bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II trial of nivolumab in combination with talazoparib in unresectable or metastatic melanoma patients with mutations in BRCA or BRCAness.
Authors: Sussman Tamara A. , Wei Wei , Hobbs Brian , Diaz-Montero C. Marcela , Ni Ying , Arbesman Joshua , Ko Jennifer S. , Gastman Brian , Funchain Pauline
Published: May 2020

TPS10082

Background: Melanoma has a response rate of 10-15% with anti-PD-1 re-challenge in the refractory setting. Newer targeted therapies in melanoma are needed, especially once patients progress on immune checkpoint inhibitor (ICI) therapy. Analysis of TCGA and the Cleveland Clinic’s Gross Family Melanoma Registry reveals that a significant proportion (~40%) of melanoma patients possess somatic (31.6%) or germline (TCGA: 4.2%; Registry: 8.3%) mutations in homologous recombination repair genes, which may serve as a therapeutic target. PARP inhibitors, specifically talazoparib, have demonstrated synthetic lethality, potent PARP trapping activity, and increased immunogenicity of tumor cells by promoting T cell and NK cell infiltration in vitro and in vivo. Moreover, augmentation of the STING pathway via PARP inhibition modulates the tumor microenvironment, impacting PD-L1 expression and type I interferon production. Therefore, the use of talazoparib in combination with the ICI, nivolumab, may have a synergistic immunomodulatory and antitumor effect. Methods: This phase II, single arm, open label trial aims to enroll 37 primary or recurrent unresectable or metastatic melanoma patients harboring a somatic or germline mutation or deletion in BRCA or BRCAness (genes including ARID1A/B/2, ATM, ATR, BAP1, BARD1, BLM, BRCA1/2, BRIP1, CDK4/12, CHEK1/2, DSS1, EMSY, ERCC3, FANCA/D2, HDAC2, IDH1, LIG3/4, MDC1, MLH1/3, MRE11, NBN, PALB2, PRKDC, RAD50/51/54, XRCC6) who have progressed on prior ICI therapy. Patients will be treated with nivolumab 480mg IV every 4 weeks and talazoparib 1mg PO daily. The primary objective is to determine clinical efficacy of the combination therapy, as measured by the objective response rate. The trial is designed to test the null hypothesis that ORR ≤ 10% and is powered to detect an effect size of ORR ≥ 30%. Secondary objectives include PFS, OS, immune-related objective response rate (irORR), irPFS, and treatment-related adverse events. Associations with clinical response will be assessed with correlative studies of PD-L1 expression, ctDNA, tumor mutational burden, copy number variation, and the phenotypic and functional characterization of circulating and tumor infiltrating immune cells. The study is currently open and enrolling patients. Clinical trial information: NCT04187833.
Personalized combination of neoadjuvant domatinostat, nivolumab and ipilimumab in macroscopic stage III melanoma patients stratified according to the interferon-gamma signature: The DONIMI study.
Authors: Reijers Irene L.M. , Dimitriadis Petros , Rozeman Elisa A. , Versluis Judith M. , Broeks Annegien , Bosch Linda J.W. , Bouwman Jasper , Cornelissen Sten , Krijgsman Oscar , Gonzalez Maria , Rao Disha , Grijpink-Ongering Lindsay G , van Dijk Marloes , Spillane Andrew , Scolyer Richard A. , Van De Wiel Bart A. , Menzies Alexander M. , Van Akkooi Alexander Christopher Jonathan , Long Georgina V. , Blank Christian U.
Published: May 2020

TPS10087

Background: Previous OpACIN and OpACIN-neo studies, investigating neoadjuvant ipilimumab (IPI) plus nivolumab (NIVO), demonstrated high pathologic response rates (74-78%) and favorable long-term outcomes in patients (pts) achieving pathologic response; at 36 and 18 months follow-up, respectively, only 1/71 (1.4%) pts with response has relapsed. In contrast, pts without pathologic response (pNR) have a poor prognosis; 15/23 (65.2%) have relapsed so far. This emphasizes the need for baseline biomarkers predictive of non-response and new neoadjuvant treatment combinations for these pts. In our previous studies, baseline interferon-gamma (IFN-γ) signature low pts were less likely to respond to neoadjuvant IPI plus NIVO. The DONIMI study tests the combination of NIVO +/- IPI with domatinostat (DOM), a class 1 histone deacetylase inhibitor, according to the IFN-γ signature in the tumor. Based on the signature previously described by Ayers et al. we have developed a neoadjuvant IFN-γ signature algorithm that will be used for the first time to classify pts in this prospective trial. Methods: The aim of this two-center investigator-initiated phase 1b study is to assess the safety and feasibility of neoadjuvant NIVO +/- DOM +/- IPI in 45 stage III melanoma pts with RECIST 1.1 measurable de-novo or recurrent disease. IFN-γ signature high pts (n = 20) will be randomized (stratified by center) to Arm A (2 cycles NIVO 240mg q3wk) or Arm B (2 cycles NIVO 240mg q3wk + DOM 200mg twice daily (BID), d1-14, q3wk). IFN-γ signature low pts (n = 25) will be randomized to Arm C (2 cycles NIVO 240mg q3wk + DOM 200mg BID, d1-14, q3wk) or Arm D (2 cycles NIVO 240mg q3wk + IPI 80mg q3wk + DOM 200mg once daily (OD), d1-14, q3wk). Based on safety data of the first 5 pts in arm D, the remaining pts will be treated with either a higher dosing scheme (200mg BID, d1-14, q3wks), a lower dosing scheme (100mg OD, d1-14, q3wks) or the same dosing scheme (200mg OD, d1-14, q3wks). The primary endpoint is safety and feasibility. A treatment arm will be declared as not feasible if 2/5 or 3/10 pts cannot adhere to the preplanned time of surgery (week 6 +/- 1week) due to treatment-related adverse events. Biopsies (week 0, 3), blood samples (week 0, 3, 6, 12) and feces (week 0, 3, 6) will be collected for translational research. The first patient was enrolled on January 23th, 2020. Clinical trial information: NCT04133948.
Phase II single-arm multi-center study of adjuvant ipilimumab in combination with nivolumab in subjects with high-risk ocular melanoma.
Authors: Rapisuwon Suthee , Patel Sapna Pradyuman , Carvajal Richard D. , Hernandez-Aya Leonel Fernando , Tsai Katy K. , Chandra Sunandana , Tan Ming Tony , Daud Adil , Sosman Jeffrey Alan , Atkins Michael B.
Published: May 2020

TPS10089

Background: Treatment of primary ocular melanoma is often very effective, with local recurrence rates of < 5%. However, distant recurrence is as high as 50% depending on features of the primary tumor. These data emphasize the need for effective adjuvant therapy for patients with locally treated ocular melanoma. Several adjuvant treatments have been developed for patients with high-risk cutaneous melanoma, including ipilimumab and nivolumab monotherapies and an ongoing trial is exploring the nivolumab/ipilimumab combination (CA209-915), but patients with high-risk ocular melanomas have been excluded from these trials. As yet there is no approved adjuvant treatment for high-risk ocular melanoma patients. Methods: We are conducting a Phase II single-arm multi-center study of adjuvant ipilimumab in combination with nivolumab in subjects with high-risk ocular melanoma. This study aims to generate efficacy and safety data for adjuvant this regimen in patients with locally treated high-risk ocular melanoma with 3-year risk of relapse > 50%. The primary endpoint is 3-year relapse-free survival rate. Secondary endpoints are median relapse-free survival, median overall survival, 3-year overall survival rate and safety. All patients will receive nivolumab 240mg IV every 2 weeks plus ipilimumab 1mg/kg IV every 6 weeks. Subjects may receive up to 25 doses of nivolumab and 8 doses of ipilimumab. The accrual goal is 50 patients across all participating institutions. Subjects treated in this study will be matched with controls selected from a contemporaneously collected OM registry, “contemporaneous control” in order to better assess efficacy. Control subjects will be from institutions not participating in this trial, will otherwise meet the trial eligibility criteria and will be further matched with trial participants for various demographic and risk factors to the extent possible. The study is enrolling in 6 comprehensive cancer centers in the US. Clinical trial information: NCT3528408.
First-in-human phase I study of anti-HER2 ADC MRG002 in patients with relapsed/refractory solid tumors.
Authors: Li Jin , Guo Ye , Xue Junli , Peng Wei , Ge Xiaoxiao , Zhao Wei , Dai Congqi , Xue Liqiong , Tang Wenbo , Hu Chaohong
Published: May 2020

TPS1101

Background: MRG002 is an antibody drug conjugate (ADC) composed of a humanized anti-HER2 IgG1 monoclonal antibody conjugated to a microtubule disrupting agent monomethyl auristatin E (MMAE). MRG002 is presently being investigated in an ongoing phase I study for safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity in patients (pts) with solid tumors. Methods: MRG002 is evaluated as monotherapy for the treatment of pts with confirmed HER2 positive locally advanced or metastatic cancers, including breast cancer (BC), gastric cancer (GC), salivary gland cancer (SGC) and others. The primary objective is to determine the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D). Secondary objectives include evaluation of PK, tumor response, and immunogenicity. In the dose escalation phase with “3+3” design, approximately 24 pts will be enrolled to identify MTD. The starting dose of MRG002 is 0.3 mg/kg, followed by 0.6, 1.2, 1.8, 2.2, 2.6, and 3.0 mg/kg. In the dose expansion phase, about 50 pts with HER2 positive advanced cancers will be enrolled to further evaluate the safety, antitumor activity, and PK at an appropriate confirmed dose. In this phase I study, each pt receives single agent MRG002 once every 3 weeks (Q3W) for a maximum of 8 treatment cycles. Pts with BC and GC should have HER2 positive advanced solid tumors per College of American Pathologists (CAP) guidelines. For other cancers, pts must have IHC status of 2+ or 3+, regardless of FISH results. Pts should have either failed or are ineligible for standard treatments. All pts must have at least 1 measurable lesion per RECIST 1.1. ECOG should be 0-1, and bone marrow, hepatic, renal, cardiac functions should be adequate. Observations include adverse events (AEs), dose-limiting toxicity (DLT), and antitumor activity, which is assessed every two treatment cycles. Further clinical trial details can be found on chinadrugtrials.org.cn (CTR20181778). Enrollment is ongoing since November 2018. Clinical trial information: CTR20181778 .
Trial in progress: A phase II open-label, randomized study of PARP inhibition (olaparib) either alone or in combination with anti-PD-L1 therapy (atezolizumab) in homologous DNA repair (HDR) deficient, locally advanced or metastatic non-HER2-positive breast cancer.
Authors: LoRusso Patricia , Pilat Mary Josephine Paula , Santa-Maria Cesar Augusto , Connolly Roisin M. , Roesch Erin Elizabeth , Afghahi Anosheh , Han Hyo S. , Nanda Rita , Wulf Gerburg M. , Assad Hadeel , Park Haeseong , Dees Elizabeth Claire , Force Jeremy Meyer , Noonan Anne M. , Brufsky Adam , Abramson Vandana G , Haley Barbara B. , Buys Saundra S. , Sharon Elad , Schalper Kurt A.
Published: May 2020

TPS1102

Background: While immunostimulatory therapies have shown great success, a major challenge remains identification of mechanisms to effectively treat the majority of patients with so-called "non-inflamed" tumors lacking marked lymphocyte infiltration and PD-L1 expression. The DNA repair proficiency of a tumor may impact its potential for immune recognition and sensitivity to immune checkpoint blockade. Preclinically, PARP inhibition in HDR-deficient tumors has been shown to trigger antitumor immunity through a STING-dependent antitumor immune response. Effects of PARP inhibitors were augmented when combined with PD-1 blockade. We hypothesize that enhanced DNA damage and cell death induced by PARP inhibition in tumors with homology directed repair (HDR) deficiency will enhance adaptive anti-tumor immune responses and increase sensitivity to PD-1 axis blockers. Methods: This is a randomized, open-label phase II clinical trial exploring the PARP inhibitor olaparib either alone or in combination with the anti-PD-L1 human monoclonal antibody atezolizumab in BRCA1/2 mutated locally advanced or metastatic non-HER2-positive breast cancer. HDR deficiency is defined as the presence of deleterious BRCA 1/2 mutations. Randomization occurs in a 1:1 fashion to two arms: (1) olaparib 300 mg PO bid continuously in 21-day cycles or (2) olaparib 300 mg PO bid continuously in combination with atezolizumab 1200 IV every 3 weeks in 21-day cycles. Patients undergo baseline evaluations and pre-treatment biopsy within 2 weeks of starting therapy. Repeat biopsies are required at the time of first tumor assessment scan (6 weeks from the start of treatment) and in the event of disease progression. Correlative studies, including detailed analysis of the genomic profile and tumor immune contexture, will be performed at each biopsy time point. The primary objective is to compare progression free survival between the study arms. If progression occurs on the olaparib monotherapy arm, cross-over to the combination arm is allowed. This study began enrolling in August 2018; 47 of the planned 72 patients have been registered. Clinical trial information: NCT02849496 .
Phase II preoperative window study of SAR439859 versus letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer.
Authors: Campone Mario , Herold Christina Isabella , Wang Qiuyan , Pelekanou Vasiliki , Cartot-Cotton Sylvaine , Ling Bethany ,   on behalf of the ACT16106 Study Investigators
Published: May 2020

TPS1108

Background: Endocrine therapy targeting ER signaling is the standard of care for women with ER+ breast cancer. Selective ER degraders (SERDs) block ER signaling through dual competitive antagonism and receptor degradation. SAR439859, a potent, oral SERD, is in clinical development for ER+/HER2- breast cancer. This study is a 14-day preoperative non-therapeutic ‘window of opportunity’ trial to assess the direct effects of SAR439859 on tumor cell proliferation by evaluating the pharmacodynamic activity of SAR439859 in ER+/HER2- breast cancer. Methods: This international, open-label, Phase II randomized study (NCT04191382; ACT16106) evaluates SAR439859 at two dose levels versus the aromatase inhibitor letrozole by assigning 126 preoperative patients 1:1:1 to receive SAR439859 400 mg/day, SAR439859 200 mg/day or letrozole 2.5 mg/day. SAR439859 dosing is based on an ongoing Phase I/II study (NCT03284957; TED14856) in metastatic breast cancer (Campone. SABCS 2019. P5-11-02). Postmenopausal women with ER+/HER2- breast cancer indicated for immediate surgery (Stage I, Stage II or operable Stage III), Eastern Cooperative Oncology Group performance status 0–1 and Ki67 levels of ≥ 15% are eligible. Exclusion criteria include disorders potentially affecting absorption of SAR439859 or letrozole, and any prior therapy for breast cancer. Patients receive study treatment for 14 days, with the last dose given on the day before surgery. Paired tumor biopsies for assessment of biomarkers are performed at baseline and during surgery. The primary study endpoint is change in Ki67, a predictor of treatment benefit and long-term survival outcomes, after 14 days of treatment compared with baseline. Secondary endpoints include proportion of patients with ≥ 50% decrease in Ki67, ER expression to assess degradation, and safety. Pharmacokinetics of SAR439859, additional tumor markers, genomic mutation profile, Preoperative Endocrine Prognostic Index and pathological Complete Response will also be assessed. The study is currently recruiting; target enrollment: n = 126. Clinical trial information: NCT04191382 .
First-in-human phase I/Ib multicenter, open-label dose escalation study to assess safety and tolerability of PMD-026 in patients with metastatic breast cancer with expansion in metastatic triple negative breast cancer.
Authors: Beeram Muralidhar , Wang Judy Sing-Zan , Mina Lida A. , Patnaik Amita , Pambid Mary Rose , Jayanthan Aarthi , Huynh My-my , Dunn Sandra Elaine , Los Gerrit , Dorr Andrew
Published: May 2020

TPS1110

Background: Metastatic triple negative breast cancer (mTNBC) has a poor prognosis with limited durable treatment options. RSK (P90 ribosomal S6 kinase) is a signaling protein at the convergence point of PDK-1 and MAPK signaling pathways. RSK1-3 phosphorylates transcription factors, including Y-box binding protein-1 (YB-1), thereby inducing drug resistance and cancer growth genes. Phosphorylated YB-1 is involved in tumor cell survival, proliferation, and drug resistance. In human breast tumor samples, RSK2 protein is expressed across all breast cancer subtypes (TNBC, ER+ and HER2+) and is associated with poor overall survival. Expression of RSK2 is found in approximately 87% of mTNBC tumors and of those tumors approximately 41% have very high expression of RSK2. PMD-026 is a potent, oral, small molecule RSK inhibitor with high selectivity for RSK2. Preclinical in vivo studies have demonstrated activity both as a single agent and in combination with standard of care therapies. Further, a CAP/CLIA certified IHC method has been developed with Roche to determine tumor expression of RSK2. Methods: This single-arm, open-label, first-in-human, phase I/Ib study evaluates the safety and efficacy of single agent PMD-026 in patients with metastatic breast cancer for whom standard therapies are no longer effective. During dose escalation, the study utilizes an accelerated titration design with single patient cohorts until the occurrence of DLT or Grade 2+ toxicity; then reverts to 3+3 design to define the maximally tolerated dose (MTD) and recommended phase II dose (RP2D). The dose expansion portion will enroll approximately 20 patients with mTNBC. Patients are dosed orally once daily in 21-day cycles with measures to adapt the dosing schedule based on the pharmacokinetic (PK) data, as needed. Tumor tissue is required for all enrolled patients; RSK2 expression will be retrospectively correlated with clinical outcomes. The primary objectives are to determine safety and tolerability of PMD-026, determine the MTD, define a RP2D, and assess anti-tumor activity of PMD-026 in patients with TNBC. Secondary objectives are to evaluate PK, time to response, mTNBC subtyping using NanoString, and duration of response of PMD-026. To date, cohorts 1 and 2 have been completed without DLT. Enrollment to cohort 3 began in January 2020. Clinical trial information: NCT04115306 .
Phase II trial of a PARP inhibitor in somatic BRCA mutant metastatic breast cancer.
Authors: Vidula Neelima , Horick Nora K. , Blouch Erica , Rivera Amalia , Basile Erin , Fax Ruth , Ellisen Leif W. , Rugo Hope S. , Bardia Aditya
Published: May 2020

TPS1113

Background: Poly(ADP-ribose) polymerase (PARP) inhibitors are now approved for patients with germline BRCA1/2 mutated HER2 negative metastatic breast cancer (MBC). However, germline BRCA1/2 mutations only account for 5-10% of breast cancer. We previously demonstrated that a subset of MBC may harbor somatic BRCA1/2 mutations detectable by cell-free DNA (cfDNA) (Vidula, SABCS, 2017). We hypothesize that somatic BRCA1/2 mutant MBC may also respond to PARP inhibition, similar to ovarian cancer, where PARP inhibition is efficacious in both somatic and germline tumors (Oza, 2017). Methods: This single arm, open label, phase II clinical trial is evaluating the efficacy of talazoparib, a PARP inhibitor, in 30 patients with somatic pathogenic BRCA1/2 mutant MBC identified by cfDNA. Patients may have triple-negative disease with receipt of at least 1 prior chemotherapy regimen, or hormone receptor positive, HER2 negative disease with at least 1 prior hormone therapy for MBC. Patients may have received a prior platinum, in the absence of progression on platinum chemotherapy. Patients must not have a known germline BRCA1/2 mutation. Patients will be treated with talazoparib 1 mg daily until progression, unacceptable toxicity, or withdrawal of consent, with clinical exams monthly, scans (CT chest, abdomen, and pelvis, and bone scan as appropriate) every 3 months, and serial cfDNA collected monthly. The primary endpoint is progression-free survival, as defined by RECIST 1.1. Subjects are enrolled in a 2-stage design, which provides 80% power to demonstrate that treatment is associated with “success” (PFS > 12 weeks) in ³ 53% patients (4% alpha). Additional endpoints include objective response rate and toxicity (per NCI CTCAE version 5.0). Correlative endpoints include determining changes in BRCA1/2 mutant allele fraction, genomic evolution including emergence of BRCA reversion mutations, and the impact of biomarker changes on outcomes. This trial is currently enrolling patients at the Massachusetts General Hospital. Successful completion of this study may help expand the patient population that is able to benefit from PARP inhibition. Clinical trial information: NCT03990896 .
LENVAGIST - A multicenter, comparative, placebo-controlled, double-blinded, phase II study of the efficacy of lenvatinib in patients with locally advanced or metastatic GIST after failure of imatinib and sunitinib.
Authors: Le Cesne Axel , Cropet Claire , Gautier Julien , Gagne Stéphanie , Francourt Katia , Remir Emilie , Hernandez Caroline , Dufresne Armelle , Ray-Coquard Isabelle Laure , Carbonnaux Mélodie , Mery Benoite , Vanacker Helene , Bertucci Francois , Launay Simon , Louvel-Perrot Delphine , Monneur Audrey , Brahmi Mehdi , Blay Jean-Yves
Published: May 2020

TPS11568

Background: GastroIntestinal Stromal Tumors (GIST) are paradigmatic models of cancers with a driver mutation of an oncogene, in which imatinib is recommended as adjuvant therapy or treatment of locally advanced and metastatic forms. After failure of imatinib (either progression or toxicity), sunitinib and regorafenib are indicated as 2nd and 3rd lines, respectively. Beyond approved drugs, tyrosine kinase inhibitors (TKI) can bring clinical benefit because some clones remain sensitive to TKI. Lenvatinib is a broad spectrum TKI targeting KIT, RET, PDGFRA, VEGFR 1-3 and FGFR 1-4, that is approved in the treatment of differentiated thyroid carcinoma and metastatic renal cell carcinoma and hepatocellular carcinoma. Methods: This prospective, randomized, placebo-controlled, double-blinded, multicenter trial evaluates the efficacy and safety of Lenvatinib in adult GIST patients (pts) who failed at least to previous imatinib and sunitinib. Seventy-four pts will be randomly allocated in a 1:1 ratio to receive either oral lenvatinib, at a daily dose of 24mg, or its matching placebo, continuously, until progression of disease (PD) or unacceptable toxicity. Randomization will be stratified according to the number of different previous anticancer drugs (2 or > 2). The primary objective is to compare the Progression-free survival (PFS) between arms. The expected median PFS are 1.5 month in the control arm and 3.0 months in the experimental arm (HR = 0.5). Seventy one events will provide 90% power to show significant improvement in PFS, using a 2-sided log-rank test at a 10% level. Secondary endpoints include the overall survival, the objective response rate, the best overall response, the quality of life and the safety profile. Patients allocated in the placebo arm who experience PD (RECIST 1.1) may switch to active lenvatinib. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify blood and tumor parameters as predictive markers of lenvatinib efficacy. Recruitment has been activated in January 2020. Ten participating sites of the French Sarcoma Group will participate in the trial. Clinical trial information: NCT04193553 .
The TNT protocol: A phase II study using talimogene laherparepvec (TVEC), nivolumab (N) and trabectedin (T) as first, second/third line therapy for advanced sarcoma, including desmoid tumor and chordoma.
Authors: Chawla Sant P. , Chua Victoria S. , Kim Katherine , Dy Paul Stendahl , Paz Micaela Kristina , Angel Nicole , Wang Kelly , Moradkhani Ania , Quon Doris , Wong Steven , Jafari Omid , Gordon Erlinda Maria
Published: May 2020

TPS11572

Background: Talimogene laherparepvec (TVEC), an oncolytic HSV expressing huGMCSF, may be synergistic with trabectedin (T) and nivolumab (N) in treating advanced sarcoma. Objectives: (1) To evaluate the best overall response by RECIST v1.1, progression-free survival rate (PFS), and overall survival rate, (2) To determine the incidence of conversion of an unresectable tumor to a resectable one, and (3) To evaluate the incidence of adverse events related to the drug combination. Methods: This is an open label phase 2 study. A total of 40 patients will receive T (1.2 mg/m2 CIV over 24 hours q3 weeks), N (240 mg IV over 30 min q 2 weeks) and TVEC (intratumorally q 2 weeks according to tumor size). Eligible patients are those with histopathologically confirmed diagnosis of locally advanced, unresectable or metastatic sarcoma including desmoid tumor and chordoma, previously untreated or treated, with measurable disease by RECIST v1.1, and at least, one accessible tumor for intratumoral injection of TVEC. Currently, 31 of the 40 patients have been enrolled. Statistical Considerations: Continuous variables will be summarized by the sample size (n), mean, standard deviation, first and third quartiles, minimum and maximum. Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. Safety (incidence and severity of adverse events and significant laboratory abnormalities) will be performed on all patients (ITT population). Patient incidence of all treatment emergent AEs will be tabulated by system organ class and preferred term. Clinical trial information: 03886311 .
A phase Ib/III randomized, double-blind, placebo-controlled study of tazemetostat plus doxorubicin as frontline therapy for patients with advanced epithelioid sarcoma.
Authors: Sen Shiraj , McKean Meredith Ann , Sierra Laura , Ainscough Jessica , Yang Jay , Hamlett Anthony , Zimmerman Tom , Merchant Melinda , Chawla Sant P.
Published: May 2020

TPS11573

Background: Epithelioid sarcoma (ES) is characterized by loss of inhibitor of integrase 1 (INI1), allowing enhancer of zeste homologue 2 (EZH2) to repress cell differentiation and promote tumorigenesis. Tazemetostat (TAZ) is an EZH2 inhibitor approved by the FDA as monotherapy for the treatment of patients (pts) aged ≥16 years with metastatic or locally advanced ES ineligible for complete resection. The most common ( > 20%) adverse events include pain, fatigue, nausea, decreased appetite, vomiting, and constipation. TAZ demonstrated anti-cancer activity in ES pts who previously received doxorubicin (dox), a commonly used front line FDA approved therapy for soft tissue sarcomas (STS), including ES. Preclinical studies have demonstrated synergy between TAZ and dox. This phase 1b/3 study (NCT04204941) is assessing the safety and efficacy of TAZ + dox in pts with advanced ES. Methods: This study is enrolling treatment-naïve adult pts with histologically confirmed STS (phase 1b) or INI1-deficient ES pts (phase 3) with ECOG performance status of 0-2 and life expectancy of ≥3 months. The open-label phase 1b portion is currently enrolling up to 24 patients with STS. The primary objectives are to evaluate the safety and tolerability of TAZ + dox, and to identify the recommended phase 3 dose (RP3D). Using a standard 3 + 3 design, TAZ will be evaluated at 3 dose levels (400 mg, 600 mg, and 800 mg orally BID) with standard fixed dose of dox (75 mg/m2 on day 1 of 21-day cycles for up to 6 cycles). After completion of dox, pts will continue to receive TAZ monotherapy until disease progression or intolerable toxicity. Up to 12 additional pts will be enrolled at the maximum tolerated dose for collection of additional safety and pharmacokinetic (PK) data. The double-blind phase 3 study will randomize (1:1) up to 140 pts to receive either TAZ (RP3D) + dox (75 mg/m2) or placebo + dox. The adaptive study design will allow sample size re-estimation (at interim analysis) to up to 200 pts. Pts may continue TAZ or placebo monotherapy after completing 6 cycles of TAZ + dox. Tumor assessments will be performed at screening and every 6 weeks from the start of dosing. The primary objective of phase 3 will be to evaluate the progression-free survival (PFS) by independent review committee. Secondary objectives will include assessment of PFS by investigators, overall survival, safety, disease control rate, overall response rate, duration of response, time to subsequent anticancer therapy, PFS on next treatment, quality of life, and PK. Clinical trial information: NCT04204941 .
An oro-buccal nanoparticle delivered cannabis medicine for pain management in cancer: A clinical trial in progress.
Authors: Clarke Stephen John , Vitetta Luis , McLachlan Andrew J , Henson Jeremy David , Rutolo David , Hall Sean
Published: May 2020

TPS12127

Background: Cannabinoid molecules derived from Cannabis sativa L. have been posited to ameliorate conditions, including pain, chemotherapy induced nausea and multiple sclerosis associated spasticity. The clinical use of cannabinoids refers to a wide variety of formulations and extracts that may contain different active ingredients and adulterants as well as inter batch variability. Novel matrix formulations (e.g., water-soluble nanoparticles) for cannabis delivery may add further efficacy and tolerability to standard routes of administration (e.g., oral / gastrointestinal, inhaled, sublingual). This is further emphasized by the dysbiotic effects on the intestinal microbiome reported for oral formulations of medicinal cannabis, and which resulted in reduced efficacy. Similar results have been reported for other psychotropic compounds, such as alcohol and nicotine. Therapeutic use of cannabinoid formulations may be mode of delivery dependent in order to achieve safe, tolerable and effective doses. Methods: A water soluble oro-buccal nanoparticle spray with a racemic 1:1 mixture of Delta9Tetrahydrocannabinol (D9THC) and Cannabidiol (CBD), which bypasses the gastrointestinal system and first pass metabolism by accessing the systemic circulation via the facial lymphatics system, was investigated in patients with advanced cancer and unrelieved pain in a single ascending dose and multiple ascending dose in a first-in-human study. Results: The THC / CBD combination delivered as a submicron particle demonstrated safety, tolerability and a pharmacokinetic profile suitable for maintenance analgesic therapy. Preliminary analysis found an overall (n = 25) improvement in pain scores, especially in the subgroup of patients with bone metastases (n = 8), who obtained a greater than 30% average reduction in pain severity. 1 Clinical trial information: ACTRN12617001480370 .
A phase Ib study of the safety and pharmacology of nilotinib to prevent paclitaxel-induced peripheral neuropathy in patients with breast cancer.
Authors: Adams Elizabeth J. , Lustberg Maryam B. , Jin Yan , Li Yang , Sparreboom Alex , Hu Shuiying
Published: May 2020

TPS12128

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of paclitaxel, but convincing evidence for a preventative technique founded on mechanistic rationale is lacking. We previously report that paclitaxel accumulation is mediated by the murine organic anion transporting polypeptide, OATP1B2 in mice (OATP1B1 and OATP1B3 in humans) (Leblanc, J Clin Invest, 2018). We found that paclitaxel induces acute and chronic neurotoxicity in mice in an OATP1B2-dependent manner, which is reversed by pre-treatment with FDA-approved tyrosine kinase inhibitor, nilotinib. Methods: This phase Ib dose finding study of nilotinib in combination with weekly paclitaxel is investigating the hypothesis that intermittent dosing of nilotinib 24 hours before paclitaxel infusion (excluding C1D1) and again 30 minutes before paclitaxel infusion will inhibit OATP1B1 and prevent CIPN. This hypothesis will be assessed using an adaptive Bayesian method for dose finding based on efficacy-toxicity trade-offs in patients with breast cancer stages I-III who qualify for paclitaxel therapy. Patients with previous ≥ grade 2 neuropathy on breast cancer therapies will be excluded. The primary objectives are to find the recommended phase II dose of nilotinib in combination with paclitaxel for early stage breast cancer, defined as the lowest intermittent dose of nilotinib that temporarily inhibits OATP1B1 function without affecting paclitaxel plasma pharmacokinetics (PK), and to determine the toxicity profile of nilotinib in combination with paclitaxel. OATP1B1 inhibition by nilotinib will be assessed via validated surrogate endogenous substrates, glycochenodeoxycholate sulfate (GCDGA-S) and chenodeoxycholate-24-glucuronide (CDCA-24G). Effective OATP1B1 inhibition will be ≥5-fold increase in AUC of GCDCA-S from pre- to post- treatment or detectable CDCA-24G levels post-treatment. The 4 nilotinib dose levels are 50 mg (dose level -1), 100 mg (dose level 1), 200 mg (dose level 2), 300 mg (dose level 3). IV paclitaxel dose of 80 mg/m2 on D1,8,15 for 12 total weekly doses will be used. Oral nilotinib will be administered 24 hours before paclitaxel infusion on C1D7,D14 and again 30 minutes before infusion on C1D8,D15. Secondary objectives are to determine paclitaxel’s effect on PK of nilotinib and vice versa. Quality of life via CIPN-20 survey, disease free survival, event free survival, overall survival are exploratory objectives. NCT04205903 enrollment opened February 2020 and is accepting patients. Clinical trial information: NCT04205903 .
Use of simulation for training family caregivers of patients receiving radiation therapy.
Authors: Mazanec Susan R , Blackstone Eric , Dorth Jennifer Anne , Sandstrom Kate , Alfes Celeste , Schiltz Nicholas K , Singer Mendel E , Rezaee Rod , Daly Barbara J.
Published: May 2020

TPS12129

Background: Positive treatment outcomes and avoidance of complications are dependent to a large extent on the care provided by family members. However, family caregivers report feeling unprepared to assume the multiple, complex tasks of caregiving, including tracheostomy care, tube feedings, wound and colostomy care, pain management, and emotional support. Despite being a critical extension of the oncology healthcare team, training of caregivers to manage symptoms, deal with communication issues with the care recipients, and take care of their own physical and emotional health as caregivers, is not integrated into clinical practice. The purpose of this clinical trial is to measure the effect of a psychoeducational caregiver intervention that incorporates simulation techniques focused on skill development to improve caregiver and patient outcomes. Simulation, commonly used in training healthcare professionals, is a form of experiential learning that creates events or situations to mimic clinical situations. Use of simulation for skills training in family caregivers of patients with cancer is rarely studied. Methods: This two-group, randomized clinical trial, which opened to accrual in December 2019, will recruit 180 caregivers from University Hospitals Seidman Cancer Center. Patients must be receiving radiation therapy for a diagnosis of stage I - III cancers of the rectum, anus, and esophagus; stage III NSCLC; or stage I – IV A/B head/neck cancer. Adult caregivers must be identified by the patient as their primary caregiver, who is providing daily assistance and/or emotional support. The intervention involves three in-person, one-on-one sessions during radiation treatments. The control group is usual care. Data will be collected at baseline, at the end of radiation treatment, and 4 and 20 weeks post-radiation treatment. The primary outcome is caregiver anxiety at 20 weeks postradiation treatment. Other caregiver outcomes include depression, health-related quality of life [HRQOL], and fatigue. Patient outcomes (HRQOL and interrupted treatment course) and healthcare utilization outcomes (unplanned hospital admission, emergency room visits, and use of intravenous fluids) will be measured. The analysis will consist of linear mixed model repeated measures, mediation and moderation tests, and Poisson regression methods. Clinical trial information: NCT04055948 .
Implementing a clinical risk prediction tool for patients undergoing active cancer treatment.
Authors: Handley Nathan , Binder Adam , Li Michael , Rogers Aliya , Csik Valerie Pracilio
Published: May 2020

TPS2086

Background: Acute care utilization (ACU), encompassing both emergency department visits and hospitalizations, is common in patients with cancer, with nearly three quarters of patients with advanced disease hospitalized at least once in the year after their diagnosis. Efforts to prospectively identify these patients prior to ACU have led to the development of a variety of scoring systems for specific cancer patient populations, including the elderly and those initiating palliative infusional chemotherapy. Prospectively identifying patients may enable early interventions to reduce ACU. However, few studies have demonstrated effective implementation of such prediction tools in clinical practice. We developed an oncology risk score (ORS) for active oncology patients (defined as patients with an active cancer diagnosis in the last 12 months who had a Medical Oncology encounter in a 180-day period ) to prospectively determine risk of ACU. Patients are defined as high risk (18% of patients, accounting for 57% of historical ACU), intermediate risk (25% of patients, accounting for 25% of ACU), or low risk (56% of patients, accounting for 18% of ACU) by the ORS. We are currently deploying a pragmatic implementation initiative to evaluate the impact of targeted nurse navigator (NN) outreach to patients defined as high risk for ACU by the ORS. Methods: The ORS is embedded within the health system electronic medical record. The ORS will be queried on a weekly basis. NNs will contact identified patients, prioritizing patients not yet identified by the navigation team by other means. Following chart review, NNs will either meet patients in person (if a visit is already planned within 24 hours) or complete standard navigation outreach and documentation (consisting of phone call and barrier assessment, as well as appropriate nursing intervention) if no visit is planned. NNs will determine follow up cadence based on clinical judgement. Efficacy will be determined using a case-control method. Case patients will be OCM patients defined as high risk by the ORS (historical n = 289); control patients will be non-OCM high risk patients (historical n = 388). The total number of patients in the case and control groups, as well as the proportion of patients in the group utilizing acute care, will be monitored over time. Proportion of high risk patients known to navigation will be tracked. ACU in medium and low risk groups will also be monitored. Targeted outreach to high risk patients using the ORS began on 2/5/2019.
Alliance A071701: Genomically guided treatment trial in brain metastases.
Authors: Brastianos Priscilla Kaliopi , Twohy Erin , Anders Carey K. , Iafrate A. John , Kaufman Peter A. , Cohen Justine Vanessa , Heist Rebecca Suk , Gerstner Elizabeth Robins , Kaufmann Timothy J. , Geyer Susan , Hoffman Laura , Kumthekar Priya , Barker Frederick G. , Carter Scott L. , Brown Paul D. , Galanis Evanthia
Published: May 2020

TPS2573

Background: Brain metastases, most commonly derived from melanoma, lung and breast cancers, are the most common brain tumor, with approximately 200,000 cases diagnosed annually in the United States. Median survival is on the order of months. For patients with clinically symptomatic brain metastases, approximately half succumb due to intracranial progression. In preclinical work, we demonstrated that brain metastases and primary tumors are often genetically distinct with frequent alterations in the CDK and PI3K pathway (Brastianos, Carter et al. Cancer Discovery 2015). Methods: We are currently accruing to a prospective multi-arm phase II study of CDK, PI3K/mTOR, and NTRK/ROS1 inhibitors in patients with brain metastases harboring alterations associated with sensitivity to these inhibitors (abemaciclib, paxalisib and entrectinib), respectively. Patients with new, recurrent or progressive brain metastases are eligible for this trial. Previously obtained tissue from brain metastases and extracranial sites (primary or extracranial metastases) are screened for the presence of these alterations, and if present in both tumor sites, patients will receive the appropriate corresponding targeted treatment. Screening is carried out with the SNaPshot NGS assay, which is a fully validated clinical test designed and developed at the MGH Center for Integrated Diagnostics. The primary endpoint of response rate (RR) in the central nervous system as per RANO criteria will be evaluated separately for each inhibitor, stratified by histology within each arm. There will be 21 evaluable patients assigned to each of the CDK and PI3K inhibitor and tumor type cohorts (breast, lung and other) and 10 patients assigned to the NTRK/ROS1 inhibitor cohort (lung) for a total of 136 evaluable patients. Although current systemic therapy for brain metastases is often ineffective, we hypothesize that targeted therapies will demonstrate efficacy in patients harboring the appropriate mutations. This study represents a novel individualized therapeutic approach in brain metastases, a disease with a critical need for effective therapy. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org ; Genentech, Kazia Therapeutics Limited, Eli Lilly; Clinical trial information: NCT03994796 .
INDIGO: A global, randomized, double-blind, phase III study of vorasidenib (VOR; AG-881) vs placebo in patients (pts) with residual or recurrent grade II glioma with an isocitrate dehydrogenase 1/2 (IDH1/2) mutation.
Authors: Mellinghoff Ingo K. , Van Den Bent Martin J. , Clarke Jennifer Leigh , Maher Elizabeth Anne , Peters Katherine B. , Touat Mehdi , De Groot John Frederick , De La Fuente Macarena Ines , Arrillaga-Romany Isabel , Wick Wolfgang , Ellingson Benjamin M. , Schoenfeld Steven , Tai Feng , Le Kha , Lu Min , Steelman Lori , Hassan Islam , Pandya Shuchi Sumant , Wen Patrick Y. , Cloughesy Timothy Francis
Published: May 2020

TPS2574

Background: Low-grade gliomas (LGGs; WHO grade II) are incurable and ultimately progress to high-grade gliomas. The current treatment options consist of surgery followed by observation (“watch and wait”) for pts with lower risk for disease progression or post-operative chemo-radiotherapy (high-risk population). There are no approved targeted therapies. IDH1 and IDH2 mutations (m IDH1/2) occur in approximately 70% and 4% of LGGs, respectively, and promote tumorigenesis via neomorphic production of D-2-hydroxyglutarate (2-HG). VOR, an oral, potent, reversible, brain-penetrant inhibitor of mIDH1/2, was evaluated in 76 pts with glioma in two phase 1 studies (dose escalation and perioperative) and was associated with a favorable safety profile at doses of < 100 mg daily. Preliminary clinical activity was observed in non-enhancing glioma pts in both studies, most recently with an objective response rate (ORR) of 30.8% at 50 mg QD in the perioperative study and > 90% 2-HG suppression at this dose level relative to untreated control samples (Mellinghoff et al., J Clin Oncol 2019). Methods: Approximately 366 pts will be randomized 1:1 to VOR (50 mg QD) or matched placebo and stratified by 1p19q status (intact vs co-deleted). Key eligibility criteria include: age ≥12 years; grade 2 oligodendroglioma or astrocytoma (per WHO 2016 criteria) not in need of immediate treatment and without high-risk features; centrally confirmed m IDH1/2 status; ≥1 prior surgery for glioma within the previous 5 years but no other anticancer therapy; Karnofsky performance status ≥80%; and centrally confirmed measurable, non-enhancing disease evaluable by magnetic resonance imaging. Crossover from placebo to the VOR arm is permitted upon centrally confirmed radiographic progression per RANO-LGG criteria. Primary endpoint is progression-free survival assessed by independent review. Secondary endpoints include safety and tolerability, tumor growth rate assessed by volume, time to next intervention, ORR, overall survival, quality of life assessed by the Functional Assessment of Cancer Therapy–Brain questionnaire, and plasma pharmacokinetics. Exploratory endpoints include seizure activity and neuro-cognitive function. Clinical data will be reviewed regularly throughout the study by an independent data monitoring committee. The study is currently enrolling pts in the US, with additional countries planned (NCT04164901). Clinical trial information: NCT04164901 .
Phase II study of pembrolizumab plus SurVaxM for glioblastoma at first recurrence.
Authors: Ahluwalia Manmeet Singh , Peereboom David M. , Ciolfi Marci , Schilero Cathy , Hobbs Brian , Ciesielski Michael J , Fenstermaker Robert Alan
Published: May 2020

TPS2581

Background: Glioblastoma is the most common primary malignant brain tumor with median survival of approximately 15-16 months. Following first recurrence, progression free survival at six months ~15%. There is no therapy in recurrent glioblastoma associated with any survival benefit and there is an urgent need for better therapeutic options. Immunotherapy is one promising option for patients with cancer. This is being explored in glioblastoma and a number of forms of active specific vaccination and immune checkpoint based approaches have been devised and are being investigated in glioblastoma. Methods: Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor. Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. SurVaxM is a 15 amino acid antigenic peptide that targets surviving capable of binding several human MHC class I molecules. Primary Objective is to assess clinical activity of Pembrolizumab and SurVaxM in patients with recurrent glioblastoma using progression free survival at 6 months (PFS-6) as determined using RANO criteria. Secondary Objective(s) includes safety and tolerability of combination, response rates, progression free survival and overall survival. Exploratory Objective include measuring cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. This is a phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of glioblastoma patients who have failed prior anti-PD1 therapy. This clinical trial will enroll 41 patients with glioblastoma at first recurrence (bevacizumab naïve) in arm 1.This will include a 6-patient toxicity/safety run-in. There will an exploratory cohort of 10 patients who have failed prior PD1 blockade for a total of 51 patients in 2 arms. Key inclusion criteria include diagnosis of glioblastoma, Age ≥18 years old, Previous first line treatment with at least radiotherapy with or without temozolomide and Documented first recurrence of GBM and Karnofsky performance status of 70 and normal organ function. Key exclusion criteria include more than one recurrence of GBM, presence of extracranial metastatic or leptomeningeal disease, patients with > 1 cm midline shift on imaging. Patients must not require > 10 mg daily of prednisone equivalent. Clinical trial information: NCT04013672 .