bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical efficacy of vaccination with the autologous tumor lysate particle loaded dendritic cell (TLPLDC) vaccine in metastatic melanoma.
Authors: Hickerson Annelies , Clifton Guy T. , Brown Tommy A , Campf Jessica , Myers John William , Vreeland Timothy J. , Hale Diane F. , Peace Kaitlin M. , Jackson Doreen O , Yu Xianzhong , Wagner Thomas , Peoples George Earl
Published: May 2019

e21025

Background: The treatment of melanoma has changed drastically with the advent of immunotherapy. The autologous tumor lysate, particle loaded, dendritic cell (TLPLDC) vaccine stimulates T-cells and may work synergistically with other immunotherapies. Here, we describe results in patients (pts) with metastatic melanoma (MM) treated with the TLPLDC vaccine together with other approved therapies. Methods: The TLPLDC vaccine is created using autologous tumor lysate loaded yeast cell wall particles to prime autologous dendritic cells ex-vivo. 1-1.5x106 TLPLDCs are given via intradermal injection monthly x 4 followed by boosters at six and nine months (mo). Pts who recurred while enrolled in our adjuvant phase IIb trial of the TLPLDC vaccine and pts with MM with measurable disease enrolled in a separate phase I/IIa trial were offered vaccination of TLPLDC vaccine in an open-label fashion in addition to other approved therapies as determined by their treating physician. Tumor response is measured by RECIST 1.1 criteria. Results: To date, 50 pts have been enrolled in the two trials (25 pts in each). Of the 42 pts with measureable disease, 30 pts received at least one dose of the vaccine, 11 progressed prior to vaccine administration, and 1 is pending. 2 pts withdrew at 2 and 7 mo. Of the remaining 28 evaluable pts, 13 pts had progressive disease with a median follow-up (f/u) of 3 (range 0-12) mo, 12 pts had stable disease with a median f/u of 7.5 (range 1-23) mo, 2 pts had a partial response with f/u of 7 and 13 mo, and one pt had a complete response with 18 mo of f/u. Overall, in pts with measureable disease, the disease control rate was 54% (15/28) and objective response rate was 11% (3/28). 8 pts were without measurable disease at enrollment, 3 recurred at a median f/u of 8 mo and 5 remain disease-free at a median of 26 mo f/u. No grade ≥ 3 toxicities were observed with combination TLPLDC vaccination and approved systemic therapies. Conclusions: Vaccination with the TLPLDC vaccine in combination with systemic approved therapies in MM pts is well tolerated and may provide clinical benefit in patients with and without measurable disease. Clinical trial information: NCT02678741.
Targeting MAP2K1 mutation with trametinib in a triple wild-type melanoma patient.
Authors: Homicsko Krisztian Gyuta , Aedo Veronica , Missiaglia Edoardo , Bisig Bettina , Michielin Olivier
Published: May 2019

e21027

Background: MAP2K1 inhibitors combined with BRAF inhibitors provide a prolonged progression-free survival for BRAF mutant patients. However, the impact of MEK inhibition of MAP2K1 mutant and BRAF/NRAS/NF1 wild type melanoma patients remains elusive. Methods: We performed next-generation sequencing using an in-house developed 400 full exon panel for one of our triple wild type (BRAF/NRAS/NF1) melanoma patient. The patient received off-label, trametinib at a dose of 2 mg o.d. We performed additional sequencing at progression. After progression, the patient was treated off-label with combined trametinib and palbociclib therapy. Furthermore, we screened the TCGA melanoma and MSK-IMPAKT databases for patients with similar mutation profiles. Results: Our patient presented with dual somatic MAP2K1 mutations at Cys121Ser and Pro124Arg with a 68% allele frequency. The tumor also harbored a minor EGFR mutant clone (11% allele frequency) and a complete loss of the CDKN2A locus. The patient received trametinib and after two months presented a partial response as per RECIST1.1. However, after two additional months, the patient progressed. A new biopsy was performed, and the treatment was modified to combine trametinib and palbociclib to co-target MAP2K1 and the loss of the CKDN2A locus. The patient progressed under dual trametinib/palbociclib therapy without any objective benefit. The on-progression biopsy showed the absence of a gatekeeper mutation of MAP2K1 and the persistence of the loss of the CDKN2A locus. We detected a large number of novel copy number variations, most notable amplification of MITF (9x), FGFR1 (10X) and of MDM2 (16x). We also detected a loss of the minor, EGFR mutant clone. The analysis of large-scale state transitions (LSTs) for deficiency in homolog recombination (HRDness) was negative in pre and post-treatment biopsies. Conclusions: Our patient provides unique evidence to target solitary MAP2K1 mutations in triple wild melanoma by MEK1 inhibitors. Resistance to MEK1 inhibition developed rapidly and likely involved FGFR1 and MDM2, which have not been previously associated with resistance to MEK inhibitor monotherapy. The addition of palbociclib could not rescue these potential resistance mechanisms.
Treatment patterns and outcomes among patients with advanced cutaneous squamous cell carcinoma (CSCC) in a US community oncology setting.
Authors: Cowey C. Lance , Robert Nicholas J. , Davies Kalatu , Espirito Janet L. , Frytak Jennifer R. , Lowy Israel , Fury Matthew G.
Published: May 2019

e21033

Background: Advanced CSCC is a term that encompasses the locally advanced (laCSCC) and metastatic (mCSCC) condition. For advanced CSCC patients who receive conventional anticancer systemic treatment, there are limited data regarding treatment patterns and clinical outcomes. Methods: This was a retrospective, observational study of adult patients with laCSCC and mCSCC who initiated first-line (1L) systemic treatment from 1/1/2008 to 12/31/2015, with follow-up to 9/30/2017. Data were abstracted from the US Oncology Network’s iKnowMedSM electronic health record database, supplemented by chart review. ECOG performance status (PS) of 0 or 1 was required for inclusion. Exclusion criteria included tumor of unknown primary site, treatment with an anti-PD-1/anti-PD-L1 agent, participation in clinical trial, and concurrent primary cancer. Duration of therapy (DOT) and overall survival (OS) were analyzed by Kaplan-Meier method. Response rate was calculated as the proportion of patients who achieved physician assessed-response. Results: 82 patients met inclusion criteria (17 laCSCC and 65 mCSCC). Median age at start of 1L treatment was 75y; 85% were male, 79% Caucasian, 88% of patients had an ECOG PS of 1, 90% had prior surgery, 84% prior radiotherapy, and 8.5% had prior organ transplant. The most common 1L regimens were carboplatin + paclitaxel (27% of patients) and cetuximab monotherapy (24%). Median 1L DOT was 2.4 mo for the overall population; 4.1 mo for laCSCC, 2.3 mo for mCSCC. Physician-assessed response rate for 1L therapy was 18.3% overall; 17.6% for laCSCC, and 18.5% for mCSCC. Median OS from the start of 1L treatment was 15.3 mo (95% CI, 10.4-21.0) overall; 16.2 mo for laCSCC, and 15.3 mo for mCSCC. Only 24 patients (29%) received 2L therapy. Conclusions: This is the largest retrospective data set regarding advanced CSCC patients treated with conventional chemotherapy. Efficacy was low in both laCSCC and mCSCC. These data provide historic benchmarks for outcomes in advanced CSCC patients prior to the FDA approval of cemiplimab-rwlc.
What impact do the proton pump inhibitors have on the efficacy of immune check point inhibitors in metastatic malignant melanoma?
Authors: Afzal Muhammad Zubair , Shirai Keisuke
Published: May 2019

e21040

Background: Acidic microenvironment facilitates the proliferation, progression, and metastasis of the tumors. Mouse models have shown that the proton pump inhibitors (PPI) cause neutralization of the acidic tumor microenvironment (TME) and inhibit the tumor growth. PPI also sensitize the resistant tumors to chemotherapeutic and immunotherapeutic effects. Moreover, PPI’s modify the gut microbiota, that impact the efficacy of immune checkpoint inhibitors (ICI). Clinical studies have shown variable impact of PPI on efficacy of ICI, ranging from no benefit at all to a negative impact. Since, PPI are one of the most commonly used medications, it is important to evaluate its impact on the efficacy of ICI. Methods: We conducted a retrospective analysis on 120 metastatic malignant melanoma patients treated with anti- CTLA-4 (ipilimumab), anti PD-1(pembrolizumab) alone or in combination. Cohort A included patients who were taking PPI at the time of ICI initiation. Cohort B included non-PPI users. Objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression free survival (PFS) were calculated. ORR and PFS were the primary outcomes. Cox regression univariate and multivariate analyses were performed. The proportions of grade 3 or 4 immune related adverse events (IrAE) were compared between PPI users and nonusers using the Fisher’s exact test. Results: Cohort A included 29 (24.2%) patients, of which 68.7% patients were male. Median age was 65 years. Majority of the patients were taking omeprazole (58.6%). Proportion of the patients taking ipilimumab and pembrolizumab or nivolumab were almost similar (48.3% vs. 44.8%, respectively). Significantly higher proportion of patients achieved ORR and DCR in cohort A [76%, OR = 3.8(1.39 – 10.5), P = 0.009) and 84%, OR = 4.3(1.37 – 13.7), P = 0.013, respectively). The median PFS was significantly higher in cohort A [A = 27.6 vs. B = 4.4 months, HR = 0.3, P = 0.005(0.1 – 0.7)]. Although, median OS was considerably higher in cohort A, the difference was not statistically significant [A = 39.3 vs. B = 28.0 months, HR = 1.01, P = 0.9(0.4-2.0). PPI did not significantly increase the Odds of having grade 3 or 4 IrAE. Conclusions: In this retrospective review, we have observed favorable outcomes in patients receiving PPI when starting on ICI contrary to some of the studies suggesting negative impact of PPI on ICI efficacy. As PPI is one of the commonly used chronic medications, prospective studies are needed to evaluate the real impact of PPI on ICI when taking concomitantly.
Utility of concurrent immunoradiation for locally advanced and/or medically inoperable melanoma and Merkel cell carcinoma.
Authors: Poulose Joyson , Wheelden Megan , Mackley Heath B. , Schmeck Carla , Zhu Junjia , Pameijer Colette , Neves Rogerio Izar , Schell Todd , Mallon Carol , Drabick Joseph J.
Published: May 2019

e21053

Background: Melanoma and Merkel Cell Carcinoma (MCC) are aggressive cutaneous malignancies with poor responses to cytotoxic chemotherapy. The use of immune checkpoint inhibitors (ICI) has substantially improved outcomes in metastatic disease and in the neoadjuvant setting. Addition of concurrent radiation therapy (RT) can augment the response of ICI, however there are little data on this combined approach as a neoadjuvant or non-operative strategy. Methods: We retrospectively analyzed outcomes of patients who received RT combined with an ICI against PD1, PD-L1, CTLA-4, or dual targets as neoadjuvant or definitive non-operative management for non-polymetastatic disease at our center from 2012 to 2018. Results: This study analyzed 14 patients, 7 males and 7 females, with a median age of 75 years. There were 10 patients with melanoma and 4 patients with MCC. Among them, 9 patients had stage III disease and 5 patients had oligometastatic disease. Prior treatments included surgery (71%), radiation (21%), and immunotherapy (21%) comprising interferon alpha (1), intralesional BCG (1), and Nivolumab (1). The ICI used were Pembrolizumab (5), Nivolumab (2), Avelumab (2), Ipilumumab (4) and Ipilumumab + Nivolumab (1). Immune related adverse events were seen in 8 patients and included endocrine (5), skin (4), and gastrointestinal (2) toxicity, majority of which were grade 1. Both grade 3 dermatitis and colitis were seen in 2 patients, and 1 patient had grade 3 colitis. There was 1 patient with grade 1 radiation dermatitis. Following concurrent ICI + RT, 4 patients who did not achieve a complete response (CR) at the irradiated site underwent surgical resection with no postoperative complications. An objective response at the irradiated site was seen in 13 (93%) patients, and 12 (86%) patients achieved a CR outside the radiated field. At the time of last follow up, 10 patients remain alive, of which 8 patients are in sustained complete remission. Conclusions: Concurrent use of ICI + RT was a safe approach in patients with locally advanced or medically inoperable melanoma and MCC with potential for durable complete remissions in the majority. Prospective studies are warranted to further validate this approach.
A phase III study comparing trastuzumab emtansine with trastuzumab, pertuzumab, and docetaxel in elderly patients with advanced stage HER2-positive breast cancer: (JCOG1607 HERB TEA study).
Authors: Shimomura Akihiko , Tamura Kenji , Mizutani Tomonori , Shibata Taro , Hara Fumikata , Fujisawa Tomomi , Niikura Naoki , Hojo Takashi , Kanbayashi Chizuko , Saji Shigehira , Masuda Norikazu , Sawaki Masataka , Yamamoto Naohito , Nagashima Fumio , Shien Tadahiko , Iwata Hiroji
Published: May 2019

TPS1100

Background: Systemic chemotherapy with anti-HER2 therapy is the standard of care for HER2-positive advanced breast cancer. Patient outcomes have improved remarkably with the use of novel anti-HER2 drugs, including trastuzumab (H), pertuzumab (P), and trastuzumab emtansine (T-DM1). The combination treatment comprising H, P, and docetaxel (D) (HPD) is highly recommended as the 1st-line treatment for patients with HER2-positive advanced breast cancer. In contrast, for elderly patients over 65 years of age, this regimen seems to be intolerable mentally and physically, and impairs their quality of life. A new standard treatment with less toxicity and non-inferior efficacy for elderly patients is needed. Methods: We have planned a randomized, multicenter, open-label, phase III trial to confirm the non-inferiority of T-DM1 compared to HPD in terms of overall survival (OS) in elderly patients with HER2-positive advanced breast cancer. The eligibility criteria are as follows: 1) histologically proven metastatic breast cancer, 2) age 65-74 years with a performance status (PS) score 0-2, or 75-79 years with a PS score 0-1, 3) HER2 overexpression or amplification confirmed in primary or metastatic tissues, and 4) no anti-HER2 therapy with chemotherapy for breast cancer, excluding (neo) adjuvant therapy. Patients are randomized to receive either HPD (H 6 mg/kg, P 420 mg/body, and D 60 mg/m2) or T-DM1 3.6 mg/kg every 3 weeks. The dose up of D (75 mg/m2) after the second cycle is defined based on the data regarding safety during the first cycle. The primary endpoint is OS. The secondary endpoints are progression-free survival, response rate, adverse events, breast cancer-related death, and deterioration of activities of daily living. The trial is designed to achieve 70% power to confirm non-inferiority of T-DM1 to HPD at a one-sided alpha of 5% with a non-inferiority margin of 1.3 in terms of hazard ratio. With a median OS of 30 months in both arms, 6 years of accrual, and 5 years of follow up, the planned sample size is 330. The trial began in January 2018 and nineteen patients have been enrolled as of January 2019. Clinical trial information: UMIN000030783.
A phase II study of dual immune checkpoint blockade (ICB) plus androgen receptor (AR) blockade to enhance thymic T-cell production and immunotherapy response in metastatic breast cancer (MBC).
Authors: Page David B. , Kim Isaac K , Chun Brie , Redmond William L , Martel Maritza , Mori Motomi , Wadell Dottie , Moxon Nicole , Mellinger Staci L. , Urba Walter John , Gucalp Ayca , Traina Tiffany A.
Published: May 2019

TPS1106

Background: ICB (atezolizumab, anti-PD-L1) is known to improve survival when added to chemo, however only in PD-L1-positive, triple-negative MBC. ICB is less effective in hormone receptor positive (HR+) MBC, or when administered following palliative chemo. Novel approaches are required to broaden clinical benefit of ICB, particularly in PD-L1-negative, HR+, or chemo-experienced MBC. Dual ICB with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab) is associated with enhanced activity in melanoma other malignancies, but has not been explored extensively in MBC. Androgen receptor (AR) blockade, in addition to known direct cytostatic effects in AR-expressing MBCs (50% of TNBC, > 75% of HR+ MBC), may also modulate immune response. AR blockade has been shown experimentally to stimulate thymic production of naïve T-cell clones, which in turn can facilitate de novo anti-tumor immune responses. Concurrent ICB can enhance the activity of these T-cell clones by interfering with PD-1-mediated peripheral tolerance. This combination approach is promising in MBC in light of known AR positivity, and the routine use of lymphodepleting chemo regimens in the curative-intent setting. Methods: This is a phase II trial of dual immune checkpoint blockade (nivolumab 240mg IV q2w; ipilimumab 1mg/kg IV q6w) plus AR blockade (bicalutamide, 150mg PO daily, dose reduction allowed) in triple-negative MBC (cohort A: AR-positive [ > 1% by IHC]; cohort B: AR-negative) or HR+ MBC (cohort C) in subjects who received 0/1 prior chemotherapies in the non-curative setting. Objectives include 24-week clinical benefit rate by iRECIST (primary), safety (CTCAE v4.0), and other response measures (RECIST1.1, PFS, OS). Efficacy for each cohort is defined as > 20% improvement in response over historical control (30% per EMBRACE clinical trial) employing a Simon 2-stage design to minimize futility (n = 46/cohort, stage I n = 15). Thymic generation of T-cells will be measured via quantitative deep sequencing of T-cell receptors (TcR, ImmunoSEQ assay) and TcR excision circles (TRECs), as well as real-time flow cytometry using surrogate cell surface markers of recent thymic emigration. Enrollment has commenced, sites: Earle A. Chiles Research Institute (Portland, OR), Memorial Sloan Kettering Cancer Center (New York, NY). Clinical trial information: NCT03650894.
Randomized phase II trial of venetoclax + fulvestrant versus fulvestrant in estrogen receptor+, HER2– locally advanced or metastatic breast cancer following recurrence or progression during or after a CDK4/6 inhibitor: VERONICA.
Authors: Lindeman Geoffrey J , Bardia Aditya , Bowen Rebecca , Flechais Aulde , Lei Guiyuan , Hogea Alexandra , Mobasher Mehrdad , Rafii Saeed
Published: May 2019

TPS1108

Background: CDK4/6 inhibitors (CDK4/6is) administered with endocrine therapy have demonstrated improvements in progression-free survival (PFS) for estrogen receptor (ER)+ advanced breast cancer (BC), but resistance occurs, and new options are needed in the post-CDK4/6i setting. BCL2 is an estrogen-responsive anti-apoptotic molecule overexpressed in 75% of BCs. The BCL2 inhibitor venetoclax (Ven) has shown improved outcomes and tolerability in hematological malignancies such as chronic lymphocytic leukemia, and has been investigated in BC. A phase 1b study of Ven + tamoxifen demonstrated safety and an efficacy signal in ER+, BCL2+ metastatic BC (mBC). Preclinical data for Ven + fulvestrant (Ful) have also shown synergy. Based on these proof-of-principle data, the current study evaluates safety and efficacy of Ven + Ful vs Ful in women with ER+, HER2– locally advanced (LA)/mBC progressing after first- or second-line of prior therapy for metastatic disease, including ≥8 wks of a CDK4/6i. Methods: VERONICA is a global, randomized, phase 2, multicenter, open-label study. Eligible patients (pts) are aged ≥18 yrs with confirmed ER+, HER2–, inoperable LA/mBC, ≥1 measurable lesion, tissue evaluable for BCL2, and ECOG performance status 0–1. Prior Ful or Ven, or prior chemotherapy for LA/mBC are prohibited. Stratified by BCL2 expression (low vs high) and number of prior lines of mBC therapy (1 vs 2), pts are randomized 1:1 to Ven 800 mg PO daily + Ful 500 mg IM (cycle 1 days 1 and 15, and day 1 of each subsequent 28-day cycle) vs Ful 500 mg IM alone. Treatment continues until disease progression or intolerable toxicity. Primary endpoint is clinical benefit rate defined as complete/partial response + stable disease for ≥24 wks from randomization. Secondary efficacy endpoints include PFS, objective response rate, duration of response, and overall survival. Safety, pharmacokinetic, biomarker (e.g. BCL2 and PI3K expression) and patient-reported outcome analyses will also be conducted. Currently, 21 of the planned 100 pts have been enrolled; enrollment is ongoing. Clinical trial information: NCT03584009.
A phase II trial of olaparib and durvalumab in metastatic BRCA wild type triple-negative breast cancer.
Authors: Mitri Zahi Ibrahim , Vuky Jacqueline , Kemmer Kathleen A. , Savin Michael A. , Parmar Swapnil , Kolodzie Annette Kolodzie , Johnson Brett , Williams-Belizaire Rochelle , Gray Joe W. , Mills Gordon B.
Published: May 2019

TPS1111

Background: There is an urgent need to develop novel non chemotherapy treatments for metastatic triple negative breast cancer (mTNBC) patients who otherwise have a poor prognosis. Immune checkpoint blockade (ICB) and PARP inhibitors (PARPi) have independently shown promise for the treatment of mTNBC, and the combination has shown early benefit in the MEDIOLA and TOPACIO trials. This trial looks to 1) evaluate the efficacy of the combination of the PARPi olaparib and the PD-L1 inhibitor durvalumab, and 2) perform extensive multi-omics including protein based image analytics (multiplex IHC, cyclic immunofluorescence) on serial biopsies to identify predictive biomarkers and resistance mechanisms. Methods: Trial Design: This is a single-arm phase II study to assess the efficacy of the combination of olaparib and durvalumab in BRCA-wildtype mTNBC. mTNBC participants will undergo a pre-treatment biopsy, then will start a 4 week induction treatment with olaparib (300 mg PO BID). At the end of 4 weeks of single agent therapy, participants will undergo a repeat on-treatment biopsy, following which durvalumab (1500 mg IV every 4 weeks) will be added to olaparib. Participants will also be offered an optional biopsy on progression. Endpoints: The primary endpoint of this study is overall response rate (ORR) to olaparib and durvalumab therapy. Secondary efficacy endpoints include clinical benefit rate, duration of response, progression-free, and overall survival. The incidence and severity of on-treatment adverse events will be collected per CTCAE 5.0. Statistical Methods: 28 participants are planned for enrollment to this study. A 2-stage analysis will be performed using a Simon 2-stage Minimax design. The null (ICB alone) and alternative (ICB + PARPi) hypotheses are: H0: π = 0.15 and Ha: π = 0.35. For the primary endpoint, a total sample size of 28 participants will achieve 80% power to detect the ORR difference of 0.20 with one-sided type I error =0.05. The trial will be terminated in stage I if 2 or less out of the first 15 participants respond. If the trial goes on to the stage II, a total of 28 participants will be studied. If the total number responding is less than or equal to 7, the combination is rejected. Current Enrollment: The study was activated on 1/7/2019. To date, 3 out of 15 patients have been accrued to stage I of the study Clinical trial information: NCT03801369.
Dora: A randomized phase II multicenter maintenance study of olaparib alone or olaparib in combination with durvalumab in platinum responsive advanced triple-negative breast cancer (aTNBC).
Authors: Sammons Sarah , Tan Tira Jing Ying , Traina Tiffany A. , Kim Sung-Bae , Im Young-Hyuck , Bachelder Carol , Marcom Paul Kelly , Dent Rebecca Alexandra
Published: May 2019

TPS1113

Background: PARP inhibition (PARPi) with olaparib is approved in HER2-negative germline BRCA mutant (g BRCAm) metastatic breast cancer. Maintenance PARPi in relapsed platinum-sensitive ovarian cancer improves median PFS regardless of gBRCA mutation status. Preclinical work has shown that platinum response strongly correlates with olaparib response in breast cancer models; hence, maintenance therapy trials are underway in aTNBC. PARPi modulates immune responses and enhances immunogenicity in many preclinical models. We hypothesize that olaparib either alone or in combination with the PD-L1 inhibitor durvalumab will have clinical efficacy as maintenance therapy in aTNBC subjects who have responded to platinum-based chemotherapy. Methods: DORA is a randomized, international, multicenter, phase II study designed to explore the efficacy of olaparib or olaparib in combination with durvalumab as maintenance therapy in platinum-sensitive aTNBC. 60 subjects will be enrolled following a minimum of 3 cycles of treatment with platinum-based (cisplatin or carboplatin) chemotherapy as a single agent or combination therapy in the first or second-line setting. Subjects deriving clinical benefit (CR / PR / SD) from platinum-based therapy will be eligible and randomized in a 1:1 ratio. Patients in arm 1 will receive olaparib orally 300mg BID continuously and in arm 2 will receive olaparib orally 300mg BID continuously in combination with durvalumab 1500mg IV every 4 weeks. Assessment of tumor response will be done every 8 weeks. Primary endpoint: progression-free survival. Secondary endpoints: overall survival, clinical benefit rate, safety. Correlative analyses: pre-treatment archival/fresh biopsy samples are mandated. Post-treatment tissue biopsy is requested. Serial ctDNA will be collected at baseline, staging, and progression to correlate with response and track emerging genomic alterations in a platinum sensitive cohort under the pressure of PARP inhibition. Whole exome DNA sequencing, IHC for PDL-1 and TILs will be performed on tissue samples. ClincalTrials.gov Identifier: NCT03167619. (Moore K, et al "SOLO-1: Phase III trial of maintenance olaparib following platinum-based chemotherapy in newly diagnosed patients with advanced ovarian cancer and a BRCA1/2 mutation" ESMO 2018; Abstract LBA7-PR). Clinical trial information: NCT03167619.
Novel anti-EGFRvIII bispecific T cell engager (BiTE) antibody construct in glioblastoma (GBM): Trial in progress of AMG 596 in patients with recurrent or newly diagnosed disease.
Authors: Rosenthal Mark , Balana Carmen , Van Linde Myra Ellen , Sayehli Cyrus , Fiedler Walter M. , Wermke Martin , Massard Christophe , Ang Agnes , Kast Johannes , Stienen Sabine , Cloughesy Timothy Francis
Published: May 2019

TPS2071

Background: GBM is the most aggressive primary brain tumor in adults and is extremely difficult to treat. Patients with GBM tend to progress rapidly within weeks or months. Median overall survival is only 12–15 months despite aggressive treatment, and less than 5% of patients survive 5 years. GBM also severely impacts quality of life and cognitive function. Approximately 50% of GBM tumors test positive for amplification or mutation of the epidermal growth factor receptor (EGFR), the most common of which is the EGFRvIII gain-of-function mutation. AMG 596 is a bispecific T cell engager (BiTE®) antibody construct designed to crosslink and engage CD3-positive T cells to EGFRvIII-positive tumor cells, inducing tumor cell lysis and T cell proliferation. A clinical trial is being conducted for this novel immunotherapy agent in patients with EGFRvIII-positive GBM. Methods: NCT03296696 is a phase 1, first-in-human, open-label, sequential dose-escalation and dose-expansion study evaluating the safety, tolerability, and pharmacokinetics and pharmacodynamics (PK/PD) of AMG 596 in patients with EGFRvIII-positive GBM. AMG 596 is administered via continuous intravenous infusion. The study is expected to enroll approximately 82 patients total and comprises two groups (Group 1: patients with recurrent GBM; Group 2: patients with newly diagnosed GBM in the maintenance treatment phase after standard of care). Key inclusion criteria include: male or female; ≥ 18 years of age; with pathologically documented and diagnosed grade IV GBM; Eastern Cooperative Oncology Group performance status ≤ 1; life expectancy ≥ 3 months per study investigator; and acceptable renal, hematological, and hepatic function. The primary endpoint evaluates the safety and tolerability of AMG 596 via collection of treatment-emergent adverse events. Additional endpoints include objective response rate per modified Response Assessment in Neuro-Oncology Criteria and PK/PD analyses of AMG 596 in serum. The study began enrolling patients in April 2018 and enrollment is ongoing. For more information, please contact Amgen Medical Information: medinfo@amgen.com. Clinical trial information: NCT03296696.
Phase I study of PD-L1 inhibition with avelumab and laser interstitial thermal therapy in patients with recurrent glioblastoma.
Authors: Hormigo Adilia , Mandeli John , Hadjipanayis Constantinos , Gnjatic Sacha , Kim-Schulze Seunghee , Ghatan Saadi
Published: May 2019

TPS2074

Background: Glioblastoma (GBM) the most frequent malignant brain tumor in the adult has a dismal prognosis and limited treatment options. Current advances have highlighted how tumors and specifically GBM evade the immune system by exploiting the mechanisms of tolerance and inducing local and systemic immunosuppression. Another hurdle in the treatment of GBM is the blood-brain barrier (BBB). Recent work suggests that MRI-guided laser interstitial thermal therapy (LITT) can increase the permeability of the BBB and may have an abscopal effect. Therefore, utilizing MRI-guided LITT, a potential immunogenic cell death-inducing procedure that disrupts the BBB and makes Avelumab a PD-L1 monoclonal antibody being more accessible to GBM tumors, seem a valid approach for immunomodulation and successful implementation of a combined regimen to treat brain cancer. Methods: This is a prospective non-randomized open label to characterize the tolerability and safety profile of Avelumab in combination with LITT in patients with recurrent glioblastoma who were treated with radiation therapy with concurrent Temozolomide chemotherapy at diagnosis, and whose tumor at recurrence measures less then 3 cm3. Avelumab is administered within a week after real-time MRI-guided LITT therapy and every 2 weeks thereafter. On part A patients are treated with intravenous Avelumab alone and on part B patients receive Avelumab in combination with MRI-guided LITT. Part A completed enrollment without DLT. Enrollment on part B began in October 2018. A Simon minimax two-stage design is being used for efficacy. Toxicity will be scored using the NCI-CTCAE 4.03 criteria. Blood samples and tumor tissue will be collected for correlative studies. Quantification of the changes in inflammatory and immunosuppressive profiles across time points for patients receiving treatment with Avelumab will be obtained. This information will instruct future immunotherapy approaches to treat GBM and the rational for those combinations. Clinical trial information: NCT03341806.
A phase I clinical trial using armored GPC3 CAR T cells for children with relapsed/refractory liver tumors.
Authors: Steffin David Henry Michael , Batra Sai A , Rathi Purva , Guo Linjie , Li Wenpeng , Courtney Amy N , Metelitsa Leonid S , Heczey Andras
Published: May 2019

TPS2647

Background: CAR T therapies have been successful against hematologic malignancies, but have benefited only a handful of patients with solid cancers. Glypican 3 (GPC3) is an attractive immunotherapeutic target due to its preferential expression on multiple pediatric and adult solid cancers and lack of expression on non-malignant tissues. GPC3-CAR T cells were tested preclinically and inclusion of the 4-1BB costimulatory endodomain with IL-15 and IL-21 co-expression enabled CAR T cells to expand and persist the most in vitro and in vivo and led to robust antitumor activity in vivo. We are now testing GPC3-CAR T cells with IL15 and IL-21 for the first time in children with relapsed/refractory liver tumors. Methods: In this Phase 1 trial (GAP, NCT02932956), we are evaluating patients in 3 cohorts: 1) GPC3-CAR alone; 2) GPC3-CAR and IL-15; 3) GPC3-CAR with IL-15 and IL-21. We will 1) define the safety and establish the Recommended Phase 2 Dose (RP2D) of GPC3-CAR T cells co-expressing IL-15 and IL-21; 2) determine persistence and anti-tumor activity of GPC3-CAR T cells; 3) examine changes in gene and protein expression in the tumor microenvironment associated with potential immune escape mechanisms. Inclusion criteria are the following: age ≤18; histology proven, GPC3-positive tumor; life expectancy>12 weeks; Child-Pugh-Turcotte score<7; serum AST<5 times ULN; total bilirubin<3 times ULN for age; INR ≤1.7; absolute neutrophil count>500/μl; platelet count>20,000/μl; Hgb≥9.0 g/dl. Toxicity will be monitored using the Common Terminology Criteria of Adverse Events v4. The RP2D will be determined by the standard 3+3 dose escalation method using 5 dose levels. Persistence will be quantified using RT-PCR and flow cytometry. Antitumor activity will be defined by 3D imaging using RECIST 1.1 criteria and the immune-related response criteria. Immune-escape will be examined using single cell RNA sequencing and imaging of paraffin-embedded tissues using codetection by indexing to evaluate candidate proteins. Data will be analyzed via descriptive statistics. Cohort 1 of this study is now open for enrollment. Clinical trial information: NCT02932956.
A phase II study of autologous tumor infiltrating lymphocytes (TIL, LN-144/LN-145) in patients with solid tumors.
Authors: Chesney Jason Alan , Lutzky Jose , Thomas Sajeve Samuel , Nieva Jorge J. , Munoz Couselo Eva , Martin-Liberal Juan , Rodriguez-Moreno Juan Francisco , Cacovean Alex , Li Huiling , Fardis Maria , Gettinger Scott N.
Published: May 2019

TPS2648

Background: Adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) has demonstrated durable complete responses in immunogenic tumors with high mutational burden in metastatic melanoma patients who had not received prior immune checkpoint inhibitors (ICI); CR rate 24%. Pembrolizumab is an approved agent for the treatment of metastatic melanoma and head & neck cancers, among others. Further, ICI have been reported to potentially enhance the efficacy of TIL therapy. One aim of this study is to improve the efficacy response for early line patients by combining TIL with anti-PD-1 in ICI-naïve patients with metastatic melanoma (Cohort 1) and head & neck cancers (Cohorts 2). In Cohort 3, TIL therapy alone is offered to NSCLC patients who have received prior systemic therapy, including ICI. Methods: IOV-COM-202 is a prospective, Phase 2 multicenter, open-label study in which 36 patients (12 per cohort) are to be enrolled in one of three cohorts; Cohorts 1 and 2: TIL therapy in combination with pembrolizumab, or Cohort 3: TIL therapy alone. Patients will have tumors resected at local centers and shipped to a central GMP facility to undergo a 22-day manufacturing process that yields cryopreserved infusion product (LN-144/LN-145) that is shipped back to treating center. All patients receive TIL therapy consisting of 1 week of preconditioning cyclophosphamide/fludarabine, followed by a single infusion of LN-144/LN-145 (Day 0) and up to 6 doses of IL-2 (600,000 IU/kg). Patients in Cohorts 1 and 2 also receive pembrolizumab on Day -1 and then Q3W for up to 2 years or until disease progression or acceptable toxicity. Co-primary endpoints for each cohort are objective response rate (ORR) per RECIST 1.1, and safety (grade ≥ 3 TEAE). Eligibility criteria: Cohorts 1 (melanoma) and 2 (head & neck): patients must not have received prior ICI (eg, anti-PD-1, anti-CTLA-4) and may have received up to 3 lines of prior systemic therapy, Cohort 3 (NSCLC): patients must have received 1-3 prior lines of systemic therapy including ICI. After tumor resection for TIL manufacturing, patients must have additional measurable disease for assessment per RECIST 1.1. Adequate bone marrow/organ function and ECOG PS of 0 or 1 is required. Clinical trial information: NCT03645928.
Adoptive transfer of tumor-infiltrating lymphocytes in patients with sarcomas, ovarian, and pancreatic cancers.
Authors: Amaria Rodabe Navroze , Bernatchez Chantale , Forget Marie-Andree , Haymaker Cara L. , Conley Anthony Paul , Livingston J. Andrew , Varadhachary Gauri Rajani , Javle Milind M. , Maitra Anirban , Tzeng Ching-Wei David , Hinchcliff Emily , Bayer Virginia , Gasior Yvonne , Hilton Tyler , Celestino Joseph , Rangel Kelly M , Yuan Ying , Lu Karen H. , Hwu Patrick , Jazaeri Amir A.
Published: May 2019

TPS2650

Background: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) has a long history of efficacy in metastatic melanoma, and is being increasingly considered across other solid tumors. Preclinical data generated at MD Anderson Cancer Center has demonstrated the ability to grow TIL from a variety of tumor types including various types of sarcomas, ovarian and pancreas cancers. We are testing the efficacy of TIL across multiple tumor types using two different manufacturing protocols. Methods: We are conducting two ongoing investigator initiated basket TIL therapy trials. The first (NCT03449108) includes cohorts with poorly differentiated soft tissue and bone sarcomas, osteosarcoma, and platinum resistant ovarian cancer. The TIL product used in this trial is an investigational cell product (LN-145, Iovance Biotherapeutics, Inc.). The second trial (NCT03610490) includes cohorts of osteosarcoma, platinum resistant ovarian cancer, and pancreatic cancer (who have progressed on, or received maximal benefit from, front-line therapy). For this trial, TIL are manufactured at MD Anderson Cancer Center using a protocol that includes the use of urelumab (an agonistic anti-CD137 antibody) combined with T cell receptor activation during TIL expansion. In both trials eligible subjects undergo tumor harvest using a surgical excisional biopsy of the tumor for TIL manufacturing, receive a modified cyclophosphamide and fludarabaine lymphodepletion regimen and up to six doses of IL-2 (600,000 IU/kg) following TIL infusion. No intervening therapy is allowed between tumor harvest and initiation of lymphodepletion. The primary endpoint for each cohort is ORR as assessed by investigators using RECIST 1.1 criteria. The Simon’s two stage design is used to monitor the efficacy of each cohort independently. In the first stage, 10 patients will be treated per cohort. If there is no confirmed response in these 10 evaluable patients, the cohort will be terminated. If the cohort moves forward to Stage II, an additional 8 patients will be treated leading to a total of 18 patients. Three or more responders out of 18 treated patients for the cohort will be considered clinically relevant to justify further investigation. Enrollment is ongoing in all cohorts in both trials. An accrual update will be provided at the annual meeting. Clinical trial information: NCT03449108, NCT03610490.
SWOG 1609 (DART): A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors.
Authors: Patel Sandip Pravin , Othus Megan , Chae Young Kwang , Giles Frank , Hayward Jourdain , McLeod Christine , Chen Helen X. , Sharon Elad , Mayerson Edward , Ryan Christopher W. , Plets Melissa , Blanke Charles David , Kurzrock Razelle
Published: May 2019

TPS2658

Background: Immune checkpoint blockade, in particular anti-CTLA-4 and anti-PD-1-directed approaches, have improved outcomes in various tumor types. However, little is known about the efficacy of these agents in advanced rare solid tumors. We sought to investigate the activity of ipilimumab and nivolumab in previously unstudied rare solid tumors, with planned biomarker evaluation pending including whole exome sequencing, RNAseq, and multiplex immune profiling via the NCI CIMACs. Methods: We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1mg/kg iv q6weeks) plus nivolumab (240mg iv q2weeks) across 37 cohorts of rare tumors. Eligible patients had incurable rare cancer, defined histologically with an incidence of less than 6 in 100,000 per year, and did not have an approved or standard therapy available that had been shown to prolong overall survival. Patients were required to be 18 years of age or older, have a Zubrod performance status of 0-2, with absolute neutrophil count ≥ 1,000/mcL, platelets ≥ 75,000/mcL, hemoglobin ≥ 8 g/dL, creatinine clearance ≥ 50 mL/min, total bilirubin ≤ 2.0 x institutional upper limit of normal (IULN), AST and ALT ≤ 3.0 x IULN, TSH or free T4 serum ≤ IULN, and normal adrenocorticotropic hormone (ACTH) ≤ IULN. The primary endpoint was overall response rate (ORR) by RECIST v1.1 (complete (CR) and partial responses (PR)); secondary endpoints included progression-free (PFS) and, overall survival (OS), stable disease (SD) ≥ 6 months, and toxicity. The primary objective of this Phase II trial was to evaluate the overall response rate (ORR, confirmed complete and partial responses [CR and PR]) by RECIST v1.1. Our objective was to distinguish between a true ORR 15% (null hypothesis) versus 30% (alternative hypothesis). A Simon’s two-stage design was used, which required an analysis on the first 6 eligible patients who received therapy. If 1 or more of the 6 patients had a response (confirmed CR or PR), an additional 10 patients were to be accrued. The study was activated on 1/13/17 with the first patient treated on 3/1/17. The trial is currently open at 862 sites across the NCTN (with 352 sites having enrolled patients) and 554 patients enrolled to date. Clinical trial information: NCT02834013.
Pembrolizumab in MMR-proficient metastatic colorectal cancer pharmacologically primed to trigger dynamic hypermutation status: The ARETHUSA trial.
Authors: Siena Salvatore , Sartore-Bianchi Andrea , Personeni Nicola , Pietrantonio Filippo , Germano Giovanni , Amatu Alessio , Bonoldi Emanuela , Valtorta Emanuele , Barault Ludovic , Di Nicolantonio Federica , Siravegna Giulia , Crisafulli Giovanni , Rimassa Lorenza , De Braud Filippo G. , Santoro Armando , Lazzari Luca , Luraghi Paolo , Amirouchene-Angelozzi Nabil , Bardelli Alberto , Marsoni Silvia
Published: May 2019

TPS2659

Background: Metastatic colorectal cancer (CRC) harbouring genetic defects in the mismatch-repair pathway (MMRd) presents with a high tumor mutational burden (TMB), and is highly sensitive to anti–programmed cell death protein 1 (PD-1) immune checkpoint inhibitors. We recently showed in preclinical models that the pharmacological treatment with temozolomide (TMZ) can induce the inactivation of MMR genes, and consequently the increase of TMB and immunogenic neoantigens, thus suggesting that TMZ could be used to prime MMR proficient (MMRp) tumors for response to checkpoint inhibitors. Accordingly, mCRC patients recruited in previous clinical trials where TMZ was administered, acquired alterations of MMR genes upon treatment and showed remarkable increase in TMB at disease progression (PD). We thus designed the ARETHUSA clinical trial to test whether a priming course with TMZ in patients can sensitize mCRC to the anti-PD1 inhibitor pembrolizumab. Methods: Arethusa (NCT03519412) is a 2-cohorts, phase II trial consisting of three different phases. In the SCREENING, 348 mCRC RAS-mutated patients will be tested for MMR status. MMRd patients will proceed directly to TRIAL for immediate pembrolizumab treatment (expected 14). MMR-proficient (MMRp) patients will be further tested for expression of O6-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry and by promoter methylation analysis. IHC-negative, promoter methylation-positive MMRp patients (expected 67) will enter in the PRIMING phase and will be treated with TMZ until PD. TMB will then be assessed on tumor biopsies at resistance. Those patients that will have > 20 mutations/megabase will proceed to TRIAL (expected 20) and will be treated with pembrolizumab. Overall response rate (primary outcome), Progression Free, and Overall Survival, and treatment related toxicities (secondary outcomes) in MMRp pembrolizumab-treated patients will be estimated., while the MMRd cohort will be used for comparison. Tissue biopsies, longitudinal blood and stool collection will be used for discovery of predictive molecular biomarkers and assessment of tumor evolution. Clinical trial information: NCT03519412.
A multicenter, phase II study of soluble LAG-3 (Eftilagimod alpha) in combination with pembrolizumab (TACTI-002) in patients with advanced non-small cell lung cancer (NSCLC) or head and neck squamous cell carcinoma (HNSCC).
Authors: Peguero Julio Antonio , Bajaj Pawan , Carcereny Enric , Clay Timothy Dudley , Doger Bernard , Felip Enriqueta , Krebs Matthew , Forster Martin , Ponce Aix Santiago , Roxburgh Patricia , Triebel Frederic
Published: May 2019

TPS2667

Background: Eftilagimod alpha (efti, IMP321) is a recombinant LAG-3Ig fusion protein that binds to MHC class II and mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. Pembrolizumab binds to the PD-1 receptor, blocking both immune-suppressing ligands, PD-L1 and PD-L2, from interacting with PD-1 to help restore effector T-cell responses. The rationale to combine efti and pembrolizumab comes from their complementary mechanisms of action. Efti activates APCs and lead to an increase in activated T cells which effect potentially reduces the number of non-responders to pembrolizumab. Combining an APC activator like efti to pembrolizumab is therefore fundamentally different from many other trials combining two checkpoint inhibitors like an anti-LAG-3 mAb with an anti-PD-1 mAb. In a previous phase I study (NCT 02676869) in metastatic melanoma the combination was found to be safe and well tolerable with encouraging signs of clinical activity. Methods: In the course of this multicenter, open label, Phase II study, patients will be recruited for each of three indications: A: 1st line, PD-X (PD-1 or PD-L1) naïve non-small cell lung cancer (NSCLC); B: 2nd line, PD-X refractory NSCLC; C: 2nd line PD-X naive head and neck squamous cell carcinoma (HNSCC). The study is designed according to Simon's optimal two-stage design, with objective response rate acc to iRECIST as primary endpoint. Secondary endpoints include progression free survival and overall survival. In case there are more responses achieved than a predefined threshold (each part counted separately) in pts recruited in the initial stage (n = 58), additional pts (51) will be recruited in stage 2. Efti will be administered for a maximum of 18 cycles (1 cycle = 3 weeks) as 30 mg subcutaneous injection every 2 weeks for the first 8 and every 3 weeks for the 10 following cycles. Pembrolizumab (200 mg intravenous infusion every 3 weeks) is administered in parallel for up to 35 cycles. Patients are followed up for progression and survival. Clinical trial information: 03625323.