Co-primary Objectives Research Articles

Safety and activity of lenalidomide in combination with obinutuzumab in patients with relapsed indolent non-Hodgkin lymphoma: a single group, open-label, phase 1/2 trial

Rituximab and lenalidomide is a preferred option for relapsed indolent B cell non-Hodgkin lymphoma. Obinutuzumab may be a superior combination partner with lenalidomide given enhanced antibody dependent cellular cytotoxicity and phagocytosis compared to rituximab. Our aim was to determine the recommended phase 2 dose, safety, and activity of lenalidomide in combination with fixed dose of obinutuzumab in relapsed and refractory indolent B cell non-Hodgkin lymphoma. In this single-arm, open-label, phase 1/2 trial, we enrolled patients with relapsed or refractory WHO Grade 1-3A follicular lymphoma, marginal zone lymphoma and small lymphocytic lymphoma and adequate performance status (ECOG 0-2) at the MD Anderson Cancer Center. We excluded patients with evidence of ongoing transformation to aggressive lymphoma. During phase 1, 1000mg intravenous obinutuzumab was administered with three predefined levels of oral lenalidomide in a 3+3 dose escalation design to establish lenalidomide 20mg as the recommended phase 2 dose. During phase 2, patients received induction therapy with six 28-day cycles of lenalidomide 20mg with intravenous obinutuzumab 1000mg. In accordance with our prior experience with lenalidomide plus rituximab, patients who were responding to the combination could receive up to 6 additional cycles (up to 12 cycles in total) of combination therapy. Dosing of obinutuzumab was continued in all responding patients after cycle 6 every 2 months for a total of 30 months from the start of therapy. The decision of number of cycles of combination therapy beyond 6 was at discretion of the investigator and was included to allow individualisation of therapy to maximise response while minimising exposure. The co-primary objectives were to evaluate the safety and overall response, defined as the proportion of patients who achieved a complete or partial response in relapsed and refractory indolent non-Hodgkin lymphoma at the end of induction therapy, according to Cheson and colleagues (2007 criteria). The secondary endpoints were complete response after induction therapy and time to event endpoints including time to progression, progression free survival, and overall survival. Analyses were intent to treat in the efficacy cohort and per-treated in the safety population in all patients who received at least one dose of either investigational agent. This trial is registered with ClinicalTrials.gov, NCT01995669. Between June 03, 2014, and 07 March 2019, we completed planned enrolment, and 66 patients started therapy including 9 patients in phase 1 and 57 patients in phase 2. All patients were evaluated for safety and the 60 patients treated at the recommended phase 2 dose of lenalidomide 20mg were evaluable for activity. Grade 3-4 haematological toxicities included neutropenia 21% (14/66) and thrombocytopenia 11% (7/66) with no cases of febrile neutropenia. Grade 3-4 non-haematological toxicities included lung infection 8% (5/66), fatigue 8% (5/66) and rash 6% (4/66). By Cheson 2007 criteria, 90% (54/60, 95% CI: 79-96) achieved an overall response at the end of induction meeting the prespecified activity endpoint. Complete responses were seen in 33% (20/60, 95% CI: 22-47) at the end of induction. Median progression free survival, time to progression and overall survival have not been reached after median follow-up of 41.7 months. Estimated 4-year progression free survival rates were 55% (95% CI: 42-73), time to progression of 56% (95% CI: 43-74) and overall survival of 84% (95% CI: 74-95). Our findings suggest that oral lenalidomide with obinutuzumab is safe and highly active in patients with relapsed and refractory indolent B cell non-Hodgkin lymphoma and is associated with prolonged remission duration. The study is limited by the lack of a control arm leading to cross-trial comparisons to evaluate activity. Future randomised trials comparing this regime to rituximab and lenalidomide are warranted. Genentech and an MD Anderson Core grant.

Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial

Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1-3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1-7), and prednisone (40 mg/m2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively. BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. Takeda Oncology.

Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results and Correlative Analyses From ATEMPT.

Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.

Results of a phase 2 study of evorpacept (E, ALX148), cetuximab (C), and pembrolizumab (P) in patients with refractory microsatellite stable metastatic colorectal cancer (MSS CRC).

3530 Background: Single-agent anti-PD-1/PD-L1 drugs are ineffective in MSS CRC. E is an engineered protein (high-affinity CD47-blocker fused to an inactive IgG Fc region), which blocks the CD47/SIRPα innate immune inhibitory phagocytosis checkpoint expressed on CRC and phagocytes, respectively. Preclinical evidence suggests ECP may be effective in MSS CRC. Methods: This phase 2, single-arm, two-stage, multicenter, investigator-initiated trial of E (15 or 10 mg/kg weekly at dose level [DL] 1 and -1, respectively), C (400 mg/m2 then 250 mg/m2 weekly), and P (200 mg every 3 weeks) in 21-day cycles enrolled patients with MSS CRC, regardless of tumor sidedness and RAS/BRAF status, refractory to ≥ 2 prior lines of therapy, including EGFR inhibitor if indicated (NCT05167409). All patients in both Stage 1 (safety run-in) and Stage 2 (expansion) received ECP until progression or unacceptable toxicity. The co-primary objectives were to determine the recommended dose (RD) of E with CP and objective response rate (ORR) by RECIST v1.1 (by one-sided exact test with α=0.05, H0 p ≤ 3% [historical controls], HA p ≥ 15%; power is 87% with N=48). Results: The safety-evaluable population included 16 patients, of whom 69% were male and median age 53 years. The primary tumor was in the right, left, and transverse colorectum in 31%, 31%, and 6% of patients, and was unknown in 31%. Mutations in KRAS, NRAS, and BRAF genes were present in 38%, 6%, and 0% of patients. The median number of prior lines of therapy was 3, including prior EGFR inhibitor in 44%. In Stage 1, 9 and 3 patients were enrolled at E DL1 and DL-1, respectively. E DL1 was established as the RD for Stage 2, in which 4 patients were enrolled. The most common any-grade treatment-emergent adverse events were headache (32%), fatigue (26%), anemia (21%), diarrhea (21%), dyspnea (16%), abdominal pain (16%), nausea/vomiting (16% each), and acneiform rash (16%). There were two on-study deaths assessed as related to all three study drugs (hemophagocytic lymphohistiocytosis and cytokine release syndrome; 1 each). While both are known associations with checkpoint inhibitors, other significant factors contributing to these event outcomes included cancer progression with high tumor burden in the former and patient decision to transition to comfort care in the latter. In the safety-evaluable population, ORR was 6.3% (1 ongoing partial response, 95% confidence interval [CI] 0.2-30.2%), disease control rate was 12.5% (95% CI 1.6-38.4%), median progression-free survival was 2.6 months (mo; 95% CI 2.1-2.9 mo), and median overall survival was 10.9 mo (95% CI 3.3 mo-infinity). Formal hypothesis testing was not performed. Conclusions: Further dose optimization of ECP is needed to establish a RD in the refractory MSS CRC population. While initial activity was seen, at the DLs evaluated, criteria for study termination were met. Clinical trial information: NCT05167409 .

Neoadjuvant immunotherapy in sarcomatoid mesothelioma (Alliance A082101).

TPS8125 Background: Sarcomatoid mesothelioma is the most aggressive form of pleural mesothelioma and is associated with the worst prognosis of the histologic variants of this disease. In the Checkmate 743 clinical trial the patients with sarcomatoid mesothelioma who received ipilimumab and nivolumab had survival outcomes that were similar to those of patients with epithelioid mesothelioma. In comparison, the patients with sarcomatoid mesothelioma who received chemotherapy had the worst outcomes in this trial, highlighting the known limited efficacy of chemotherapy against this histologic variant. Checkmate 743 demonstrated that ipilimumab and nivolumab is a new standard of care for non-epithelioid mesothelioma. Surgery typically has not been offered to this group of patients given their historically poor outcomes. With the significant survival gains seen patients with sarcomatoid mesothelioma treated with immunotherapy, we hypothesized that surgery may extend the benefits seen with immunotherapy. Methods: Alliance for Clinical Trials in Oncology A082101 is a prospective, phase 2 nonrandomized clinical trial for patients with sarcomatoid mesothelioma. The co-primary objectives are to determine the percentage of patients with potentially resectable sarcomatoid mesothelioma able to proceed with surgery after neoadjuvant ipilimumab and nivolumab, and the progression-free survival (PFS) at 12 months (12-month PFS) after the initiation of ipilimumab and nivolumab. For sample size determination, we assumed that if the true rate of surgery is 75% or greater, it would indicate that neoadjuvant immunotherapy is feasible to be given prior to surgery. On the other hand, if the true rate of surgery is 50% or less it would indicate that neoadjuvant immunotherapy is not worthy of further investigation. Twenty-six (26) eligible patients will be needed to receive neoadjuvant immunotherapy. If 16 or fewer of the 26 eligible patients proceed to surgery, it will be concluded that the experimental therapy is not worthy of further investigation. Otherwise, it will be concluded that the experimental therapy is worthy of further investigation. Safety monitoring will be done through a 6-week run-in for the first 10 patients to assess for pre-operative and post-operative toxicities and complications. Sequential boundaries will be used to monitor severe toxicity and complication rates. Accrual will be halted if excessive numbers of severe toxicity and complications in pre-operative and post-operative phases are seen. The accrual and safety data will be summarized in reports for semiannual reviews by Alliance Data and Safety Monitoring Board. Tumor and blood-based biomarkers will be included as exploratory biomarkers. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT05647265 .

Neoadjuvant dynamic marker-adjusted personalized therapy comparing trastuzumab-deruxtecan versus pacli-/docetaxel + carboplatin + trastuzumab + pertuzumab in HER2+ early breast cancer: WSG-ADAPT-HER2-IV.

TPS631 Background: In HER2+ early breast cancer (EBC), combination of standard chemotherapy (CTx) with anti-HER2-antibodies has shown higher efficacy versus CTx alone and/or anti-HER2-antibodies alone. Next to a need for treatment escalation in high-risk disease, there is also a substantial subset of patients (pts) (e.g., elderly pts; those with low - intermediate clinical risk) who need de-escalated but still effective treatment. Based on results from WSG ADAPT HER2+ subtrials, antibody-drug-conjugates (e.g., trastuzumab-emtansine (T-DM1), trastuzumab-deruxtecan (T-DXd)) are excellent candidates for de-escalation approaches in HER2+ EBC due to their high efficacy and low toxicity. Methods: WSG-ADAPT-HER2-IV (NCT05704829) is a multicenter, interventional, prospective, two-arm, randomized, open-label, controlled (neo-)adj., phase-II trial evaluating the efficacy and safety of T-DXd vs. standard-of-care (SOC) PAC+T+P in low-intermediate-risk or DOC/PAC+CARBO+T+P in intermediate-high-risk HER2+ EBC in pre- and postmenopausal pts. Pts will be assigned to 2 treatment groups, depending on risk of recurrence: Cohort 1 (HER2+ EBC, low-intermediate risk of recurrence per Investigator´s decision, 12 wks treatment) and cohort 2 (HER2+ EBC, intermediate-high risk, 18 wks treatment) will be randomized 2:1 to either T-DXd or SOC neoadj. treatment. After 12/18-wks of neoadj. treatment, pathological response (pCR) assessment is performed. Pts with pCR will receive further SOC post-neoadj. treatment according to AGO guidelines. Those with non-pCR qualify for a cross-over treatment: Pts with neoadj. T-DXd will receive SOC CTx + anti-HER2-treatment. Pts. with neoadj. SOC treatment and non-pCR (≥ 5mm residual tumor) receive T-DXd until completion of 52 wks of treatment. After post-neoadj. Treatment, 2 – 5.5 years follow-up will be performed, during which pts may receive any SOC treatment according. Co-primary objectives are comparison of pCR-rates after 12/18 wks of neoadj. treatment with T-DXd vs. SOC (PAC+T+P or PAC/DOC+Carbo+T+P) in pooled risk cohorts and to evaluate whether 3-year dDFS equals or exceeds 92% in T-DXd-treated pts from both risk cohorts. It is planned to randomize 402 pts (269 pts to cohort 1; 133 to cohort 2). Study start was in January 2024 (45 sites, enrollment period 24 months). Estimated trial duration of is 5.5 years. Translational analyses:Potential resistance markers and molecular alterations will be assessed in tumor tissue from primary diagnosis, after 3 wks and after neoadj. treatment, and at recurrence. ctDNA/ctRNA from optional blood samples will be assessed for mutations and gene expression relevant in HER2+ EBC. Clinical trial information: NCT05704829 .

Abstract RF02-06: AVIATOR/TBCRC045: A randomized phase II study of vinorelbine (N) + trastuzumab (H) alone or combined with avelumab (A) +/- utomilumab (U) in patients (pts) with HER2+ metastatic breast cancer (MBC) (NCT03414658)

Abstract Background: Chemotherapy (chemo) + H is standard of care therapy for pts with refractory HER2+ MBC. It is unknown whether the addition of immune checkpoint inhibitor (ICI) or a 4-1BB agonist (U) improves efficacy of standard chemo + H for this population. Methods: Eligible pts had HER2+ MBC previously treated with H, pertuzumab (P), and T-DM1. Pts previously treated with N or ICI were excluded. 100 pts were randomized 1:2:2 to tx with NH, NHA, or NHAU. ER status and presence of liver metastases were stratification factors. The original co-primary objectives were to compare progression-free survival (PFS) of (1) NHA vs NH; and (2) NHAU vs NHA. In 2021, due to discontinuation of clinical development of U, an unplanned interim futility analysis reviewed by IDMC led to closure of NHAU and randomization of the final 13 pts to NH or NHA. For the comparison of NH vs NHA, with 60 pts randomized (20 vs 40) there was 88% power for a log-rank test to detect improvement in median PFS (mPFS) from 2 to 4 mos with one-sided alpha of 0.1. Corresponding 2-sided 80% confidence intervals (CI) were reported for the stratified Cox model hazard ratios (HR), along with stratified one-sided log-rank p-value. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and safety/tolerability. Results: 100 pts were randomized from 7/2018-3/2023, and 97 pts started tx on trial: 18 NH, 45 NHA, and 34 NHAU (prior to its closure). Pts were 99% female, with median age 54 yrs (range 26-78 yrs); 70% White, 14% Black, and 8% Asian; 7% were Hispanic. 66% of pts had hormone receptor-positive tumors, and 76% had visceral metastases. All pts were previously treated with H, P, and T-DM1, and 17% had prior trastuzumab deruxtecan. 63% of pts had received ≥3 lines of HER2 tx for MBC (range 1-13 lines), and median interval from MBC diagnosis to randomization was 32 mos (interquartile range 22-61 mos). mPFS and ORR results are shown in the Table. One patient remained progression-free on tx at analysis. NHA was associated with a statistically significant improvement in PFS compared to NH (HR=0.56 (80% CI 0.37-0.86, p=0.04)). No difference in PFS was observed between NHAU vs NHA (HR=1.20 (80% CI 0.84-1.73) as final estimate after closure of NHAU for futility). Of 9 pts with confirmed responses in NHA arm, 3 pts had DOR &amp;gt;12 mos. Grade 3-4 treatment-emergent adverse events (AEs) were similar by tx: 61% NH, 62% NHA, and 67% NHAU. There were no grade 5 treatment-related AEs. Immune-related all grade AEs in the A-containing arms (n=79 safety-evaluable pts treated with A) included: AST increase (n=15), ALT increase (n=9), hyper/hypothyroidism (n=8), adrenal insufficiency (n=2), and pneumonitis (n=1), of which two events were grade 3 (adrenal insufficiency and AST increase) and none were grade 4. Only 3 pts (1 in NHA; 2 in NHAU) stopped trial tx for unacceptable AEs. Required baseline and on-tx biopsies were performed; PD-L1 and TIL data will be presented. Conclusions: This trial demonstrated significant improvement in PFS with addition of avelumab to NH among pts with heavily pre-treated HER2+ MBC. 4-1BB agonist did not improve PFS. To our knowledge, this is the first randomized trial to report results of chemo/H +/- ICI in HER2+ MBC. Further investigation of ICI with chemo/H for pts with refractory HER2+ MBC is warranted, and the potential predictive value of immune biomarkers should be explored. *one-sided stratified log rank test p-value Citation Format: Adrienne Waks, Ruichao Shi, Meredith Regan, Chau Dang, Cesar Santa-Maria, Kelly Westbrook, Vandana Abramson, Rashmi Murthy, Rita Nanda, Hope Rugo, Amy Clark, Candace Mainor, Claire Dees, Valentina Hoyos, Kathy Miller, Erica Stringer-Reasor, Natasha Hunter, Sun Young Oh, Michelle DeMeo, Amanda Okpoebo, Erin Elias, Busem Kurt, Nancy Lin, Mothaffar Rimawi, Antonio Wolff, Elizabeth Mittendorf, Shom Goel, Sara Tolaney, Sherene Loi, Ian Krop. AVIATOR/TBCRC045: A randomized phase II study of vinorelbine (N) + trastuzumab (H) alone or combined with avelumab (A) +/- utomilumab (U) in patients (pts) with HER2+ metastatic breast cancer (MBC) (NCT03414658) [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 RF02-06.

Safety and immunogenicity of a single dose of Tdap compared to Td in pregnant women in Mali and 3 its effect on infant immune responses: a single-centre, randomised, double-blind, active-controlled phase 2 study

While maternal pertussis vaccination is a strategy to reduce infant morbidity, safety and immunogenicity data are limited in sub-Saharan Africa. We aimed to evaluate the safety of a single dose of tetanus, diphtheria and acellular pertussis vaccine (Tdap) vaccine compared to tetanus and diphtheria vaccine (Td) vaccine in pregnant women in Bamako, Mali and to assess the pertussis toxin (PT) antibody response at birth. In this phase 2, single-centre, randomised, double-blind, active-controlled study, from 23 January 2019 to 10 July 2019, healthy 18-39 year old women in the second trimester of a singleton pregnancy were randomised 2:1 to receive Tdap or Td. Blood was tested for serum immunoglobulin G (IgG) against PT and other vaccine antigens using a qualified Meso Scale Discovery multiplex immunoassay. The co-primary objectives evaluated safety and birth anti-PT levels. Infant immune responses to whole-cell pertussis vaccine (DTwP) were assessed. Statistical analysis was descriptive. This trial is registered with clinicaltrials.gov, NCT03589768. 133 women received Tdap and 67 received Td, with 126 and 66 livebirths, respectively. In the Tdap group, 22 serious adverse events (SAEs) including one maternal death occurred in 20 participants (15·0%), with 10 SAEs in 10 participants (14·9%) in the Td group. Among infants, 18 events occurred among 13 participants (10.3%) and 8 SAEs in 6 participants (9.1%), including three and two infant deaths, occurred in Tdap and Td groups, respectively. None were related to study vaccines. Anti-PT geometric mean concentration (GMC) at birth in the Tdap group was higher than in the Td group (55.4 [46.2-66.6] IU/ml vs 7.9 [5.4-11.5] IU/ml). One month after the third dose of DTwP, the GMC in infants born to mothers in the Tdap group were lower compared to the Td group (20.2 [13.7-29.9] IU/ml vs 77.2 [32.2-184.8] IU/ml). By 6 months of age, the anti- PT GMCs were 17.3 [12.8-23.4] IU/ml and 67.1 [35.5-126.7] IU/ml in Tdap and Td groups, respectively. At birth, anti-tetanus toxin (TT) GMCs were higher in infants in the Td vs Tdap group (5.9 [5.0-7.0] IU/ml vs 4.1 [3.5-4.8] IU/ml). Anti-diphtheria toxin GMCs were similar in both groups. Tdap administered to pregnant women in Mali is safe and well-tolerated. Infants of mothers who received Tdap were born with high PT and protective anti-TT antibody levels. By six months of age, after primary vaccination, the PT levels were lower in the Tdap group compared to the Td group. The blunted immune responses to primary DTwP vaccination in the Tdap infant group warrant further study. This project was funded by National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), under contract numbers 75N93021C00012 (The Emmes Company), and HHSN27220130000221 (University of Maryland, Baltimore). Dr. Susana Portillo was supported by NIH award no. T32AI007524. NIAID, NIH provided Tdap vaccine (BOOSTRIX).

A phase II trial of induction systemic mFOLFIRINOX followed by hepatic arterial infusion of floxuridine and dexamethasone given concurrently with systemic mFOLFIRI as a first-line therapy in patients with unresectable liver-dominant intrahepatic cholangiocarcinoma (HELIX-1).

511 Background: Most patients with intrahepatic cholangiocarcinoma (ICC) have unresectable or multifocal liver-dominant disease. Survival after first-line systemic therapy remains poor, with median progression-free (mPFS) and overall survival of 7.2 and 12.8 months, respectively. Hepatic arterial infusion (HAI) therapy with floxuridine maximizes liver-specific treatment with minimal systemic toxicity and potentially offers improved disease control when combined with systemic therapy. Methods: HELIX-1 (NCT04251715) is an investigator-initiated, first-line, single-center, single-arm phase II clinical trial for patients with liver-dominant unresectable or multifocal ICC. The trial was designed with a patient safety run-in evaluating toxicity from the combined therapy. Pre-trial screening included laparoscopy, biopsies, and PET/CT. Eligible patients were treated with systemic mFOLFIRINOX for 4 cycles in order to select those likely to benefit from HAI. Patients with disease control on restaging proceeded to HAI pump placement and treatment with HAI floxuridine for 14 days followed by systemic mFOLFIRI on a 28-day cycle. The co-primary objectives were to assess safety of the combined therapeutic strategy and the disease control rate (DCR) at 6 months (RECIST v1.1) at end of trial (EOT). Results: A total of n=5 patients with liver-only ICC enrolled in the trial and completed the entire study protocol. The median age was 60 years (range 42-69) with a dominant lesion size of 9.8cm (range 8.4-14.5). All patients had both right and left hemiliver involvement with a median of 9 intrahepatic tumors (range 1-15). No patients experienced grade 3 or 4 adverse events, or hepatic dysfunction leading to cessation of HAI therapy. The DCR at 6 months was 100%, with a mPFS of 18.2 months. All five patients achieved partial radiographic response (PR) while receiving HAI therapy, and remain alive with liver-only disease at a median of 18.4 months (range 12.7-20) after study enrollment. After continuing treatment with HAI and systemic mFOLFIRI beyond the EOT, two patients transitioned to HAI treatment only and then to biochemical and radiographic surveillance without therapy after demonstrating PR and CA19-9 normalization. Conclusions: Integration of HAI floxuridine with mFOLFIRI following mFOLFIRINOX induction for patients with liver-only advanced ICC is well-tolerated and demonstrates longer DCR in comparison to historical controls. The combined regimen minimized systemic toxicity and allowed a large proportion of patients to transition to liver-only HAI treatment with maintained disease control. Future directions include combining HAI with new first-line systemic regimens for patients with advanced ICC. Clinical trial information: NCT04251715 .

Immunogenicity, Reactogenicity, and Safety of AS01E-adjuvanted RSV Prefusion F Protein-based Candidate Vaccine (RSVPreF3 OA) When Co-administered With a Seasonal Quadrivalent Influenza Vaccine in Older Adults: Results of a Phase 3, Open-Label, Randomized Controlled Trial.

Co-administration of vaccines against respiratory syncytial virus (RSV) and influenza can be considered given their overlapping seasonality, and may increase vaccine uptake and compliance. In this phase 3, open-label, randomized study, we evaluated the immunogenicity, reactogenicity, and safety of the AS01E-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA) when co-administered with a seasonal quadrivalent influenza vaccine (FLU-QIV) in older adults. Participants aged ≥60 years (randomized 1:1) received either RSVPreF3 OA and FLU-QIV simultaneously on day 1 (Co-Ad group) or FLU-QIV on day 1 followed by RSVPreF3 OA on day 31 (sequential administration [SA] group). The co-primary objectives were to demonstrate noninferiority of RSVPreF3 OA in terms of RSV-A neutralization geometric mean titer (GMT) ratio and FLU-QIV in terms of hemagglutination inhibition GMT ratio for each FLU-QIV strain, when co-administered versus when administered alone at 1-month post-vaccination. Noninferiority was demonstrated if the upper limit of the 95% confidence interview of the group GMT ratio (SA/Co-Ad) was ≤1.5. Secondary descriptive objectives comprised additional immunogenicity assessments, reactogenicity, and safety. Of the 885 participants who received one dose of the study vaccines, 837 were included in the per protocol set. Demographic and baseline characteristics were balanced between the groups. Both co-primary objectives were met for both vaccines. Reported adverse events in both groups were mild-to-moderate, with a low frequency of grade 3 events. Data from this study demonstrate that RSVPreF3 OA can be co-administered with FLU-QIV. Co-administration is well tolerated, with an acceptable safety profile. NCT04841577.

Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial

Cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy. Seventy-six patients were enrolled; of these, 33 achieved a cCR (43%, 95% confidence interval (CI): 32%, 55%), and 32 of 33 who achieved a cCR opted to forgo immediate cystectomy. The positive predictive value of cCR was 0.97 (95% CI: 0.91, 1), meeting the co-primary objective. The most common adverse events were fatigue, anemia, neutropenia and nausea. Somatic alterations in pre-specified genes (ATM, RB1, FANCC and ERCC2) or increased tumor mutational burden did not improve the positive predictive value of cCR. Exploratory analyses of peripheral blood mass cytometry and soluble protein analytes demonstrated an association between the baseline and on-treatment immune contexture with clinical outcomes. Stringently defined cCR after gemcitabine, cisplatin, plus nivolumab facilitated bladder sparing and warrants further study. ClinicalTrials.gov identifier: NCT03451331.

Study protocol: A comparison of mobile and clinic-based spirometry for capturing the treatment effect in moderate asthma.

Several inefficiencies in drug development trial implementation may be improved by moving data collection from the clinic to mobile, allowing for more frequent measurements and therefore increased statistical power while aligning to a patient-centric approach to trial design. Sensor-based digital health technologies such as mobile spirometry (mSpirometry) are comparable to clinic spirometry for capturing outcomes, such as forced expiratory volume in 1 s (FEV1); however, the impact of remote spirometry measurements on the detection of treatment effect has not been investigated. A protocol for a multicenter, single-arm, open-label interventional trial of long-acting beta agonist (LABA) therapy among 60 participants with uncontrolled moderate asthma is described. Participants will complete twice-daily mSpirometry at home and clinic spirometry during weekly visits, alongside continuous use of a wrist-worn wearable and regular completion of several diaries capturing asthma symptoms as well as participant- and site-reported satisfaction and ease of use of mSpirometry. The co-primary objectives of this study are (A) to quantify the treatment effect of LABA therapy among participants with moderate asthma, using both clinical spirometry (FEV1c ) and mSpirometry (FEV1m ); and (B) to investigate whether FEV1m is as accurate as FEV1c in detecting the treatment effect using a mixed-effect model for repeated measures. Study results will help inform whether the deployment of mSpirometry and a wrist-worn wearable for remote data collection are feasible in a multicenter setting among participants with moderate asthma, which may then be generalizable to other populations with respiratory disease.

89Zr-DFO-girentuximab for PET/CT imaging of clear cell renal cell carcinoma: Results from phase 3 ZIRCON study.

4554 Background: Conventional tools (eg, CT, MRI, biopsy) have limitations for characterizing renal mass histology; approx. 25% of patients with an indeterminant renal masses (IDRM) &lt;4cm undergo surgery for benign disease. Accurate noninvasive techniques to risk stratify the IDRM remains an unmet need. Girentuximab is a monoclonal antibody that targets carbonic anhydrase IX (CAIX), an enzyme highly expressed in clear cell renal carcinoma (ccRCC). Radiolabeled 89Zr-DFO-girentuximab is highly specific for CAIX and can aid differentiation between ccRCCs and other renal lesions. ZIRCON evaluated the performance of 89Zr-DFO-girentuximab PET/CT for detection of ccRCC. Methods: In this open label, multicenter trial, patients with an IDRM (≤7cm; cT1) who were scheduled for partial nephrectomy within 90 days from planned 89Zr-DFO-girentuximab administration were eligible. Enrolled patients received a single dose IV (37 MBq±10%; 10mg girentuximab) on Day 0 and underwent PET/CT imaging on Day 5 (±2d). Blinded central histology review determined ccRCC status. The co-primary objectives were to evaluate both the sensitivity and specificity of 89Zr-DFO-girentuximab PET/CT imaging in detecting ccRCC in patients with IDRM, using histology as the standard of truth. Key secondary objectives included sensitivity and specificity of TLX250-CDx PET/CT imaging in the subgroup of patients with IDRM ≤4cm (cT1a). Other secondary objectives included positive and negative predictive values, and evaluation of safety and tolerability. The Wilson 95% confidence intervals (CI) lower bound for sensitivity and specificity had to be &gt;70% and 68% respectively for ≥2 independent readers to declare the study successful. Results: 300 patients received 89Zr-DFO-girentuximab (mean age, 62±12y; 71% Male). Of 288 patients with central histopathology of surgical samples, 193 (67%) had ccRCC, and 179 (62%) had cT1a. Of 284 evaluable patients, the average across all 3 readers for sensitivity and specificity was 86% [80%, 90%] and 87% [79%, 92%] resp. for coprimary, and 85% [77%, 91%] and 90% [79%, 95%] resp. for key secondary endpoints. For all evaluable patients, positive and negative predictive values were ≥ 91.7% and ≥ 73.7%, resp. PET+ ccRCC had higher mean CAIX expression compared with PET- ccRCC patients (p&lt;0.05). Sensitivity and specificity were consistent with masses ≤2cm (n=46) of which, 26 were ccRCC+, 13 ccRCC−, and 3 unevaluable at central histopathology. Of 263 adverse events (AEs) in 124 patients, 2 AEs of mild intensity were treatment related. Conclusions: ZIRCON study confirms 89Zr-DFO-girentuximab PET/CT is a well-tolerated and accurate modality for noninvasive identification of ccRCC in IDRM. This tool could be included in the diagnosis/management of patients with IDRM, limiting unnecessary treatment of benign lesions. Clinical trial information: NCT03849118 .

Neoadjuvant immunotherapy in sarcomatoid mesothelioma (Alliance A082101).

TPS8602 Background: Sarcomatoid mesothelioma is the most aggressive form of pleural mesothelioma and is associated with the worst prognosis of the histologic variants of this disease. In the Checkmate 743 clinical trial the patients with sarcomatoid mesothelioma who received ipilimumab and nivolumab had survival outcomes that were similar to those of patients with epithelioid mesothelioma. In comparison, the patients with sarcomatoid mesothelioma who received chemotherapy had the worst outcomes in this trial, highlighting the known limited efficacy of chemotherapy against this histologic variant. Checkmate 743 demonstrated that ipilimumab and nivolumab is a new standard of care for non-epithelioid mesothelioma. Surgery typically has not been offered to this group of patients given their historically poor outcomes. With the significant survival gains seen patients with sarcomatoid mesothelioma treated with immunotherapy, we hypothesized that surgery may extend the benefits seen with immunotherapy. Methods: Alliance for Clinical Trials in Oncology A082101 is a prospective, phase 2 nonrandomized clinical trial for patients with sarcomatoid mesothelioma. The co-primary objectives are to determine the percentage of patients with potentially resectable sarcomatoid mesothelioma able to proceed with surgery after neoadjuvant ipilimumab and nivolumab, and the progression-free survival (PFS) at 12 months (12-month PFS). For sample size determination, we assumed that if the true rate of surgery is 75% or greater, it would indicate that neoadjuvant immunotherapy is feasible to be given prior to surgery. On the other hand, if the true rate of surgery is 50% or less it would indicate that neoadjuvant immunotherapy is not worthy of further investigation. Twenty-six (26) eligible patients will be needed to receive neoadjuvant immunotherapy. If 16 or fewer of the 26 eligible patients proceed to surgery, it will be concluded that the experimental therapy is not worthy of further investigation. Otherwise, it will be concluded that the experimental therapy is worthy of further investigation. Safety monitoring will be done through a 6-week run-in for the first 10 patients to assess for pre-operative and post-operative toxicities and complications. Sequential boundaries will be used to monitor severe toxicity and complication rates. Accrual will be halted if excessive numbers of severe toxicity and complications in pre-operative and post-operative phases are seen. Tumor and blood-based biomarkers will be included as exploratory biomarkers. Clinical trial information: NCT05647265 .

Phase 1b/2 study of abemaciclib combined with chemoimmunotherapy in pediatric and young adult patients with relapsed/refractory neuroblastoma (JPCS Part C).

TPS10068 Background: Survival for high-risk neuroblastoma (NBL) remains poor with over 50% of patients experiencing disease relapse. The addition of dinutuximab (DIN) and granulocyte macrophage colony-stimulating factor (GM-CSF) to irinotecan (IRN) and temozolomide (TMZ) in patients with first relapse achieved an overall response rate of 42% in the study ANBL12211 and is now standard of care. However, there remains a significant unmet need to improve outcomes for children with relapsed/refractory NBL. Deregulation of the Cyclin D/cyclin-dependent kinase (CDK) 4 &amp; 6 pathway has been observed in NBL, rendering CDK4 &amp; 6 inhibition logical to explore. Abemaciclib is an orally administered, selective CDK4 &amp; 6 inhibitor approved to treat breast cancer. JPCS (NCT04238819) is designed to assess the pharmacokinetics, safety, and tolerability of abemaciclib added to standard treatment regimens for relapsed/refractory pediatric solid tumors. Part A defined the recommended phase 2 dose (RP2D) of abemaciclib in combination with IRN and TMZ. In Part C, the addition of DIN + GM-CSF to the JPCS Part A regimen will be evaluated. The co-primary objectives of Part C are to determine the RP2D and to estimate the anti-tumor activity of abemaciclib added to the ANBL1221 chemoimmunotherapy backbone in patients with first relapse/refractory NBL. Methods: JPCS Part C is a two-stage, non-randomized, open-label, Phase 1b/2 study for patients &lt; 21 years of age with first relapse/refractory NBL. Stage 1 aims to identify the maximum tolerated dose (MTD) of abemaciclib at a starting dose of 55 mg/m2 combined with DIN, GM-CSF, IRN and TMZ using a 3+3 design. One dose de-escalation (30 mg/m2) will be possible if the starting dose is not tolerated. Further tolerability and initial anti-tumor activity will be evaluated in an expansion cohort at the MTD. Up to 11 evaluable patients will enroll in Stage 1 at the MTD; the MTD will be declared the RP2D if adequate safety and tolerability are observed and ≥6 patients achieve minimal response or better per International Neuroblastoma Response Criteria (INRC). Following determination of the RP2D, Stage 2 will enroll 35 patients. If ≥26 of 46 total patients achieve an INRC minimum response or better, further investigation of this regimen could be warranted. As of 31 Jan 2023, Part C is open for enrollment at one site (US) and additional sites are being evaluated.

Safety and efficacy of the tumor-selective adenovirus enadenotucirev, in combination with nivolumab, in patients with advanced/metastatic epithelial cancer: a phase I clinical trial (SPICE)

BackgroundNovel combination therapies to overcome anti-PD-1 resistance are required. Enadenotucirev, a tumor-selective blood stable adenoviral vector, has demonstrated a manageable safety profile and ability to increase tumor immune-cell infiltration in...

LBA03-01 89 Zr-DFO-GIRENTUXIMAB FOR PET/CT IMAGING OF INDETERMINATE RENAL MASSES–RESULTS FROM PHASE 3 ZIRCON STUDY

LBA03-01 ⁸⁹ Zr-DFO-GIRENTUXIMAB FOR PET/CT IMAGING OF INDETERMINATE RENAL MASSES–RESULTS FROM PHASE 3 ZIRCON STUDY

Abstract PD18-01: Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033)

Abstract Background: The ATEMPT trial primary analysis found that one year of adjuvant trastuzumab emtansine (T-DM1) achieved a 3-year iDFS of 97.8% for patients with stage I HER2+ breast cancer, but was not associated with fewer clinically relevant toxicities (CRTs) compared with paclitaxel and trastuzumab (TH). In this end-of-study analysis, we report 5-year survival outcomes and correlative analyses from the trial. Methods: Patients with stage I centrally confirmed HER2+ breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for one year or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or paclitaxel 80 mg/m2 IV with weekly trastuzumab IV followed by trastuzumab for 9 months. The co-primary objectives were to compare the incidence of CRTs between the 2 arms and to evaluate iDFS in patients receiving T-DM1. To investigate proteomic correlates of recurrence, spatial proteomic analyses were performed on samples from 13 patients experiencing iDFS events (cases) and 24 matched controls using the NanoString GeoMx Digital Spatial Profiler. The impact of HER2 heterogeneity on outcomes was investigated among 17 cases and 51 matched controls by fluorescence in-situ hybridization (FISH). HER2 genetic heterogeneity was assessed by scrutinizing the whole tumor area and defined as the occurrence of HER2 gene amplification in &amp;gt;5% but &amp;lt; 50% invasive tumor cells. The risk of recurrence was evaluated centrally with the HER2DX genomic assay from 225 primary tumor samples. Germline whole genome sequencing (WGS) was conducted among 55 patients experiencing T-DM1-induced thrombocytopenia and/or bleeding and 55 matched controls to identify genomic correlates for this side effect. Results: A total of 497 patients who initiated protocol therapy were included in this analysis (383 T-DM1 and 114 TH). After a median follow up 5.8 years, among patients receiving T-DM1 there were a total of 11 iDFS events, with 3 distant recurrences. The 5-year iDFS for T-DM1 was 97.0% (95% CI, 95.3-98.8%), the 5-year recurrence-free interval (RFI) was 98.6% (95% CI: 97.4-99.8%) and the 5-year overall survival (OS) for T-DM1 was 97.8 % (95% CI, 96.3-99.3%). Although the study was not powered to evaluate the efficacy of TH, among the 114 patients receiving TH, a total of 9 iDFS events were observed, including 2 distant events; the 5-year iDFS with TH was 91.3% (95% CI: 86.0-96.9%), 5-year RFI was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). A total of 56 samples were evaluable for heterogeneity analyses, among which 14% (n=8) harbored HER2 genetic heterogeneity. Spatial proteomic analyses found that NF1 (adjusted p=0.72 × 10-6) and CTLA-4 (adjusted p=0.15 × 10-3) were significantly upregulated in primary samples from cases, while cleaved caspase 9, CD25, GITR, ICOS, p53 and PD-L2 were significantly upregulated in controls (all with adjusted p&amp;lt; 0.05). Germline WGS found that the top gene associations with thrombocytopenia and thrombocytopenia or bleeding were ALMS1 (p=0,19 × 10-3) and APBA3 (p=0,23 × 10-3), respectively, although none reaching the threshold for genome wide significance. rs62143195 and rs114169776 were the top single nucleotide polymorphisms associated with thrombocytopenia and thrombocytopenia or bleeding, respectively. Data on the impact of HER2 heterogeneity and of HER2DX score on survival outcomes will be presented. Conclusion: With longer follow-up, adjuvant T-DM1 confirmed outstanding long-term outcomes among patients with stage I HER2+ breast cancer, demonstrating a 5-year RFI of 98.6%. Spatial proteomic analyses identified a potential association between NF1 and CTLA-4 expression with recurrence. Details on the impact of HER2 heterogeneity and HER2DX assay on prognosis will be presented. Citation Format: Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, Sara Tolaney. Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-01.

VIOLET: A phase I/II trial evaluation of radioligand treatment in men with metastatic castration-resistant prostate cancer with [161Tb]Tb-PSMA-I&amp;T.

TPS281 Background: [177Lu]Lu-PSMA is an effective class of therapy for men with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response is partially explained by the presence of micrometastatic deposits. Single tumor cells and micrometastases are energy-sheltered deposits receiving low absorbed radiation, due to the ~0.7mm mean path-length of Lutetium-177 (177Lu). Terbium-161 (161Tb) has abundant emission of Auger electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161Tb has shown superior in-vitro and in-vivo results in comparison with 177Lu. We hypothesize that [161Tb]Tb-PSMA-I&amp;T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 to 36 men with progressive mCRPC. The phase I dose-escalation is designed with a 3+3 model to establish the safest dose of [161Tb]Tb-PSMA-I&amp;T (dose levels: 4.4, 5.5 and 7.4 GBq). The maximum tolerated dose (MTD) will be defined as the highest dose level at which a dose-limiting toxicity occurs in less than 1/3 or 2/6 participants. The phase II dose-expansion will include 24 participants at the MTD. Up to six cycles of [161Tb]Tb-PSMA-I&amp;T will be administered intravenously every six weeks, with each subsequent dose for each patient reduced by 0.4GBq. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy and a second-generation anti-androgen, PSMA-positive disease on PSMA PET/CT (SUVmax ≥20), no sites of discordance on FDG PET/CT, adequate bone marrow, hepatic and renal function, ECOG performance status ≤2, and no prior treatment with another radioisotope. The co-primary objectives are to establish the MTD of [161Tb]Tb-PSMA-I&amp;T, and safety profile [CTCAE v5.0]. Secondary objectives include measuring absorbed radiation dose [Gray], evaluating anti-tumour activity [PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective response rate], and evaluation of pain [BPI-SF] and health-related quality of life [FACT-P and FACT-RNT] over the first 12 months after treatment commences. Exploratory objectives include ctDNA analysis at baseline, during treatment and at progression, and optional tissue biopsies, to determine biomarkers of treatment response and resistance. Patient enrolment began in October 2022, with recruitment expected to continue for 24 months. Clinical trial information: NCT05521412 .

Results from phase 3 study of 89Zr-DFO-girentuximab for PET/CT imaging of clear cell renal cell carcinoma (ZIRCON).

LBA602 Background: The increasing detection of renal masses presents a significant patient management challenge. Diagnostic options include cross-sectional imaging, which cannot reliably differentiate benign and malignant renal masses, and biopsy, which is invasive and subject to sampling errors. These limitations highlight the unmet need for accurate noninvasive techniques to guide patient management. Girentuximab is a monoclonal antibody that targets carbonic anhydrase IX (CAIX), an enzyme highly expressed in clear cell renal carcinoma (ccRCC). Radiolabeled 89Zr-DFO-girentuximab (TLX250-CDx) is highly specific for CAIX and can aid differentiation between ccRCCs and other renal lesions. The ZIRCON study evaluated the performance of TLX250-CDx PET/CT for detection of ccRCC in adult patients with indeterminate renal masses (IDRM). Methods: ZIRCON was an open-label, multicenter clinical trial. Patients with an IDRM (≤ 7 cm; tumor stage cT1) who were scheduled for partial nephrectomy within 90 days from planned TLX250-CDx administration were eligible. Enrolled patients received a single dose of TLX250-CDx IV (37 MBq ± 10%; 10 mg girentuximab) on Day 0 and underwent PET/CT imaging on Day 5 (± 2 days) prior to surgery. Blinded central histology review determined ccRCC status. The coprimary objectives were to evaluate both the sensitivity and specificity of TLX250-CDx PET/CT imaging in detecting ccRCC in patients with IDRM, using histology as the standard of truth. Key secondary objectives included sensitivity and specificity of TLX250-CDx PET/CT imaging in the subgroup of patients with IDRM ≤ 4 cm (cT1a). Other secondary objectives included positive and negative predictive values, safety, and tolerability. The Wilson 95% confidence intervals (CI) lower bound for sensitivity and specificity had to be &gt; 70% and 68% respectively for ≥ 2 independent readers to declare the study successful. Results: 300 patients received TLX250-CDx; mean age was 62 ± 12 y; 71% were males. Of 288 patients with central histopathology of surgical samples, 193 (67%) had ccRCC, and 179 (62%) had CT1a; Of 284 evaluable patients included in primary analysis, the average across all 3 readers for sensitivity and specificity was 86% [80%, 90%] and 87% [79%, 92%] respectively for coprimary endpoints; and 85% [77%, 91%] and 90% [79%, 95%] respectively for key secondary endpoints. For all readers, the lower boundaries of 95% CI for coprimary and key secondary endpoints were &gt; 75%. For all evaluable patients, positive and negative predictive values were ≥ 91.7% and ≥ 73.7%, respectively. Of 263 treatment-emergent adverse events (TEAEs), 2 TEAEs were treatment related. Conclusions: This study confirms that TLX250-CDx PET/CT is well tolerated and can accurately and noninvasively identify ccRCC, with promising utility for designing best management approaches for patients with IDRM. Clinical trial information: NCT03849118 .