bluuebunny/crossref_metadata_2025 huggingface dataset:
Designing and implementing an evidence-based and longitudinal implicit bias training curriculum for school of medicine members and healthcare providers.
Authors: Hamel Lauren M. , Robinson Leah M. , Chamblee Marquita , Dougherty David W. , Sood Beena
Published: June 2022

e24136

Background: Implicit bias negatively influences decisions and communication in oncology care, and may also lead to disparities in cancer treatment and outcomes. The School of Medicine (SOM) at Wayne State University (WSU), based in the diverse yet segregated city of Detroit, Michigan, has faced the consequences of bias. Fortunately, within SOM/WSU, expertise on the problem of and solutions to implicit bias have flourished. We leveraged that expertise to design and implement a comprehensive and longitudinal implicit bias curriculum for SOM members and healthcare providers, including hematology/oncology faculty, providers, and trainees. We designed the curriculum to satisfy State of Michigan implicit bias training requirements for all healthcare providers. To date, we have implemented two modules. Prior to the second module, we received IRB-approval to recruit curriculum participants as study participants and tested effectiveness. Methods: The curriculum is comprised of 1½ hour modules offered every three months. Topics include how implicit bias influences clinical communication with a focus on the oncology care context, how structural racism influences health policy, among others. To evaluate, we utilize Kirkpatrick’s Four-Level Training Evaluation Model, to assess outcomes at 4 levels: 1. reaction, 2. learning, 3. behavior change and 4. long-term results. After obtaining passive consent from participants, we gathered effectiveness data at Levels 1 and 2. Results: We implemented two modules (How Patient and Physician Race-Based Attitudes Influence Clinical Communication & Structural Racism 101: Basic Training for Doctors) in 2021 via Zoom. More than 160 people attended each module with many participants representing oncology-focused hospitals and academic departments. All participants received a certificate of participation as a part of the state requirements for implicit bias training, and CME credit. For Session 2 we asked participants to respond to a survey before (n = 106) and after (n = 35) the session assessing Levels 1 and 2. Participant evaluations (Level 1) were very positive, with many participants noting that they plan to put what they have learned into practice immediately. A common critique was the desire for more topics and more time to discuss. Findings show increased knowledge (Level 2) of structural racism (pre: 92% vs. post: 97%); spatial racism (pre: 87% vs. post: 91%); and how racism influences health policy (pre: 80% vs post: 86%). Conclusions: We successfully implemented a longitudinal implicit bias curriculum for SOM members and healthcare providers. Next steps include continuing to implement and assess the curriculum, and collecting data at Levels 3 and 4. This type of curriculum could be an important tool to decrease bias in cancer care and improve cancer care equity.
Adjusting the TMIST study design to accommodate slower than expected accrual: ECOG-ACRIN EA1151.
Authors: Pisano Etta , Gatsonis Constantine , Schnall Mitchell D. , Yaffe Martin , Troester Melissa A. , Gareen Ilana F. , Collins Laura C. , Curtis Amarinthia , Cole Elodia B , Cormack Jean , Steingrimsson Jon , Carlos Ruth C , Miller Kathy , Comstock Christopher
Published: June 2022

TPS10614

Background: The ECOG-ACRIN Tomosynthesis Mammographic Imaging Screening Trial (TMIST), which opened in 2017, is a randomized trial designed to assess whether Tomosynthesis Mammography (TM) should replace Digital Mammography (DM) for breast cancer screening. It is hypothesized that women assigned to TM for 3-5 screening rounds will have fewer advanced breast cancers than the women assigned to DM. Advanced cancers are those that have distant metastases or positive nodes, are invasive tumors greater than or equal to 2.0 cm in size, or are invasive tumors greater than 1.0 cm in size that are triple negative or HER 2+. The initially planned enrollment of 164,946 women was due to be completed by the end of 2020, with follow-up concluded by 2025. There were substantial challenges in meeting this timeline, including the organizational and funding structure of the NCI National Clinical Trials Network which is dependent upon sites using their existing staffing resources (not always readily available at the time of study activation). This led to longer than anticipated start of enrollment for most interested sites and lower than anticipated annual enrollment per participating site based ultimately on the staffing support that could be allocated to manage TMIST. In addition, research staffing shortages and periodic research operations closures due to COVID-19 have also impacted enrolling TMIST sites, though unevenly, since the start of the pandemic. Enrollment plateaued at approximately 2,100 subjects per month by the end of 2020. With that accrual rate expected, the trial design was modified to reduce the sample size so that the study could be completed by 2027. Methods: With the approval of the NCI CIRB, we changed how the primary endpoint measure for TMIST is assessed from the number of advanced cancers that occur by 4.5 years after randomization to the time from randomization to occurrence of advanced cancers. All advanced cancers occurring within 7 years of randomization are now included and all participants followed for at least three years. In addition, the power of the study of the study was modified from 0.9 to 0.85, while the originally assumed effect size at 4.5 years was retained These changes allowed a reduction of sample size to 128,905, with subject recruitment projected to end in 2024. As of February 14, 2022, there are 125 sites open, 114 in the U.S. and 11 in other countries, with an additional 31 sites planning to open. As of February 14, 2022, a total of 63,845 women have been enrolled in the trial worldwide at 115 sites, with 20% of US participants self-identifying as belonging to minority racial and ethnic groups and 70% consenting to optional blood and/or buccal cell collection. Clinical trial information: NCT03233191.
A randomized phase III study assessing the efficacy of liquid biopsy in early diagnosis of recurrence and second malignancies in lung cancer survivors.
Authors: Raoof Sana , Gomez Daniel Richard
Published: June 2022

TPS10617

Background: Lung cancer survivors are highly enriched for extensive smoking histories and have an increased risk of subsequent primary cancers, including those of the larynx, mouth and throat, esophagus, pancreas, bladder, thyroid, stomach, small intestine, colon, rectum, and kidney. Guideline-concordant surveillance after definitive treatment for lung cancer consists of periodic chest CT scans, which do not visualize the majority of second malignancies that this population ultimately develops. Disadvantaged and minority patients are diagnosed with recurrence and second primary cancers at later stages due to reduced compliance with survivorship surveillance. To address these issues, we propose utilizing multi-cancer early detection (MCED) liquid biopsies. MCED liquid biopsies are part of a rapidly growing field of research that assesses parallel cancer screening for multiple cancer types with point of care blood, urine, or saliva sampling. We selected a methylation-based screening liquid biopsy for multiple reasons: 1) it has the highest PPV and specificity of any test clinically validated in the multi-cancer detection setting thus far, 2) it produces a tissue of origin, allowing for targeted workup of positive findings, and 3) it requires only a single test, which we believe will minimize attrition among vulnerable populations with decreased access to healthcare. We designed a 9,000-patient prospective, multi-institutional randomized clinical trial to assess the efficacy of liquid biopsy in early diagnosis of recurrence and second malignancies in lung cancer survivors. To ensure over 25% of participants are of minority status, we have recruited multiple community hospitals to the study in partnership with Memorial Sloan Kettering Cancer Center. Patients included in this study are survivors of non-metastatic non- small cell lung cancer, status-post definitive treatment (surgery or radiation) with no evidence of disease for at least one year. Participants will be randomized 1:1 to standard surveillance or standard surveillance plus six-monthly methylation-based liquid biopsy tests over a two-year study period, and strict guidelines on follow-up of positive liquid biopsy testing will be provided to reduce harms from false positives or over-diagnosis. Methods: The primary endpoint of this study is the incidence of late stage cancer (distant recurrence or new primary cancer of stage III/IV). Secondary endpoints include cancer-specific mortality, eligibility for definitive interventions once cancer is diagnosed, and utilization of liquid biopsy versus standard of care scans. This is the first randomized controlled trial of screening liquid biopsy in a survivorship population and the first trial utilizing liquid biopsy in a large minority population.
Longitudinal immunological responses of COVID-19 vaccination in patients with solid tumors on active treatment: A pilot study.
Authors: Cao Lifen , Kopp Shelby Rose , Rayman Patricia A. , Mallat Naji , Leyfman Yan , Martin James Michael , Selfridge Jennifer Eva , Diaz-Montero C. Marcela , Montero Alberto J.
Published: June 2022

TPS10618

Background: Coronavirus disease 2019 (COVID-19), caused by betacoronavirus SARS-CoV-2, is associated with an increased risk of severe infection or death in cancer patients compared to the general population. The CANVAX trial recently demonstrated that short term immune responses to SARS-CoV-2 vaccines are modestly impaired in patients with cancer— particularly those who receive myelosuppressive chemotherapy. Because little is known regarding longitudinal antibody or T-cell responses in cancer patients who receive cytotoxic chemotherapy or non-myelosuppressive targeted systemic therapy, the aim of this longitudinal study is to assess immune B and T cell responses to SARS-CoV-2 over a 12-month period in solid tumor patients who receive chemotherapy or non-immunosuppressive therapy compared to healthy individuals without cancer. Methods: This is an ongoing prospective non-interventional clinical trial (NCT05238467). Approximately 100 patients will be enrolled into three different arms. Accrual began in May 2021 and 37 patients have been enrolled. Eligible patients must not have prior COVID-19 infection < 6 months from study enrollment and have a diagnosis of a solid tumor (breast, genitourinary, or gastrointestinal cancers), who either: received myelosuppressive chemotherapy within 60 days prior to initial or booster COVID vaccination, or who started on chemotherapy within 30 to 60 days after the initial or booster COVID vaccination (Arm A); or received non-immunosuppressive treatments (Arm B); or have no history of cancer or prior history of cancer but beyond 12 months from completion of curative cancer treatment (Arm C, control cohort). Whole blood will be collected in accordance with standard operating procedures. Blood samples analyzed for the presence of antibodies against the major antigenic components of SARS-CoV-2 including the spike glycoprotein (S), receptor binding domain (R) and nucleocapsid phosphoprotein (N). Antibody levels will be quantified utilizing quantitative ELISA. T-cell responses will also be quantified. The primary endpoint is seroprotection rate with an antibody titer protective (1:40) at any point: baseline, 2, 6, and 12 months. The secondary endpoint is to evaluate differences in longitudinal immunological responses to SARS-CoV-2 over a 12-month period. The difference of the seroprotection rate among 3 cohorts of participants will be examined using chi-square test. Moreover, the effect of treatment (chemotherapy, endocrine, TKIs) on seroprotection will be estimated using multivariable logistic regression controlling the effects of confounders, such as age, gender and cancer type. COVID antibody titers measured over time (baseline, 8 weeks, 6, 9, 12 months after the second vaccination) will be analyzed using mixed-effect models. Clinical trial information: NCT05238467.
postMONARCH: A phase 3 study of abemaciclib plus fulvestrant versus placebo plus fulvestrant in patients with HR+, HER2-, metastatic breast cancer following progression on a CDK4 & 6 inhibitor and endocrine therapy.
Authors: Kalinsky Kevin , Layman Rachel M. , Kaufman Peter A. , Graff Stephanie L. , Bianchini Giampaolo , Martin Miguel , Zhou Yanhong , Knoderer Holly , Litchfield Lacey , Wander Seth Andrew
Published: June 2022

TPS1117

Background: The use of cyclin dependent kinase 4 and 6 (CDK4 & 6) inhibitors plus endocrine therapy (ET) has transformed the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). However, most patients will experience disease progression. Identification of treatment options following progression is an unmet medical need. Additionally, as CDK4 & 6 inhibitors are now being deployed in the adjuvant setting, determination of optimal therapy following metastatic relapse is an important question. In patients with disease progression following a CDK4 & 6 inhibitor-based regimen, continuing CDK4 & 6 inhibition with abemaciclib while switching the ET backbone may provide benefit and delay the need for cytotoxic chemotherapy. Abemaciclib is an oral, selective, and potent CDK4 & 6 inhibitor administered continuously and approved as monotherapy or with ET for treatment of HR+, HER2- ABC. Abemaciclib has also been approved with ET for the adjuvant treatment of HR+, HER2-, node-positive, early breast cancer at high risk of recurrence and a Ki-67 score ≥20%. Fulvestrant is a selective ER degrader (SERD) approved for treatment of HR+, HER2- ABC. The postMONARCH study investigates whether abemaciclib plus fulvestrant will improve outcomes in patients with HR+, HER2- ABC after disease relapse or progression after adjuvant or first-line treatment with a CDK4 & 6 inhibitor plus ET. Methods: postMONARCH is a Phase 3, global, multicenter, randomized, double-blind, placebo-controlled study in patients with HR+, HER2- ABC and with disease progression on treatment with a prior CDK4 & 6 inhibitor plus an aromatase inhibitor as initial therapy for ABC or recurrence on/after treatment with a CDK4 & 6 inhibitor plus ET in the adjuvant setting. Eligible patients are randomized 1:1 to receive abemaciclib 150 mg twice daily or placebo, plus fulvestrant. Stratification factors include geography, presence of visceral metastasis, and duration of prior CDK4 & 6 inhibitor-based regimen. The study is powered at 80% with a cumulative Type I error of 0.025 to detect the superiority of abemaciclib plus fulvestrant versus placebo plus fulvestrant in terms of investigator-assessed progression free survival. Key secondary endpoints include overall survival, PFS by blinded independent central review, objective response rate, safety, patient-reported outcomes, and pharmacokinetics. This study opened in Jan 2022, plans for approximately 122 centers in 18 countries, and anticipates enrolling ̃350 patients. Clinical trial information: NCT05169567.
KEYNOTE-B49: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy in patients with HR+/HER2- locally recurrent inoperable or metastatic breast cancer.
Authors: Rugo Hope S. , Sohn Joohyuk , Jerez Gilarranz Yolanda , Gonzalez-Cortijo Lucia , Sonnenblick Amir , Sabanathan Dhanusha , Korbenfeld Ernesto Pablo , Egle Daniel , Poirier Brigitte , Zagouri Flora , Matikas Alexios , Aksoy Sercan , Demirci Umut , Ramos-Elias Pier , Im Seock-Ah , Cardoso Fatima , Jia Liyi , Baccan Carlos , Tryfonidis Konstantinos , Schmid Peter
Published: June 2022

TPS1118

Background: HR+/HER2− advanced breast cancer that progresses on endocrine therapy is treated with chemotherapy (chemo). The phase 1b KEYNOTE-028 trial showed durable activity with pembrolizumab (pembro) monotherapy in previously treated HR+/HER2−, PD-L1–positive (combined positive score [CPS] ≥1) advanced breast cancer. KEYNOTE-B49 (NCT04895358) is a phase 3, randomized, double-blind study of pembro + chemo vs placebo (pbo) + chemo in centrally assessed PD-L1–positive, HR+/HER2− locally recurrent inoperable or metastatic breast cancer (mBC) after progression on prior endocrine therapy. Methods: ∼800 patients (pts) with HR+/HER2− locally recurrent inoperable or mBC who are candidates for chemo (no prior chemo for metastatic disease) with PD-L1 CPS ≥1 and documented progression on prior endocrine therapy will be enrolled. Prior endocrine therapy comprises ≥2 lines (≥1 in combination with a CDK4/6 inhibitor) in the metastatic setting or 1 line with CDK4/6 inhibitor treatment for mBC in pts who had a relapse within 24 mo of primary surgery. Pts without prior CDK4/6 inhibitor treatment may enroll if they had progressed within 6 mo of starting endocrine therapy for metastatic disease and had previously relapsed within 24 mo of primary tumor surgery while on adjuvant endocrine therapy. Pts are randomized 1:1 to receive pembro 200 mg IV or pbo Q3W, each in combination with investigator’s choice of chemo: paclitaxel 90 mg/m2 IV on days 1, 8, and 15 Q4W; nab-paclitaxel 100 mg/m2 IV on days 1, 8, and 15 Q4W; liposomal doxorubicin 50 mg/m2 IV on day 1 Q4W; or capecitabine 1000 mg/m2 PO BID on days 1–14 Q3W. Randomization is stratified by tumor PD-L1 (CPS 1–9 vs ≥10), presence of visceral metastases (yes vs no), and chemo on-study (taxanes vs liposomal doxorubicin vs capecitabine). Treatment is continued until disease progression, unacceptable toxicity, withdrawal, or, for pembro/pbo, completion of 35 cycles (̃2 years); chemo can be continued per investigator discretion. Tumor PD-L1 status is determined centrally using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies; Carpinteria, CA, USA). Radiologic assessments are performed Q9W for 54 wk and then Q12W thereafter. AEs occurring from randomization until 30 d after treatment discontinuation (90 d for serious AEs) are graded per NCI-CTCAE v 5.0. Primary endpoints are PFS per RECIST v1.1 by BICR and OS in pts with PD-L1 CPS ≥10 and ≥1 tumors, separately. Enrollment is ongoing at 204 international sites. Clinical trial information: NCT04895358.
Neoadjuvant survivin-targeted immunotherapy maveropepimut-S (MVP-S) to increase Th1 immune response in Ki67-high hormone receptor-positive (HR+) early-stage breast cancer (ESBC).
Authors: Stanton Sasha E. , MacDonald Lisa Diana , Mellinger Staci L. , Moxon Nicole , Kelly Tracy , Hirsch Heather Anne , Fiset Stephan , Young Kristina Hoot , Page David B.
Published: June 2022

TPS1119

Background: HR+ ESBC is associated with suboptimal pathologic complete response rate (pCR, ̃10%) following neoadjuvant cytotoxic chemotherapy. Neoadjuvant anti-endocrine therapy with aromatase inhibitors (AI) may serve as an effective alternative. Efficacy can be gauged using the surrogate Ki67 cell proliferation histologic marker. Patients with poor Ki67 response (defined as Ki67 > 10%) following neoadjuvant AI exhibit poor prognosis and therapeutic resistance to both anti-endocrine therapy and chemotherapy. In a genomic analysis among Ki67-high HR+ tumors, we identified 8-fold upregulation of BIRC5 (survivin), a gene that regulates apoptosis and the cell cycle and that is associated with poor clinical outcome. Maveropepimut-S (MVP-S, previously named DPX-Survivac) leverages the non-aqueous, lipid-based DPX delivery platform to educate a specific and persistent T cell-based immune response to 5 HLA-restricted peptides from Survivin, a cancer-associated protein commonly upregulated in several cancers. Treatment with MVP-S and intermittent, low-dose cyclophosphamide (CPA) has shown tumor infiltration of survivin-specific T cells. Previous clinical trials have shown that MVP-S is well-tolerated, immunogenic, and could lead to clinical response in several cancer indications. Further exploration of the regimen in breast cancer could extend the application of this immunotherapy for this unmet medical need. Methods: NCT04895761 is phase I trial evaluating the safety and immunologic effects of neoadjuvant MVP-S plus letrozole (arm A, n = 6), with/without tumor-directed MR-guided radiotherapy (arm B, n = 6), or intermittent low-dose cyclophosphamide or CPA (arm C, n = 6). Postmenopausal patients with T1c+ HR+HER2- breast cancer with Ki67 > 10% will receive two doses of MVP-S and 7 weeks of neoadjuvant letrozole prior to surgery (all arms), whereas arm B will be treated additionally with concurrent 10Gy x 2 tumor boost radiation to facilitate immunogenic cell death, and arm C (n = 6) will be treated additionally with intermittent low-dose CPA (50mg BID) to facilitate regulatory T cell depletion. The primary objective is safety. Biomarker objectives are to evaluate for each treatment arm: 1) systemic type I survivin-specific immune response, as measured by IFN-γ ELISPOT; 2) changes in immune environment by GeoMx digital spatial genomic profiling; 3) and changes in tumor infiltrating lymphocytes (TILs) and Ki67. These data will be used to identify the most immunogenic MVP-S combination therapy for study in phase II trial powered to assess clinical outcome (pCR). Clinical trial information: NCT04895761.
TWT-203: Phase 1b/2 dose-confirming study of CFI-402257 as a single agent in advanced solid tumors and in combination with fulvestrant in patients with ER+/HER2- advanced breast cancer after disease progression on prior CDK4/6 and endocrine therapy.
Authors: Wesolowski Robert , Bray Mark R. , Michelson Glenn C. , Roberts-Thomson Emily L. , Denny Trisha , Cescon David W.
Published: June 2022

TPS1123

Background: TTK (Threonine Tyrosine Kinase also known as Monopolar spindle 1 [Mps1]), is a dual-specificity serine-threonine kinase critical for anaphase promoting complex/cyclosome inhibition at the spindle assembly checkpoint, and is required for chromosome alignment and error correction. Inhibition of TTK causes cells to prematurely exit mitosis with unattached chromosomes, resulting in aneuploidy and cell death. Higher TTK tumor levels correlate with worse prognosis and may contribute to the survival and proliferation of aneuploid cells. CFI-402257, a potent and selective inhibitor of TTK inhibits the growth of a variety of human cancer-derived cell lines with IC50 of 8-40 nM. A first-in-human phase 1 study of CFI-402257 administered orally as a single agent, demonstrated a tolerable safety profile and evidence of clinical activity in patients with advanced solid tumors. The MTD was 168 mg daily, and the study expanded to 3 cohorts: solid tumors, HER2-negative breast cancer, and hormone receptor positive (HR+/HER2-) breast cancer in combination with fulvestrant. The dose limiting toxicity was manageable and reversible dose-dependent neutropenia. Investigator-confirmed partial responses (cPR) were observed in 5 patients (10.6%) with 25 (53.2%) exhibiting disease control. In the HR+/HER2- breast cancer population previously treated with cyclin dependent kinase 4/6 inhibitors (CDK4/6i) and aromatase inhibitors, there were 4 cPR’s with a median duration of response of 256 days, with responses emerging after 2 cycles of therapy. Responses were observed with CFI-402257 as a single agent and in combination with fulvestrant. Based on these data, study TWT-203 will focus on advanced solid tumors and advanced HR+/HER2- breast cancers in combination with an approved endocrine therapy. Methods: Safety and clinical activity of CFI-402257 monotherapy will be evaluated in patients with advanced solid tumors (Part A) or in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer (Part B). Part A will confirm the RP2D using a 3+3 design with a starting dose of 126 mg daily. Part B evaluates CFI-402257 in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer following progression on prior CDK4/6i and endocrine therapy. Initially 6 patients will be treated with CFI-402257 and fulvestrant, and safety, tolerability, and PK evaluated, with further expansion to confirm the RP2D and characterize CFI-402257 activity. Efficacy endpoints include overall response rate and disease control rate. Safety endpoints include incidence of treatment emergent adverse events. Exploratory objectives include characterization of protein and molecular alterations relevant to the cell cycle and CFI-402257 response.
Phase I trial of an alpha-lactalbumin vaccine in patients with moderate- to high-risk operable triple-negative breast cancer (TNBC).
Authors: Budd George Thomas , Johnson Justin M. , Esakov Rhoades Emily , Moore Halle C. F. , Kruse Megan Lynn , Roesch Erin Elizabeth , Abraham Jame , Elliott Brenna , Lach Donna , Tuohy Vincent K.
Published: June 2022

TPS1125

Background: Triple-negative breast cancer (TNBC) is the subtype of breast cancer with the worst prognosis and is the subtype most often associated with germline mutations of BRCA1 and certain other genes. Alpha-lactalbumin (aLA) is a milk protein that is expressed in lactating breasts but not at other times or in other normal tissues. Expression of aLA is found in approximately 70% of TNBC (Cancers PMID: 27322324) so is an attractive immunologic target for TNBC based on the “retired protein hypothesis” (Semin Immunol PMID: 31926646). Pre-clinical studies have shown that vaccination with aLA provides treatment of established and, more potently, protection from development of autochthonous tumors in transgenic murine models of breast cancer and against 4T1 transplantable breast cancer in BALB/c mice (Nat Med PMID: 20512124). We are conducting a Phase I trial in patients with early stage TNBC to demonstrate the safety of this approach and to document the ability to produce a meaningful immunologic response to aLA. Methods: Patients with ER-negative, PR-negative, HER2-negative breast cancer of pathologic stage I-III or who had residual disease after standard pre-operative systemic therapy are being entered into a Phase I trial of alpha-lactalbumin with a GMP-grade zymosan adjuvant in Montanide ISA 51 VG vehicle. Participants must be within 3 years of initiation of treatment and have no evidence of recurrence. Patients receive a total of 3 vaccinations administered once every 2 weeks with doses escalated using a 3+3 trial design. Toxic events of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater are considered dose-limiting. Dose levels being tested are alpha-lactalbumin/zymosan 0.01 mg/0.01 mg, 0.1 mg/0.1 mg, and 1 mg/1 mg. Patients are being monitored for toxicity until 84 days after the first vaccination or resolution of toxicity, whichever is later. Blood is being drawn prior to therapy and 14, 28, and 56 days after the first vaccination to assess cellular response using enzyme-linked immunosorbent spot (ELISpot) assays of interferon-gamma and interleukin-17 production in response to aLA. Humoral response to aLA vaccination is being assessed by enzyme-linked immunosorbent assay (ELISA). After identification of the Maximum Tolerated Dose we will expand the dose levels associated with effective tumor immunity and enroll a cohort of patients without cancer planning to undergo prophylactic bilateral mastectomy. Funding Source: Department of Defense (W81XWH-17-1-0592 and W81XWH-17-1-0593). Clinical trial information: NCT04674306.
Evaluation of a three-part equity intervention for women of color with breast cancer.
Authors: Rivers Jamil , Robles-Rodríguez Evelyn
Published: June 2022

TPS1129

Background: Women of color (WOC) with breast cancer miss and fail key points in care due to racial disparities in cancer services. Conscious and unconscious bias means that these women are not treated in a timely way or as rigorously. They are offered fewer options, and the patient navigation and education needed for them to self-advocate is ignored. Black women in particular have the highest breast cancer death rates. Care delivery differs even independent of such variables as literacy, income, and education. Separately and incrementally, findings to date have shown the potential oof patient navigation, equity assessment, and mobile support to reverse these disparities. In pilot investigations –– partnering with academic cancer centers –– The Chrysalis Initiative (a nonprofit patient advocacy and research organization) has validated the potential of combining these approaches in a three-part intervention. Based on preliminary work, it is hypothesized patients will: experience significantly greater adherence to the recommended continuum of care, without disruption or barriers; more often seek second opinions and additional supportive resources, and engage in clinical trials; demonstrate less co-morbidities, through more preventive measures and healthful lifestyle; suffer fewer interactions perceived to be influenced by racism; undergo less financial distress, with guidance on managing and planning costs; feel more confident and more optimistic in their outlook; and achieve better clinical results and lower costs. Methods: To determine and document the full impact, both quantitatively and qualitatively, of the experimental three-part intervention, the trial is: delivering navigation/coaching services to the study population, using counselors who are predominantly WOC who have experienced the challenges of breast cancer care. Surveys and interviews pre- and post-intervention will add to impact measures; providing the experimental group with the BC Navi App on both iOS and Android devices . Developed in partnership with InTouch, the app supports engagement and tracking. It provides a dashboard for care evaluation to supplement EMR data; conducting an equity assessment of breast cancer services of partnering clinical programs through use of focus groups with staff, patients, and community; procedural checks; and data collection from center EHR systems. The review audits 40 domains of care based on NCCI, NCI, ASCO, ACR, and other standards. The assessment team works closely and collaboratively with each cancer center’s clinical and administrative staff to reveal disparities and find consensus on ways to close gaps. This trial in progress is randomizing 200 subjects to the coaching/mobile app intervention arm and 100 to benefits of the equity assessment only, with comparison to nonWOC with breast cancer. The trial aims to disseminate the three-part intervention in easily reproducible form.
A randomized phase III clinical trial of acupuncture for chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors.
Authors: Dooley Andee , Han Katherine , Zhi Wanqing Iris , Piulson Lauren , Seluzicki Christina , Bao Ting
Published: June 2022

TPS12145

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect in cancer survivors that can last long after completion of neurotoxic chemotherapy. Patients with CIPN often experience neuropathy symptoms such as pain, tingling, numbness, paresthesia, and dysesthesia, which can lead to significant functional decline and diminished quality of life (QoL). Our prior study showed that more than half of breast cancer survivors who received taxane-based chemotherapy experienced persistent peripheral neuropathy symptoms for a mean duration of 5.6 years after completing chemotherapy. This outcome highlights the importance of developing effective CIPN treatments to improve cancer survivors’ QoL. Identifying nonpharmacological approaches to reduce CIPN symptoms and improve cancer survivors’ outcomes is urgently needed. Acupuncture is a widely used, minimally invasive Traditional Chinese Medicine technique that has shown promising evidence as an effective and safe treatment for CIPN. We hypothesize that acupuncture may reduce CIPN pain and improve overall CIPN symptoms in cancer survivors. Methods: We are conducting a two-arm, parallel randomized clinical trial comparing electroacupunture (EA) versus sham acupuncture (SA) in cancer survivors at Memorial Sloan Kettering Cancer Center, New York, NY. The EA arm includes a total of ten sessions of EA over eight weeks using a standardized, semi-fixed protocol developed by our group based on the previously published pilot study (NCT03183037). The SA arm includes a sham technique that uses a combination of non-acupuncture points and a non-insertion procedure in ten sessions over eight weeks. The primary outcome of this study is the Brief Pain Inventory-Short Form (BPI-SF) average pain item. The secondary outcomes are quantitative sensory testing measures and additional patient-reported outcomes that include the BPI-SF pain interference subscale, Neuropathic Pain Scale (NPS), Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx), CIPN-20, PROMIS Global Health Scale, and Patients’ Global Impression of Change (PGIC). The primary end point is week 12 and the secondary end point is week 24; treatment effects are assessed at baseline and at weeks 4, 8, 12, 18, and 24. Eligibility criteria includes: 1) Moderate-to-severe CIPN pain, defined by a score of 4 or greater on a 0–10 numeric rating scale; 2) completion of neurotoxic chemotherapy at least three months prior to enrollment; and 3) no changes in anti-neuropathy medications within three months of enrollment. We have accrued 30 participants as of February 2022, with a total accrual target of 250 participants. Accrual completion is anticipated by December 2024. Funding resource: NIH R37 CA248563. Clinical trial information: NCT04917796.
Improving care coordination for adolescents and young adults with cancer.
Authors: Haines Emily Ruth , Lux Lauren , Matson Melissa , Swift Catherine , Kleissler Daniel , Smitherman Andrew Brian , Birken Sarah
Published: June 2022

TPS1598

Background: In the US, many of the 90,000 adolescents and young adults (AYAs) (i.e., individuals ages 15-39) diagnosed with cancer each year do not receive services to address the range of needs they experience during cancer treatment. AYAs’ unmet needs are associated with higher distress, poorer health-related quality of life, and higher physical symptom burden. However, AYAs often do not use services available to them through their cancer programs, even when they face no access issues (e.g., cost, insurance status, local service capacity). AYAs report barriers to service use including lack of awareness, challenges navigating large volumes of information and complex health systems, and hesitance to broach needs with providers without prompting. To facilitate a systematic and patient-centered approach to addressing AYAs' unmet needs, we leveraged user-centered design to develop the AYA Needs Assessment & Service Bridge (NA-SB). NA-SB includes a patient-reported outcome measure assessing AYAs’ physical, psychosocial, and practical needs, and a collection of referral pathways for connecting AYAs to services based on the needs they report. In this feasibility pilot study, we are evaluating the implementation of NA-SB in the University of North Carolina Lineberger Comprehensive Cancer Center (UNC) AYA Cancer Program. Methods: Eligible participants include AYAs ages 18-39 currently undergoing cancer treatment at UNC (n = 25-50). The needs assessment portion of NA-SB is administered electronically through REDCap during routine clinical encounters with the AYA team. After an AYA completes the needs assessment, an AYA provider (i.e., social worker/nurse practitioner) reviews their responses and initiates referral pathways. Six weeks following their completion of the needs assessment, AYAs complete a survey assessing their perceptions of (1) the usability of the NA-SB needs assessment, (2) the feasibility, acceptability, and appropriateness of implementing NA-SB, and (3) the extent to which their needs have been met. We are also assessing participating providers’ perceptions of NA-SB’s implementation through periodic check-in calls. Results: We will report descriptive statistics on participant demographics, needs reported, and quantitative outcomes. We will analyze data from provider check-in calls inductively to further elaborate on implementation experiences and determinants. Conclusion: By harnessing patient-reported data to facilitate care coordination for AYAs, NA-SB has the potential to improve processes of care and subsequent outcomes for AYAs, an underserved and understudied population. This pilot study represents a critical first step towards translating NA-SB into routine cancer care for AYAs. Clinical trial information: NCT04586127.
Window-of-opportunity study of ONC201 in pediatric patients with diffuse intrinsic pontine glioma (DIPG) and thalamic glioma.
Authors: Odia Yazmin , Koschmann Carl Johannes , Tarapore Rohinton , Allen Jeffrey , Zaky Wafik Tharwat , Hall Matthew David , Daghistani Doured , Khatib Ziad , Aguilera Dolly , MacDonald Tobey J. , de Blank Peter , McGovern Susan L. , Mueller Sabine , Kline Cassie , Vitanza Nicholas A. , Allen Joshua E. , Gardner Sharon L.
Published: June 2022

TPS2082

Background: H3 K27M-mutant diffuse midline glioma is a universally fatal malignancy primarily affecting children and young adults; while radiotherapy (RT) provides transient benefit, no effective systemic therapy is currently available. ONC201, a first-in-class imipridone, is an oral, blood-brain barrier penetrating, selective small molecule antagonist of dopamine receptor D2/3 and agonist of the mitochondrial protease ClpP. Previously, ONC201 monotherapy demonstrated durable objective responses in adults with recurrent H3 K27M-mutant glioma. This phase 1 trial was designed to evaluate ONC201±RT in pediatric patients with H3 K27M-mutant midline glioma DIPG. Methods: This multicenter, open-label, dose escalation and expansion phase 1 study of ONC201 is comprised of eight arms that will evaluate the recommended phase 2 dose (RP2D) of ONC201, biomarkers, and pharmacokinetics (PK) of ONC201±RT in various treatment settings. Arm G previously defined the RP2D for ONC201 administered twice weekly on consecutive days in patients with H3 K27M-mutant glioma who had completed radiotherapy. Arm H, for which enrollment is ongoing, will estimate the influence of tumor location and blood-brain barrier integrity on PK and intratumoral ONC201 exposure in biopsy-eligible pediatric tumors (DIPG or contrast-enhancing thalamic glioma). Patients eligible for Arm H will be aged 2-≤19 years, ≥2 weeks from last RT administration, and have a Karnofsky/Lansky performance score ≥50; prior confirmation of H3 K27M mutation is not required. In Arm H, single-agent ONC201 administration will occur on two consecutive days each week during each 21-day cycle at the RP2D defined in Arm G. Evidence of disease progression is not required; as such, ONC201 may be administered in the maintenance setting or for recurrent disease. Arm H has a planned enrollment of 27 patients. Each patient will undergo biopsy at a single prespecified biopsy window, which will be assigned at enrollment (Table); plasma for PK analysis will be collected from all patients at all time points shown in the Table, with additional collection pre-dose and 0.5 h post first dose. Clinical trial information: NCT03416530. [Table: see text]
Trial in progress: A phase 1-2, first-in-human, open label, dose escalation and expansion study of AU-007, a monoclonal antibody that binds to IL-2 and inhibits IL-2Rα binding, in patients with advanced solid tumors.
Authors: Vasselli James Robert , Frentzas Sophia , Weickhardt Andrew James , de Souza Paul L. , Tang Jenny , Wyant Tim , Amit Inbar , Ofran Yanay , Knickerbocker Aron
Published: June 2022

TPS2671

Background: AU-007 is a computationally designed, monoclonal antibody that binds to IL-2 on its CD25 binding epitope. AU-007 bound IL-2 (A/IL-2) cannot bind to high affinity trimeric IL-2 receptors (IL-2R) consisting of CD25, CD122, and CD132 expressed on Tregs and vascular endothelium, but its binding to low affinity dimeric IL-2Rs (CD122 and CD132) expressed on T effector and NK cells is unhindered. Thus, AU-007 redirects endogenously produced or exogenous IL-2 (aldesleukin) towards activation of immune stimulating T effector and NK cells, while diminishing Treg activation and expansion. AU-007 will also bind and redirect newly secreted endogenous IL-2 resulting from A/IL-2 driven T cell expansion in the tumor, converting a Treg mediated autoinhibitory loop into an immune stimulating loop. AU-007 is unique in the IL-2 therapeutic field as engineered exogenous, recombinant “non-CD25” IL-2s in development cannot address the autoinhibitory effect of endogenous IL-2. Preclinically, AU-007 has been demonstrated to capture endogenous human IL-2 in vivo. AU-007 with a single low dose of IL-2 has demonstrated efficacy in multiple cancer models and has an excellent safety profile in non-human primates. Methods: This first-in-human, multicenter, open label Phase 1- 2 study evaluates the safety, tolerability, and initial efficacy of AU-007 +/- aldesleukin in patients with advanced solid tumors (CT-2021-CTN-03938-1). Phase 1 consists of 3 escalation arms each starting with a single 1+2 escalation cohort followed by 3+3 escalation cohorts to define the recommended Phase 2 dose (RP2D) or maximum tolerated dose (MTD). Patients with melanoma, renal cell carcinoma (RCC) and 17 selected solid tumors are eligible. Prior treatment with check point inhibitors is allowed. In Arm A, escalating doses of Q2w AU-007 are evaluated in sequential escalation cohorts. In Arm B, a single dose of aldesleukin is given with the initial AU-007 dose. AU-007 is given at a fixed dose Q2w with an escalating single aldesleukin dose in sequential escalation cohorts. In Arm C, AU-007 is evaluated in combination with aldesleukin, both given Q2w. AU-007 is administered at a fixed dose with an escalating dose of aldesleukin in sequential cohorts. The Phase 2 cohort expansion portion of the study evaluates the initial efficacy at the RP2D defined in escalation cohorts A, B, and C in 3 matching expansion cohorts of up to 20 patients each. Patients with advanced melanoma, RCC and other tumors including, but not limited to, Merkel Cell Carcinoma, NSCLC, and urothelial cancer are eligible. Enrolment to the study commences in Australia, with US sites planned to open later in 2022. Clinical trial information: CT-2021-CTN-03938-1.
A phase 1/2 dose escalation/expansion study of OR2805 alone or in combination in subjects with advanced solid tumors.
Authors: Tolcher Anthony W. , Vandross Andrae Lavon , Moser Justin C , Gordon Michael S. , Harrop Katherine , Lechleider Robert
Published: June 2022

TPS2693

Background: M2-like macrophages are thought to promote an immunoinhibitory environment and prevent activation and proliferation of T cells, leading to resistance to checkpoint inhibitor (CPI) therapy. OR2805 is a fully human monoclonal antibody identified in a patient who had an exceptional response to CPI. OR2805 recognizes CD163, an immunosuppressive scavenger receptor highly expressed on M2 tumor-associated macrophages (TAMs). OR2805 treatment reprograms M2 macrophages to take on an immunostimulatory, M1-like phenotype. In macrophage/T cell coculture assays, OR2805 treatment relieved the suppressive effect of M2c macrophages as demonstrated by increased T-cell proliferation and stimulation of IFN-γ and perforin release. OR2805 restored the IFN-γ production of exhausted T cells and showed a synergistic effect on cocultures treated in combination with CPI. OR2805 monotherapy demonstrated significant anti-tumor activity in lung cancer xenograft models in NSG-SGM3 mice. Relieving the immune suppression of CD163-expressing TAMs by OR2805 to improve anti-tumor T-cell responses will be evaluated alone and in combination with CPI therapy. Methods: This phase 1/2, open-label, multicenter, dose-escalation/expansion study is assessing the safety, tolerability and preliminary activity of OR2805 alone and in combination with anti-PD-1 or chemotherapy in up to 325 adults (≥18 years) with histologically or cytologically confirmed metastatic or locally advanced solid tumors. The study is divided into 3 parts. Part A will enroll subjects with advanced solid tumors of any histology to describe the preliminary safety profile of OR2805 and determine the recommended phase 2 dose (RP2D) of OR2805 alone and in combination with an anti-PD-1 monoclonal antibody. Part B will further characterize the safety and preliminary antitumor activity of OR2805 either alone or in combination with an anti-PD-1 or chemotherapy in previously treated non-small cell lung cancer (NSCLC), melanoma and liposarcoma, as well as in previously untreated NSCLC in combination with an anti-PD-1 antibody. Part C will evaluate OR2805 monotherapy in relapsed squamous cell carcinoma of the head and neck and other tumor types with an emphasis on correlative biomarker analysis. OR2805 will be infused on Day 1 of 21-day cycles. Primary endpoints are adverse events, laboratory abnormalities, dose-limiting toxicities, and dose-level safety and activity. Secondary endpoints are objective response rates, duration of response, complete response, progression-free survival, overall survival, PK, and antidrug antibodies. Exploratory biomarkers of OR2805-mediated pharmacodynamic effects and immune stimulation will be explored. The study was opened September 2021 and is enrolling at sites in the United States with planned expansion within the US and to Europe. Clinical trial information: Clinical trial information: NCT05094804.