bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-Müllerian hormone (AMH) as a marker of ovarian reserve and premature ovarian insufficiency (POI) in children and women with cancer: A systematic review.
Authors: Cameron David A. , Anderson Richard , Clatot Florian , Demeestere Isabelle , Lambertini Matteo , Nelson Scott M , Peccatori Fedro
Published: June 2021

e24057

Background: Female patients undergoing anticancer treatment are at elevated risk of ovarian damage including development of POI. AMH is a key serum biomarker of ovarian reserve. However, its role to identify risk of POI in cancer patients prior to and after treatment is less well understood. Methods: A systematic literature search for AMH in women with cancer was conducted up to 30 August 2020, with formal bias assessment. We aimed at evaluating AMH as a biomarker of ovarian reserve and POI before and after anticancer treatment. Exploratory subgroups were based on age, cancer type and length of follow-up. Results: : Eighty publications (including 7,708 patients) were included in this analysis. All papers reporting AMH before and after treatment reported a large reduction in AMH following treatment, in both adult and paediatric populations. Effect sizes varied depending on the treatment and diagnosis, but ranged from 42% to below the limit of detection, and many reported declines of ≥90%. A majority (25/34, 74%) of studies also reported at least partial recovery of AMH at follow-up. Pre-treatment AMH correlated with post-treatment levels in all studies and younger patient age with higher post-treatment AMH in 21/29 (72%) studies. In 18/32 (58%) publications, oligo/amenorrhea correlated with lower post-treatment AMH. No studies reported correlations between post-treatment AMH and pregnancy, although pregnancy was reported in some patients with low or undetectable AMH. 70% of publications found that within-study variations in treatment (estimated by chemotherapy or radiotherapy type, dosage, duration and/or number of cycles) correlated with AMH reductions and degree of recovery, indicating its potential value as a marker of gonadotoxicity. In women with breast cancer, recovery of AMH was reported in some patients in 10/18 publications; however, AMH levels showed no recovery in many patients receiving alkylating agents or cyclophosphamide-based chemotherapies. In lymphoma, patients receiving ABVD-based regimens had at least partial post-treatment recovery of AMH at follow-up compared with those receiving cyclophosphamide-containing regimens. 16/20 (80%) publications in pediatric cancer patients showed significant reductions in AMH compared with pre-treatment levels or controls. The diagnostic value of post-treatment AMH for POI was supported in 5/5 (100%) studies. AMH levels measured 1–2 years after treatment appeared to be equally reliable at indicating longer-term menstrual outcomes as studies with longer followup. Conclusions: AMH levels were strongly impacted by anticancer treatment, with recovery in some women determined by treatment regimen, age, and pretreatment AMH level. There was evidence for its role in diagnosis of POI, nut further studies are required to clarify its value to assist in patient management.
Patient perceptions of palliative care in the process of allogeneic hematopoietic cell transplantation.
Authors: Melody Megan Elizabeth , Bruning Chimere , Mack Rachel , Parrott Kimberley , Taylor Richard , Foran James M. , Roy Vivek , Ayala Ernesto , Kharfan-Dabaja Mohamed , Murthy Hemant S. , Kilpatrick Molly , Robinson Maisha
Published: June 2021

e24082

Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is associated with significant short- and long-term sequelae that affect patients’ overall quality of life (QoL) and their physical and psychological well-being. Studies have shown improvement in patient QoL and physician satisfaction with palliative care involvement in the allo-HCT process. However, patient and physician perceptions regarding palliative care often impact timely referral. We conducted a prospective study to examine patient perceptions of palliative care both before and after palliative care consultation during evaluation for allo-HCT. Methods: This is a prospective, single-center study, of patients > 18 years of age, who were referred for a palliative care consultation as part of standard evaluation for allo-HCT. Patients were administered a pre- and post-visit internally derived questionnaire to assess their understanding and comfort level with palliative care. The primary objective of this study was to examine patient perceptions of palliative care consultation during evaluation for allo-HCT. Primary end point was the change in patient pre- and post- questionnaire responses. Secondary endpoint was the completion of advance care planning documentation pre- and post- consultation. Results: We enrolled 32 patients (male = 14) undergoing evaluation for allo-HCT with a primary diagnosis of AML (n = 8), NHL (n = 8), MDS (n = 7), ALL (n = 2), and other (n = 7). Following consultation with palliative care there was a statistically significant increase in patient understanding of the reason for the appointment, p = 0.0006. There was also a significant increase in patient’s knowledge of palliative care, with only 28% describing their knowledge as “good” or “excellent” prior to consultation and 79.3% after consultation, p < 0.0001. There was an observed positive, non-statistically significant, trend in patient comfort level with palliative medicine with only 20.7% (n = 6) describing their comfort as “high” or “very high” prior to consultation and 51.7% (n = 15) after consultation, p = 0.60. There was a higher rate of completion of advance care planning documentation following consultation with palliative medicine 56.3% vs 71.4%, p = 0.042. Conclusions: Palliative care consultation prior to allo-HCT increases a patient’s understanding of the role of palliative medicine as part of their allo-HCT and improves advance care planning. These findings need to be validated in a larger, multicenter, patient cohort.
Patient-reported outcomes in cancer patients admitted during the COVID 19 pandemic in a tertiary Spanish hospital.
Authors: Velasco Durantez Veronica , Rodríguez González Adán , Solis-Hernandez Maria Pilar , Iglesias Gomez Clara , Revuelta Alfonso , Jiménez-Fonseca Paula , Mihic Góngora Luka , Contreras Toledo Debora Corina , Valcárcel González Sena , Fernandez Arrojo Sara , Gómez David , del Río Fernández Jorge , Izquierdo Marta , Alvarez-Fernandez Carlos , Villanueva Noemí , Esteban Emilio ,   Onco HUCA
Published: June 2021

e24098

Background: Patient reported outcomes measures (PROMs) represent a tool to objectively assess the health of cancer patients. PROMs may complement oncological evaluations by adding patients’ perspectives on their care priorities. Aim: to address more accurately the management of tumor related symptoms or drug related toxicities to bring he therapies more accurately to bring patients the best quality of life possible. Methods: Data was collected from our electronic registry after proper authorization and corresponding anonymization. Patients were systematically asked for symptoms as fever, diarrhea, dyspnea, vomiting and nausea. These symptoms were graded according to their severity using the Common Toxicity Criteria v5.0. Results: 49 patients admitted to Medical Oncology Hospitalization were included from July of 2020 to January 2021, 80% in advanced disease. Median age 63yo, 32% above 70 yo. Baseline data showed that 27% patients (19% stage IV) had fever at admission, decreasing at 48h to 4%. Patients who had vomiting at admission were 33% (28% stage IV) median grade 2 becoming 20% and grade 1 at 48h. Nausea was present in 49% patients (35% stage IV) at the time of admission with a median grade 1.5, and it decreased to 16% at 48h with a median grade 2. Diarrhea was reported in 12% patients (6% stage IV) median grade 2 at baseline and it was reduced to 10% median grade 1 at 48h. The median severity of diarrhea at admission was 2 and only 1 at 48h. At admission, 33% (all stage IV) of patients presented dyspnea with a median grade 3, while at 48h it was present in 26% of patients and reduced to median grade 2. Conclusions: By systematically measuring symptoms, patients achieved better control of diarrhea, dyspnea, vomiting and nausea after admission. It should be noted that nausea was the variable that decreased the most at 48h, followed by fever, vomiting, dyspnea and diarrhea. All patients with stage IV disease had dyspnea and most of them had nausea and vomiting. These results reflect that these symptoms are more usual in patients with advanced disease compared to those with localized disease. PROMS also help us educate patients by teaching them how to manage treatments, thus improving therapeutic adherence.
Comparing the clinical impact of pancreatic cyst surveillance programs: A trial of the ECOG-ACRIN cancer research group (EA2185).
Authors: Weinberg David , Steingrimsson Jon , Zeh Herbert , Carlos Ruth , O'Dwyer Peter J.
Published: June 2021

TPS10608

Background: The optimal surveillance strategy for pancreatic cysts, which occur in up to 20% of the adult population, is ill defined. Although risk of malignant degeneration of these cysts is low, pancreatic cancer mortality remains high. Two cyst surveillance guidelines, one proposed by an international consensus group (Fukuoka) and the other by the American Gastroenterological Association (AGA), are accepted standards. Both rely on radiographic and endoscopic ultrasonographic imaging. They differ in indications for, and intervals between, imaging tests, with the Fukuoka guideline advocating more intensive imaging. Clinical guidelines that provide discordant recommendations may undercut the quality and/or value of care, and have implications for societal health care costs. The primary objective of this prospective trial is to compare the clinical effectiveness and associated resource utilization of the Fukuoka and AGA guidelines for pancreatic cyst surveillance. Secondary objectives include a comparison of resource utilization and patient reported outcomes. We are also collecting and banking radiomics data and biospecimens to identify novel methods that might improve cancer risk stratification. Methods: 4606 asymptomatic patients with newly identified pancreatic cysts ≥1cm in diameter are being randomized 1:1 to high intensity (Fukuoka) or low intensity (AGA) surveillance. The primary endpoint is a composite of any pancreatic cancer without surgery, unresectable pancreatic cancer or cancer > T1a, N0 at surgery, and benign disease at surgery. This sample size will provide 90% power to identify a 30% relative difference in the primary outcome at 5 years between the two study arms. Study duration is 8 years in total, allowing for 2 years of cohort enrollment, 5 years of prospective follow-up, and six months reserved for study initiation and close out. Study participants must be ≥ 50 years and ≤ 75 years with an ECOG Performance Status 0-1 at baseline. Participants must have received a CT or MRI within 6 months of registration that identifies a new ≥1 cm pancreatic cyst. Patients with a prior diagnosis of a pancreatic cyst, pancreatic malignancy or a history of pancreatic resection are not eligible. Additional exclusion criteria include a history of acute or chronic pancreatitis, a family history of pancreatic adenocarcinoma in 1 or more first degree relatives, imaging findings or clinical signs that would prompt immediate surgical consideration (enhancing mural nodule, solid component in cyst, pancreatic duct > 10mm, cyst causing obstructive jaundice), a comorbid illness that precludes pancreatic cyst resection, pregnancy or current participation in an established surveillance program. As of February 4, 2021, thirty three (33) participants have been enrolled from two hundred (200) potential sites. Clinical trial information: NCT04239573 .
HER2CLIMB-04: Phase 2 open label trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ unresectable locally advanced or metastatic breast cancer with and without brain metastases (trial in progress).
Authors: Krop Ian E. , Ramos Jorge , Zhang Chiyu , Hamilton Erika P.
Published: June 2021

TPS1097

Background: Tucatinib (TUC) is an oral, reversible, small molecule tyrosine kinase inhibitor highly selective for human epidermal growth factor receptor 2 (HER2) with minimal inhibition of human epidermal growth factor receptor (EGFR). In the pivotal, randomized HER2CLIMB trial (NCT02614794), the combination of TUC + trastuzumab (T) + capecitabine (C) demonstrated statistically significant and clinically meaningful improvements in progression free survival (PFS), overall survival (OS), and PFS in patients (pts) with brain metastases (BM), compared to T + C alone. These data supported regulatory approvals in the US and internationally for TUC in combination with T + C in pts with HER2+ metastatic breast cancer (MBC). Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate of trastuzumab and a topoisomerase I inhibitor payload approved in the US for treatment of HER2+ MBC in pts who have received 2 or more prior anti-HER2 regimens in the metastatic setting. Approval was based on data from the single arm Destiny-Breast01 trial (NCT03248492) where treatment with T-DXd resulted in a confirmed objective response rate (cORR) of 61.4% (95% CI: 54.0, 68.5) in pts with HER2+ MBC who had prior ado-trastuzumab emtansine treatment. Despite these advances, HER2+ MBC remains incurable, and pts will eventually progress on currently available therapies. Combining TUC and T-DXd may result in further improvement on the efficacy seen with either agent alone. Methods: HER2CLIMB-04 (NCT04539938) is a single arm, open-label phase 2 trial evaluating safety and antitumor activity of TUC + T-DXd in pts with HER2+ unresectable locally-advanced or MBC who have received 2 or more prior HER2-based regimens in the metastatic setting. Pts with BM, including active BM, may be enrolled. Ten pts will be enrolled in the safety lead-in portion of the trial and followed for at least 1 cycle. If safety of the combination is acceptable, the trial will continue until approximately 60 response-evaluable pts have been enrolled, approximately evenly distributed between pts with and without BM. The primary endpoint is cORR by investigator (INV) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints are PFS, duration of response (DOR), and disease control rate (DCR) by INV per RECIST v1.1, OS, and safety. Exploratory endpoints will include cORR, PFS, DOR, DCR by independent central review per RECIST v1.1, pharmacokinetic analyses, biomarker analyses, and changes in patient-reported outcomes using the European Quality of Life 5-Dimension 5-Level instrument. Enrollment began in late 2020 in the United States. Clinical trial information: NCT04539938 .
acelERA Breast Cancer (BC): Phase II study evaluating efficacy and safety of giredestrant (GDC-9545) versus physician’s choice of endocrine monotherapy in patients (pts) with estrogen receptor-positive, HER2-negative (ER+/HER2-) locally advanced or metastatic breast cancer (LA/mBC).
Authors: Martin Miguel , Lim Elgene , Chavez Mac Gregor Mariana , Shivhare Mahesh , Ross Graham , Patre Monika , Roncoroni Laura , Louka Maria , Sohn Joohyuk
Published: June 2021

TPS1100

Background: The standard-of-care therapy for ER+ BC typically involves modulation of estrogen synthesis and/or ER activity. Despite disease progression with standard treatments, growth and survival of the majority of tumors are thought to remain dependent on ER signaling; therefore, pts with ER+ BC can still respond to second- or third-line endocrine treatment (ET) after progression on prior therapy (Di Leo 2010; Baselga 2012). ESR1 mutations may drive estrogen-independent transcription and proliferation leading to resistance. The highly potent, nonsteroidal oral selective ER degrader, giredestrant, achieves robust ER occupancy and is active regardless of ESR1 mutation status. Phase I data have shown that giredestrant is well tolerated and active both as a single agent and in combination with the cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), palbociclib (Lim 2020). Single-agent giredestrant has also shown encouraging antitumor activity in pts previously treated with fulvestrant and/or a CDK4/6i. Methods: acelERA BC (NCT04576455) is a randomized, open-label, multicenter phase II study evaluating the efficacy and safety of giredestrant vs. physician’s choice of ET (fulvestrant or aromatase inhibitor) in males, or postmenopausal or pre/perimenopausal females with ER+/HER2– LA/mBC who have received 1–2 prior lines of systemic therapy in the LA or mBC settings, at least one of which must be ET. Randomization: 1:1 to receive giredestrant (30 mg PO QD on Days 1–28 of each 28-day cycle) or physician’s choice of ET per local guidelines. Men and pre-/perimenopausal women will receive a luteinizing hormone-releasing hormone agonist. Eligibility: ≥18 years, ECOG PS 0–1, histologically or cytologically confirmed diagnosis of LA (recurrent or progressed) or metastatic adenocarcinoma of the breast, measurable disease (per modified RECIST v1.1) or evaluable bone lesions, and ER+/HER2– tumors (locally assessed). Primary endpoint: progression-free survival (PFS; investigator-assessed per RECIST v1.1). Secondary endpoints: overall survival, objective response rate, duration of response, clinical benefit rate, PFS in pts with baseline ESR1 mutations, and quality of life. Safety, pharmacokinetics, biomarkers, and health status utility will also be assessed. Stratification: site of disease (visceral vs. nonvisceral), prior treatment with CDK4/6i (yes vs. no), and prior treatment with fulvestrant (yes vs. no). PFS will be compared using a stratified log-rank test; median PFS, using Kaplan–Meier analyses. Recruitment for the global enrollment phase is ongoing, the first patient was enrolled November 27, 2020. Clinical trial information: NCT04576455 .
NBE-002: A novel anthracycline-based antibody-drug conjugate (ADC) targeting ROR1 for the treatment of advanced solid tumors—A phase 1/2 clinical trial.
Authors: Tolcher Anthony W. , Meric-Bernstam Funda , McKean Meredith , Beerli Roger R , Waldmeier Lorenz , Gebleux Rémy , Hellmann Ina , Chrom Pawel , Grawunder Ulf
Published: June 2021

TPS1108

Background: The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly expressed during embryonic development, but is minimally present or absent on post-partum healthy tissues. ROR1 is expressed in a variety of hematological and solid tumors and is associated with aggressive cancer phenotype and poor clinical outcomes. NBE-002 is an ADC targeting ROR1, obtained by site-specific, enzymatic conjugation of the anthracycline-derivative PNU-159682, modified with a non-cleavable linker to a humanized recombinant IgG1 monoclonal antibody, based on a novel anti-human ROR1 monoclonal antibody XBR1-402 (Peng et al. (2017) J. Mol. Biol. 429: 2954-73). Direct anti-tumor activity of NBE-002 was evaluated in immunodeficient, ROR1 expression-low/-intermediate/-high PDX models of several carcinoma and sarcoma subtypes. The most pronounced anti-tumor effect was achieved in triple-negative breast cancer (TNBC), at doses as low as 0.033 mg/kg, suggesting a best-in-class therapeutic index in light of the high tolerability in preclinical toxicology models. Administration in a fully immune competent setting (EMT6/ROR1 orthotopic breast cancer model) led to a strong anti-tumor response and a long-lasting anti-tumor immune protection dependent on CD8 T cells. Methods: NBE-002-01 (NCT04441099) is a first-in-human, open-label, multi-center, phase (Ph) 1/2 study of NBE-002 in adult patients with advanced solid tumors. Ph 1 of the study consists of a Dose Escalation Cohort (DEC), utilizing an accelerated titration design, followed by a traditional 3+3 design, and an optional Safety Expansion Cohort (SEC). Ph 2 will include two parallel Expansion Cohorts (EC), enrolling patients with advanced TNBC (EC1) or other solid tumors (EC2), with Simon’s two-stage design. Key eligibility criteria include Eastern Cooperative Oncology Group performance status of 0-2 (Ph 1) or 0-1 (Ph 2), adequate organ function defined as: hemoglobin ≥9.0 g/dL, neutrophils ≥1500 /µL, platelets ≥100000/µL, aspartate and alanine aminotransferases ≤2.5x the upper limit of normal (ULN), total bilirubin ≤1.5x ULN, creatinine ≤1.5x ULN, left ventricular ejection fraction ≥50%. The primary objectives are to assess safety and tolerability and to establish the recommended dose for further development (Ph 1), and to evaluate anti-tumor activity of (Ph 2). Secondary and exploratory objectives include characterization of immunogenicity as well as pharmacokinetic and pharmacodynamic profiles. NBE-002 is given intravenously once every three weeks until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-specific criteria are met. Ph 1 dose escalation was initiated on 17 JULY 2020 and is still recruiting in the US. Ph 2 is planned to be initiated in 2022. Clinical trial information: NCT04441099 .
A phase II clinical trial of talazoparib monotherapy for PALB2 mutation-associated advanced breast cancer.
Authors: Gruber Joshua James , Gross Wyatt , McMillan Alex , Ford James M. , Telli Melinda L.
Published: June 2021

TPS1109

Background: PALB2 (Partner and Localizer of BRCA2) plays a critical role in the maintenance of genomic integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. Our recently reported phase II clinical trial (Gruber, et al. JCO 2019) showed that talazoparib monotherapy was associated with single agent activity in germline PALB2 (gPALB2) mutation-associated advanced breast cancers. Of 5 patients with a germline PALB2 mutation, all 5 had reduction in target lesions > 20% with 3 of 5 achieving a RECIST 1.1 response. All patients had visceral metastases and were heavily pretreated; one response occurred in a patient with 8 prior lines of therapy for metastatic breast cancer. Clinical activity of the PARP inhibitor olaparib was also demonstrated in breast cancer patients with gPALB2 mutations in the Olaparib Expanded trial (TBCRC 048). Thus, we believe there is significant value in generating additional PARP inhibitor monotherapy data in subjects with advanced PALB2 mutation-associated breast cancer. We propose this phase II trial to better estimate the rate of RECIST 1.1 objective response in this patient population. Methods: This is a single-arm, two-stage, non-randomized study to assess the objective response rate (ORR) of talazoparib monotherapy in patients with PALB2 mutation-associated advanced breast cancer. Eligible subjects will be adults with inoperable locally advanced or metastatic breast cancer with a germline or somatic PALB2 mutation with 0-3 prior therapies for advanced disease. Eligible patients must have a deleterious or suspected deleterious mutation in PALB2 on a CLIA approved commercial germline or next generation sequencing tumor assay. Study treatment is talazoparib 1 mg PO daily. In stage 1, ORR will be assessed after 15 patients; if at least 2 responses are observed then an additional 15 patients will be enrolled; if less than 2 responses are observed the study will be terminated. The primary objective is to evaluate whether talazoparib monotherapy can induce a 30% ORR in subjects with advanced breast cancer associated with a PALB2 mutation. Response will be assessed by RECIST 1.1. Secondary objectives include safety, PFS, clinical benefit rate, and patient-reported quality-of-life. Exploratory endpoints will assess for the presence of PALB2 loss-of-heterozygosity, biallelic mutations, correlation of ctDNA profile with treatment response and the correlation of germline versus somatic mutations with response rate. This trial is currently activated and enrolling at Stanford Cancer Center and it is expected that 4 additional sites will be added. Conclusion: This trial will evaluate gPALB2 as a biomarker for PARP inhibitor monotherapy in advanced or metastatic HER2- breast cancer. Clinical trial information: pending .
REGOSTA: A randomized, placebo-controlled, double-blinded, multicenter study evaluating the efficacy and safety of regorafenib (REGO) as maintenance therapy after first-line treatment in patients (pts) with osteosarcoma (OS) and non-osteosarcomas (non-OS) of bone (non-Ewing, non-chondrosarcomas and non-chordomas).
Authors: Duffaud Florence , Chabaud Sylvie , Gautier Julien , Ferlay Celine , Vizoso Séraphine , Brahmi Mehdi , Benezech Sarah , Dufresne Armelle , Marec-Berard Perrine , Ray-Coquard Isabelle Laure , Kalbacher Elsa , Collard Olivier , Penel Nicolas , Rios Maria , Bompas Emmanuelle , Chevreau Christine , Mir Olivier , Boudou-Rouquette Pascaline , Blay Jean-Yves , Piperno-Neumann Sophie ,   French Sarcoma Group
Published: June 2021

TPS11576

Background: Pts with OS and non-OS of bone are treated with a multimodal sequence therapy of neoadjuvant chemotherapy (CT), surgery and adjuvant CT, followed by a close surveillance until recurrence. At recurrence, the prognosis remains poor with objective response rates of 3-29%, and a median Progression-Free Survival (PFS) of less than 4 months in OS. There is a clinical need to reduce the risk of recurrence after the initial treatment sequence. The REGOBONE study reported a significant clinical benefit of regorafenib compared to placebo in patients with relapsed OS (median PFS: 16.4 versus 4.1 weeks). Methods: This multicenter trial is ongoing to study the efficacy and safety of maintenance REGO in pts > = 16 years, with complete remission after initial treatment sequence of their bone sarcoma. 168 pts will be randomly allocated in a 1:1 ratio to receive either oral REGO or its matching placebo (control arm) at a daily dose of 120mg, continuously and for a maximum of 12 months. Randomization will be stratified according to the following risk factors: metastases (mets) at diagnosis and/or poor response to neoadjuvant CT versus no mets at diagnosis and good response to neoadjuvant CT. The primary objective is to compare the efficacy (Relapse-Free Survival) between the 2 arms. The expected 3-year RFS rates are 55% in the control arm and 74.6% in the REGO arm (HR = 0.5). 66 events will provide 80% power to show significant improvement in RFS, using a 2-sided log-rank test at a 5% level. Secondary endpoints include Time to Treatment Failure, Overall Survival, Quality of Life, safety profile, and compliance to treatment. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify predictive biomarkers for efficacy of REGO as maintenance therapy using liquid biopsies. As of Feb 1st, 2021, 3 patients have been randomized. 15 sites of the French Sarcoma Group will participate. Clinical trial information: NCT04055220.
Safety and efficacy study of retifanlimab and epacadostat in combination with radiation and bevacizumab in patients with recurrent glioblastoma.
Authors: Campian Jian Li , Abraham Christopher , Luo Jingqin , Talcott Grayson , Katumba Ruth , Kim Albert H , Dunn Gavin P. , Ansstas George , Johanns Tanner Michael , Ciorba Matthew A , Chheda Milan G , Huang Jiayi
Published: June 2021

TPS2070

Background: Recurrent glioblastoma (rGBM) after chemoradiotherapy has a dismal outcome with very limited treatment options. Addition of reirradiation to bevacizumab appears to improve progression-free survival (PFS) but does not improve overall survival (OS). Immune checkpoint inhibitors of programmed cell death-1 (PD-1) pathway appear to have limited single-agent activity for rGBM due to its immunesuppressive microenvironment. Indoleamine 2,3 dioxygenase 1 (IDO1) is an inducible and rate-limiting enzyme that catabolizes tryptophan (Trp) into kynurenine (Kyn). IDO1 is over-expressed in 50̃90% of GBM patients, and high IDO1 levels correlate with reduced OS. Epacadostat is a highly potent and selective oral inhibitor of IDO1 and may increase tumor sensitivity to anti-PD-1 blockade. Retifanlimab is a humanized anti-PD-1 monoclonal antibody directed against PD-1. The purpose of this study is to evaluate the safety and efficacy of combining retifanlimab plus or minus epacadostat with reirradiation and bevacizumab for rGBM patients. Methods: This is an open-label nonrandomized phase II study of two sequential cohorts for bevacizumab-naïve adults with rGBM: retifanlimab + bevacizumab+ radiation (cohort A), and retifanlimab + epacadostat + bevacizumab + radiation (cohort B). Each cohort will enroll 24 evaluable patients. Key eligibility criteria include candidates for reirradiation and bevacizumab, age ≥ 18 years, Karnofsky performance status ≥ 60%, and dexamethasone dose ≤ 4 mg/day. The primary endpoint is OS. Secondary endpoints include PFS, neurologic functions, and toxicity. The correlative endpoints include studies assess the anti-glioma immune response, serum Kyn/Trp ratio, and RNA expression of IDO1 and PD-L1 from available tissue. The trial is actively enrolling. At the time of abstract submission, 16 of the planned 24 patients in Cohort A have been enrolled. Clinical trial information: NCT03532295. [Table: see text]
A phase 1/2 study of selinexor in combination with standard of care therapy for newly diagnosed or recurrent glioblastoma.
Authors: Odia Yazmin , Goldlust Samuel Aaron , Mehta Minesh P. , Lassman Andrew B. , Colman Howard , Kumthekar Priya , Mason Warren P. , Harrison Rebecca A. , Butowski Nicholas A. , Venur Vyshak , Plotkin Scott Randall , Schulder Michael , Boockvar John A , Duic J Paul , Li Kai , Liu Yang , Tamir Sharon , Mundy Gregory , Shacham Sharon , Wen Patrick Y.
Published: June 2021

TPS2071

Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a median overall survival (OS) of 15 months for patients with newly diagnosed GBM (ndGBM) and 5-7 months for patients with recurrent GBM (rGBM). To improve the prognosis of patients with GBM, novel therapies are urgently needed. Selinexor is a first-in class, oral, selective inhibitor of nuclear export that blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing death of cancer cells. Selinexor is an FDA-approved treatment for patients with heavily pretreated multiple myeloma, for patients who received at least one prior therapy, and for patients with relapsed/refractory diffuse large B-cell lymphoma. Increased XPO1 expression in gliomas was associated with higher pathological stage and poorer prognosis. In a phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. In preclinical studies, selinexor showed synergy with radiation, temozolomide, or lomustine. The current trial tests the hypothesis that the addition of selinexor to standard therapy will improve clinical outcomes for patient with ndGBM or rGBM. Methods: This phase 1 dose finding study is followed by a 1:1 randomized phase 2 (n= 350) efficacy exploration trial to independently evaluate 3 regimens: Arm A – radiation +/- selinexor in unmethylated O6-methylguanine-DNA-methyltransferase (uMGMT) ndGBM; Arm B – radiation and temozolomide +/- selinexor in mMGMT ndGBM; Arm C – lomustine +/- selinexor in first relapsed rGBM following frontline radiation and temozolomide. The phase 1 primary endpoint is maximum tolerated dose/recommended phase 2 dose, with secondary endpoints of overall response rate (ORR) per modified Response Assessment in Neuro-Oncology (mRANO), duration of response (DOR), progression free survival (PFS), and OS. The phase 2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS at 6 months, ORR, and DOR. For Arm C, the phase 2 primary endpoint is OS, while key secondary endpoints are PFS, PFS at 6 months, ORR, and DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy in Arms A and B, and 80% power to detect a hazard ratio of 0.70 for Arm C. We are currently enrolling patients nationwide. Clinical trial information: NCT04421378.
Association of combined phase I/II study of a novel bicyclic peptide and MMAE conjugate BT8009 in patients with advanced malignancies with Nectin-4 expression.
Authors: McKean Meredith , Falchook Gerald Steven , Bendell Johanna C. , Bashir Babar , Palmisiano Neil , Watson Roshawn , McKenna Mary-Anne , Campbell Carly , Smethurst Dominic Paul , Jeffrey Phil , Kirui Julius , Arkenau Hendrik-Tobias , Fontana Elisa
Published: June 2021

TPS2668

Background: BT8009 is a Bicycle Toxin Conjugate (BTC), a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting Nectin-4 tumor antigen, linked to cytotoxin (monomethyl auristatin E [MMAE]) via a valine-citrulline (val-cit) cleavable linker. Nectins (Nectin-1, -2, -3, and -4) and nectin-like molecules (Necl) are Ca2+ independent immunoglobulin-like cell adhesion molecules. Recent studies have shown the importance of Nectin-4 in several human cancers, including lung, ovarian, breast and bladder cancer; however, the precise roles and clinical relevance of Nectin-4 in tumors remain largely unknown. The Nectin-4 targeted enfortumab vedotin, linked to MMAE via a val-cit linker, is highly active in late-stage bladder cancer and demonstrates notable additional clinical activity as a single agent and in combination with pembrolizumab1. Skin toxicities, bone marrow suppression, peripheral neuropathy and diabetes have been associated with enfortumab, with some of these toxicities already noted with MMAE-bearing antibody therapies. We anticipate a similar toxicity profile for BT8009 in clinical studies. BT8009 exhibited a favorable preclinical profile and was effective in a range of cell-derived xenograph tumor models. Methods: Study BT8009-100 (NCT04561362) will evaluate safety and tolerability of weekly and every other week BT8009 administration, alone and in combination with q4w nivolumab. Determination of both a realistic phase 2 dose and a sequence will also be key to further exploration of safety and efficacy signals, along with an early examination of the role of baseline immunohistochemistry-ascertained levels of tumor Nectin-4. Patients will be recruited with advanced solid tumors associated with Nectin-4 expression after exhausting SOC options (i.e., bladder, breast, pancreatic, head and neck, gastric, esophageal and ovarian). Patients must have available tumor tissue, acceptable hematologic and other critical organ function and be willing to participate. Appropriate ethical and regulatory approvals and advice will be in place and adhered to. Exclusion criteria include uncontrolled brain metastases, uncontrolled hypertension, concomitant CYP3A4 inhibitors and significant history of autoimmune disease for the nivolumab cohorts. PK serial collections will be taken on D1 through D15. Radiologic tumor assessments for response per RECIST will be taken every two months. 1. Enfortumab Vedotin. FDA_data. 761137Orig1s000MultiDiscliplineR.pdf (fda.gov). Clinical trial information: NCT04561362.
A phase 1 dose-escalation study of intravenously (IV) administered TAK-676, a novel STING agonist, alone and in combination with pembrolizumab in patients (pts) with advanced or metastatic solid tumors.
Authors: Falchook Gerald Steven , Luke Jason J. , Strauss James F. , Gao Xin , LoRusso Patricia , VOON PEI JYE , Li Cong , Shaw Michael , Gregory Richard C. , Horn Kristin , Gibbs John , Lineberry Neil , Stumpo Kate , Malek Karim , Olszanski Anthony J.
Published: June 2021

TPS2670

Background: Immuno-oncology therapies, including immune checkpoint inhibitors (CPIs), are revolutionizing cancer treatment. However, primary and secondary resistance to CPIs remains a significant challenge. CPI resistance has been associated with reduced interferon (IFN) signaling, altered antigen presentation, and an immunosuppressive tumor phenotype. Stimulating innate immune cells to develop a proinflammatory tumor environment that activates IFN signaling and downstream adaptive antitumor immune mechanisms is predicted to overcome such resistance. Stimulator of Interferon Genes (STING) is a key mediator of type 1 IFN-dependent innate immune modulation. Most STING agonists evaluated clinically have required intratumoral administration, which has significant logistical challenges and excludes many pts whose tumors are not accessible for injection. TAK-676 is a novel STING agonist under clinical investigation as an IV administered systemic therapy in pts with solid tumors. Methods: The primary objective of this study is to determine the safety and tolerability of TAK-676 alone and in combination with pembrolizumab. Secondary objectives are to: determine the pharmacologically active dose and recommended phase 2 dose; characterize TAK-676 pharmacokinetics; assess preliminary antitumor activity; and assess STING agonism gene signature induction. An exploratory objective is to assess immune cell activation and clinical response. The study comprises a single-pt safety lead-in with single-agent (SA) TAK-676 0.1 mg IV, followed by dose escalation using Bayesian Logistic Regression Model design. Dose escalation will start in the combination arm when ≥2 dose levels in the SA arm have been evaluated and considered safe. In both arms, pts will receive TAK-676 on days 1, 8, and 15 in 21-day cycles for up to 1 year. In the combination arm, pts will also receive pembrolizumab 200 mg IV on day 1 of each cycle. Adult pts with histologically confirmed advanced or metastatic solid tumors who have no standard therapeutic options or are intolerant to them, with an Eastern Cooperative Oncology Group (ECOG) performance status 0–1, and ≥1 Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1- evaluable lesion are eligible; pts with tumors that have relapsed, are refractory or naïve to anti-programmed death 1 (PD-1) or anti-programmed death ligand 1 (PD-L1) therapy are eligible for the combination arm. Planned enrollment is ̃76 pts; recruitment is ongoing. Clinical trial information: NCT04420884.
A phase 1, multicenter, open-label, dose-escalation, safety, pharmacodynamic, pharmacokinetic study of Q702 with a cohort expansion at the RP2D in patients with advanced solid tumors.
Authors: Alistar Angela Tatiana , El-Khoueiry Anthony B. , Mahalingam Devalingam , Mita Monica M. , Kang Hwankyu , Yang Yeong-In , Ahn Jiye , Kim Jeongjun , Choi Baejung , Jeon Yeejin , Jung Chunwon , Jeon Borami , Kim Jaeseung , Nam Kiyean
Published: June 2021

TPS2673

Background: Immune checkpoint inhibitors directly targeting T cell activation have been successfully used in the treatment of various malignancies, nevertheless, the durable ORRs are low for certain indications. The low ORRs have been attributed to the immune suppressive tumor microenvironment (TME), composed of innate immune suppressive components such as tumor associated macrophages (TAM) and myeloid-derived suppression cells (MDSC). The potential contributions of innate immune modulation to anti-tumor immunity, suggest the need for the novel strategies to elicit a more efficient/robust immune response against the targeted malignant cells. Axl, Mer and CSF1R receptor tyrosine kinases play vital roles in promoting an immune suppressive TME by affecting TAM and MDSC populations and by decreasing antigen presentation on tumor cells. Q702 is a novel Axl/Mer/CSF1R inhibitor, able to modulate the TAM and MDSC population leading to CD8+ T cell activation and to increase antigen presentation of the tumor cells in syngeneic animal models. Q702, as a monotherapy, shows significant tumor growth inhibition in multiple syngeneic tumor models, and demonstrates synergistic effects with anti-PD-1 treatment particularly in high myeloid containing tumor models. Interestingly, intermittent administration of Q702 monotherapy demonstrates a more favorable immune cell population changes, possibly through preventing immune exhaustion secondary to negative feedback with continuous activation. These results suggest that Q702 monotherapy or in combination with existing therapies have a good potential to become a novel treatment strategy for patients with advanced solid tumors. Methods: “A Phase 1, Multicenter, Open-label, Dose-Escalation, Safety, Pharmacodynamic, Pharmacokinetic Study of Q702 with a Cohort Expansion at the RP2D in Patients with Advanced Solid Tumors. (NCT04648254)” is open and recruiting patients at 4 US investigative sites. Patients with histologically or cytologically confirmed advanced or metastatic solid tumors, that have progressed following SOC or for which there is no SOC which confers clinical benefit are being enrolled in this study. The study follows a standard dose escalation. The study will enroll up to 78 patients. The primary endpoint is to establish safety, PK profile and define the recommended phase 2 dose. The secondary and exploratory endpoints include establishing pharmacokinetic/pharmacodynamic relationship, potential biomarkers and preliminary anti-tumor activity. Clinical trial information: NCT04648254.
First-in-man phase I clinical trial evaluating TTI-101, an orally bioavailable, small molecule inhibitor of STAT3, in patients with advanced solid tumors.
Authors: Tsimberidou Apostolia Maria , de Achaval Sofia , Alibhai Imran , Kaseb Ahmed Omar
Published: June 2021

TPS3158

Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is a key signaling node and a master regulator of the key hallmarks of cancer, including tumor angiogenesis, resistance to apoptosis, metastasis, and immune evasion. STAT3 activation is observed in ̃70% of all cancers and up to 95% of hepatocellular carcinomas (HCC). Thus, inhibition of STAT3 signaling is expected to have a therapeutic effect against a wide range of cancers. TTI-101 is a first-in-class, orally bioavailable, selective small molecule that binds STAT3 and prevents phosphorylation, homodimerization, nuclear translocation, and ultimately, STAT3-mediated transcriptional activity. TTI-101 has demonstrated anti-tumor activity across a broad range of preclinical cancer models, including a Hep Pten- (hepatocyte-specific deletion of Pten) murine model of liver cancer, which recapitulates the pathogenesis of HCC in non-alcoholic fatty liver disease (NAFLD) with chronic inflammation and liver fibrosis leading to cancer at 11 months. TTI-101 treatment starting at 11 months arrested tumor growth as well as reversed liver injury and fibrosis (1). Given these findings, a clinical trial is being conducted examining the effect of this novel, targeted therapeutic agent in patients with advanced solid malignancies. Methods: This single-site Phase I trial (NCT03195699) is evaluating TTI-101 as monotherapy in patients with advanced solid tumors who are refractory to prior therapies. The primary objectives of this dose-escalation study include establishing tolerability and safety at each dose level, pharmacokinetics (PK), and establishing the recommended phase 2 dose (RP2D). The secondary and exploratory objectives include assessing clinical outcomes of patients and pharmacodynamics (PD) of TTI-101 via timed, paired tumor biopsies. The initial dose-escalation study is stratified by disease type (HCC and non-HCC) with independent dose-escalation schemas and will be followed by dose expansion cohorts where safety, PK and PD will be evaluated. TTI-101 is administered orally, twice daily for a 28-day cycle. Key eligibility criteria include: 18 years of age or older, having metastatic or unresectable solid tumor refractory to standard therapies, and measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, an Eastern Cooperative Oncology Group (ECOG) score of 0-2, and normal organ function. Additional criteria are specified for patients with HCC including Child-Pugh class A. HCC cohorts 1-4 and non-HCC cohorts 1-3 have been completed without dose limiting toxicities (DLTs). Enrollment to the HCC dose expansion began in February 2021. 1. Jung KH, et al. Multifunctional Effects of a Small-Molecule STAT3 Inhibitor on NASH and Hepatocellular Carcinoma in Mice. Clin Cancer Res. 2017;23(18):5537-46. Clinical trial information: NCT03195699.
Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) Study: A randomized phase III study of atezolizumab (atezo) monotherapy versus mFOLFOX6/bevacizumab/atezo in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) or microsatellite instability high (MSI-H) metastatic colorectal cancer (mCRC)—NRG-GI004/SWOG-S1610.
Authors: Overman Michael J. , Yothers Greg , Jacobs Samuel A. , Sanoff Hanna Kelly , Cohen Deirdre Jill , Guthrie Katherine A , Henry Norah Lynn , Ganz Patricia A. , Kopetz Scott , Lucas Peter C. , Blanke Charles David , Wolmark Norman , Hochster Howard S. , George Thomas J. , Rocha Lima Caio Max Sao Pedro
Published: June 2021

TPS3618

Background: The superiority of inhibition of programmed cell death-1 (PD-1) pathway in dMMR/MSI-H over chemotherapy with either anti-vascular endothelial growth factor receptor (VEGFr) or anti- epithelial growth factor receptor (EGFr) antibodies in mCRC has been demonstrated in a phase III trial (N Engl J Med 2020; 383:2207). However, more patients had progressive disease as the best response in the anti-PD1 monotherapy arm (29.4% vs. 12.3%) with mean progression-free survival (PFS) of 13.7 months. Preclinical models have demonstrated synergistic interactions between FOLFOX, anti-VEGF, and anti-PD-1. We hypothesize that the dMMR/MSI-H mCRC patients may be more effectively treated by the combination of PD-1 pathway blockade and mFOLFOX6/bevacizumab (bev) rather than with anti-PD-L1 therapy (atezo) alone. Methods: Initially a three-arm study, the mFOLFOX6/bev arm was closed to new enrollment on 6-4-20 due to emerging data; the redesigned COMMIT trial was reactivated on 1/29/2021 as a prospective phase III open-label trial that randomizes (1:1) mCRC dMMR/MSI-H pts (N=211) to either atezo monotherapy or mFOLFOX6/bev+atezo combination. Stratification factors include BRAFV600E status, metastatic site, and prior adjuvant CRC therapy. Primary endpoint is PFS as assessed by site investigator. Secondary endpoints include overall survival (OS), objective response rate (RECIST v1.1), safety profile, disease control rate, duration of response, and centrally-reviewed PFS. Health-related quality of life is an exploratory objective. Archived tumor tissue and blood samples will be collected for correlative studies. Key inclusion criteria are: mCRC without prior chemotherapy for advanced disease; dMMR tumor determined by local CLIA-certified IHC assay (MLH1/MSH2/MSH6/PMS2) or MSI-H by local CLIA-certified PCR or NGS panel; and measurable disease per RECIST. Clinical trial: NCT02997228. Support: U10CA180868, -180822, -180888, -180819, UG1CA189867, U24CA196067; Genentech, Inc. Clinical trial information: NCT02997228.