bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase I study of CX-4945 administered orally twice daily to patients with advanced basal cell carcinoma.
Authors: Eroglu Zeynep , Cowey Charles Lance , Soong John , McCormick Daniel , Fan Phoebe , Chen Jimmy , Elgendy Mohamed , Jang Sekwon , Chang Anne Lynn S. 
Published: May 2020

TPS10080 Background: Smoothened inhibitors (SMOi) targeting the Hedgehog (Hh) pathway have been approved for the treatment of patients with locally advanced Basal Cell Carcinoma (laBCC) or metastatic BCC (mBCC). Unfortunately, resistance against SMO inhibitors (SMOi) can develop. Targeting the signaling cascade downstream of SMO, in this case via a novel small molecule inhibitor, could obviate this issue. Casein Kinase 2 (CK2) affects the terminal component of the Hh signaling pathway by promoting Gli2 stability and Gli2’s interaction with target genes. Given the interplay between CK2 and GLI-2 and the importance of Hh signaling activation, CX-4945, a potent CK2 inhibitor, may provide benefits for the BCC patients with resistance or intolerance to SMOi. Methods: A phase I trial (NCT03897036) to explore various treatment durations of CX-4945 was designed for patients with laBCC or mBCC; with endpoints include safety (CTCAE v5) and objective response rate by RECIST 1.0 for mBCC and composite response for laBCC. Major eligibility criteria include progression or intolerability to SMO inhibitors; laBCC patients must not be surgical candidates and must have received prior radiation unless contraindicated, and basosquamous histology is excluded. The first phase of the trial uses a 3+3 design to test the tolerance of a CX-4945 dose of 1000 mg bid for a duration of 28 days continuously. If 2 out of 3, or 2 out of 6 patients experience a DLT, the regimen of 1000 mg bid for 21 days followed by 7 days off (already tested in prior CX-4945 Phase I trials in other tumor types) will be selected as the recommend phase 2 dose (RP2D). Upon determining the RP2D, a dose-expansion phase will further evaluateCX-4945 in two cohorts (laBCC & mBCC), with 10 patients enrolled in each. Currently, we are enrolling patients and collecting sufficient data for the determination of RP2D in this patient population; thus, further assessments are required to determine the safety, tolerability, and efficacy of CX-4945 in advanced BCC. Clinical trial information: NCT03897036.
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 .