Open Label Research Articles

Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial

ObjectivesTo evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain.DesignThe PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel...

Early Cold Stored Platelet Transfusion Following Severe Injury: A Randomized Clinical Trial.

To determine the feasibility, efficacy, and safety of early cold stored platelet transfusion compared to standard care resuscitation in patients with hemorrhagic shock. Data demonstrating the safety and efficacy of early cold stored platelet transfusion are lacking following severe injury. A phase 2, multicenter, randomized, open label, clinical trial was performed at five U.S. trauma centers. Injured patients at risk of large volume blood transfusion and the need for hemorrhage control procedures were enrolled and randomized. The intervention was the early transfusion of a single apheresis cold stored platelet unit, stored for up to 14 days vs. standard care resuscitation. The primary outcome was feasibility and the principal clinical outcome for efficacy and safety was 24-hour mortality. Mortality at 24 hours was 5.9% in patients who were randomized to early cold stored platelet transfusion compared to 10.2% in the standard care arm (difference, -4.3%; 95% CI, -12.8% to 3.5%; P=0.26). No significant differences were found for any of the prespecified ancillary outcomes. Rates of arterial and/or venous thromboembolism and adverse events did not differ across treatment groups. In severely injured patients, early cold stored platelet transfusion is feasible, safe and did not result in a significant lower rate of 24-hour mortality. Early cold stored platelet transfusion did not result in a higher incidence of arterial and/or venous thrombotic complications or adverse events. The storage age of the cold stored platelet product was not associated with significant outcome differences.

Elective induction of labor versus expectant management at 39 weeks among low-risk nulliparous pregnant women: A randomized controlled trial in India (ELITE-39 trial).

The aim of the present open label randomized controlled trial was to compare the rate of cesarean section (CS) after elective induction with that of expectant management in low-risk nulliparous women at 39 weeks. This randomized controlled trial from a tertiary maternity care center enrolled low risk nulliparous pregnant women at 38-38+4 weeks between April 1, 2019 and December 31, 2021. Participants were randomized into either the elective induction group (e-IOL) or the expectant management (EM) group though computer generated block randomization. The primary outcome was cesarean rate and the secondary outcome include adverse maternal and perinatal outcome between e-IOL and EM groups. We performed intention to treat analysis. A total of 360 women were enrolled into the present study. Analysis was performed for 179 women in the e-IOL group and 180 women in the EM group. The baseline demographic characteristics including Bishop score were comparable between the groups. The CS rate in both groups was 17.3% (31/179) and 25% (45/180), which is comparable (P = 0.08). There was one intrapartum stillbirth in the e-IOL group, and two babies succumbed in the neonatal period in the EM group. The maternal and perinatal outcomes between the groups were not found to be significantly different. Elective induction of low-risk nulliparous women at 39 weeks was not associated with increased cesarean section rate. The maternal and perinatal outcomes were comparable. Large, multicentric real time randomized controlled trials are needed to understand the benefit of elective induction in low-risk nulliparous women. This should include centers with large volume of deliveries especially from emerging countries also.

Impact of surgical risk factors for non-union on lumbar spinal fusion outcomes using cellular bone allograft at 24-months follow-up

BackgroundThe current report investigates fusion rates and patient-reported outcomes following lumbar spinal surgery using cellular bone allograft (CBA) in patients with risk factors for non-union.MethodsA prospective, open label study was conducted in subjects undergoing lumbar spinal fusion with CBA (NCT 02969616) to assess fusion success rates and patient-reported outcomes in subjects with risk factors for non-union. Subjects were categorized into low-risk (≤ 1 risk factors) and high-risk (> 1 risk factors) groups. Radiographic fusion status was evaluated by an independent review of dynamic radiographs and CT scans. Patient-reported outcome measures included quality of life (EQ-5D), Oswestry Disability Index (ODI) and Visual Analog Scales (VAS) for back and leg pain. Adverse event reporting was conducted throughout 24-months of follow-up.ResultsA total of 274 subjects were enrolled: 140 subjects (51.1%) were categorized into the high-risk group (> 1 risk factor) and 134 subjects (48.9%) into the low-risk group (≤ 1 risk factors). The overall mean age at screening was 58.8 years (SD 12.5) with a higher distribution of females (63.1%) than males (36.9%). No statistical difference in fusion rates were observed between the low-risk (90.0%) and high-risk (93.9%) groups (p > 0.05). A statistically significant improvement in patient-reported outcomes (EQ-5D, ODI and VAS) was observed at all time points (p < 0.05) in both low and high-risk groups. The low-risk group showed enhanced improvement at multiple timepoints in EQ-5D, ODI, VAS-Back pain and VAS-Leg pain scores compared to the high-risk group (p < 0.05). The number of AEs were similar among risk groups.ConclusionsThis study demonstrates high fusion rates following lumbar spinal surgery using CBA, regardless of associated risk factors. Patient reported outcomes and fusion rates were not adversely affected by risk factor profiles.Trial registrationNCT 02969616 (21/11/2016).

Abstract PO1-19-10: Durvalumab + datopotamab deruxtecan in patients with PD-L1 positive advanced/metastatic triple-negative breast cancer: Arm 8 of the phase 1b/2, open label, platform BEGONIA study

Abstract Background: Patients (pts) with advanced/metastatic triple-negative breast cancer (a/mTNBC) have limited treatment options and poor prognosis. Immune checkpoint inhibitors combined with chemotherapy is the standard of care for pts with PD-L1 positive tumors; still, most pts progress within a year, highlighting a need for new treatments. BEGONIA is an ongoing Simon 2-stage, multicenter, multi-arm platform study evaluating the safety and efficacy of durvalumab (D), an anti–PD-L1 monoclonal antibody, with or without paclitaxel, in combination with novel oncology therapies as first-line treatment for a/mTNBC (NCT03742102). Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate (ADC) consisting of a humanized anti-trophoblast cell surface antigen 2 (TROP2) IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload via a plasma stable, tumor selective, tetrapeptide-based cleavable linker. TROP2 is broadly expressed on breast and other epithelial tumors and Dato-DXd monotherapy showed antitumor activity in heavily pretreated mTNBC pts (Bardia SABCS 2022 P6-10-03). Pts treated with Dato-DXd+D in Arm 7 of BEGONIA showed a 74% objective response rate (ORR) with median 7.2 months follow-up (Schmid SABCS 2022 PD11-09). Although responses were observed in both PD-L1–high and –low-expressing tumors, most pts (87%) had PD-L1–low-expressing tumors. In Arm 8 of BEGONIA, pts determined to have PD-L1 positive tumors by pre-existing/local testing will be recruited and treated with Dato-DXd+D to evaluate efficacy and safety in a PD-L1–high population. Methods: Eligible female pts are aged ≥18 years with untreated unresectable, locally advanced or mTNBC; ≥6 months between completion of treatment for earlier-stage breast cancer and recurrence of distant disease; ≥12 months since prior taxane therapy; ECOG PS 0/1; adequate organ function; and ≥1 nonirradiated measurable lesion. For inclusion in Arm 8, a PD-L1 positive tumor as determined by local immunohistochemistry (IHC) testing is required (either pre-existing or obtained during prescreening). Exclusion criteria for Arm 8 are clinically significant corneal disease; history or suspicion of interstitial lung disease/pneumonitis; underlying pulmonary disorder; prior exposure to immune-mediated therapy; or prior treatment with an ADC containing a topoisomerase I inhibitor. Arm 8 will evaluate Dato-DXd (6 mg/kg) + D (1120 mg) given intravenously every 3 weeks until disease progression or unacceptable toxicity. Tumors will be assessed per RECIST v1.1 every 6 weeks for 48 weeks, then every 12 weeks thereafter. A safety run-in will not occur for Arm 8, as Dato-DXd+D was evaluated in Arm 7 and was tolerable with no DLTs reported. Part 1 of Arm 8 will enroll 30 pts. The primary endpoint of Part 1 is safety and tolerability. A futility analysis will be performed with an option to expand Arm 8 to Part 2, where an additional 27 pts will be enrolled if expansion criteria are met. The primary endpoint for Part 2 is ORR. Secondary endpoints include ORR (Part 1 only), testing for antidrug antibodies and treatment pharmacokinetics (Part 1 only), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). ORR will be summarized with descriptive statistics and 95% Clopper-Pearson confidence intervals. Kaplan-Meier analysis will be used for DoR, PFS, and OS. All tumor response and survival endpoints will be based on investigator assessments. Additional PD-L1 testing with the VENTANA PD-L1 (SP263) Assay will be performed on pretreatment tumor samples; high expression is defined as ≥10% of the tumor area populated by PD-L1–expressing tumor or immune cells. TROP2 expression will be assessed by IHC. Enrollment is ongoing. Funding: AstraZeneca/Daiichi Sankyo Citation Format: Peter Schmid, Cynthia Ma, Robert Huisden, Ross Stewart, Katrin Heider, Petra Vuković, Neelima Denduluri. Durvalumab + datopotamab deruxtecan in patients with PD-L1 positive advanced/metastatic triple-negative breast cancer: Arm 8 of the phase 1b/2, open label, platform BEGONIA study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-19-10.

Abstract PO2-19-11: NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative Breast Cancer

Abstract Background The standard of care for patients with early triple-negative breast cancer (TNBC) is neoadjuvant chemotherapy followed by surgery. Recently, immune checkpoints inhibitors (ICI) added to neoadjuvant chemotherapy have shown efficacy. Among TNBC, BRCA mutations and other homologous recombination deficiency (HRD) signals are relatively frequent. As opposed to other types of breast cancer, TNBC show a high neoantigen load, a large number of tumour infiltrating lymphocytes (TILs), and a high PD-L1 expression. In BRCA/HRD breast cancer, PARP inhibitors (PARPi) exhibit a distinct anticancer activity. In addition, they show immunomodulatory effects by promoting PD-L1 expression and DNA damage, increasing neoantigen load. Chemotherapy-free regimens combining PARPi and ICI result in promising synergistic activity as shown in the metastatic setting, supporting investigation in the neoadjuvant setting. Trial design NOBLE is an EORTC phase 2, randomized, international, multicentre, open label, clinical trial. Eligible patients will undergo central screening for tumoral BRCA/HRD (Institute Curie, 455 patients), 152 patients will be randomized 1:1 between olaparib vs olaparib and durvalumab for 4 cycles (16 weeks) of neoadjuvant treatment. Thereafter, patients will undergo surgery. All patients will be followed-up to 2 years (y) after surgery. The trial will be conducted in 3 steps (screening/randomization): Step 1 – Feasibility (60/20): to assess the central testing failure rate, the turn-around time for central testing and the prevalence of tBRCA/HRD; Step 2 (193/64) – Futility; and Step 3 (202/152) – Expansion of recruitment. The primary endpoint is the rate of pathologic complete response (pCR) at the time of surgery, defined as ypT0/is ypN0. Secondary endpoints are response based on RECIST v1.1, surgery rate, 2-y event-free-survival, 2-y overall survival, safety, and quality of life. The study is expected to be activated in early autumn 2023 and the primary endpoint will be available approximately 5 years after the screening of the first patient. Main inclusion criteria Histologically confirmed primary TNBC, defined as: - ER and PgR ≤ 10% - HER2-negative per ASCO CAP guidelines Stage T1c-T2 N0-N1 M0 BRCA mutation and/or HRD based on methylation as determined by central testing ECOG status 0-1 Written informed consent Age ≥18 years No prior systemic therapy nor surgery for the current Main exclusion criteria Previous treatment with a PARPi or an immune-checkpoint inhibitor History of previous invasive breast cancer Bilateral and/or multifocal and/or multicentric BC Autoimmune or inflammatory disease Specific aims The aim of this study is to provide a safe and effective neoadjuvant treatment free of chemotherapy to a distinct subpopulation among patients with TNBC. We will evaluate the pCR after neoadjuvant treatment with olaparib alone and with olaparib in combination with durvalumab in patients with TNBC showing a BRCA1/2 mutation or HRD based on methylation. Statistical methods The sample size was calculated based on the minimax Simon two-stage design including an interim analysis for futility of the primary endpoint. Decision rules are pre-specified in the study protocol. Each treatment arm will be analyzed independently. There will be no formal comparison between the two experimental treatment arms. A minimization technique will be used for random treatment allocation stratifying for the type of HRD alteration, PD-L1 expression level and for TILs. Accrual We expect to start recruiting in September 2023. We aim to screen 455 patients to randomize 152 patients. Contact information for people with a specific interest in the trial Etienne Brain (study coordinator): etienne.brain@curie.fr Anne-Sophie Hamy-Petit (study co-coordinator): anne-sophie.hamy-petit@curie.fr Citation Format: Emanuel Buhrer, Eleni Xenophontos, Anne-Sophie Hamy-Petit, Jose Casas-Martin, Céline Callens, Thomas Meyskens, Coralie Poncet, Anastasia Lanzi, Etienne Brain. NOBLE – Neoadjuvant Olaparib and Durvalumab for patients with BRCA-associated TripLE Negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-11.

Abstract PO4-20-05: An open label phase III randomized trial to evaluate the efficacy of Post-chemotherapy Axillary Conservation Surgery in breast cancer (PACS)

Abstract Background- Axillary lymph nodes (ALN) status is the most important prognostic factor in breast cancer. Traditionally, a complete axillary lymph node dissection (ALND) has been standard of care for those patients who have a positive node pre-chemotherapy. However, lately axillary conservation is paving its way in the post-chemotherapy setting as well to avoid significant morbidity of ALND. Most sentinel node biopsy studies have failed to achieve the desired false negative rate(FNR). (Boughey JC et al, JAMA. 2013 Oct; Kuehn T et al, Lancet Oncol. 2013; Boileau JF et al, J Clin Oncol. 2015 Jan).We previously reported a low FNR of low axillary sampling (LAS) in the post-chemotherapy setting. (Parmar et al, JCO-GO, 2021) We are conducting a phase III, randomised controlled trial of LAS versus complete ALND in post-chemotherapy negative (ypN0) axilla. Aims and objectives- The primary objective is to assess the non-inferiority of LAS in patients who are rendered ypN0 by pre-operative chemotherapy with disease-free survival as primary end point. The secondary objectives are comparing the morbidity of ALND (lymphedema, paraesthesia, and shoulder dysfunction) in the LAS and ALND arms, and to evaluate the impact on overall survival, local, regional, and distant recurrence free survival and quality of life. Trial design- This is a prospective, open label, randomised, phase III trial where histologically proven, non-metastatic, cT1-4,N0-2 breast cancer patients who are rendered ycN0 after pre-operative systemic chemotherapy are being accrued. Patients with prechemo N3 disease, inflammatory breast cancer, recurrent disease, pregnancy associated breast cancer are being excluded from the study. The chemotherapy regimens and surgical assessment is as per standard institutional protocols. After obtaining informed consent, patients undergo LAS during surgery and lymph nodes(LN) are sent for frozen section analysis. If any LN is found to be involved, a complete ALND is carried out. If the staging procedure is negative, then patients are randomised into 2 groups- observation v/s complete ALND. Stratification factors are T stage, N stage, Hormone receptor status, Her2 receptor status and number of chemotherapy cycles taken. Morbidity assessment is done with- Constans shoulder score, arm volumetry, paraesthesia assessment, and a QOL questionnaire- Self-reported Breast cancer Lymphedema Symptom Experience Index (BCLSEI). A baseline assessment pre-surgery is followed by 6 monthly morbidity assessments and regular oncologically relevant follow-up up to 5 years. A two-sided log-rank test with an overall sample size of 2316 with a 10% dropout rate (1158 in ALND and 1158 in LAS group) achieves 80% power at a 0.05 significance level to detect a hazard ratio of 1.16 (upper limit of non-inferiority) when the proportion surviving in the control group is 0.71. An interim analysis will be carried out at 25% events and conditional power will be calculated. If the conditional power is below 20%, then the study will be discontinued for futility. The study has been approved by Institutional Ethics Committee (CTRI/2022/07/044461) Expected Study and Results- We started accrual in February 2023 and have screened 63 and randomized 45 patients until now. Ours is a first large randomised prospective study in the post-chemotherapy axillary management setting which will help us understand the efficacy of axillary conservation surgery in patients who are node negative post neoadjuvant chemotherapy. In future, lesser morbid procedures than LAS like targeted axillary dissection can be tested in the same trial. However, LAS as a technique of axillary conservation suits resource constraints and high volume setting such as ours. Citation Format: Shalaka Joshi, Jessicka Shah, Pallavi Daphale, Rohini Hawaldar, Anuradha Daptardar, Ayushi Sahay, Tanuja Shet, Palak Popat, Tabassum Wadasadawala, Nita Nair, Vani Parmar, Bipin Bandre, Shabina Siddique, Vaibhav Vanmali, Sudeep Gupta, Rajendra Badwe. An open label phase III randomized trial to evaluate the efficacy of Post-chemotherapy Axillary Conservation Surgery in breast cancer (PACS) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-20-05.

Abstract PO4-22-11: Study to Compare the Safety of Immediate One-stage IBBR With Expander-Implant Two-stage IBBR Augmented With TiLoop® Bra(COSTA)

Abstract Background: The use of TiLOOP@ Bra in implant-based breast reconstruction (IBBR) becomes standard of care in mainland China. But evidence is limited about complication of one-stage and two-stage IBBR using TiLOOP@ Bra. A prospective randomized trial was conducted to compare the safety of immediate IBBR with that of immediate-delayed IBBR, both with TiLOOP@ Bra. Methods: We did an open label, randomized, controlled trial in eleven hospitals in the mainland China. Inclusion criteria: Women aged above 18 with cT0-T2N0M0 breast carcinoma which requires to undergo nipple or skin-sparing mastectomy (NSM or SSM) and immediate IBBR. Randomization was done electronically, stratified per center and in blocks of four of six to achieve approximately balanced groups of patients assigned to undergo one-stage or two-stage IBBR. Both procedures were undergone pectoralis major and TiLOOP@ Bra to build pockets. The primary endpoint of the present study was the incidence of postoperative complications (within 90 days after surgery), while the secondary endpoints were the quality of life at 18 months after surgery, satisfaction with breast appearance, aesthetic scores of reconstructed breasts, type of reoperation and TiLOOP@ Bra angiopathological assessment. This study is registered at clinicaltrials.gov, number NCT03589924. Findings: Between June 2018 and May 2022, a total of 418 eligible patients were randomly assigned to either two-stage implant reconstruction (n=194) group or immediate one-stage implant reconstruction (n=224) group. In terms of surgical procedures, NSM was more commonly (72.7%) chosen, with the two-stage implant reconstruction group having a lower proportion compared to the immediate one-stage implant reconstruction (66.3% vs. 78.3%; p=0.010). At 3 months after breast reconstruction surgery, the incidence of complications was lower in the two-stage implant reconstruction group than that in the immediate one-stage implant reconstruction group, with significant difference of 14.5% vs 23%; p=0.038. The incidence of nipple or areola necrosis was lower in the two-stage implant reconstruction group compared to the immediate one-stage implant reconstruction group, with statistically significant difference of 9.8% vs 17.1%; p=0.048. The implant loss rate was only 0.7%. It was discovered that the incidence of severe complications was lower in the two-stage implant reconstruction group than in the immediate one-stage implant reconstruction group (2.6% vs. 3.7%), and the difference was not statistically significant. Patients who experienced complications had a higher proportion of chemotherapy (69.2% vs. 38.9%; p&amp;lt; 0.001), endocrine therapy (74.4% vs. 53.9%; p=0.002), and targeted therapy (24.4% vs. 9.6%; p=0.001), and the differences were statistically significant. In terms of surgical procedures, 67 (85.9%) patients who experienced complications underwent NSM, while the proportion of NSM in patients who did not experience complications was lower at 69.6%, which were 231 patients, and the difference was statistically significant (p=0.011). In addition, the complication incidence of patients who received implants sizes of 300-400ml was higher than that of the group that did not (32.1% vs. 17.8%; p=0.012). Conclusion: Both one-stage and two-stage TiLOOP@-assisted IBBR demonstrated perioperative safety. The complication rate within three month of two-stage is lower than one-stage. The implant loss rate was only 0.7% perioperatively. Our results suggest that use of TiLOOP@ Bra be considered carefully for one-stage NSM with IBBR but can be considered for SSM patients. Citation Format: Benlong Yang, Jian Liu, Haibo Wang, Yiding Chen, Cuizhi Geng, Nanyan Rao, Siyuan Han, Antai Zhang, Jinping Shi, Qiang Zhang, Wenhe Zhao, Jiong Wu. Study to Compare the Safety of Immediate One-stage IBBR With Expander-Implant Two-stage IBBR Augmented With TiLoop® Bra(COSTA) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-22-11.

Abstract PO5-19-08: Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP): An Open Label Randomized Phase II Trial

Abstract Background: Immune checkpoint inhibition (ICI) is synergistic with HER2-directed therapy in pre-clinical models. Clinically, pembrolizumab (K)-mediated ICI plus HER2-directed therapy with trastuzumab (H) was safe and demonstrated modest activity in H-resistant HER2-positive (HER2+) metastatic breast cancer. Because ICI may confer more robust activity when administered earlier in the course of disease, H and K administered in the curative-intent, treatment-naive setting may allow for de-escalation of cytotoxics; confer life-long, tumor-specific immunity; and ultimately, improve cure rates. Moreover, the synergy of H and K with paclitaxel (T) may overcome the need for dual HER2-blockade with H plus pertuzumab (P). In this randomized, multicenter, phase II, open-label trial the efficacy and safety of neoadjuvant THP vs THP-K vs TH-K are explored. Methods: Patients (pts) ≥18y with previously untreated, stage II-III, HER2+ breast cancer are being randomized and stratified by clinical nodal status (positive vs. negative) and hormone receptor status (positive vs. negative). In arm A, pts receive T at 80mg/m2 weekly for 12 weeks, H at 8mg/Kg (loading dose) and then 6mg/Kg every 3 weeks x 3 doses, P at 840 mg (loading dose) and then 420mg/Kg every 3 weeks x 3 doses (THP). In arm B, pts receive THP plus K at 200mg every 3 weeks x 4 doses (THP-K). In arm C, pts receive TH-K. After enrollment of 22 pts to arm C, a prespecified interim efficacy analysis was conducted, and enrollment to this arm was subsequently terminated. Enrollment to the other arms continues with 32/58 pts enrolled to arm A and 33/58 pts enrolled to arm B as of 2/14/2023. Definitive surgery is 3-6 weeks after the last dose. After surgery, pts are treated per the treating physician’s discretion per local clinical standard. The primary end point is pathologic complete response (pCR) rate in the breast and axilla (ypT0/Tis ypN0). Secondary end points include pCR rate by ypT0ypN0 and ypT0/Tis, residual cancer burden index, event free survival, breast conserving surgery rate, safety and overall survival. Exploratory correlative studies will characterize potential immune biomarkers predictive of efficacy and/or toxicity. Funding sources: BCRF, Merck NCT03747120 Citation Format: Heather McArthur, Jorge Henrique Santos Leal, Isaac Chan, Nisha Unni, Stephen Shiao, Joshua Gruber, Samira Syed, Namrata Peswani, Navid Sadeghi, Glenda Delgado, Dawn Klemow, Reva Basho, Meredith Carter, Mai Badran, Nasir Qureshi, Jessica Curtin, Joshua Weese, Stephanie Rice, Michelle Phillips, David Chan, Hugo Hool, Dorothy Park, Mary El-Masry, Philomena McAndrew, Swati Sikaria, Laura Spring, Aditya Bardia, Mourad Tighiouart, Farnaz Dadmanesh, Armando Giuliano, Katherine Sanchez, David Page. Neoadjuvant HER2-targeted Therapy +/- Immunotherapy with Pembrolizumab (neoHIP): An Open Label Randomized Phase II Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-19-08.

Abstract PO4-27-06: Design of Active Phase 3 ENABLAR-2 Study Evaluating Enobosarm +/- Abemaciclib in Patients with AR+ER+HER2- 2nd-Line Metastatic Breast Cancer Following Tumor Progression on an Estrogen Blocking Agent Plus Palbociclib or Ribociclib

Abstract Background: Targeting the androgen receptor (AR) with an oral selective agonist, enobosarm, is a novel approach to overcome ER and CDK4/6 resistance to suppress metastatic breast cancer (mBC). Preclinical studies in CDK4/6 inhibitor and estrogen blocking agent resistant PDX mBC models demonstrated that enobosarm alone or in combination with another CDK 4/6 inhibitor suppressed PDX mBC growth. In a subgroup analysis from a Phase 2 study, enobosarm demonstrated efficacy in the treatment of AR+ ER+ HER2- metastatic breast cancer in patients who had tumor progression on estrogen blocking agent and a CDK 4/6 inhibitor with a best overall response rate of 30% (2CRs and 1 PR). A Phase 3 ENABLAR-2 multi-center, open label, study evaluating enobosarm +/- abemaciclib is open and active for the treatment of HR+HER2- mBC. Methods: The two-staged Phase 3 ENABLAR-2, open-label, randomized, multicenter study is being conducted in AR+ER+ HER2- 2nd-line mBC who have progressed on estrogen blocking agent plus palbociclib or ribociclib. In the Stage 1 of the study (160 patients), five treatment arms will be assessed with the primary efficacy endpoint of ORR: enobosarm 9 mg QD, enobosarm 1 mg QD + abemaciclib, enobosarm 3 mg QD + abemaciclib, enobosarm 9 mg QD + abemaciclib, and an estrogen blocking agent, active control (a nonsteroidal AI, exemestane +/- everolimus, or SERD). Secondary efficacy endpoints include progression-free survival (PFS). In Stage 2 of the study, patients will be randomized to receive enobosarm +/- abemaciclib (based on outcome of ORR in Stage 1) or estrogen blocking agent, active control, with the primary endpoint of PFS and secondary efficacy endpoints including, ORR, CBR, OS, as well as changes in quality-of-life measurements (SPPB, EORTC-QLQ, body composition measured by DEXA). Randomization will be stratified by AR% nuclei staining and by line of treatment for metastatic disease. Subjects will receive study drug until disease progression is observed. Preliminary Results: To date, 3 patients have been treated with enobosarm 9 mg in combination with abemaciclib. The combination therapy was well tolerated with no new safety findings. There were no drug-drug interactions between enobosarm and abemaciclib. Two patients have achieved BOR of a partial response with up to 79% and 56% reduction in their target lesion recorded by local reads on day 224 post-treatment initiation (PTI). The third patient has achieved a stable disease and continues to receive treatment (on study 10+ months). Conclusions: Preliminary data of efficacy and safety of enobosarm in combination with abemaciclib are encouraging. The Phase 3 ENABLAR-2 study is underway to further evaluate enobosarm monotherapy or in abemaciclib combination therapy in 2nd-line metastatic breast cancer population. Clinical trial information: NCT05065411. Research Sponsor: Veru Inc Citation Format: Kristine Rinn, Hannah Linden, Lee Schwartzberg, Gary Barnette, Domingo Rodriguez, Itay Shalev, Mitchell Steiner, Adam Brufsky, Joyce O'Shaughnessy. Design of Active Phase 3 ENABLAR-2 Study Evaluating Enobosarm +/- Abemaciclib in Patients with AR+ER+HER2- 2nd-Line Metastatic Breast Cancer Following Tumor Progression on an Estrogen Blocking Agent Plus Palbociclib or Ribociclib [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-06.

Abstract PS07-03: Randomized trials of oestrogen-alone and breast cancer incidence: a meta-analysis

Abstract Background Findings from cohort studies compared with those from the Women's Health initiative (WHI) randomized, placebo-controlled clinical trial regarding estrogen-alone and breast cancer risk are discordant. The WHI randomized trial enrolled 10,729 postmenopausal women with prior hysterectomy, mean age 64 years (33.2% 50-59), no prior breast cancer and a non-suspicious baseline mammogram. After 7.2 years intervention and 16.2 years cumulative follow-up, conjugated equine estrogen (CEE)-alone (vs placebo) significantly reduced breast cancer incidence by 22% (P = 0.005) and significantly reduced breast cancer mortality by 40% (P = 0.04) (Chlebowski JAMA 2020). In contrast, cohort studies had opposite findings, estrogen-alone use was associated with significantly higher breast cancer incidence and significantly higher breast cancer mortality. Therefore, we identified all available estrogen-alone randomized clinical trials where breast cancer findings were reported to conduct a meta-analysis examining the totality of the randomized clinical trial evidence regarding estrogen-alone influence on breast cancer incidence. Methods We conducted PubMed and Google Scholar searches on randomized trials and: estrogen, hormone therapy, and breast cancer, and searches from a prior meta-analyses and reviews. In the current meta-analysis, for trials with published relative risks (RR) and 95% confidence intervals (CI), each log-RR was multiplied by weight = 1/V, where V = variance of the log-RR, and V was derived from the corresponding 95% CI. For smaller trials with only breast cancer numbers, a different method was used, the corresponding log-RR = (O – E)/weight, where O is the observed case number in the oestrogen-alone group and E the corresponding expected case number, E = nP. Findings Ten randomized trials, incorporating WHI findings, and findings from nine smaller trials included 14,272 randomized participants and 591 incident breast cancers. Of 9 smaller trials, 6 required negative baseline screening mammograms; mean entry age: 50 to 56 years in 5 trials and 62 to 71 years in 4 trials. In the nine smaller trials, 1.2% (24 of 2029) vs 2.2% (33 of 1514) randomized to estrogen-alone vs placebo (open label, one trial) were diagnosed with breast cancer, respectively (RR 0.65 95% CI 0.38-1.11, P = 0.12). For 5 trials evaluating estradiol formulations, RR = 0.63 95% CI 0.34-1.16, P = 0.15. In the WHI trial, 4.5% (238 of 5310) vs 5.5% (296 of 5429) randomized to estrogen-alone were diagnosed with breast cancer, respectively (RR 0.78 95% CI 0.65-0.93, P = 0.005)). Combining smaller trials and WHI results, 3.6% (262 of 7339) vs 4.7% (329 of 6943) randomized to estrogen-alone vs placebo were diagnosed with breast cancer, respectively (overall RR 0.77 95% CI 0.65-0.91, P = 0.002). Results from a sensitivity analysis for the smaller trials using exact conditional logistic regression were essentially unchanged (RR 0.64 95% CI 0.35-1.13). Interpretation The totality of randomized clinical trial evidence supports a conclusion that estrogen-alone use, among postmenopausal women with prior hysterectomy, significantly reduces breast cancer incidence. This consistent pattern seen in these randomized trials suggests the WHI CEE-alone findings are not “stand alone” outcomes or due to chance. Citation Format: Rowan Chlebowski, Aaron Aragaki, Kathay Pan, Joanne Mortimer, Karen Johnson, Jean Wactawski-Wende, Meryl LeBoff, Sayeh Lavasani, Dorothy Lane, Rebecca Nelson, JoAnn Manson. Randomized trials of oestrogen-alone and breast cancer incidence: a meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS07-03.

Comparative evaluation of intensified short course regimen and standard regimen for adults TB meningitis: a protocol for an open label, multi-center, parallel arms, randomized controlled superiority trial (INSHORT trial)

BackgroundDespite several incremental improvements in the management of tuberculous meningitis (TBM), the mortality rates remain high. In spite of national and international guidelines, variation in the choice, dose, and duration of drugs exist between countries and clinicians. We propose to evaluate a shorter and more effective regimen containing agents with augmented intracerebral drug exposure and anti-inflammatory approaches to improve disability-free survival among patients with TBM. Our strategy incorporates the various developments in the field of TBM over the last two decades and only few trials have evaluated a composite of these strategies in the overall outcomes of TBM.MethodsAn open label, parallel arms, randomized controlled superiority trial will be conducted among 372 participants across 6 sites in India. Eligible participants will be randomly allocated in 1:1:1 ratio into one of the three arms. The intervention arm consists of 2 months of high-dose rifampicin (25 mg/kg), moxifloxacin (400 mg), pyrazinamide, isoniazid, aspirin (150 mg), and steroids followed by rifampicin, isoniazid, and pyrazinamide for 4 months. The second intervention arm includes all the drugs as per the first arm except aspirin and the patients in the control arm will receive treatment according to the National TB Elimination Program guidelines. All participants will be followed up for 1 year after the treatment. DiscussionCurrent WHO regimens have agents with poor central nervous system drug exposure and is too long. It does not reflect the accumulating evidence in the field. We propose a comprehensive clinical trial incorporating the emerging evidence accrued over the last two decades to shorten the duration and improve the treatment outcomes. This multi-centric trial may generate crucial evidence with policy and practice implications in the treatment of TBM.Trial registrationClinical Trial Registry India CTRI/2023/05/053314. Registered on 31 May 2023 (https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=ODYzMzg=&Enc=&userName=CTRI/2023/05/053314). ClinicalTrials.gov NCT05917340. Registered on 6 August 2023 (https://classic.clinicaltrials.gov/ct2/show/NCT05917340).Protocol versionVersion 1.3 dated 12 July 2023.

Activated carbon cloth versus silver-based dressings in a population with diabetic foot ulcer: a randomised controlled trial.

Activated carbon cloth (ACC), known as Zorflex dressing, has emerged as an innovative approach in managing bacterial infection in diabetic foot ulcer (DFU) treatment. This pilot study was undertaken to determine the efficacy of Zorflex ACC dressing (Chemviron Carbon Cloth Division, UK) compared to standard silver-based dressing on DFUs. An open label, comparative, randomised controlled trial enrolling patients who attended the diabetic foot clinic was conducted between August 2022 and August 2023. The primary endpoint was a difference of 20% in wound area reduction with the ACC dressing compared to silver-based dressing within eight weeks. The secondary endpoints were proportion of complete healing, time to healing and adverse events. The cohort comprised 40 patients. The mean wound reduction percentage at 8 weeks for patients in the ACC arm was 85.40±16.00% compared with 65.08±16.36% in the silver-based dressing arm. Complete healing was observed in six of 20 patients in the ACC arm compared to two of 20 in the silver-based dressing arm. These data suggest that the ACC dressing promotes better ulcer healing in DFU patients than the silver-based dressing.

Abstract PO4-19-11: A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer

Abstract Background The androgen receptor (AR) is expressed in approximately 30% of breast cancers. Phase I and II trials of bicalutamide in HR-negative and enzalutamide in both triple negative breast cancer (TNBC) and hormone receptor (HR) positive populations have shown safety and favorable clinical benefit rates (CBR). Additionally, cell cycle (CC) inhibitors, such as abemaciclib, have demonstrated improved progression free survival (PFS) for patients with HR-positive metastatic breast cancer (MBC) in combination with ET in the first line and subsequent lines of therapy. A preclinical study showed that anti-androgen therapies enhanced CKD4/6 induced cytostatic effect in AR-positive TNBC cell lines. We performed a retrospective, institutional study evaluating metastatic HR+ tumor samples with immunohistochemistry (IHC) from patients treated with CDK4/6 inhibitor, palbociclib. We found a statistically significant increase in event free survival (EFS) for those that had any expression of AR (&amp;gt;0%, median EFS 19 months vs 5 months, HR 0.26, p=0.01). Additionally, AR expression was associated with intact phosphorylated retinoblastoma (Rb) expression (100%, P=0.02), which may represent a mechanism by which CC inhibition is effective in AR+ MBC. Trial Design NCT 05095207 is an ongoing, Phase Ib/II, open label, multi-center study. The primary objective for the phase I portion is to determine the recommended phase II dose (RP2D) of abemaciclib in combination with bicalutamide. The primary objective for the phase II portion is to determine the disease control rate (DCR) at 6-month treatment with abemaciclib and bicalutamide. Patients with HER2-negative MBC who are AR+ (IHC &amp;gt;1%) are eligible. HR-positive participants must have had one prior line of ET in the metastatic setting and no more than 2 prior lines of cytotoxic chemotherapy. HR-negative participants may have had up to 4 prior lines of cytotoxic chemotherapy. In the Phase I portion, up to 12 patients are given abemaciclib 100 mg oral, twice daily on days 1 to 28 and bicalutamide 150 mg oral, daily on days 1 to 28. If there is no toxicity after cycle 1 for the first 3 patients, the dose of abemaciclib will increase to 150 mg twice daily. However, if there is a dose limiting toxicity (DLT) within the first cycle (28 days) of therapy, the dose will decrease to 50 mg twice daily. In the Phase II portion, 51 patients will receive abemaciclib at the RP2D twice daily in addition to bicalutamide 150 mg daily on days 1 to 28. The estimated study duration is 36 months. The drugs will be administered until disease progression or unacceptable toxicity. The primary end points include the DLT and the RP2D for abemaciclib administered with bicalutamide and the DCR at 6 months. The secondary end points include the frequency of adverse effects, the DCR stratified by HR status, and PFS. Exploratory endpoints are to determine whether Ki67, cyclin D1, p16, and phosphorylated Rb expression at baseline are predictors of response to abemaciclib and to determine potential mechanisms for resistance to treatment. For Phase Ib, we will utilize the Bayesian optimal interval (BOIN) design, the RP2D will be selected as the dose closest to the target toxicity rate of 0.3. The observed DLT rate at the current dose is ≤ 0.236, the next cohort will be treated at the next higher dose level, if it is ≥ 0.359 the next cohort will be treated with the next lower dose level. For Phase II, we will assess the DCR using a Simon 2 stage optimal design. If among the 46 evaluable patients, 12 or fewer achieve disease control, the treatment will be rejected, however if 13 or more have disease control, the treatment will be considered worthy for further study. We define inactivity as DCR of 0.20 and activity as DCR of 0.35. To date, the study has recruited 21 participants, the goal accrual is 60 patients. Citation Format: Nicole Casasanta, Chrystal Landry, Theresa Shao, Paula Klein, Julie Fasano, Aarti Bhardwaj, Natalie Berger, Erin Moshier, Gargi Atul Joshi, Rita Vaccaro, Joseph Sparano, Amy Tiersten. A Multicenter, Phase Ib/II Study of Abemaciclib in Combination with Bicalutamide for Androgen Receptor-positive, HER2-negative Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-11.

Abstract PO3-20-06: TRUDI: A phase II study of neoadjuvant TRastuzumab derUxtecan and Durvalumab for stage III HER2-expressing Inflammatory breast cancer

Abstract Background: Despite being a rare presentation of breast cancer, inflammatory breast cancer (IBC) is responsible for up to 10% of all breast cancer-related deaths. Most IBCs express HER2, with up to 40% of all IBCs being HER2-positive and 40% being HER2-low. Additionally, IBC more often exhibits PD-L1 expression compared to non-IBC, suggesting a preeminent role for immune evasion in the development and progression of IBC. No systemic treatment approaches have been yet developed specifically for IBC, and standard treatments commonly lead to poor outcomes. Trastuzumab deruxtecan (T-DXd) is an anti-HER2 antibody-drug conjugate currently approved for patients with pretreated HER2-positive and HER2-low metastatic breast cancer. Early-phase data highlighted the safety and potential synergy of combining T-DXd with the immune checkpoint inhibitor durvalumab. The aim of TRUDI is to evaluate the clinical activity and safety of neoadjuvant T-DXd with durvalumab among patients with HER2-expressing IBC. Trial Design: TRUDI is an ongoing, open label, multicenter, two cohort investigator-initiated phase II neoadjuvant trial for patients with stage III HER2-expressing IBC. The trial was activated in May 2023, with enrollment ongoing. Eligible participants are women and men with previously untreated, stage III (T4d, any N) breast cancer, clinically determined to be IBC. Patients will be included in two cohorts, depending on the locally determined HER2 status (with any hormone receptor [HR] status): Cohort 1 (n=36) for patients with HER2-positive disease (HER2 IHC 3+ or 2+/ISH amplified); Cohort 2 (n=27) for patients with HER2-low disease (HER2 IHC 1+ or 2+/ISH not amplified). Patients will receive eight cycles of T-DXd (5.4 mg/kg IV every 21 days) combined with durvalumab (1125 mg IV every 21 days), followed by modified radical mastectomy and post-mastectomy radiation. Post-surgical systemic treatment will follow local standards. Tumor tissue will be collected at baseline, cycle 1 day 8, and at surgery; blood will be collected at baseline, cycle 4 day 1, cycle 7 day 1 and at surgery; stool will be collected at baseline, after 3-6 weeks of treatment and surgery. The primary endpoint is pathologic complete response (pCR; ypT0/Tis ypN0). Patients in each cohort will be enrolled based upon Simon two-stage designs: in Cohort 1, if ≥8/20 patients with HER2-positive IBC experience pCR then a total of 36 patients will be enrolled. In Cohort 2, if ≥1/18 patients with HER2-low IBC experience pCR then a total of 27 patients will be enrolled. Secondary endpoints include the residual cancer burden at surgery, event free survival, distant progression or distant disease-free survival, as well as safety of the regimen. Exploratory objectives will investigate biomarker analyses on tissue, blood, and microbiome to explore the association of HER2 expression, immune variables, and stool composition on the efficacy of T-DXd with durvalumab among patient with HER2-expressing IBC. To our knowledge, this is the first and only ongoing study testing the combination of an anti-HER2 antibody-drug conjugate with immunotherapy for the neoadjuvant treatment of patients with IBC. Clinical trial information: NCT05795101. Citation Format: Paolo Tarantino, Samuel Niman, Antonio Giordano, Faina Nakhlis, Jennifer Bellon, Wendy Woodward, Azadeh Nasrazadani, Sadia Saleem, Anthony Lucci, Michelle DeMeo, Naoto Ueno, Sara Tolaney, Vicente Valero, Meredith Regan, Rachel Layman, Filipa Lynce. TRUDI: A phase II study of neoadjuvant TRastuzumab derUxtecan and Durvalumab for stage III HER2-expressing Inflammatory breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-20-06.

Abstract PO1-01-08: The impact of drug-drug interactions between palbociclib and proton pump inhibitors on clinical outcomes of patients with hormone receptor positive, HER2-negative, early breast cancer: an exploratory analysis of the PALLAS study

Abstract Background: Data suggest that concomitant intake of proton pump inhibitors (PPI) may create drug-drug interactions, potentially impacting efficacy of agents including palbociclib, which is widely used in the treatment of metastatic hormone-receptor-positive/HER2-negative (HR+/HER2-) breast cancer. In the open label, randomized, phase 3 PALLAS trial, the addition of palbociclib for two years to standard adjuvant endocrine therapy (ET) in patients with HR+/HER2- early breast cancer (EBC) did not improve invasive disease-free survival (IDFS) compared to adjuvant ET alone. We explored whether concomitant use of PPIs could have affected clinical outcomes in patients treated with palbociclib in PALLAS. Methods: This is an exploratory, unplanned analysis of the PALLAS trial (AFT-05/ABCSG-42/PrE0109/BIG-14-13, NCT02513394), which enrolled 5796 patients with stage II-III HR+/HER2- EBC. Patients were randomized to receive either 2 years of palbociclib (125 mg oral capsules once daily on days 1-21 of a 28-day cycle) with adjuvant ET or ET alone. Primary endpoint was IDFS in the intention-to-treat population. The present exploratory analysis included patients who received at least one dose of palbociclib. Definitions of IDFS, distant relapse-free survival (DRFS) and overall survival (OS) were according to the PALLAS protocol (STEEP criteria), using first day of palbociclib intake as start date. Only PPI concomitant intake during palbociclib treatment was considered. To determine the association of concomitant PPI use with IDFS, DRFS, and OS, uni- and multivariable Cox models with time-dependent PPI (the latter adjusted for age, prior chemotherapy, progesterone receptor, grade, tumor stage, nodal stage, body mass index (BMI)) were used. Also, the association between PPI use and neutropenia was investigated in patients initiating PPI prior to randomization vs never. Odds ratios (OR) unadjusted and adjusted for age and BMI estimated with logistic regression models are reported. Results: Of 2840 patients treated with palbociclib + ET, 533 (18.8%) had concomitant PPI and palbociclib intake. Median duration of PPI intake was 10.8 months (interquartile range 2.3-22.3). Most patients received omeprazole as PPI (n=265, 49.7%). PPI intake was significantly associated with older age, post-menopausal status, use of aromatase inhibitors as ET, higher BMI, and worse ECOG status (all p&amp;lt; 0.001). Concomitant PPI intake was not significantly associated with survival outcomes (Table 1). Unadjusted all grade neutropenia rates were slightly lower in patients who initiated PPI prior study start vs patients never initiating (79% vs 85%, unadjusted OR 0.66, 95%CI 0.50-0.88). After adjustment for BMI and age, the difference between the groups decreased (adjusted OR = 0.77, 95%CI 0.57-1.04). Similar effect sizes were found for grade 3/4 neutropenia rates (54% vs 64%, unadjusted OR 0.66, 95%CI 0.52-0.83, adjusted OR 0.81, 95%CI 0.64-1.03). Conclusions: Our exploratory analysis did not demonstrate a statistically significant relationship between concomitant use of PPIs and palbociclib and survival outcomes of patients in the PALLAS trial. Nonetheless, careful consideration of concomitant medications and of drug-drug interactions is important when studying novel agents in the adjuvant breast cancer setting. Support: AFT, Pfizer; https://acknowledgments.alliancefound.org Table 1. Association between PPI intake and survival outcomes. Citation Format: Elisa Agostinetto, Georg Pfeiler, Dominik Hlauschek, Erica Mayer, Matteo Lambertini, Evandro de Azambuja, Meritxell Bellet- Ezquerra, Jane Meisel, Gabor Rubovszky, Nicholas Zdenkowski, Yelena Novik, Manuel Ruíz - Borrego, Karen Gelmon, Eleftherios Mamounas, Hiroji Iwata, Dongrui Lu, Lidija Sölkner, Christian Fesl, Michael Gnant, Angela DeMichele. The impact of drug-drug interactions between palbociclib and proton pump inhibitors on clinical outcomes of patients with hormone receptor positive, HER2-negative, early breast cancer: an exploratory analysis of the PALLAS study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-08.

Abstract PO1-11-06: Evaluating Symptom Clusters in Patients with Breast Cancer Experiencing Aromatase Inhibitor-Associated Musculoskeletal Symptoms

Abstract Background: Although treatment with an aromatase inhibitor (AI) for 5-10 years decreases 10-year breast cancer mortality by about 40%, up to 25% of patients will stop treatment early because of treatment-related, intolerable joint and muscular pain and stiffness, called aromatase inhibitor-associated musculoskeletal symptoms (AIMSS). We previously identified that nociplastic pain, or chronic pain in the absence of tissue damage or inflammation, is associated with increased likelihood of developing AIMSS. Other studies have found that symptom clusters, such as the SPPADE symptoms (sleep disturbance, pain, physical function impairment, anxiety, depression, and low energy/fatigue) are prevalent and co-occur in patients with cancer. Here we examine the prevalence of SPPADE symptoms for patients experiencing AIMSS and willing to enroll on a clinical trial examining use of cannabidiol (CBD) to treat their symptoms. Methods: Patients with stage 0-3 hormone receptor-positive breast cancer experiencing AIMSS (defined as worst joint pain ≥4/10 during prior 7 days that developed or worsened since starting AI therapy) were eligible for enrollment in this single arm, single center phase 2 open label clinical trial (NCT04754399). Enrolled patients completed validated questionnaires at baseline and then received CBD (Epidiolex) for 15 weeks. Patient-reported outcomes (PRO) data was collected serially, including the following questionnaires which addressed SPPADE symptoms: Brief Pain Inventory (BPI) to assess pain, PROMIS Profile 29+2 v2.1 to assess multiple symptoms, and Fibromyalgia Survey (FMS) to assess nociplastic pain. Results: 39 patients enrolled on this clinical trial. The median age at enrollment was 57 (range 37-59) and 21% of patients were over age 70. The majority of patients were white (92%) and average BMI was 31 (SD 6.6). Anastrozole was the most used aromatase inhibitor (74%), followed by exemestane (18%), and letrozole (8%). 5 patients (13%) required concomitant GnRHa therapy. Baseline PRO data was obtained from 37 patients. BPI average pain score over the week prior to enrollment was 5.1 (SD 1.5) and worst pain score was 7.2 (SD 1.3). Pain interference reported on the BPI was 4.1 (SD 2.1). Compared to the general population, enrolled patients reported better physical function (T-score 60.2, SE 3.7), less depression (T-score 45.5, SE 4.7) and fatigue (T-score 46.7, SE 5.1), and similar levels of anxiety (T-score 51, SE 7.1) and sleep disturbance (T-score 49.5, SE 5.9) on the PROMIS Profile. On the FMS, 62% of patients had evidence of nociplastic pain, with average score 13.3 (SD 5.7). The median number of sites of pain in the body reported by patients was 8 (range 1-16). Conclusions: While patients enrolling on an AIMSS clinical trial reported a high degree of daily pain that regularly interferes with their activities, for most patients these symptoms did not appear to have a negative impact on mood, affect, or other symptoms that typically cluster with pain. Though it is difficult to extrapolate results from a small population, the unexpected absence of co-occurring symptoms in this population raises additional questions about the interplay of AIMSS and other symptoms commonly reported in interventional AIMSS studies. Follow-up PRO data will be obtained in this clinical trial, allowing us to examine the impact of CBD use on pain, pain interference, and other patient-reported symptoms, as well as to explore which patients are more likely to obtain benefit from CBD treatment. Funding support provided by Conquer Cancer, the ASCO Foundation and the Rising Tide Foundation for Clinical Cancer Research. Citation Format: Fleege Nicole, N. Lynn Henry. Evaluating Symptom Clusters in Patients with Breast Cancer Experiencing Aromatase Inhibitor-Associated Musculoskeletal Symptoms [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-11-06.

Abstract PS16-03: Intratumoral dosing of INT230-6 in Early-Stage Breast Cancer Patients Induces Tumor Cell Necrosis and Immunomodulatory Effects: A Phase II Randomized Window-Of-Opportunity Study – the INVINCIBLE Trial

Abstract Background: Larger tumors pose an increased risk for breast cancer (BC) recurrence post-surgery. In addition, most BC outside of the triple negative subtype are considered immunological quiescent and minimally responsive to immunotherapies. One potential method to combat disease recurrence risk and induce immune activation pre-surgery is through a local therapy that could cause cell death to expose tumor antigens, provide adjuvants for anti-tumor immune priming, and thus potentially increase responsiveness to immunotherapies or rates of pathological complete response in combination with chemotherapy. We have conducted a randomized, Phase 2 presurgical Window-Of-Opportunity trial for intratumoral (IT) INT230-6 comprising vinblastine, cisplatin and a diffusion enhancer (SHAO) in patients with early-stage operable BC, the INVINCIBLE trial (NCT04781725). Previous in vivo and clinical studies demonstrated that INT230-6 induces cancer cell death and halts replication while maturing dendritic cells and recruiting T-cells into the tumor. In this trial, IT injections of INT230-6 were conducted to 1) evaluate the safety of regional cytotoxic use on BC, 2) assess the drug’s ability to cause necrosis, 3) assess immune response within the tumor, microenvironment and systemically prior to surgical resection, and 4) understand the genetic pathways involved in immune activity. Methods: Women awaiting surgery for newly diagnosed early-stage intermediate or high-grade T1-T2 invasive BC were recruited to the trial. The study has two parts. Part I was a randomized (2:1) open label trial comparing 1-3 doses of INT230-6 injected weekly versus no treatment prior to surgery to evaluate safety, feasibility, and optimal drug dosing. Part II was a double-blinded randomized (2:1) trial where patients received one IT dose of INT230-6 vs saline injection IT. Results: We successfully recruited 91 patients with age ranges of 40-77 yrs (mean of 60 yrs) with tumor size ranging from 1.1 - 4.8 cm (mean 2.5 cm; SD 0.9 cm). The most common (&amp;gt;10%) AEs were injection site pain, injection site reaction and nausea/vomiting. Approximately 90% of AEs were grade 1. In the study INT230-6 induced necrosis in 64% of subjects (37 out of 58, range 0 to 100%); whereas saline induced partial necrosis in 25% of patients (5 out of 20, range 0 to 10%). The table below shows the results of necrosis for INT230-6 use in the entire study compared to saline injection for all subjects and those with tumors of size T2. A single injection of INT230-6 caused necrosis in various histologies, including invasive lobular carcinoma. Gene expression analysis showed significant differential gene expression between the baseline biopsy and surgical specimens using INT230-6. Pathway analysis identified genes associated with TCR signaling, B cells and T cell activation that were significantly upregulated in the post INT230-6 treatment samples. There was a relative increase in CD4 and CD8 T cells and B and mast cells. Conclusion: Preliminary evidence shows that a single dose of INT230-6 can cause significant intratumoral necrosis compared to saline especially in tumors &amp;gt;2. cm. INT230-6 stimulates an immune response in breast cancers prior to surgery with minimal adverse effects and good tolerability. Given its immune activation properties, INT230-6 shows promising potential in future breast cancer neoadjuvant studies. Table 1: INVINCIBLE Study Tumor Necrosis Results Intratumoral INT230-6 injection compared to IT saline injection Citation Format: Angel Arnaout, Lewis Bender, Megan Hopkins, Vanessa Lopez Ozuna, Linda Liao, Susan Robertson, Vida Talebian, Kianoosh Keyhanian, Arif Awan, Franco Abbate, Ian Walters, Gregory Pond, John Bartlett, Lazlo Radvanyi, Melanie Spears. Intratumoral dosing of INT230-6 in Early-Stage Breast Cancer Patients Induces Tumor Cell Necrosis and Immunomodulatory Effects: A Phase II Randomized Window-Of-Opportunity Study – the INVINCIBLE Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS16-03.

Abstract PO4-19-01: The SURVIVE-HERoes trial – a secondary adjuvant treatment intervention study with trastuzumab-deruxtecan in patients with HER2 positive/HER2 low early breast cancer and a molecular relapse, based on a positive ctDNA result

Abstract Background: Despite current adjuvant treatment strategies, ≥ 20% of patients with early breast cancer (EBC) experience a metastatic relapse. In the new era of highly effective antibody drug conjugates (ADCs), secondary adjuvant treatment options for EBC patients at a high risk of relapse arise. The ADC trastuzumab-deruxtecan (T-DXd) has so far shown promising efficacy in patients with HER2-positive and HER2-low metastatic breast cancer (DESTINY Breast 03 and -04 trial) and is currently tested in the post-neoadjuvant setting in patients with non-pCR (DESTINY Breast 05 (TRUDY) trial). However, to successfully apply ADCs as a secondary adjuvant treatment, identification of patients who would benefit the most is required. The detection of minimal residual disease (MRD) using liquid biopsy, e.g. ctDNA, may offer a promising approach for patient selection. The efficacy of such a secondary adjuvant treatment in terms of delaying or even preventing distant metastases has yet to be evaluated in a randomized clinical trial. Trial design: The SURVIVE-HERoes trial is a prospective, randomized, open label comparative Phase III superiority trial in patients with intermediate to high-risk HER2-positive or HER2-low EBC, who participate in the large breast cancer surveillance trial SURVIVE (NCT05658172) and experience a molecular relapse as determined by a positive ctDNA result, but show no evidence of relapse or metastatic disease based on imaging by CT-scan and SPECT. In total, 180 patients will be enrolled and randomized with 2:1 allocation to treatment with T-DXd + (only endocrine therapy, if HR positive) versus standard of care (including endocrine treatment +/- CDK4/6-inhibitors or Neratinib). The treatment period lasts 12 months during which ctDNA levels will be repeatedly measured every 3 months (additional ctDNA testing will be performed at month 24 and 36). Stratification factors are HER2-, hormonal- and nodal status. Recruitment start is planned for Q1 2024. Eligibility criteria: Eligible patients are adult females/males, with HER2-positive or HER2-low EBC, as defined in the ASCO-CAP guidelines, and a positive ctDNA result (obtained in the SURVIVE study) that has to be confirmed ≤ 8 weeks before randomization. Primary anti-tumor therapy (surgery, adjuvant chemo- or radiotherapy) has to be completed ≥14 months, (postneo)-adjuvant treatment with anti-HER2-antibodies, T-DM1, Capecitabine, Pembrolizumab and Olaparib ≥ 4 weeks before randomization. Adequate bone marrow and cardiac function and no signs of ILD are mandatory. Statistics: The primary objective of SURVIVE-HERoes is the comparison of ctDNA clearance rates 6 months after randomization between the two study arms, which will be analysed using the chi square test for two independent proportions. Secondary objectives include the comparison of overall survival (OS), invasive disease-free survival (IDFS), distant disease-free survival (DDFS), distant recurrence-free survival (DRFS), breast cancer specific survival (BCSS), invasive breast cancer free survival (IBCFS) and quality of life (QoL) between the study arms as well as the safety and tolerability of T-DXd. Secondary survival endpoints will be estimated by the Kaplan Meier method and compared between the randomization arms using log-rank tests and cox regression models. Special aims: This trial is a proof of principle study with the aim to establish the efficacy of secondary adjuvant treatment with the ADC T-DXd in patients with HER2-positive/HER2-low early breast cancer, who are at high risk of relapse, as evidenced by detection of ctDNA in the blood. Conclusion: If SURVIVE-HERoes is successful, it could lead to a treatment shift towards early intervention with secondary adjuvant targeted therapies following liquid-biopsy based MRD detection. Contact: University Hospital Ulm, Dpt. Obstetrics &amp; Gynecology, Germany, mail: studienzentrale.ufk@uniklinik-ulm.de Citation Format: Sophia Huesmann, Franziska Mergel, Kerstin Pfister, Angelina Fink, Forca Mehmeti, Peter Möller, Tanja Fehm, Volkmar Müller, Klaus Pantel, Thomas Friedl, Andreas Hartkopf, Brigitte Rack, Wolfgang Janni. The SURVIVE-HERoes trial – a secondary adjuvant treatment intervention study with trastuzumab-deruxtecan in patients with HER2 positive/HER2 low early breast cancer and a molecular relapse, based on a positive ctDNA result [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-01.

Abstract LBO1-02: Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial

Abstract Background: Neoadjuvant dual targeting of HER2 with trastuzumab (H) and pertuzumab (P) plus chemotherapy is the standard of care for high-risk HER2-positive (HER2+) breast cancer (BC). Compelling data show the contribution of the immune system in prognosis and response/resistance to HER2 directed therapies, supporting combination of immune checkpoint inhibitors with anti HER2 antibodies. We designed APTneo to test the role of adding atezolizumab to neoadjuvant dual targeting of HER2 with chemotherapy, and the value of also using anthracyclines in this setting. Methods: In this multicenter open label phase III trial (NCT03595592), 661 patients (pts) with high-risk early and locally advanced (LA) centrally confirmed HER2+ BC were randomized to neoadjuvant HPCT (H and P d1, carboplatin and paclitaxel iv d1 and 8) given q3 wks for 6 cycles w/o (n=223, ARM A) or with atezolizumab 1200 mg iv d1 (n=438, ARM B). In Arm B pts were randomized to Arm B1 (n=218) to receive anthracycline and cyclophosphamide (AC) + atezolizumab iv d1 q3 wks for 3 cycles followed by HPCT + atezolizumab for 3 cycles, or to arm B2 (n=220) to receive HPCT + atezolizumab for 6 cycles. After surgery pts continued adjuvant HER2 directed therapies w/wo atezolizumab until completion of 1 year. Among intent-to-treat (ITT) pts, 44.8% were LABC, 35% hormonal receptor (HR) negative and 30.4% PD-L1 positive. Primary endpoint is event-free survival (EFS) of Arm B vs A. A key secondary endpoint is the rate of pCR (ypT0/Tis, ypN0) w/wo atezolizumab. Primary population for all efficacy endpoints is ITT. We also assessed baseline PD-L1 status (Ventana SP142) and stromal Tumor Infiltrating Lymphocytes (sTILs). Results: pCR rate in Arm B (57.8%) vs Arm A (52.0%) was not significantly increased (adjHR 1.33, 95% CI 0.95-1.86; p=0.091). Also, the difference in pCR rate in Arm B1 (61.9%) vs Arm B2 (53.6%) was not significant (adjHR 1.402, 95% CI 0.95-2.07; p=0.089). Compared to Arm A, Arm B1 had a 9.9% significantly higher pCR rate (multivariate analysis in Table). The different pCR rate in arms B1 and A was similar regardless of HR and PD-L1 status. High sTILs (≥30%) and PD-L1positive tumors had a higher likelihood of pCR in all arms. Serious adverse events (SAE) after start of therapy occurred in 6.8% pts in Arm A and 14.1% in Arm B (p=0.0064). SAE were numerically more frequent in Arm B1 than Arm B2 (16.7% and 11.6%, respectively), due to hematological toxicity with AC. Immune-related SAE were quite infrequent and similar in B1 (4.7%) and B2 (7.8%), respectively. No grade 5 AE did occur. Conclusions: Addition of atezolizumab to chemotherapy and HP did not significantly increase the rate of pCR in women with HER2+ BC. An exploratory analysis showed that adding atezolizumab to neoadjuvant AC followed by HPCT led to higher pCR rate compared to HPCT and atezolizumab. This could be because of anthracyclines themselves or to drug-drug enhancement of anthracyclines and immune modulation. Atezolizumab did not cause major tolerability issues. Molecular studies of collected biospecimens are ongoing. Patients will continue to be followed up for EFS and overall survival analyses. Table. Supported in part by unrestricted grant from Hoffman-La Roche, Ltd, Switzerland Citation Format: Luca Gianni, Elisabetta Munzone, Mauro Mansutti, Giampaolo Bianchini, Yann Izarzuzaga, Elena Rota Caremoli, Luc Dirix, Lucia Del Mastro, Santiago González-Santiago, Andreas Schneeweiss, Jose Ponce, Chiun-Shen Huang, Pauline Wimberger, Sevilay Altintas, Miguel Martín, Nicoleta Antone, Christian F. Singer, Ugo De Giorgi, Ana Godoy Ortiz, Hans-Joachim Lueck, Riccardo Spezia, Angelica Fasolo, Giuseppe Viale, Pinuccia Valagussa. Pathologic complete response (pCR) of neoadjuvant therapy with or without atezolizumab in HER2-positive, early high-risk and locally advanced breast cancer: APTneo Michelangelo randomized trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr LBO1-02.