicated11830426Adjudicated as drug-related ILD8 (2.5)6 (1.9)3 (0.9)04 (1.2)21 (6.5) BC, 5.4 mg/kg (N=111) Investigator-reported4 (3.6)3 (2.7)001 (0.9)8 (7.2)Cases adjudicated120014Adjudicated as drug-related ILD00001 (0.9)1 (0.9)n (%), except where noted Conclusions: These analyses confirm that ILD is an important identified risk for DS-8201a. Further analyses are ongoing to better understand the potential risk factors associated with the incidence of on-treatment ILD. When ILD is suspected, early diagnosis through appropriate imaging, laboratory tests, and pulmonary consultation as well as prompt management with steroids are recommended. Citation Format: Powell CA, Camidge DR, Gemma A, Kusumoto M, Baba T, Kuwano K, Bankier A, Kiura K, Tamura K, Modi S, Tsurutani J, Doi T, Iwata H, Krop IE, Zhang L, Jasmeet S, Saito K, Shahidi J, Yver A, Takahashi S. Characterization, monitoring and management of interstitial lung disease in patients with metastatic breast cancer: Analysis of data available from multiple studies of DS-8201a, a HER2-targeted antibody drug conjugate with a topoisomerase I inhibitor payload [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-06.

A Study of Tbo-Filgrastim (Granix) to Disrupt the Bone Marrow Microenvironment in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation

Multiple myeloma is the second most common hematologic malignancy in the US. The current standard of care for transplant eligible patients is therapy with high-dose melphalan (HDM) followed by autologous stem cell transplant (ASCT). Although ASCT improves progression-free (PFS) and overall survival (OS), it is not curative and virtually all patients will relapse. Attempts to improve upon HDM by adding other agents to transplant protocols have largely resulted in unacceptable increases in toxicity.Preclinical studies performed by our group suggest that granulocyte-stimulating factor (G-CSF) disrupts the bone marrow microenvironment, resulting in a striking loss of plasmablasts, plasma cells, and decreased expression of chemokine/cytokines contributing to plasma cell maintenance. Tbo-filgrastim (Granix, Teva Pharmaceuticals) is a recombinant methionyl human granulocyte colony-stimulating factor. We hypothesized that tbo-filgrastim treatment may provide a potent and well-tolerated method to disrupt the ‘myeloma cell niche’, rendering patients more sensitive to HDM.Methods: Here, we report results from an open label, single center, phase II randomized study to test the efficacy and safety of tbo-filgrastim plus HDM (tbo-filgrastim arm) versus HDM alone (SOC arm) prior to ASCT (NCT02112045). Patients were randomized 1:1 to tbo-filgrastim on Day -7 through Day -2 (480 or 960 mcg/day, based on weight) and melphalan on Day -2 prior to ASCT (140 or 200 mg/m2, based on age) or melphalan alone. The primary objective was to compare CR rate at day 100. Secondary objectives included comparison of the toxicity, overall response rate, PFS, OS, and rate of neutrophil and platelet engraftment between the two arms. Eligible patients were ≥18 years with symptomatic multiple myeloma enrolled within 12 months of receiving at least 2 cycles of any systemic therapy, were undergoing their first ASCT, and had an adequate ASCT collection product (at least 2 million CD34+ cells/kg). Target enrollment was 176 patients, with an interim analysis of efficacy and futility planned after 88 patients reached Day 100 post-ASCT. Early stopping rules for unacceptable toxicity were in place. Responses were evaluated by IMWG criteria.Results: Ninety patients were enrolled (median age 59.5, range 33 to 77) and 89 were evaluable for response. The early stopping rules for toxicity were not met. The planned interim analysis showed that the proportion of patients in CR at Day 100 was similar between the arms and the study was halted for futility (39.5% on the tbo-filgrastim arm vs. 37.8% on SOC arm). The overall response rate (CR + VGPR + PR) between the tbo-filgrastim and the SOC arm was 95% vs 93%, respectively. At the interim analysis, with median follow-up time for the study of 21.7 months, (range 8.8 to 25.8), the median PFS and OS had not been reached for either arm. There was no difference in PFS between the tbo-filgrastim and the SOC arm (84% vs 80%, respectively, p=0.60). There was no difference in OS between the tbo-filgrastim and the SOC arm (90.9% vs 95.6%, respectively, p=0.43). All patients in the study achieved neutrophil (ANC > 0.5 K/cumm) and platelet (> 20 K/cumm) engraftment. The median time to neutrophil engraftment for the tbo-filgrastim arm was 5 days (range, 3-9) vs 4 days (range, 3-7) in the SOC arm, p<0.001. There was no difference in the median time to platelet engraftment between the arms (11 days in the tbo-filgrastim arm, range 2-23, and 10 days in the SOC arm, range 1-24, p=0.67). Adverse events for both arms were typical of those observed in the ASCT population.Conclusions: The administration of tbo-filgrastim in the setting of HDM prior to ASCT is feasible, without excess toxicity or loss of engraftment. There was no difference in Day +100 CR or ORR rates, PFS, or OS in patients treated with tbo-filgrastim plus HDM versus HDM alone with a median follow-up of 21.7 months. The lack of efficacy may be secondary to the high pre-ASCT response rates seen with modern agents. DisclosuresJacoby:Celgene: Speakers Bureau; NovoNordisk: Consultancy. Schroeder:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Vij:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Ixazomib, Thalidomide and Dexamethasone Is an Effective and Well Tolerated Re-Induction Regimen Leading to Salvage Autologous Stem Cell Transplantation (sASCT): Results from the Re-Induction Interim Analysis of UK-MRA Myeloma XII (ACCoRD) Trial

Ixazomib, Thalidomide and Dexamethasone Is an Effective and Well Tolerated Re-Induction Regimen Leading to Salvage Autologous Stem Cell Transplantation (sASCT): Results from the Re-Induction Interim Analysis of UK-MRA Myeloma XII (ACCoRD) Trial

A Phase II Study of Sequential Pembrolizumab (PEM) Followed By AVD for Frontline Treatment of Classical Hodgkin Lymphoma (CHL): Quantifying Response Following PEM Monotherapy with FDG-PET-Derived Metabolic Tumor Volume and Total Lesion Glycolysis

Background:Pembrolizumab (PEM), a PD-1 inhibitor, is US FDA approved for the treatment of relapsed/refractory cHL based on results of a pivotal trial demonstrating an overall response rate of 69% and complete response (CR) rate of 22%. We hypothesized that PEM monotherapy would result in a higher CR rate (50%) in previously untreated patients owing to greater immunocompetence. Consequently, we initiated a phase 2 clinical trial of upfront sequential PEM and AVD (Adriamycin, Vinblastine, Dacarbazine) chemotherapy. While several of the initial patients had dramatic responses to PEM x's 3 on PET2, they only met Lugano criteria for partial responses. In an attempt to better reflect and quantify the response to checkpoint inhibition, we amended our protocol to include additional analysis of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) which have been investigated as predictors of response in cHL and DLBCL. Herein, we report an interim analysis of toxicity and efficacy, measured by Deauville score, MTV and TLG in the first 13 patients to complete PEM monotherapy.Methods:Patients ≥ 18 years of age with newly diagnosed cHL stages I-IV, including unfavorable early stage disease with at least one risk factor according to the NCCN criteria, were eligible. Patients had a pre-therapy PET-CT, followed by 3 cycles of PEM at 200 mg every 3 weeks and interim PET-CT (PET2) after single agent PEM for primary analysis. Subsequently, patients received 4-6 cycles of AVD chemotherapy based on initial stage. MTV representing the total volume of the metabolically active tumor in a volume of interest (VOI) was calculated using the fixed 41% SUVmax threshold corresponding to the dimensions of the tumor. TLG, combining the volumetric and metabolic information of FDG-PET, was calculated by multiplying the SUVmean of the segmented VOI and the MTV. These measurements were performed using SyngoVia software, Multi-foci segmentation tool (Siemens). Blinded central review of the visually assessed Deauville score was performed, and if different from the report by one of four nuclear medicine radiologists, a second central review was performed to adjudicate. Correlative studies include serum and biopsy samples pre/post PEM to assess immune biomarkers of response.Results:Fifteen patients were enrolled from September 2017, through a data cut off of July 10, 2018, at Northwestern University. Thirteen patients have completed lead-in PEM monotherapy and have undergone PET2. Median age was 30 years (range, 23-77). Eight patients had unfavorable early stage disease and 7 had advanced stage. Early stage risk factors included bulky disease (n=8), B-symptoms (n=5), and elevated ESR (n=5). Overall, therapy was well tolerated. Grade 3 events included lymphopenia (n=1) and diarrhea (n=1). Only one grade 4 immune-related adverse event (transaminitis) occurred, which resolved with steroid therapy and a delay in therapy. PET2 was scored as Deauville 2 or 3 in six cases including three with large mediastinal masses, and as D 4 or 5 in 7 cases with residual activity (Figure 1). PET2 MTV and TLG could be calculated for 12 of 13 cases, (MTV: 42 - 774 cm2, median 134 cm2; TLG: 257 - 5924; median 814). All 12 patients who completed a subsequent scan (PET3) after 2 cycles of AVD are now in a metabolic CR (Deauville 1-3), including all 7 cases with residual activity after PET2.Conclusion: These interim data suggest that upfront PEM x's 3 is highly active in previously untreated cHL. PEM monotherapy resulted in complete metabolic responses in some patients including those with large mediastinal masses, and near complete responses, best represented by the decline in MTV and TLG compared with Deauville scores or Lugano criteria. Our preliminary data suggest that MTV and TLG are useful additional interim indicators of biologic activity when assessing response after PD-1 inhibitor therapy. [Display omitted] DisclosuresAllen:Merck: Research Funding; Bayer: Consultancy. Evens:Bayer: Consultancy; Janssen: Consultancy; Affimed: Consultancy; Novartis: Consultancy; Tesaro: Research Funding; Abbvie: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees. Pro:kiowa: Honoraria; Takeda Pharmaceuticals: Honoraria, Other: Travel expenses; portola: Honoraria; Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding. Advani:Millenium: Other: Institutional Research Support; Merck: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Agensys: Other: Institutional Research Support; Takeda: Other: Consultancy/Advisory Role; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Kyowa: Other: Consulting/Advisory Role; Janssen Pharmaceutical: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; AstraZeneca: Other: Consultancy/Advisory Role; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Infinity: Other: Institutional Research Support. Winter:Merck: Honoraria, Research Funding.

Reducing overestimation of the treatment effect by interim analysis when designing clinical trials.

Several researchers in the statistical and medical communities have noted the overestimation of the treatment effect when a trial is stopped early in the interim analysis for efficacy; however, methods to reduce this overestimation are rarely used because the overestimation mechanisms are not well understood by many in clinical trial practice. A trial design that leads to less overestimation is needed. A computer simulation of hypothetical clinical trials is used to visually explain why the overestimation occurs. A quantitative evaluation of the magnitude of the overestimation is made according to the characteristics of the trial design, such as the total number of events, number of events in the interim analysis, proportion of the number of events to total events and the type of α-spending function. When the total number of events was more than or equal to 300 and the proportion of the interim events was larger than 50%, the overestimation was acceptable. Moreover, even if the total number of events was 150, the overestimation was sufficiently small when the proportion of the interim events was >70% and a Pocock type α-spending function was used. The overestimation decreased when the total number of events and the proportion of the number of events in the interim analysis increased. In addition, the overestimation of the Pocock type α-spending function was smaller in comparison with that of the O'Brien-Fleming type, which is widely accepted for confirmatory trials. We recommend setting the proportion of events in the interim analysis at 50% when the O'Brien-Fleming type α-spending function is used in confirmatory trials to reduce the risk of overestimation. In contrast, the Pocock type boundary could be used in explanatory trials.

730P - A pilot study of gemcitabine, nab-paclitaxel, PEGPH20 (PAG) and rivaroxaban for advanced pancreatic adenocarcinoma: Interim safety and efficacy analysis

Background: PEGPH20 (P) degrades hyaluronan (HA), a key component of pancreatic adenocarcinoma (PDAC) tumor microenvironment, leading to reduction of tumor interstitial pressure, decompression of tumor blood vessels and improvement in delivery of chemotherapeutics. A prior study of P with chemotherapy in PDAC (HALO-202) found an increased risk of thromboembolic (TE) events, 43%, effectively reduced with enoxaparin prophylaxis. Rivaroxaban (R) is a safe and effective oral anticoagulant for treating cancer-related TE. Methods: Patients considering frontline therapy for advanced PDAC and with KPS ≥ 70 were studied. 28 patients without prior TE (cohort 1) and 14/28 planned patients with prior TE (cohort 2) were enrolled. Patients received treatment with PAG (P; 3 µg/kg IV 2x/wk x 3 wks in C1, then 1x/wk x 3 wks in C2+, plus standard dose and schedule nab-paclitaxel and gemcitabine (AG)) every 28 days, with R (15 mg twice daily for 21 days, followed by 20 mg once daily). Primary endpoint is TE event rate. Secondary endpoints include PFS, OS, major bleeding rate and RR. Results: All 42 patients are evaluable for efficacy and safety. Key patient characteristics: median age = 61, M/F 22/20, stage III/IV 5/37. Median follow-up is 10.9 mo. One (2.4%) grade 4 TE event occurred. Two grade 3 GI hemorrhages occurred, both resolved with supportive measures. Best responses: complete response 2 (4.8%), partial response 19 (45.2%), stable disease 15 (35.7%), progressive disease 2 (4.8%), and overall disease control rate of 85.7%. Median PFS is 7.0 mo, mOS has not been reached. Safety and efficacy are similar across both cohorts (see Table).Table: 730PVariableCohort 1Cohort 2OverallSafetyn = 28n = 14n = 42TE Events1 (3.6%)0 (0%)1 (2.4%)Major Bleeding2 (7.1%)0 (0%)2 (4.8%)EfficacyComplete Response1 (3.6%)1 (7.1%)2 (4.8%)Partial Response14 (50.0%)5 (35.7%)19 (45.2%)Stable Disease8 (28.6%)7 (50.0%)15 (35.7%)Progressive Disease2 (7.1%)0 (0%)2 (4.8%)Not Evaluable3 (10.7%)1 (7.1%)4 (9.5%)PFS6.0 mo8.0 mo7.0 moOSNot ReachedNot ReachedNot Reached Open table in a new tab Conclusions: Interim analysis shows R is safe and effectively prevents TE events in patients receiving PAG. Responses and disease control rate are encouraging in this tumor HA-level unselected patient population. Updated safety and efficacy data will be reported. Clinical trial identification: NCT02921022. Legal entity responsible for the study: Memorial Sloan Kettering Cancer Center. Funding: Halozyme Therapeutics, Inc. Disclosure: All authors have declared no conflicts of interest.

NEW THERAPEUTIC APPROACHES AND THEIR READOUT: O.19First-in-human intrathecal gene transfer study for giant axonal neuropathy: review of safety, immunologic responses and interim analysis of efficacy

Giant axonal neuropathy (GAN) is a rare childhood onset neurodegenerative disorder of the peripheral and central nervous system. Recessive GAN mutations cause loss of function of gigaxonin, a cytoskeletal regulatory protein, leading to progressive sensorimotor and optic neuropathy, CNS involvement and respiratory failure. We report on a single site, phase I, non-randomized, open label dose escalation gene transfer study for GAN (NCT02362438), a first-in-human intrathecal (IT) AAV9 mediated gene transfer trial for any indication. 9 GAN patients have been dosed at three dose levels (ranging from 3.5 × 1013vg to 1.8 × 1014vg) with scAAV9-JeT-GAN, with up to 2 year post-gene transfer follow up. We review safety and immunologic response to the gene vector and transgene (serum and CSF AAV9 neutralizing antibody titers, interferon-γ ELISpot analysis to GAN and AAV9 epitopes, CSF and peripheral cytokine analysis and white blood cell flow cytometry), and present an interim efficacy analysis. GAN natural history study data is used for comparison of outcome measures which include: Motor function measure 32 (MFM32), Neuropathy impairment score (NIS), Friedreich's Ataxia rating scale (FARS), myometry, grip and pinch strength, timed testing, electrophysiology, and neuroimaging. We highlight the overall safety and feasibility of an intrathecal route of AAV9 based gene transfer. The efficacy interim analysis highlights several key aspects: Feasibility for adequately targeting the nervous system, preferred IT dosing regimens needed for effective transduction, relevance of baseline neurologic impairment and disease progression in patient selection and stratification. This data also provides insight into the immunological implications of gene transfer with concomitant immunosuppressive regimens and their impact on AAV9 gene transfer safety and efficacy. This study is a proof of concept for IT gene transfer as a strategy for gene replacement targeting the central nervous system.

Treatment and secondary prophylaxis with ethanol lock therapy for central line-associated bloodstream infection in paediatric cancer: a randomised, double-blind, controlled trial

Central line-associated bloodstream infections (CLABSIs) affect about 25% of children with cancer, and treatment failure is common. Adjunctive ethanol lock therapy might prevent treatment failure but high-quality evidence is scarce. We evaluated ethanol lock therapy as treatment and secondary prophylaxis for CLABSI in children with cancer or haematological disorders. This randomised, double-blind, placebo-controlled superiority trial, with two interim futility and efficacy analyses (done when the first 46 and 92 evaluable participants completed study requirements), was done at two paediatric hospitals in the USA and Australia. Patients aged 6 months to 24 years, inclusive, with cancer or a haematological disorder and new CLABSI were eligible. Participants were randomly assigned (1:1) to receive either ethanol lock therapy (70% ethanol) or placebo (heparinised saline) for 2-4 h per lumen daily for 5 days (treatment phase), then for up to 3 non-consecutive days per week for 24 weeks (prophylaxis phase). The primary composite outcome was treatment failure, consisting of attributable catheter removal or death, new or persistent (>72 h) infection, or additional lock therapy during the treatment phase, and recurrent CLABSI during the prophylaxis phase. This trial is registered with ClinicalTrials.gov, number NCT01472965. 94 evaluable participants were enrolled between Dec 14, 2011, and Sept 12, 2016, of whom 48 received ethanol lock therapy and 46 received placebo. The study met futility criteria at the second interim analysis. Treatment failure was similar with ethanol lock therapy (21 [44%] of 48) and placebo (20 [43%] of 46; relative risk [RR] 1·0, 95% CI 0·6-1·6; p=0·98). Some adverse events, including infusion reactions and catheter occlusion, were more frequent in the ethanol lock therapy group than in the placebo group. Catheter occlusion requiring thrombolytic therapy was more common with ethanol lock therapy (28 [58%] of 48) than with placebo (15 [33%] of 46; RR 1·8, 95% CI 1·1-2·9; p=0·012). Discontinuation of lock therapy because of adverse effects or patient request occurred in a similar proportion of participants in the ethanol lock therapy (nine [19%] of 48) and placebo groups (ten [22%] of 46; p=0·72). Ethanol lock therapy did not prevent CLABSI treatment failure and it increased catheter occlusion. Routine ethanol lock therapy for treatment or secondary prophylaxis is not recommended in this population. American Lebanese Syrian Associated Charities to St Jude Children's Research Hospital and an Australian Government Research Training Scholarship.

Phase II Study of Brentuximab Vedotin Plus Ibrutinib for Patients with Relapsed/Refractory Hodgkin Lymphoma

Background:Brentuximab vedotin (BV), an antibody drug conjugate (ADC), selectively delivers anti-tubulin agent monomethyl auristatin E (MMAE) to CD 30+ cells. In a a multi-center phase II trial in patients with relapsed/refractory Hodgkin lymphoma (HL), BV showed an overall response rate (ORR) of 75%, a complete response (CR) rate of 34%, and a median duration of response (DOR) of 6.7 months (Younes A et al, JCO 2012). Although this drug has high ORR in HL, the CR rate and the DOR can be improved.Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has demonstrated antitumor activity in B-cell lymphomas. Ibrutinib is also an irreversible inhibitor of interleukin-2-inducible kinase (ITK), which has a critical role in T cell signaling. Inhibition of ITK leads to increased Th1 based immune response (Dubovsky JA, Blood 2013). As a single agent at standard dose, ibrutinib does not have antitumor activity in HL cell line (Figure 1). However, we have shown that standard dose ibrutinib is synergistic with BV in L428, a HL cell line (Figure 1). Based on our preclinical model, we hypothesize that ibrutinib may enhance the antitumor activity of BV in HL patients. It is also possible Ibrutinib may enchance the activity of BV through ITK inhibition of T cells in the HL microenvironment. Thus we designed and conducted a phase II trial using the combination of ibrutinib plus BV in patients with R/R HL. We report the planned interim analysis of efficacy and safety.Patients and Methods:This is a prospective, multicenter phase II trial with a 3-patient lead-in cohort in patients with relapsed/refractory HL. All patients must be > 15 years old and have biopsy proven relapsed/refractory HL. Patients are treated with 1.8 mg/kg of BV intravenously every 3 weeks and ibrutinib 560 mg PO daily (420 mg PO daily in the lead-in cohort). Patients could have received prior BV. The primary endpoint was the CR rate according to Lugano 2014. Secondary endpoints were toxicities, ORR, duration of response, and, BTK/ITK receptor occupancy, and changes in T/B/NK cell subsets in peripheral blood.Results:Sixteen out of 39 patients were accrued thus far, all 16 pts were evaluable for toxicity, and 13 patients were evaluable for efficacy (3 lead-in pts excluded). The baseline characteristics (Figure 1) are: male (56%), Caucasian (75%), median age of 33 (17-69), stage III/IV at diagnosis (50%), primary refractory to induction (50%), refractory to last therapy (37%), and 4 patients had prior BV (25%). The overall best response (CR+PR) rate was 69%, CR rate was 46%, stable disease rate was 31%, and no progressive disease (PD) was seen. The disease control rate (CR+PR+SD) was 100%. One patient who was refractory to prior BV achieved a PR, and an additional patient who had a previous best response of PR to BV now achieved a CR.Treatment was well tolerated. There were no Grade 4 events. Grade 3 possibly-related toxicities included neutropenia (n=2) and hypokalemia (n=1). Grade I/II possibly related toxicities >20% included diarrhea (n=8, 7 grade 1), nausea (n=6, all grade 1), fatigue (n=5, all grade 1), rash (n=5, 4 grade 1), and thrombocytopenia (n=4, all grade 1).Conclusion:The combination of BV + ibrutinib is well tolerated. Although the ORR of 69% maybe similar to BV alone, the CR of 46% and disease control rate of 100% appears promising. Especially encouraging is the 1 PR and 1 CR seen in patients previously exposed to BV. The study has met the interim analysis endpoint and warrants further accrual to investigate the final CR rate. [Display omitted] DisclosuresChen:Pfizer: Consultancy; Merck: Consultancy, Speakers Bureau; Genentech: Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Affimed: Research Funding; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Herrera:Seattle Genetics: Research Funding; Merck: Consultancy; Genentech: Consultancy; BMS: Consultancy; Pharmacyclics: Consultancy. Kwak:Pepromene Bio: Consultancy, Equity Ownership; Celltrion, Inc: Consultancy; InnoLifes: Consultancy, Equity Ownership.

Choice of futility boundaries for group sequential designs with two endpoints

BackgroundIn clinical trials, the opportunity for an early stop during an interim analysis (either for efficacy or for futility) may relevantly save time and financial resources. This is especially important, if the planning assumptions required for power calculation are based on a low level of evidence. For example, when including two primary endpoints in the confirmatory analysis, the power of the trial depends on the effects of both endpoints and on their correlation. Assessing the feasibility of such a trial is therefore difficult, as the number of parameter assumptions to be correctly specified is large. For this reason, so-called ‘group sequential designs’ are of particular importance in this setting. Whereas the choice of adequate boundaries to stop a trial early for efficacy has been broadly discussed in the literature, the choice of optimal futility boundaries has not been investigated so far, although this may have serious consequences with respect to performance characteristics.MethodsIn this work, we propose a general method to construct ‘optimal’ futility boundaries according to predefined criteria. Further, we present three different group sequential designs for two endpoints applying these futility boundaries. Our methods are illustrated by a real clinical trial example and by Monte-Carlo simulations.ResultsBy construction, the provided method of choosing futility boundaries maximizes the probability to correctly stop in case of small or opposite effects while limiting the power loss and the probability of stopping the study ‘wrongly’. Our results clearly demonstrate the benefit of using such ‘optimal’ futility boundaries, especially compared to futility boundaries commonly applied in practice.ConclusionsAs the properties of futility boundaries are often not considered in practice and unfavorably chosen futility boundaries may imply bad properties of the study design, we recommend assessing the performance of these boundaries according to the criteria proposed in here.