Alternative Dosing Schedules Research Articles

Efficacy, effectiveness and immunogenicity of reduced HPV vaccination schedules: A review of available evidence.

Current National Advisory Committee on Immunization (NACI) guidance recommends human papillomavirus (HPV) vaccines be administered as a two or three-dose schedule. Recently, several large clinical trials have reported the clinical benefit of a single HPV vaccine dose. As a result, the World Health Organization released updated guidance on HPV vaccines in 2022, recommending a two-dose schedule for individuals aged 9-20 years, and acknowledging the use of an alternative off-label single dose schedule. The objective of this overview is to provide a detailed account of the available evidence comparing HPV vaccination schedules, which was considered by NACI when updating recommendations on HPV vaccines. To identify relevant evidence, existing systematic reviews were leveraged where possible. Individual studies were critically appraised, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence. Available evidence suggests that a one, two, or three-dose HPV vaccine schedule may provide similar protection from HPV infection. While antibody levels against HPV vaccine types were statistically significantly lower with a single dose schedule compared to two or three doses, titres were sustained for up to 16 years. The clinical significance of lower antibody titres is unknown, as there is no established immunologic correlate of protection. While the available evidence on single-dose HPV vaccination schedules shows a one-dose schedule is highly effective, continued follow-up of single-dose cohorts will be critical to understanding the relative duration of protection for reduced dose schedules and informing future NACI guidance on HPV vaccines.

Safety and Preliminary Efficacy of Once-Weekly Split-Dose Selinexor in Soft Tissue Sarcoma: Results of the Phase Ib METSSAR Clinical Trial.

The approved dose of Selinexor, 60 mg twice-weekly, is associated with several clinically relevant toxicities. Preclinical studies show that a sustained-release formulation of selinexor results in a lower toxicity profile. The phase 1b METSSAR trial assessed the safety and tolerability of an alternative dosing schedule of selinexor (to mimic the sustained-release formulation) in advanced soft tissue sarcoma (STS) patients. Selinexor was administered in a split-dose schedule (40 mg, 20 mg, 20 mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15, and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAEs). Secondary objectives were EORTC QLQ-C30 quality of life (QoL) assessment, and preliminary efficacy. Twenty patients with 12 STS subtypes were enrolled and received a median of four cycles of treatment. There were no grade ≥ 3 TRAEs. Dysgeusia, nausea, fatigue, and thrombocytopenia were the most common grade ≤ 2 TRAEs. No treatments were discontinued due to TRAE, but four patients (20%) required dose reduction. Median change in global health status (GHS) score from baseline to cycle 2 (by QLQ-C30 v3.0) was - 8.33, and only 39% of patients reported a clinically meaningful decline in GHS score (≥10 points). Median symptom scale scores on treatment were increased for fatigue (+12.35), nausea/vomiting (+18.52), and anorexia (+16.67), but reduced for pain (- 3.70). The median progression-free survival (PFS) was 4.0 months (95% confidence interval 1.9-7.5). Split-dose once-weekly selinexor was reasonably well tolerated in this heterogeneous group of advanced STS patients with a better, or at least similar, clinician- and patient-reported toxicity profile compared to the standard dosing regimen. Further clinical evaluation is warranted, as better dose delivery can lead to improved antitumor efficacy.

Evaluation of cytokine release syndrome (CRS) in patients with relapsed or refractory multiple myeloma (RRMM) receiving step-up priming doses and longer dosing intervals of elranatamab: MagnetisMM-9.

7522 Background: Elranatamab (ELRA) is a humanized BCMA-CD3 bispecific antibody. In the phase 2 registrational MagnetisMM-3 (MM-3) trial, SC ELRA was given as 2 step-up priming doses (12 mg on C1D1 and 32 mg on C1D4) followed by 76 mg QW in patients (pts) with RRMM. Overall, 56.3% of pts had CRS (grade 2, 14.3%; no grade ≥3). Most events occurred after doses 1 (44.5%), 2 (20.2%), and 3 (5.9%); 0.8% (1 pt) had CRS with doses 4+. Recurrent CRS (>1 event) occurred in 15.1% of pts (Lesokhin Nat Med 2023). Methods: MagnetisMM-9 (MM-9; NCT05014412) is a phase 1/2, open-label, nonrandomized study of ELRA examining an alternative 2-dose step-up priming regimen (4 and 20 mg on C1D1 and C1D4, respectively). Eligible pts had RRMM and were refractory to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody. After the priming doses, ELRA 76 mg was given QW for 6 cycles (Part 1) or for 1 cycle followed by 116 or 152 mg Q2W for 5 cycles (Part 2A). The RP2D from Part 2A (152 mg) was evaluated in Part 2B (dose expansion). The rate of grade ≥2 CRS per ASTCT criteria during C1 is the primary endpoint for both parts. Secondary endpoints include evaluation of AEs and PK. Here, we report the overall safety and CRS profile associated with the 4/20 mg priming regimen. Results: For 85 treated pts, median age was 64.0 y; 49.4% were male; 23.5% had EMD; 31.8% had high-risk cytogenetics. Pts had a median of 5.0 (range, 1-12) prior LOTs; 85.9% had triple-class refractory disease. After a median follow-up of 7.4 mo, the most common (>50%) AEs were CRS (63.5%; grade ≥2, 15.3%) and neutropenia (54.1%; all grade ≥2). ICANS occurred in 4.7% of pts (all grade ≤2). The grade ≥2 CRS rate in C1 was 14.1% (90% CI, 8.4-21.9). CRS rates after the first 3 doses are in the the table. For doses 4+, any grade (grade ≥2) CRS was observed in 10.6% (3.5%) of pts overall, 12.1% (3.0%) of pts continuing to receive 76 mg (n=33), 25.0% (0%) of pts receiving 116 mg (n=12), and 5.0% (5.0%) of pts receiving 152 mg (RP2D; n=40). Overall, recurrent CRS was observed in 20.0% of pts. The geometric means (CV%) of free ELRA concentrations 24 h (Cmax-24h) after step-up doses 1 and 2 were 85.64 (48%) and 242.8 (55%). Conclusions: The 4/20 mg step-up priming regimen and alternative dosing schedules resulted in similar safety and incidence of overall and grade ≥2 CRS events vs the regimen used in MM-3 (12/32 mg), with no new safety signals identified. However, the CRS profile in this study differed, with more CRS after doses 2, 3, and 4+ and a higher prevalence of recurrent CRS. The Cmax-24h of free ELRA (CV%) after the priming doses were lower than those in MM-3 (107.4 [47%] and 405.1 [72%], respectively). Thus, the priming regimen used in MM-3 remains the optimal regimen for mitigating CRS. Future analyses of ongoing studies will be used to confirm these results. Clinical trial information: NCT05014412 . [Table: see text]

Abstract 7575: BPI-460372, a covalent, irreversible TEAD inhibitor in Phase I clinical development

Abstract The Hippo signaling pathway is critical for the regulation of organ development, tissue homeostasis, and tumorigenesis by controlling the activation status of yes-associated protein (YAP) or its homolog PDZ-binding motif (TAZ). As a major downstream effector, the transcription factor TEAD is activated by forming a complex with YAP/TAZ. Hippo pathway aberrations leading to TEAD activation have been reported in many cancers. Inhibiting TEAD function by directly blocking the palmitoylation pocket of TEAD is a potential therapeutic approach for cancer treatment. Betta Pharma has discovered a selective, covalent and irreversible TEAD inhibitor known as BPI-460372. The discovery of BPI-460372 was first reported in AACR 2023. Here we present additional preclinical and clinical data characterizing BPI-460372 as a promising candidate drug. In the dose-escalating part of the Phase Ι study, the exposure of BPI-460372 increased proportionally over 10 to 80 mg dose range after oral administration and exhibited linear pharmacokinetics, with a clearance rate suitable for once-daily dosing. The compound is generally well tolerated, with no drug-related Grade ≥3 adverse event observed. Remarkably, we have not seen renal toxicities that was perceived as a potential risk associated with certain TEAD inhibitors. Preliminary efficacy was observed in a few subjects. In preclinical studies, we found that intermittent dosing schedule of 3 days on/4 days off, compared with continuous dosing at equivalent weekly exposure, can ameliorate kidney damage and improve early renal injury biomarkers while maintaining anti- tumor activity. Thus, alternative dosing schedule could further improve the therapeutic window and enable combination studies in clinical development. Collectively, these results support further development of BPI-460372 for the treatment of cancers harboring Hippo pathway alterations. Citation Format: Xiaohong Han, Jing Guo, Xiangyu Jin, Lingyin Zhu, Hongling Shen, Xiaofeng Xu, Mengjie Zhang, Xiaoyun Liu, Yanju Liu, Hongke Cheng, Shunna Guo, Lieming Ding, Jiabing Wang, Hong Lan, Mengzhao Wang. BPI-460372, a covalent, irreversible TEAD inhibitor in Phase I clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7575.

Safety and immunogenicity of Innovax bivalent human papillomavirus vaccine in girls 9–14 years of age: Interim analysis from a phase 3 clinical trial

BackgroundWorld Health Organization human papillomavirus (HPV) vaccination recommendations include a single- or two-dose schedule in individuals 9–20 years old and advice for generating data on single-dose efficacy or immunobridging. The ongoing Phase 3 trial of Innovax’s bivalent (types 16 and 18) HPV vaccine (Cecolin®) assesses in low- and middle-income countries alternative dosing schedules and generates data following one dose in girls 9–14 years old. Interim data for the 6-month dosing groups are presented. MethodsIn Bangladesh and Ghana, 1,025 girls were randomized to receive either two doses of Cecolin at 6-, 12-, or 24-month intervals; one dose of Gardasil® followed by one dose of Cecolin at month 24; or two doses of Gardasil 6 months apart (referent). Serology was measured by enzyme-linked immunosorbent assay (ELISA) and, in a subset, by neutralization assays. Primary objectives include immunological non-inferiority of the Cecolin schedules to referent one month after the second dose. Safety endpoints include reactogenicity and unsolicited adverse events for 7 and 30 days post-vaccination, respectively, as well as serious adverse events throughout the study. ResultsInterim analyses included data from the two groups on a 0, 6-month schedule with 205 participants per group. One month after Dose 2, 100% of participants were seropositive by ELISA and had seroconverted for both antigens. Non-inferiority of Cecolin to Gardasil was demonstrated. Six months following one dose, over 96% of participants were seropositive by ELISA for both HPV antigens, with a trend for higher geometric mean concentration following Cecolin administration. Reactogenicity and safety were comparable between both vaccines. ConclusionsCecolin in a 0, 6-month schedule elicits robust immunogenicity. Non-inferiority to Gardasil was demonstrated one month after a 0, 6-month schedule. Immunogenicity following one dose was comparable to Gardasil up to six months. Both vaccines were safe and well tolerated (ClinicalTrials.gov No. 04508309).

Abstract B041: A phase 1 study of DS-8201a in combination with olaparib in HER2-expressing malignancies (CTEP #10355): Results of module 1 dose escalation

Abstract Background: DS-8201a is a HER2-targeting antibody drug conjugate with a topoisomerase 1 (top1) inhibitor payload. Preclinical evidence suggests that inhibiting PARP can potentiate top1 inhibitor-induced DNA damage and cytotoxicity. However, the clinical activity of combined top1-inhibiting chemotherapy and PARP inhibition has been limited by toxicity. We hypothesized that targeted delivery of a top1 inhibitor via DS-8201a may reduce systemic toxicity while maintaining synergistic cytotoxic activity in combination with olaparib. This combination is being investigated in the ongoing phase 1 trial CTEP #10355 (NCT04585958) in patients (pts) with advanced solid tumors expressing HER2. We present the safety analysis of pts enrolled to Module 1 (Mod 1) of dose escalation (continuous olaparib). Preliminary efficacy results are explored. Methods: Accrual was limited to pts ≥18 years old with advanced or recurrent solid tumors expressing HER2, defined as HER2 IHC ≥1+ (local testing allowed) or amplification of ERBB2 by NGS or ISH. In Mod 1, pts received DS-8201a IV once every 3 weeks and olaparib twice daily (BID) continuously in a 3+3 dose escalation design. Dose Level 1 (DL1) of Mod 1 evaluated DS-8201a dosed at 4.4mg/kg with olaparib 100mg BID Days 1-21. Dose Level 2 (DL2) of Mod 1 evaluated DS-8201a dosed at 5.4mg/kg with olaparib 100mg BID Days 1-21. The primary objective was to evaluate the safety and tolerability of combined DS-8201a + olaparib as graded by CTCAE v5. Secondary objectives include assessment of clinical activity as measured by objective response rate (ORR), clinical benefit rate (CBR; partial response [PR] + complete response [CR] + stable disease [SD] ≥6 months [mo]), median progression-free survival (PFS), and duration of response (DOR). Results: As of 30-Nov-2022, 10 pts were treated in Mod 1, with median age of 62.5 years. 10% were Asian, 10% were African American, and 80% were white. 40% had endometrial cancer and 60% had ovarian cancer. 6 of 7 pts treated on DL1 were DLT-evaluable, of which 1 patient experienced a DLT of Grade (G) 4 neutropenia. All 3 pts in DL2 were DLT-evaluable, and each experienced a DLT (2 pts with G4 febrile neutropenia, 1 pt with G4 neutropenia). Most common TRAEs in Mod 1 included: ANC decrease (60% G4, 20% G3, 20% G1/2), platelet count decrease (20% G4, 20% G3, 40% G1/2), and anemia (70% G3, 20% G1/2). All Mod 1 pts required dose holds, dose reductions, and/or discontinuation of olaparib. Of the 10 pts in Mod 1, 40% achieved a RECIST response (1 CR, 3 PR). 40% had SD lasting ≥6 mo, for a CBR of 80%. Median PFS is estimated at 7.4 mo (95% CI 4.7mo-not reached), with 7 patients alive and progression-free at 6 mo. Conclusion: Continuous dosing of olaparib in combination with DS-8201a yielded an unacceptable safety profile and dose escalation in Mod 1 was not continued. An alternative dosing schedule was initiated in Module 2 (Mod 2) evaluating DS-8201a IV every 3 weeks and olaparib BID Days 8-14; accrual to Mod 2 is ongoing. There is preliminary evidence of clinical activity of this combination. Citation Format: Elizabeth K. Lee, Andrea E. Wahner Hendrickson, Gerardo Colon-Otero, Cheryl A. Pickett, Niya Xiong, Su-Chun Cheng, Madeline Polak, Hannah Sawyer, Martin Hayes, Ursula A. Matulonis, Geoffrey I. Shapiro, Panagiotis A. Konstantinopoulos. A phase 1 study of DS-8201a in combination with olaparib in HER2-expressing malignancies (CTEP #10355): Results of module 1 dose escalation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B041.

EE678 Time and Cost Savings from Adopting an Alternative Dosing Schedule with Pembrolizumab for Patients with Advanced Melanoma in Greece

EE678 Time and Cost Savings from Adopting an Alternative Dosing Schedule with Pembrolizumab for Patients with Advanced Melanoma in Greece

Belantamab Mafodotin in Combination with Lenalidomide Plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma: Safety and Efficacy Analysis of DREAMM-6 Trial Arm-a

Introduction: Belantamab mafodotin (belamaf) is a first-in-class, antibody-drug conjugate that targets B-cell maturation antigen. In the recent ALGONQUIN study, clinical activity associated with belamaf in combination with the immunomodulatory drug pomalidomide were increased in triple-class exposed/refractory multiple myeloma (MM) patients, highlighting the potential for belamaf-based combinations in this population (Trudel, et al. Blood. 2022;140 (Suppl 1):7306-07). Preclinical data indicate that belamaf combined with other immunomodulatory agents, such as lenalidomide (Len) may also provide additional benefit. Arm A of the Phase I/II DREAMM-6 (NCT03544281) study aimed to assess the safety and clinical activity of belamaf doses/schedules in combination with the standard of care (SOC) of Len plus dexamethasone (Dex) in patients with relapsed/refractory MM (RRMM). Methods: Patients were eligible to participate if they had received ≥1 prior line of therapy (LOT). In Part 1 (dose escalation), up to two dose levels of belamaf (1.9 mg/kg [dose level -1 Q4W]; 2.5 mg/kg Q4W [dose level 1]) and alternative dosing schedules were administered in combination with the fixed SOC dose. In Part 2 (dose expansion), patients received belamaf at the following doses/schedules: 1.9 mg/kg Q8W, 1.9 mg/kg Q4W, 2.5 mg/kg Q4W, or 2.5 mg/kg Q4W split dose (50% on Days 1 and 8 of a given cycle). For this study, Len 25 mg was administered orally (10 mg if estimated glomerular filtration rate <60 mL/min/1.73m 2) on days 1-21 and Dex 40 mg was administered (20 mg for patients >75 years old, patients with BMI <18.5, or patients with prior tolerability issues to Dex) on Days 1, 8, 15, and 22 of every 28-day cycle. The primary outcome of Part 1 was the number/percent of subjects with adverse events (AE) or dose-limiting toxicity (as reported previously). The primary outcome of Part 2 wassafety profile (AEs and serious AEs) and efficacy (overall response rate [ORR]). Pharmacokinetics (PK) and anti-drug antibodies were secondary outcomes. Duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were exploratory endpoints. Results: Overall, 45 patients were enrolled across Parts 1 and 2. At the final analysis cutoff date (Feb 28, 2023), the median (range) age was 68 (36-80) years; patients had received a median (range) of 3 (1-10) prior LOTs, and 26/45 (57.8%) patients were Len-exposed (Table). The median (range) follow-up was 23.7 (0.5- 51.3) months. Incidence of AEs resulting in permanent discontinuation and dose reduction/delays of any study treatment were similar across groups; however, interpretation is limited due to the small sample size. The most common drug-related Grade 3+ AEs were keratopathy, visual acuity decline, and neutropenia. Safety and efficacy data are presented in the Table below. The ORR ranged from 58% to 75% across groups. The greatest depth of response (≥very good partial response [VGPR] 56%, ≥complete response 44%) was observed in the 2.5 mg/kg Q4W cohort. Interpretation of DOR, PFS, and OS was limited due to the small sample size in each cohort (Table). PK characteristics of belamaf were consistent with those previously reported for belamaf monotherapy considering baseline patient characteristics. Higher Cycle 1 peak and average concentrations (C ave) were observed with higher doses, with large overlap among cohorts; lower peak concentrations were seen with the split dosing regimen. Len PK were consistent with historical data. PK data indicated no drug-drug interaction between belamaf and Len. A positive trend was observed between belamaf Cycle 1 C ave and the probability of achieving PR or better. Conclusion: Belamaf in combination with SOC (Len/Dex) demonstrated deep and durable responses with a manageable safety profile in patients with RRMM. As anticipated, there was no drug-drug interaction between belamaf and Len. These findings support the use of belamaf in combination with SOC for patients with RRMM.

Reduction in Patient Waiting Times in Pharmacies by a Protocol to Minimize Inquiries to Doctors under an Agreement between a Hospital and Community Pharmacies

Cooperative care between hospitals and community pharmacies is important to safe and effective pharmacotherapy for outpatients. We developed a protocol comprising three agreements about alternative drugs and dosing schedules with the aim of minimizing inquiries about prescriptions to doctors. The protocol was implemented under an agreement between core hospitals in Gifu City and community pharmacy members of the Gifu City Pharmaceutical Association from October 2019. Here, we examined the impact of this protocol on patient waiting time in pharmacies. Before introduction of the protocol, median patient waiting time for questionable prescriptions requiring an inquiry to a doctor was significantly longer than that for prescriptions not requiring an inquiry (23.0 min vs. 10.0 min, p<0.001). After introduction of the protocol, median time for prescriptions which were questionable but nevertheless under the protocol did not require an inquiry to a doctor was significantly reduced compared with those which were questionable and still did require an inquiry (15.0 min vs. 24.0 min, p=0.038). In conclusion, introduction of a protocol aimed at minimizing inquiries about prescriptions to doctors from a community pharmacy was useful in reducing the waiting time of patients, and also likely in decreasing the working times of medical doctors and pharmacists.

Alternative Trastuzumab Dosing Schedules Are Associated With Reductions in Health Care Greenhouse Gas Emissions.

Cancer care-related greenhouse gas (GHG) emissions harm human health. Many cancer drugs are administered at greater-than-necessary doses, frequencies, and durations. Alternative dosing strategies may enable reductions in cancer care GHG emissions without compromising patient outcomes. We used streamlined life-cycle analysis in a case-control simulation to estimate the relative reductions in GHG emissions that would be expected to result from using each of three alternative dosing strategies of trastuzumab (6-month adjuvant treatment duration, once every 4-week dosing, and both) in human epidermal growth factor receptor 2 (HER2)+ breast cancer. Using primary data and conversion factors from the environmental science literature, we estimated per-patient relative reduction in GHG emissions and, using SEER data, health impacts (in terms of disability-adjusted life-years [DALYs] and excess mortality per kg CO2) on bystanders for each alternative dosing strategy. Compared with the trastuzumab dosing strategy commonly used at baseline (12-month duration of adjuvant therapy and once every 3-week dosing in all settings), adoption of both 6-month adjuvant trastuzumab and once every 4-week trastuzumab dosing would reduce GHG emissions by 4.5%, 18.7%, and 14.6% in the neoadjuvant, adjuvant, and metastatic settings, respectively. We estimate that US-based adoption of alternative trastuzumab dosing would reduce annual DALYs and excess lives lost due to environmental impact of US-based trastuzumab therapy for HER2+ breast cancer by 1.5 and 0.9, respectively. Alternative dosing strategies may materially reduce the population health impacts of cancer care by reducing environmental impact. Regulatory decision making and health technology assessments should consider a treatment's environmental and population health impacts. Clinical trials of alternative dosing strategies are justified on the basis of environmental and population health impacts.

A phase 1/2 dose escalation study of the BCL-2 inhibitor ZN-d5 and the WEE1 inhibitor azenosertib (ZN-c3) in patients (Pts) with acute myeloid leukemia (AML).

TPS7077 Background: B-cell lymphoma 2 (BCL-2) is an anti-apoptotic protein and pathway inhibition combined with chemotherapy and/or targeted therapeutics has led to significant clinical benefit in pts with AML. Disruption of cell cycle regulation may complement BCL-2 inhibition as many malignant cells are dependent on proteins that regulate cell cycle progression. The cell cycle checkpoint protein, WEE1, is highly expressed in genomically unstable malignancies and inhibition of WEE1 induces tumor cell apoptosis. It has been previously reported that the combination of ZN-d5 (an oral, selective BCL-2 inhibitor) and azenosertib (an oral, highly potent WEE1 inhibitor) synergistically enhance killing of AML cells both in vitro and in vivo, as well as in TP53-mutated models (Izadi, AACR 2022). Based on this strong pre-clinical rationale, a Phase 1/2 study was designed to evaluate the novel combination of ZN-d5 and azenosertib in pts with relapsed/refractory (R/R) AML. Methods: This phase 1/2 open-label study (ZN-d5-004C, NCT05682170) is determining the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and clinical activity of ZN-d5 + azenosertib in pts with AML. The phase 1 dose-escalation stage is based on a Bayesian Optimal Interval design. Phase 2 is an open-label expansion to be conducted if supported by safety and efficacy data from the dose-escalation stage. Prior to initiating dose-escalation for the ZN-d5 + azenosertib combination, an azenosertib monotherapy cohort is being enrolled, as it has not been previously administered to pts with hematologic malignancies. For the dose-escalation azenosertib monotherapy (n≈15) and ZN-d5 combination (n≈40) cohorts, pts must have relapsed/refractory (R/R) disease after ≥1 line of AML therapy that may include the BCL-2 inhibitor, venetoclax. In phase 1, an azenosertib monotherapy cohort will be opened prior to investigation of ZN-d5 + azenosertib in combination. In phase 2, ZN-d5 + azenosertib will be given at the RP2D. Alternative dosing schedules may also be investigated based on emerging clinical data. The primary endpoints are adverse events and dose-limiting toxicities. Secondary endpoints include the rate and duration of remission according to the European LeukemiaNet 2017 criteria, including complete remission (CR), CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR), stable disease, progressive disease, relapse after remission (including molecular relapse), remission rate (CR + CRi), overall response rate (CR + CRi + MLFS + PR), and rate of and time to relapse. Pts will remain on study until disease progression, failure to respond, remission if additional therapy is clinically indicated, withdrawal of consent, loss to follow-up, or death. Clinical trial information: NCT05682170 .

Alternative trastuzumab dosing schedules and association with health care greenhouse gas emissions.

e13644 Background: Climate change due to greenhouse gas (GHG) emissions by humans imperils health. Health care is a major source of GHG emissions and thus reducing health care’s environmental impact should be a global priority. GHG emissions associated with the production and administration of cancer drugs, as well the downstream societal costs in human health terms, are undescribed. The extent to which a given cancer drug’s dosing frequency and duration impact GHG emissions is unknown. Methods: Using trastuzumab for HER2-positive breast cancer as a use case, we conducted a case-control simulation study of single, U.S. academic medical center data to estimate the expected reductions in GHG emissions with three alternative dosing strategies (6-month adjuvant treatment duration, extended-interval dosing, and both) using streamlined life-cycle analysis. We estimated the per-patient relative reduction in GHG emissions expected to occur with each of the alternative dosing strategies and, in exploratory analysis, the societal health costs ( e.g., disability-adjusted life-years [DALYs] and excess mortality per kg CO2) associated with therapy-related GHG emissions, using conventional versus alternative dosing strategies. Results: Adoption of 6-month adjuvant trastuzumab reduced expected per-patient GHG emissions in the adjuvant setting by 10%. Adoption of both 6-month adjuvant trastuzumab and pharmacokinetically-supported every 4-week trastuzumab dosing reduced GHG emissions by 4.5%, 18.7%, and 14.6% in the neoadjuvant, adjuvant, and metastatic settings, respectively. An estimated 8.1 DALYs and 4.6 excess lives are lost annually worldwide as a result of U.S.-based administration of conventionally dosed trastuzumab. Adoption of alternative dosing in the U.S. is estimated to enable avoidance of approximately 1.5 DALYs and 0.9 excess lives lost annually. Conclusions: Alternative dosing strategies, suggested to be noninferior by pharmacokinetic and clinical evidence, are estimated to reduce the societal health costs imposed on bystanders that arise from cancer care’s environmental impact. Environmental impact and its resultant societal health costs should be considered in clinical trial design, re-interpretation of previously conducted trials, regulatory decision-making, and health technology assessments of both new and existing cancer therapies.

Phase 1/2 study of XTX101, a masked, tumor-selective Fc-modified anti-CTLA4, in patients with advanced solid tumors.

e14685 Background: XTX101 is a tumor-selective, anti-CTLA-4 monoclonal antibody (mAb) engineered with covalently linked peptides that mask CTLA-4 antigen-binding regions. The masking peptides are cleaved by matrix metalloproteases that are more active in the tumor microenvironment (TME) compared with healthy tissues. XTX101 is designed with 2 Fc domain mutations (S239D and I332E) which enhance binding to Fcγ receptors and are intended to improve effector function, resulting in depletion of regulatory T-cells in the TME. In a murine model, XTX101 at 0.3 mg/kg achieved similar tumor growth inhibition as 3 mg/kg of an ipilimumab analog, suggesting higher relative potency of XTX101 over ipilimumab (Powderly SITC 2021). Methods: Interim results of first-in-human, Phase 1 portion of study XTX101-01/02-001 (NCT04896697) are reported here. Part 1A examines XTX101 monotherapy in 3+3 dose escalation. Part 1B is evaluating pharmacodynamic (PD) biomarkers. Results: As of January 27, 2023, 22 patients (pts) with advanced solid tumors were enrolled including colorectal (n = 3), pancreatic (n = 3), non-small cell lung (n = 3), squamous cell skin (n = 2), breast (n = 2), uterine (n = 2), cervical, prostate, Fallopian tube cancer, leiomyosarcoma and Merkel cell carcinoma in Part 1A, and melanoma and colorectal cancer in Part 1B. Pts had a median of 3 prior lines of therapy (1-10). Dose levels (DL) of 7, 20 and 60 mg every 3 weeks (Q3W) were cleared (1 dose limiting toxicity (DLT) of colitis among 8 patients treated at 60 mg Q3W), while 2 DLTs of colitis were reported among 6 pts at 180 mg Q3W. An alternative dosing schedule of 150 mg every 6 weeks (Q6W) was implemented based on clinical and pharmacokinetic (PK) data, and no DLTs were reported among 5 pts at this alternative schedule. There were no grade (G) 4 or 5 treatment-related (TR) adverse events (AEs) on the study. G3 TRAEs included colitis (n = 4), infusion reaction (IR, n = 3) and lymphopenia (n = 2). There were no skin, endocrine or liver-related TRAEs of any grade. One patient with squamous cell lung cancer treated at 150 mg Q6W dose had an unconfirmed partial response and continues on treatment. PK exposure with 150 mg Q6W schedule were comparable to 2 cycles of 60 mg Q3W. Among 8 pts treated at 60 mg Q3W and 5 treated at 150 mg Q6W, 2 out of 13 patients (15%) experienced G3 colitis, 1 pt G2 colitis and 1 pt G2 diarrhea. All colitis AEs improved with immunosuppression and resolved. There were 2 IRs at 60 mg Q3W, while no IR occurred with the Q6W schedule. Based on the totality of clinical and PK data, 150 mg Q6W is the recommended Phase 2 dose (RP2D), and enrollment in part 1B is ongoing at this dose. Conclusions: XTX101 is a Fc-engineered, masked, tumor-activated, anti-CTLA-4 mAb in development for advanced solid tumors. At RP2D, the preliminary safety profile is differentiated from systemically active anti-CTLA4 mAb. Updated clinical data, PK, immunogenicity and PD data from the study will be presented. Clinical trial information: NCT04896697 .

Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor–Positive Breast Cancer

Successful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events. To compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor-positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of -6%. This multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor-positive breast cancer who were candidates for breast surgery were screened from February 1, 2017, to August 31, 2019. Blood samples were collected at baseline and final visit; tissue biomarker changes were assessed from diagnostic biopsy and surgical specimen. Biomarkers were measured in different laboratories between April 2020 and December 2021. Exemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery. Serum estradiol concentrations were measured by solid-phase extraction followed by liquid chromatography-tandem mass spectrometry detection. Toxic effects were evaluated using the National Cancer Institute terminology criteria, and Ki-67 was assessed by immunohistochemistry. A total of 180 women were randomized into 1 of the 3 arms; median (IQR) age was 66 (60-71) years, 63 (60-69) years, and 65 (61-70) years in the once-daily, 3-times-weekly, and once-weekly arms, respectively. In the intention-to-treat population (n = 171), the least square mean percentage change of serum estradiol was -89%, -85%, and -60% for exemestane once daily (n = 55), 3 times weekly (n = 56), and once weekly (n = 60), respectively. The difference in estradiol percentage change between the once-daily and 3-times-weekly arms was -3.6% (P for noninferiority = .37), whereas in compliant participants (n = 153), it was 2.0% (97.5% lower confidence limit, -5.6%; P for noninferiority = .02). Among secondary end points, Ki-67 and progesterone receptor were reduced in all arms, with median absolute percentage changes of -7.5%, -5.0%, and -4.0% for Ki-67 in the once-daily, 3-times-weekly, and once-weekly arms, respectively (once daily vs 3 times weekly, P = .31; once daily vs once weekly, P = .06), and -17.0%, -9.0%, and -7.0% for progesterone receptor, respectively. Sex hormone-binding globulin and high-density lipoprotein cholesterol had a better profile among participants in the 3-times-weekly arm compared with once-daily arm. Adverse events were similar in all arms. In this randomized clinical trial, exemestane, 25 mg, given 3 times weekly in compliant patients was noninferior to the once-daily dosage in decreasing serum estradiol. This new schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting. ClinicalTrials.gov Identifier: NCT02598557; EudraCT: 2015-005063-16.

Abstract P5-02-27: Serum thymidine kinase activity as a prognostic marker in women with metastatic breast cancer treated with two different schedules of palbociclib plus second-line endocrine therapy within the CCTG MA38 trial

Abstract Background: Thymidine kinase-1 is a cell proliferation marker downstream of the CDK4/6 pathway, whose activity can be measured in serum to reflect tumor proliferation. The CDK4/6 inhibitor palbociclib (P) is approved for the treatment of patients (pts) with hormone receptor positive metastatic breast cancer (MBC) in first or second line endocrine-based treatment settings. Approximately 10-15% of pts exhibit de novo resistance to P, with circulating levels of thymidine kinase activity (TKa) previously shown as a potential marker of early treatment resistance. Therapeutic strategies to address primary resistance to P are currently lacking. Little is known of the clinical efficacy of alternative dosing schedules of P, and its effect on TKa. Here we report serum TKa measured at different timepoints from samples collected within the MA38 (NCT02630693) study. Methods: MA38 is an open label randomised Phase 2 trial comparing two different schedules of P plus second-line ET in pts with ER-positive, HER2-negative MBC. Pts were assigned to receive physician’s choice ET plus either standard P dosing (125mg daily for 21 days on a 28-day cycle), or 100mg daily continuously. Serum samples were collected at baseline (BL; n=135), at 12 weeks (W12; n=122) and 24 weeks (W24; n=95). TKa was measured with DiviTum®, a refined ELISA-based assay (lower limit of detection [LLOD] = 100 DuA). Kaplan-Meier method estimated BL, W12 and W24 (95% CI) median PFS (mPFS; from randomization until progression by RECIST criteria or death) and overall survival (OS; from randomization until death from any cause) in groups of patients defined by dichotomizing TKa as “high” or “low” at the median. Results: MA38 enrolled 180 pts from December 2015 and February 2017 across Canada. Median follow up was 19 months. Overall, the median age was 60, and 90% of pts were post-menopausal. All pts had estrogen receptor-positive disease, and 64% had visceral metastases. On study, 56% received fulvestrant with P, 34% aromatase inhibitor and 10% tamoxifen. TKa was successfully measured in 100% of samples. Median TKa (mTKa) at BL was 234 DuA (IQR 138.5 - 438). BL TKa was not associated with clinical or pathological characteristics. TKa was prognostic at BL with mPFS of 5.5 months (mo) in pts with high TKa vs 16.3 mo with low TKa (HR=2.43; 95% CI, 1.6-3.7; p&amp;lt; 0.001). Similar results were obtained employing other previously reported cut off values. At multivariate analysis, BL TKa was independent from other prognostic factors including age, ECOG status and presence of visceral metastases (adjusted HR= 2.34; 95%CI 1.5- 3.6; p &amp;lt; 0.001). In terms of OS, BL TKa was an independent prognostic factor (adjusted HR=2.0; 95% CI, 1.1-3.7; p=0.02). At 12 mo, OS rate was 68% in pts with high BL TKa vs 92% in low TKa. Both for PFS and OS, no interaction between BL TKa and study arm was observed. At W12 mTKa was 129.5 DuA (IQR 100 - 219.8) and below LLOD (IQR 100 - 180) at W24. At these timepoints, landmark analyses showed no significant difference in PFS according to TKa. However, at W12 high TKa was significantly associated with worse OS (HR 2.0; 95%CI 1.0- 4.0; p=0.03), with a similar trend at W24 (HR 2.5; 95%CI 0.9-6.4; p=0.06). Conclusions: Baseline TKa is a reliable prognostic marker of both PFS and OS in pts treated with P and ET, further substantiating previous data. Monitoring TKa during treatment may provide important clinical information. A significant relationship between TKa and assigned treatment arm was not observed, suggesting TKa is not influenced by P treatment dose or intensity. These data confirm the role of baseline TKa as a new marker for patient stratification, and supports further investigation for the assessment of the clinical utility of TKa as a monitoring biomarker in the advanced setting. Citation Format: Amelia McCartney, Chiara Biagioni, Bingshu Chen, Lois Shepherd, Karen Gelmon, Anil A. Joy, Wendy Parulekar, Mattias Bergqvist, Ilenia Migliaccio, Angela Leo, Matteo Benelli, Emanuela Risi, Erica Moretti, Luca Livraghi, Laura Biganzoli, Luca Malorni. Serum thymidine kinase activity as a prognostic marker in women with metastatic breast cancer treated with two different schedules of palbociclib plus second-line endocrine therapy within the CCTG MA38 trial [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 P5-02-27.

Continuous maintenance (Maint) capecitabine (Cape) dosing for colorectal (CRC) and pancreatic cancers (PC): A single-institution, retrospective, real-world study.

789 Background: Cape is an oral fluoropyrimidine (FP) used as maint therapy in CRC and PC. While the standard FDA dosing is 1250 mg/m2 twice daily (BID) for 14 days followed by 7 days off in a 21-day cycle, there are variations across institutions as to the preferred schedule. To improve tolerability and convenience, our institution adopted a “continuous” dosing schedule where cape is taken BID Monday-Friday (M-F) with a treatment break on Saturday and Sunday. Here, we describe our institution’s experience with continuous maint dosing in advanced CRC and PC patients (pts) and explore real-world outcomes. Methods: Pts ≥ 18 years of age treated with continuous maint cape (+/- bevacizumab) after any line of therapy for stage 4 CRC/PC or locally advanced PC between 1/2016-12/2020 were identified in the COTA real-world database. The final study population included 35 PC and 85 CRC pts. Pt characteristics were analyzed descriptively and progression-free survival (PFS) was calculated using Kaplan Meier methods. Results: Among the 35 PC pts, the median age was 66 years (IQR: 61-73), 57.1% were females, and 65.7% were Caucasian. Among the 85 CRC pts, the median age was 54 years (IQR: 47-66), 47.1% were females, and 55.3% were Caucasian. Most PC (71.4%) and CRC (57.7%) pts were initially prescribed a total daily cape dose of 2 g (range 0.5-4 g). Dose adjustments, including dosage/schedule changes, occurred 11 times amongst PC and 36 times amongst CRC pts, and the leading cause was toxicity (72.7% in PC, 55.6% in CRC). Among PC pts, 14.3% had a dose reduction, 3% had a dose increase, and 11.4% switched to an alternative dosing schedule. Among CRC pts, these rates were 32.9%, 12.9%, and 9.4%, respectively. The leading cause of maint discontinuation was progression of disease (POD) (55.6% in PC, 59.3% in CRC). Additional outcomes are summarized in the table. Conclusions: Although maint FP is an established standard of care, it is often underutilized due to inherent inconveniences and toxicities associated with FDA cape dosing or intravenous FP therapy. The PFS reported here using a continuous cape dosing (predominantly starting at 2 g daily dosing) was in range with those previously reported in PC/CRC 1st-line maint studies using FDA cape dosing or intravenous FP. The rates of cape discontinuation attributed to toxicity we report may be confounded by not controlling for the treatment setting. We argue fixed cape dosing (1 g BID) M-F should be considered a standard maint regimen based on efficacy, convenience, tolerability, and feasibility of dose adjustments.[Table: see text]

2/1 dose schedule of sunitinib is superior than the 4/2 regimen for the first-line therapy of clear cell metastatic renal cell carcinoma - An Indian experience.

Sunitinib remains the first-line treatment for favorable risk metastatic clear cell renal cell cancer (mccRCC). It was conventionally given in the 4/2 schedule; however, toxicity necessitated trying the 2/1 regimen. Regional variations in treatment response and toxicity are known, and there is no data from the Indian subcontinent about the outcomes of the alternative dosing schedule. Clinical records of all consecutive adult patients who received sunitinib as first-line therapy for histologically proven mccRCC following cytoreductive nephrectomy from 2010-2018 were reviewed. The primary objective was to determine the progression-free survival (PFS), and the secondary objectives were to evaluate the response rate (objective response rate and clinical benefit rate), toxicity, and overall survival. A list of variables having a biologically plausible association with outcome was drawn and multivariate inverse probability treatment weights (IPTW) analysis was done to determine the absolute effect size of dosing schedules on PFS in terms of "average treatment effect on the treated" and "potential outcome mean." We found 2/1 schedule to be independently associated with higher PFS on IPTW analysis such that if every patient in the subpopulation received sunitinib by the 2/1 schedule, the average time to progression was estimated to be higher by 6.1 months than the 4/2 schedule. We also found 2/1 group to have a lower incidence than the 4/2 group for nearly all ≥ grade 3 adverse effects. Other secondary outcomes were comparable between both treatment groups. Sunitinib should be given via the 2/1 schedule in Indian patients.

Cows enrolled in a pilot randomized clinical trial evaluating pegbovigrastim administered to dairy cows at dry-off had reduced incidence of intramammary infection.

The objective of this pilot study was to determine if an alternative dosing schedule of pegbovigrastim (PEG; Imrestor; Elanco Animal Health) affects mammary gland health, rear udder width, or milk production of healthy dairy cows. 20 pregnant late-lactation Holstein cows in November 2019 through April 2020. Cows were randomly assigned to receive subcutaneous injections with either 15 mg of PEG (PEG group; n = 10) or a sham injection with saline (0.9% NaCl) solution (control group; 10) administered 7 days before dry-off and at dry-off. Quarter milk samples were collected for bacterial culture and somatic cells before and after dry-off and after calving. Mammary gland width was assessed before and after dry-off. Daily milk yields were evaluated after calving. The incidence of intramammary infection was 5 times greater for quarters of cows in the control group than for quarters of cows that received PEG. The effect of treatment on somatic cell count was not significant, but the effects of period and a treatment-by-period interaction were identified. Treatment did not significantly affect milk production in the subsequent lactation, but the effects of period and an interaction of treatment by period were identified. Rear udder width after dry-off was not significantly affected by treatment, but an effect of period was identified. In this pilot study, cows treated with PEG using an alternative dosing schedule had reduced incidence of intramammary infection and an interaction of treatment by sampling period was observed for milk yield. These results suggest that further studies with larger numbers of cows are warranted.

A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)

PurposeThe purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients. Patients and methodsPatients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm. ResultsThere were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: population for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 patients), and hand–foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0–13.7) months in arm A, 8.6 (IQR 3.8–13.4) in arm B, and 7.1 (IQR 4.4–12.4) in arm C. ConclusionsThe alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher numerical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. Clinicaltrials.gov identifierNCT02835924.

MM-404 Real-World Belantamab Mafodotin Use: A US Retrospective Longitudinal Pharmacy and Medical Open-Source Claims Database Assessment

Belantamab mafodotin (belamaf) is an approved (August 2020), first-in-class, B-cell maturation antigen-targeting antibody-drug conjugate for patients with relapsed/refractory multiple myeloma (RRMM) who have received ≥4 prior therapies, including anti-CD38 monoclonal antibodies (mAB), proteasome inhibitors (PI), and immunomodulatory agents. The DREAMM-2 study, with single-agent belamaf, reported an overall response rate of 32% and an 11-month duration of response. Belamaf can cause ocular events manageable by dose holds/reductions. Examination of prior multiple myeloma (MM) treatments and belamaf treatment patterns for US patients initiating belamaf in real-world clinical practice. This descriptive, retrospective cohort study using IQVIA's longitudinal pharmacy and medical open-source US claims databases identified belamaf claims (August 2020-February 2022). Patients were followed for ≥6 months. The treatment period was the index date (first observed belamaf claim) through the last observed belamaf claim +21 days. The measures were demographic/clinical characteristics, prior MM treatments, recycled treatments, belamaf dose, and use patterns. Overall, 695 patients received belamaf (53% male, median age 70 years). Prior to belamaf, corticosteroid (99%), PI (89%), anti-CD38 mAB (83%), and immunomodulator (65%) treatments were common. A median of 4 therapeutic classes were used: 491 (71%) patients had ≥1 recycled treatment. Median follow-up was 307 (180-532) days; 210 (30%) patients had ≥6 months follow-up. The median belamaf treatment duration was 86 (22-455) days. The median number of administrations was 3. During follow-up, 49 patients (23%) had a 29-56-day treatment gap, and 63 (30%) had a treatment gap >56 days. Doses were administered a median of 22 days apart. The median belamaf dose was 170 mg at first dose/160 mg at fourth dose. Among patients with >1 evaluable dose (n=167), 119 (71%) had no dose reduction and 48 (29%) had ≥1. Eighty patients (38%) had concomitant therapies, most commonly dexamethasone (n=66). Belamaf is a treatment option for RRMM patients. Real-world evidence suggests that its use in clinical practice is generally consistent with the label indication, managed with dose reductions/holds, and that patients remain on therapy (consistent with the DREAMM-2 trial). Ongoing studies are examining alternative dosing schedules and combinations. GSK (214283). This abstract was previously presented at the 2022 International Myeloma Workshop.