Three-week Cycle Research Articles

Multimodal Treatment of Primary Advanced Ovarian Cancer.

Epithelial ovarian cancer is the second most common malignancy of the female genital tract, with approximately 7,400 new cases annually in Germany. With 5,500 deaths per year, ovarian cancer is the leading gynecologic cause of death. Epithelial ovarian cancer is characterized by morphologic heterogeneity with 4 molecular biological subtypes (immunoreactive-like, differentiated-like, proliferative-like, mesenchymal-like) with different prognosis. Significantly improved survival is achieved by optimal debulking with no residual disease (R0). Systematic lymphonodectomy of clinical negative lymph nodes has no effect on overall survival in advanced ovarian cancer. Interval debulking in advanced ovarian cancer after three cycles of neoadjuvant chemotherapy with carboplatin/paclitaxel is controversial. Standard chemotherapy for advanced ovarian cancer consists of six cycles of carboplatin AUC5 and paclitaxel 175 mg/m2, in a three-week cycle. Intraperitoneal chemotherapy is not a standard therapy. Anti-hormonal therapy with an aromatase inhibitor plays a minor role in therapy of both low grade serous ovarian cancer (LGSOC) and high grade serous ovarian cancer (HGSOC). A major achievement in ovarian cancer therapy has been the results of the SOLO-1 trial, in which olaparib as a first line maintenance monotherapy resulted in an overall 70% lower risk of disease progression in patients with advanced Breast Cancer Gene (BRCA)-mutated ovarian cancer.

Abstract 1374: The novel PARP1-selective inhibitor AZD5305 has reduced hematological toxicity when compared to PARP1/2 inhibitors in pre-clinical models

Abstract Current clinical poly (ADP-ribose) polymerase (PARP) inhibitors target both PARP1 and PARP2 and they all cause clinical cytopenias with varying severity. Understanding the mechanism underlying the hematological toxicity of these agents is key for the rational design of a best-in-class molecule with greater therapeutic potential, both as monotherapy and in combination with chemotherapy. We validated the rat as a physiologically competent translational model to investigate PARP inhibitor-driven hematological toxicity. Here we demonstrate that in comparison with a representative PARP1/2 inhibitor, olaparib, the novel highly potent PARP1-selective inhibitor and trapper, AZD5305, does not cause hematological toxicity as a monotherapy in pre-clinical rat models at predicted clinically efficacious exposures. Thus, monotherapy toxicity of PARP1/2 inhibitors likely depends on PARP2 inhibition. Next, we proceeded to investigate whether PARP1-selective inhibition would be better tolerated in chemotherapy combinations than PARP1/2 inhibition. We performed a rat in vivo study comparing daily olaparib or daily AZD5305 at matched exposures in combination with one cycle of intravenous carboplatin for 14 days. We show that olaparib and PARP1-selective AZD5305 cause comparable exacerbation of carboplatin-induced peripheral blood effects implicating PARP1 inhibition in combination-driven hematological toxicity. Importantly however, AZD5305+carboplatin showed improved hematological tolerability over olaparib+carboplatin because peripheral reticulocytes and bone marrow erythroid precursor cells recover in the presence of continuous AZD5305 but not in the presence of continuous olaparib. Importantly, this differentiation was maintained in a subsequent rat in vivo study, where daily olaparib or daily AZD5305 were combined with two three-weekly cycles of a higher dose of carboplatin to more closely mimic clinical protocol. AZD5305+carboplatin was associated with a more rapid recovery of reticulocytes, red blood cells and hemoglobin following both cycles of carboplatin. In contrast, olaparib+carboplatin was associated with a slower recovery resulting in a more sustained reduction in red cells and hemoglobin during both the first and second cycle of carboplatin. Thus, in rodents the novel potent PARP1-selective inhibitor AZD5305 has improved hematological tolerability over dual PARP1/2 inhibitors, both as a monotherapy and in carboplatin combinations. Citation Format: Sonja J. Gill, Ruth Macdonald, Carmen Pin, Rob Collins, Emilyanne Leonard, Gareth Maglennon, Andy Pike, Peter Cotton, Glen Hawthorne, Jordan Pugh, Rebecca Sargeant, Daniel Sutton, James Atkinson, Stewart Jones, Sarah Chinery, Mark Anderton. The novel PARP1-selective inhibitor AZD5305 has reduced hematological toxicity when compared to PARP1/2 inhibitors in pre-clinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1374.

Treatment of Patients with Advanced Biliary Tract Cancer with Either Oxaliplatin, Gemcitabine, and Capecitabine or Cisplatin and Gemcitabine-A Randomized Phase II Trial.

This study is an investigator-initiated randomized phase II trial focusing on the treatment of advanced biliary tract cancer with either oxaliplatin 50 mg/m2 and gemcitabine 1000 mg/m2 on day 1 in a two-week cycle with capecitabine 650 mg/m2 twice-daily continuously or cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and day 8 in a three-week cycle. One-hundred patients were included. Forty-seven patients received oxaliplatin, gemcitabine, and capecitabine with a median progression-free survival (mPFS) of 5.7 months (95% CI 3.0–7.8) and a median overall survival (mOS) of 8.7 months (95% CI 6.5–11.2). Forty-nine patients received cisplatin and gemcitabine with a mPFS of 7.3 months (95% CI 6.0–8.7) and a mOS of 12.0 months (95% CI 8.3–16.7). This trial confirms a mOS of 12 months with cisplatin and gemcitabine, as found in earlier trials. With a superior tumor control rate of 79% vs. 60% (p = 0.045), a difference in the mPFS of 1.6 months (HR = 0.721, p = 0.1), and a difference in the mOS of 3.3 months (HR = 0.731, p = 0.1), cisplatin and gemcitabine should still be considered the standard first-line treatment for advanced biliary tract cancer.

COVID-19 and community healthcare: perspectives from Nairobi's informal settlements.

Urban slums are often characterized by overcrowding, inaccessibility of basic services such as running water and abject poverty. These may affect adherence to COVID-19 containment measures and worsen the effect of the virus on slum residents. We explore the overall practices and impact of the COVID-19 mitigation measures on the lives of Nairobi’s urban poor. This was done through a three-week cycle of telephone interviews with residents, local healthcare providers, religious leaders and key decision makers in two of Nairobi’s slums. As the number of COVID-19 cases increase in Kenya, greater efforts are needed to protect those in environments that make it challenging to implement the containment measures. Collaborative effort is needed to firmly and quickly implement social protections and food security measures, protection against domestic violence, and strengthening response at Level One (community level).

Abstract P5-04-02: Safety and efficacy from first-in-human immunotherapy combining NK and T cell activation with off-the-shelf high-affinity CD16 NK cell line (haNK) in patients with 2nd-line or greater metastatic triple-negative breast cancer (TNBC)

Abstract TNBC is an aggressive subtype of breast cancer with limited treatment options. We hypothesize that effective response against TNBC requires a coordinated approach that orchestrates both the innate and adaptive immune system. We further hypothesize that by orchestrating the activation of the entire immune system, we could accomplish immunogenic cell death with durable responses in this disease. We describe a first-in-human novel combination immunotherapy protocol of chemoradiation, cytokine-induced NK and T cell activation, checkpoint inhibition, and off-the-shelf high-affinity NK cell infusion. We instituted this first in human immunotherapy protocol consisting of low-dose metronomic chemoradiation therapy, combined with a novel IgG1 Fc-engineered IL-15-complexed protein (N803), adenoviral and yeast tumor-associated antigen vaccines (MUC1, brachyury, CEA), followed by off-the-shelf high-affinity NK cells (haNK), and a PD-L1 checkpoint inhibitor. A phase 1b trial in pts with metastatic TNBC was initiated in 9 pts, 8 of whom had relapsed after two or more lines of prior therapy (3rd-line). All pts received this combination therapy instituted over a three-week cycle as outpatients. Safety was assessed and efficacy assessment is ongoing. Nine pts have been treated to date in an outpatient setting. All pts had at least 1 grade ≥3 TRAE, primarily chemotherapy-related neutropenia or anemia. Grade ≥3 haNK-related AEs (fever and fatigue) were observed in 2 subjects. No SAEs were attributed to investigational agents. No pts experienced cytokine release syndrome. To date, early efficacy results are as follows: a disease control rate (CR+PR+SD) of 78% (7/9 pts); ORR (PR+CR) of 56% (5/9 pts). Two pts (22%; 2/9) achieved a complete response (CR). To date, median follow up time is 301 days. 7 pts are alive, and the duration of response ranges from 2 mo to over 12 mo. In pts with CR or PR, peripheral blood (PB) analysis showed >13x increase in TCR diversity at 2 mo after initial treatment with increasing overall diversity thereafter; conversely, in pts with SD, PB TCR diversity increased <2x or decreased. Four patients remain on study. This first in human clinical trial of combination chemoradiation, cytokine fusion protein, NK cell therapy, and a checkpoint inhibitor demonstrated a safe and tolerable immunotherapy protocol. Early efficacy data is encouraging with a 78% disease control rate, 56% ORR and 22% (2/9) CR in pts with metastatic TNBC, 2nd-line or greater. Citation Format: Mira Kistler, Chaitali Nangia, Christina To, Lennie Sender, John Lee, Frank Jones, Omid Jafari, Tara Seery, Shahrooz Rabizadeh, Kayvan Niazi, Amy Rock, Patrick Soon-Shiong. Safety and efficacy from first-in-human immunotherapy combining NK and T cell activation with off-the-shelf high-affinity CD16 NK cell line (haNK) in patients with 2nd-line or greater metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-02.

COVID-19 and community healthcare: perspectives from Nairobi’s informal settlements

Urban slums are often characterized by overcrowding, inaccessibility of basic services such as running water and abject poverty. These may affect adherence to COVID-19 containment measures and worsen the effect of the virus on slum residents. We explore the overall practices and impact of the COVID-19 mitigation measures on the lives of Nairobi’s urban poor. This was done through a three-week cycle of telephone interviews with residents, local healthcare providers, religious leaders and key decision makers in two of Nairobi’s slums. As the number of COVID-19 cases increase in Kenya, greater efforts are needed to protect those in environments that make it challenging to implement the containment measures. Collaborative effort is needed to firmly and quickly implement social protections and food security measures, protection against domestic violence, and strengthening response at Level One (community level).

1034P - Phase I study of intraperitoneal TRX-E-002-1 in subjects with persistent or recurrent ovarian, fallopian tube or primary peritoneal cancer: Three-month follow-up results of the dose escalation phase

BackgroundThe poor outcomes associated with current therapies for recurrent epithelial ovarian cancer (EOC) are thought to reflect the existence of drug-resistant ovarian cancer stem cells (OCSCs). TRX-E-002-1 is a novel, third generation benzopyran molecule that induces caspase-dependent and -independent apoptosis in CD44 positive ovarian cancer stem-like cells and CD44 negative ovarian somatic cancer cells. The dose escalation phase of a progressive design trial investigating intraperitoneal (IP)-administered TRX-E-002-1 monotherapy and in combination with standard of care for recurrent EOC (NCT02903771) has been completed with a Maximum Tolerated Dose (MTD) of 5mg/kg established. MethodsWomen with platinum resistant, persistent or recurrent EOC were enrolled into the dose escalation phase of the study (Part A) in which TRX-E-002-1 monotherapy was administered IP weekly for 2 three-week cycles, after which combination with standard intravenous chemotherapy was allowed to a maximum of 8 cycles. Subjects were followed up for 3 months after the end of treatment. The study objectives were to establish the MTD and to evaluate safety, tolerability, pharmacokinetics and anti-tumour activity of TRX-E-002-1. ResultsA total of 9 subjects were evaluable for efficacy. Four of 9 patients completed 8 cycles (6 months); 2 remained progression-free at the 3-month endpoint post-treatment (9 months). Preliminary data on activity include 1 partial response (during combination treatment) and 5 patients with stable disease on monotherapy per RECIST criteria. The most common drug-related adverse events, not generally dose limiting, were abdominal pain (27%), fatigue (13%), vomiting (10%) and nausea (10%). There was limited accumulation of TRX-E-002-1 with multiple dosing across multiple concentration‐time points. PK profiles were comparable between all subjects with plasma concentrations progressively declining to<10% maximal concentrations by 24hours. ConclusionsIP administered TRX-E-002-1 as a first-in-class, dual acting, anti-cancer therapy has demonstrated preliminary activity for the treatment of platinum resistant ovarian cancer. Clinical trial identificationNCT02903771. Editorial acknowledgementDr Caroline Markey, Markey Medical Consulting. Legal entity responsible for the studyKazia Therapeutics Limited. FundingKazia Therapeutics Limited. DisclosureJ. Coward: Honoraria (institution): Takeda Pharmaceuticals; Research grant / Funding (self): AstraZeneca; Leadership role, Overseas Trainee Sub-committee member: Royal Australasian College of Physicians. K. Moore: Honoraria (self), Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Clovis; Advisory / Consultancy, Research grant / Funding (institution): Immunogen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Tesaro; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy: Aravive; Advisory / Consultancy, Research grant / Funding (institution): OncoMed; Advisory / Consultancy: Samumed; Advisory / Consultancy: Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Janssen; Advisory / Consultancy: Cue; Research grant / Funding (self): Lilly; Research grant / Funding (self): PTC Therapeutics; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Agenus; Leadership role, Chair: NRG Oncology OVarian Committee; Leadership role, Associate Director: GOG Partners. D. Berg: Full / Part-time employment: Kazia Therapeutics Limited. J. Garner: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: Kazia Therapeutics Limited. D. Dizon: Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Kazia Therapeutics; Honoraria (self): AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self): Regeneron; Advisory / Consultancy: iMab. All other authors have declared no conflicts of interest.

358P - Complete responses in patients with second-line or greater metastatic triple negative breast cancer (TNBC) following first-in-human immunotherapy combining NK and T cell activation with off-the-shelf high-affinity CD16 NK cell line (haNK)

BackgroundTNBC is an aggressive subtype with limited treatment options. We hypothesize that effective response against TNBC requires a coordinated approach that orchestrates both the innate and adaptive immune system. We further hypothesize that by orchestrating the activation of the entire immune system, we could accomplish immunogenic cell death with durable responses in this disease. We describe a first-in-human novel combination immunotherapy protocol of chemoradiation, cytokine-induced NK and T cell activation, checkpoint inhibition, and off-the-shelf high-affinity NK cell infusion. MethodsWe instituted this novel immunotherapy protocol consisting of low-dose metronomic chemoradiation therapy, combined with a novel IgG1 Fc-engineered IL-15-complexed protein (NabFc-N803), adenoviral and yeast tumor-associated antigen vaccines (MUC1, brachyury, CEA), a PD-L1 checkpoint inhibitor, and off-the-shelf high-affinity NK cells (haNK). A phase 1b trial in pts with metastatic TNBC was initiated in 9 pts, 8 of whom had relapsed after two or more lines of prior therapy (3rd-line). All pts received this combination therapy instituted over a three-week cycle as outpatients. Safety was assessed and efficacy confirmed by CT. ResultsNine pts have been treated to date. All pts received at least 3 treatment cycles. 8 grade ≥3 treatment-related AEs were observed in 4 pts to date, of which 2 had haNK-related SAEs consisting of fever and fatigue. No pts experienced cytokine release syndrome. To date, early efficacy results are as follows: a disease control rate (CR+PR+SD) of 78% (7/9 pts); ORR (PR+CR) of 56% (5/9 pts). Two pts (22%; 2/9) achieved a complete response (CR). To date, 8 pts are alive, and the duration of response ranges from 2mo to over 12mo. 7 pts remain on study to date. ConclusionsThis first in human clinical trial of combination chemoradiation, cytokine fusion protein, checkpoint inhibitor, and NK cell therapy demonstrated a safe and tolerable immunotherapy protocol. Early efficacy data is encouraging with a 78% disease control rate, 56% ORR and 22% (2/9) CR in pts with metastatic TNBC, 2nd-line or greater. Clinical trial identificationNCT03387085. Legal entity responsible for the studyNantKwest, Inc. FundingNantKwest, Inc. DisclosureP. Soon-Shiong: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantCell; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantKwest; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantHealth; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: NantBio; Shareholder / Stockholder / Stock options: Celgene. S. Rabizadeh: Leadership role, Officer / Board of Directors: NantBio; Leadership role, Officer / Board of Directors: NantCell. J.H. Lee: Leadership role, Officer / Board of Directors: NantKwest; Leadership role, Officer / Board of Directors: NantCell. L. Sender: Leadership role, Officer / Board of Directors: NantKwest. F. Jones: Leadership role, Full / Part-time employment: NantCell; Leadership role, Officer / Board of Directors: Etubics. K. Niazi: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NantBio. T. Seery: Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer. A. Rock: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: NantCell. All other authors have declared no conflicts of interest.

Outcomes with different administration schedules of VRD as first-line therapy in multiple myeloma: a retrospective analysis

Induction therapy for multiple myeloma with subcutaneous (SQ) bortezomib (V), lenalidomide (R), and dexamethasone (D) (VRD) has traditionally been administered as a three-week cycle regimen, with SQ bortezomib given on days 1,4,8,11 and lenalidomide on days 1 to14. A modified schedule of weekly bortezomib over a 21 [len: days 1-14] or 28 day cycle [len: days 1-21] is frequently used in practice to reduce the risk of neuropathy. This study evaluates the response rates and outcomes with different schedules of subcutaneous (SQ) bortezomib and lenalidomide.

QoL from TASCO1: Health-related quality of life of trifluridine/tipiracil-bevacizumab and capecitabine-bevacizumab as first-line treatments in metastatic colorectal cancer patients not eligible for intensive chemotherapy—Results from the TASCO1 phase II study.

676 Background: TASCO1 is a phase II study which evaluated the safety and efficacy of trifluridine/tipiracil + bevacizumab (TT-B) and capecitabine + bevacizumab (C-B) in first-line unresectable mCRC patients non-eligible for intensive therapy. Promising activity was shown on progression-free survival with TT-B (9.2 months) and C-B (7.8 months). Here we present the Quality of Life (QoL) analysis of the two treatment arms. Methods: In TASCO1, patients were randomized 1:1 to receive TT-B (n = 76) on a four-week cycle or C-B (n = 77) on a three-week cycle. QoL was assessed in TASCO1 at baseline and at each 12 weeks thereafter, until discontinuation of study treatment, using the QLQ-C30 and QLQ-CR29 questionnaires. Responses were described separately in each arm using descriptive statistics. Results: For QLQ-C30, 121 patients completed baseline questionnaire. No clinically relevant difference was observed on treatment in mean change of score from baseline for the global health status, functioning scales, and for most of the symptom scales, except for nausea/vomiting and diarrhoea (worsening in the TT-B group and stable in the C-B group for both symptoms), fatigue (stable in the TT-B group and worsening in the C-B), loss appetite (worsening in the two groups) and insomnia (improvement in the two groups). For QLQ-CR29, 117 patients completed baseline questionnaire. No clinically relevant difference on treatment was observed in mean change of score from baseline for most of items except for the following: hair loss, trouble with taste (worsening for both symptoms in the TT-B group while stable for hair loss and improvement for trouble with taste in the C-B group), sore skin, dry mouth (stable in the TT-B group and worsening in the C-B group for both symptoms), and anxiety (stable in the TT-B group and improvement in the C-B group). Conclusions: The Global Health Scale was maintained in Trifluridine/tipiracil+bevacizumab arm as well as in the capecitabine+bevacizumab arm. No clinically relevant difference from baseline was observed over time in both groups except for few sub-scales. Clinical trial information: NCT02743221.

Pembrolizumab and Decitabine for Refractory or Relapsed Acute Myeloid Leukemia

Background: The powerful “graft versus leukemia” effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic stem cell transplantation in reducing relapse of high-risk acute myeloid leukemia (AML) provides the rationale for the investigation of immune-based therapy in those with relapsed or refractory AML. There is considerable pre-clinical evidence for potential synergy between PD-1 checkpoint blockade and hypomethylating agents.Aims: To determine the feasibility of a novel combination of pembrolizumab and decitabine in relapsed/refractory adult AML patients.Methods: 17-H-0026, (PD-AML, NCT02996474) was an investigator sponsored, single-institution, single-arm open-label ten subject study approved by the NHLBI IRB and conducted in accordance with the Declaration of Helsinki (FDA IND: 131826). Pembrolizumab 200 milligrams was administered intravenously on day 1 of every three-week cycle, with decitabine 20 milligrams per meter squared administered on days 8-12 and 15-19 (i.e.: total of 10 days) of alternative cycles starting with cycle 1. Up to eight cycles (24 weeks) of therapy were given.Results: Ten high-risk patients (median age 62, range 30-81) were enrolled, seven with refractory disease (including two with therapy-related myeloid neoplasm) and three with early relapse (less than 6 months from completion of last therapy).This novel combination therapy was well tolerated, with a toxicity profile largely consistent with that expected from decitabine. No grade 5 adverse events occurred. Most grade 4 adverse events were hematological. Non-hematological grade 4 events were seen in only two subjects; febrile neutropenia, hypotension and sepsis in one, and sepsis in the other. Two patients suffered from hypothyroidism as an immune-related adverse event (after 2 and 4 cycles respectively) and a third patient developed central diabetes insipidus thought possibly associated with pembrolizumab.In summary, 4 of the 10 patients had stable disease at the end of 8 cycles (24 weeks), 4 progressed prior to cycle 8, 1 patient was taken off study due to grade 4 toxicity (sepsis) in cycle 5 in a morphological leukemic free state (MLFS) and 1 patient achieved an MRD negative complete response at the end of 8 cycles.Specifically, a 74 year-old male patient, enrolled at second relapse, achieved a CR3 lasting 337 days (compared with prior CR2 of 185 days) which was MRD negative at the end of eight cycles, and was still alive 14 months from start of treatment. A 81 year old male patient, with refractory treatment related myeloid neoplasm achieved a MRD-negative MLFS but was removed from study early due to grade 4 toxicity. The 4 patients with stable disease at the end of planned eight cycles included a 71 year-old male patient in early first relapse who decreased blasts from 4.4% at enrollment to 0.1% at the end of 8 cycles.Median overall survival for patients on this study was 7 months (range 2 to ongoing at 14 months) with a median time of follow-up in survivors of 13 months (range 7-14 months). Updated survival data will be reported at the meeting.Additional planned laboratory correlates include assessment of changes in leukemic clonality, T-cell receptor repertoire diversity and bone marrow-resident immune cell profiles during therapy.Conclusion/summary: This first proof of principle study demonstrates the feasibility of the combination of pembrolizumab and decitabine in relapsed/refractory adult AML patients.. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Addition of Docetaxel to First-line Long-term Hormone Therapy in Prostate Cancer (STAMPEDE): Modelling to Estimate Long-term Survival, Quality-adjusted Survival, and Cost-effectiveness

BackgroundResults from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources. ObjectiveTo assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting. Design, setting, and participantsWe modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy. InterventionSOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75mg/m2) was administered alongside SOC for six three-weekly cycles. Outcome measurements and statistical analysisThe model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results and limitationsThe model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled. ConclusionsDocetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available. Patient summaryStarting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body.

Zoledronic acid in the management of mesothelioma - a feasibility study (Zol-A Trial): study protocol for a randomised controlled trial

BackgroundNitrogen containing bisphosphonates such as zoledronic acid (ZA) are known to contain certain anti-cancer properties. These have been investigated in the past in various cancers such as breast, prostate and colon. ZA in particular has shown promising results in pre-clinical studies. We propose a multicentre double-blind randomised controlled feasibility study to assess the recruitment and acceptability of ZA/placebo alongside chemotherapy in malignant pleural mesothelioma (MPM).MethodsPatients will be recruited for a 13-month period from October 2016 to November 2017. Eligible patients will be identified via the regional mesothelioma multidisciplinary team meeting. Those who receive chemotherapy will be randomised to receive either ZA or placebo alongside their chemotherapy. Those who decline chemotherapy will be offered to join the trial on the non-randomised open-labelled arm of the trial. Patients will receive a maximum of six cycles of ZA/placebo, at three-weekly cycles. All patients will be followed up for six months from randomisation.Semi-structured interviews to gather data on acceptability of trial procedures, tolerability of ZA and other relevant information will take place after the participants have completed their six cycles of treatment. For a better understanding about non-participation in mesothelioma trials we also aim to interview those who decline to take part in the trial.DiscussionThe qualitative and quantitative data gathered in this feasibility trial will hopefully pave the way to designing a robust full phase III trial to investigate the potential synergistic effect of ZA and current standard treatment for MPM, cisplatin-pemetrexed combination chemotherapy.Trial registrationISRCTN Registry, ISRCTN45536692. Registered on 9 August 2016. EudraCT no. 2015–004433-26.

Changes in the contraction ratio of transversus abdominis and quality of life in patients after total hip replacement and three-compartment knee arthroplasty with implant posterior stabilization

Core stability is a reference term for the performance of the deep trunk muscles, which provide functional stability of the lumbopelvic area and control the human body in static and dynamic positions. The study group consisted of 30 patients between the age of 42 and 76 years (mean=61.4) after total hip arthroplasty (total hip replacement, Group I) and total knee arthroplasty (three-compartment arthroplasty with posterior stabilization of the implant - Group II). In 18 (60%) patients, hip endoprosthesis was performed, whereas in 12 (40%), three-compartment knee endoprosthesis with posterior stabilization has been implanted. In the study group, Rehabilitative Ultrasound Imaging (RUSI) of the transversus abdominis muscle thickness was conducted at rest and in contraction, the transversus abdominis activation ratio was specified, the SF-36 Life Quality Questionnaire was applied and a three-week treatment cycle was performed. The tests were carried out twice, i.e. before and after treatment. In the group of patients after total hip replacement, the transversus abdominis (TrA) contraction ratio before the beginning of the exercise programme was 0.79±0.06, and after its completion 0.9 ±0.02. The observed difference was statistically significant at p&lt;0.001. In the group of patients after three-compartment knee arthroplasty, the TrA contraction ratio before the beginning of the exercise programme was 0.78±0.09, and after its completion0 0.91±0.02. The difference of these values was statistically significant at the level of p&lt;0.05. The results of the SF-36 questionnaire in both groups indicate improvement in physical functioning. The observed difference was statistically significant at p&lt;0.001. The performed three-week physiotherapy treatment in conjunction with deep muscle training increases the thickness of the TrA muscle during rest and contraction testing, and increases the transversus abdominis contraction ratio in Rehabilitative Ultrasound Imaging in the study groups. Furthermore, improvement in the level of physical functioning was observed within the studied groups.

Multicenter Phase 2 Trial of Cis/Carboplatin, nAb-Paclitaxel, and CeTUXimab (CACTUX) as First-Line Therapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

Standard first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (RM-HNSCC) is 5-FU, cetuximab and platin (EXTREME). The EXTREME regimen resulted in a median progression-free survival (PFS) of 5.6 months, tumor response rate (RR) 36%, and overall survival (OS) 10.1 months. The risk of grade 4 adverse events (AEs) was 31%. More effective and less toxic regimens are needed. In this multicenter phase 2 trial, we hypothesized that substitution of 5-FU in EXTREME with nab-paclitaxel would increase the median PFS from 5.6 (historical) to 7.6 months (35% increase, power 0.80, P= .05, one-sided test, N= 70 patients). Patients with incurable RM-HNSCC were treated with the CACTUX regimen as first-line therapy: nab-paclitaxel (100 mg/m2/week), cetuximab (400 mg/m2, then 250 mg/m2/week), and carboplatin (AUC 5, Day 1) or cisplatin (75 mg/m2, Day 1) in three-week cycles x 6, then maintenance nab-paclitaxel (Days 1, 8) and cetuximab (weekly) until disease progression. Tumor response assessments (RECIST 1.1) were performed every two cycles. Efficacy endpoints included PFS, RR and OS. AEs were graded using CTCAE v3.0. Thirty-two patients were the subject of this planned interim analysis. Patient/tumor characteristics included a median age of 58 years, HPV-related oropharynx (19 patients), and HPV-unrelated HNSCC (13 patients). The median PFS was 6.3 months (95% CI: 4-9.4), RR of 50% and median OS was 18.4 months. Current status: alive without progression (8 patients), alive with progression (7), and expired (17). Grade 4 AEs occurred in 6 patients (19%). Only seven patients (22%) received PD-1 inhibitor immunotherapy (IT) after progression: median PFS with IT was 2.2 months (range 0.3-9.5). The CACTUX regimen resulted in a median PFS of 6.3 months and RR of 50%. The median OS of 18.4 months is the highest ever reported with first-line therapy for patients with incurable RM-HNSCC.

RESPONSE BY STAGE IN CD30‐POSITIVE (CD30+) CUTANEOUS T CELL LYMPHOMA (CTCL) PATIENTS RECEIVING BRENTUXIMAB VEDOTIN (BV) VS PHYSICIAN'S CHOICE (PC) IN THE PHASE 3 ALCANZA STUDY

Introduction: The phase 3 ALCANZA study showed significant improvements in rate of objective response lasting ≥4 months (ORR4) with BV vs PC of methotrexate (MTX) or bexarotene (Bex) for the treatment of CD30+ CTCL. Here, we examine response according to disease stage and across disease compartments in patients (pts) treated on the ALCANZA study. Methods: Adults with previously treated CD30+ mycosis fungoides (MF) or primary cutaneous anaplastic large cell lymphoma (pcALCL) were randomized to BV 1.8 mg/kg IV, Q3W, for up to 16 three-week cycles, or PC of MTX 5–50 mg PO, QW, or Bex 300 mg/m2 (target dose) PO, QD, for up to 48 weeks. Pts were classified according to baseline Tumor-Node-Metastasis-Blood (TNMB) stage per investigator (INV) as part of global assessment; presence of baseline blood disease was also determined by independent review (IRF). Pts with B2 disease were ineligible. ORR4 was determined by IRF of global response in all compartments using consensus criteria (modified severity weighted assessment tool for skin evaluation by INV, radiographic assessment by IRF, and MF Sézary cell count by IRF). We compared ORR4, ORR, and complete response (CR) rate by disease stage, TNMB stage, and baseline blood disease in the intent-to-treat (ITT) population. Results: The ITT population included 128 pts (97 MF, 31 pcALCL). After a median follow-up of 22.9 months, ORR4 with BV was greater than PC in both MF (50% vs 10%) and pcALCL (75% vs 20%). This was consistent across all MF disease stages; stage IA–IIA, 40% vs 22% (95% CI for rate difference: −16.6%, 49.4%); stage IIB, 63% vs 5% (25.4%, 80.9%); stage IIIA–IIIB, 50% vs 0% (−45.2%, 98.7%); stage IVA, 100% vs 0% (14.9%, 100.0%); and stage IVB, 29% vs not applicable. Table 1 shows response according to baseline clinical and TNMB stage per INV. For MF, ORR4 was 25% (1/4) with BV vs 13% (1/8) with PC for pts with blood involvement (≥B1), and 43% (10/23) with BV vs 12% (3/26) with PC for pts with nodal involvement (≥N1). Out of 35 MF pts with blood disease per IRF (non-B0 blood stage), ORR in the blood compartment was 94% with BV vs 41% with PC; CR rate in the blood compartment was 89% vs 41%. In pcALCL pts, the ORR4 was 89% (8/9) with BV vs 27%% (3/11) with PC in pts with skin-only disease (95% CI for rate difference: 17.9%, 88.3%), and 57% (4/7) with BV vs 0% (0/4) with PC in pts with extracutaneous disease (−9.0%, 93.2%). Conclusions: Significant and durable clinical activity was observed across disease stages and compartments with BV in CTCL pts requiring systemic therapy. Total N (%) ORR4 n (%) ORR n (%) CR n (%) Total N (%) ORR4 n (%) ORR n (%) CR n (%) Keywords: brentuximab vedotin; CD30; cutaneous T-cell lymphoma (CTCL).

Lenalidomide, doxorubicin hydrochloride and dexamethasone versus bortezomib, lenalidomide, and dexamethasone prior to scheduled stem cell transplant in newly diagnosed myeloma.

8001 Background: In younger, medically fit patients (pts) with newly diagnosed (ND) multiple myeloma (MM), autologous stem cell transplant (SCT) remains a standard of care. Prior to SCT, induction triplets with at least one of the newer compounds are recommended. Bortezomib (V), lenalidomide (R) and dexamethasone (D; VRD) ranks amongst the most effective treatments. VRD + SCT proved superior over VRD alone in a randomized, controlled trial (RCT). We found encouraging efficacy and low toxicity with RAD (RD and adriamycin) + SCT and decided to compare RAD versus VRD induction in an RCT. Methods: The DSMM XIV study was set up according to a double 2x2-factorial design to enroll NDMM pts up to 65 years (yrs). Post-induction (PI) CR rate was the efficacy endpoint for the initial study phase. We hypothesized CR rate with RAD would be non-inferior to an estimated 20% CR with VRD. The study was powered to confirm non-inferiority of RAD at a 10% margin with a one-sided α level of .05. Minimal residual disease (MRD) was analyzed by eight-color flow cytometry (EuroFlow standards) on marrow samples. Results: 476 pts were randomized between 05/2012 and 06/2016, 469 of whom (median age 55 (range, 32–65) yrs) received at least one dose of study drug. 18.3% of pts had ISS stage III MM and 17.2%, elevated LDH. 11.3% of pts had del17p; 11.1% had t(4;14); and 4% had t(14;16). 232 pts were randomized to 3 four-week RAD cycles and 237 to 3 three-week VRD cycles, respectively. 89.7% of RAD versus 93.2% of VRD pts completed all induction cycles. PI CR rate was 11.8% (90% CI, 7.9%-16.3%) with RAD versus 13.0% (90% CI, 8.9-18.0) with VRD, (P = .697). 72/317 pts (22.7%) with paired baseline/PI samples achieved negative MRD at a median sensitivity level of 6.73x10-6. 47 (20.3%) RAD versus 35 (14.8%) VRD pts experienced treatment-emergent SAEs (P = .144). Treatment-related induction mortality was 0% in either arm. Conclusions: To the best of our knowledge, this is the first RCT to compare two lenalidomide-based triplets prior to SCT. The endpoint was met with comparable PI CR rates for RAD and VRD, respectively. Tolerability was encouraging in both arms. Follow-up data is needed to analyze time-dependent endpoints. Clinical trial information: NCT01685814.

Outcomes by CD30 expression in patients with CTCL receiving brentuximab vedotin (BV) vs physician's choice (PC) in the Phase 3 ALCANZA study.

7517 Background: The Phase 3 ALCANZA study showed significant, durable responses with CD30-directed antibody-drug conjugate BV vs PC of methotrexate (MTX) or bexarotene (Bex) for CD30-positive (CD30+) cutaneous T cell lymphoma (CTCL). Uniform CD30 expression is characteristic of primary cutaneous anaplastic large cell lymphoma (pcALCL), but is variable among other subtypes including mycosis fungoides (MF). We examined activity of BV and MTX / Bex by CD30 expression in pts treated on the ALCANZA study. Methods: Adults with previously treated CD30+ MF or pcALCL were enrolled. MF pts had ≥2 skin biopsies from separate lesions, pcALCL had ≥1. Patients were scored CD30+ if ≥1 biopsy had ≥10% CD30+ lymphoid cells using an investigational Ventana diagnostic test, centrally assessed by one pathologist. We compared the proportion of MF subgroup pts (n=50 per treatment arm) with objective response lasting ≥4 months (ORR4; ALCANZA primary endpoint) and PFS in pts with all biopsies ≥10% CD30+ (CD30min ≥10%) vs ≥1 biopsy &lt;10% CD30+ (CD30min &lt;10%). Pts were randomized 1:1 to BV 1.8 mg/kg IV, Q3W, or PC for up to 16 three-week cycles. Results: 125/184 (68%) MF and 44/47 (94%) pcALCL pts were screened and scored CD30+. High inter-lesional variability in CD30 expression was seen in MF pts; 55/125 CD30+ MF pts (44%) had ≥1 biopsy with low (&lt;10%) or undetectable CD30. 100/125 CD30+ MF pts were eligible and enrolled. In the BV arm, ORR4 was higher in MF pts with CD30min ≥10% vs &lt;10%; median PFS with BV was higher in the CD30min &lt;10% group (Table). ORR4 with BV was greater than PC over all CD30 expression ranges (CD30min &lt;5%, 38% vs 13%; CD30 ≥5–≤20%, 35% vs 10%; CD30 &gt;20%, 76% vs 7%, respectively). Conclusions: Notable inter-patient or inter-lesional variability in CD30 expression was seen in MF pts. Highly superior ORR4 and PFS endpoints were seen with BV over PC regardless of CD30min expression level. Clinical trial information: NCT01578499. [Table: see text]

Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice (Methotrexate or Bexarotene): The Phase 3 Alcanza Study

Brentuximab Vedotin Demonstrates Significantly Superior Clinical Outcomes in Patients with CD30-Expressing Cutaneous T Cell Lymphoma Versus Physician's Choice (Methotrexate or Bexarotene): The Phase 3 Alcanza Study

Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer

Background: The primary objective of this study was to compare the progression-free survival (PFS) at 12 weeks between patients treated with IGF-1R pathway modulator AXL1717 (AXL) and patients treated with docetaxel (DCT).Material and methods: The study was conducted at 19 study centers in five countries. A total of 99 patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) of the squamous cell carcinoma (SCC) or adenocarcinoma (AC) subtypes in need of additional treatment were randomized and treated with either 300 or 400 mg of AXL as daily BID treatment (58 patients) or DCT given as 75 mg/m2 in three-week cycles (41 patients) as monotherapy in a 3:2 ratio for each NSCLC subtype. Patients were treated in the primary study treatment period for a maximum of four treatment cycles.Results: The 12-week PFS rate, median PFS and overall survival (OS), as well Kaplan-Meier hazard ratio for PFS and OS, did not show any statistically significant differences between the treatment groups. For the primary endpoint, the AXL group had a lower percentage of patients (25.9%) who were progression-free at Week 12 as compared to the DCT group (39.0%), although the difference was not statistically significant. The most notable difference in the incidence of treatment emergent adverse effects (TEAEs) was the lower incidence of treatment-related grade 3/4 neutropenia in patients treated with AXL.Conclusion: These results suggest neither of the treatments to be superior of the other when treating locally advanced or metastatic NSCLC. Considering the lower incidence of grade 3/4 neutropenia in the AXL group this treatment warrants further research.