Administration Of Carboplatin Research Articles

Reducing renal function assessment prior to platinum-based chemotherapy: a real-world evaluation.

Platinum-based chemotherapy, a widely used backbone of systemic cytotoxic anticancer treatment, is associated with nephrotoxicity. Currently, renal function is generally assessed prior to each administration of cisplatin or carboplatin, but there is no guideline regarding the frequency of renal function determination. The primary objective was to determine the median time to a clinically relevant dosage adjustment (>10%) due to change in renal function in patients treated with cisplatin and carboplatin. Secondly, variables influencing changes in renal function were assessed. We conducted a retrospective analysis of serial renal function assessments in platinum-treated patients with cancer in two academic medical centers, using a query to extract data from the electronic health records between 2017 and 2019. In total, 512 patients receiving cisplatin and 628 patients receiving carboplatin were included. In total, 15% of all cisplatin-treated patients were found to have a renal function less than 60 mL/min at least once during treatment, with a median time to renal function decline of 67 days (range 5-96 days), which did not differ between treatment regimens. For carboplatin 21% of patients were found to have had a dosage variation of more than 10% at least once during treatment, with a median time-to-event period of 64 days (range 5-100 days). Dose adjustments during platinum-based chemotherapy resulting from renal function decline occur after a median time of ≥64 days. Our data provide substantiated guidance to recommend renal function assessment during platinum-based chemotherapy in clinically stable patients to once every 3 weeks.

Carboplatin desensitization - simplified 4-step 2-bag method.

Our cancer program adopted a method for carboplatin desensitization (4-step 2-bag method) that administers the same intensity of drug exposure with a simplified approach to product management in comparison to a published protocol (4-step 4-bag method). The intensity of carboplatin administration for 1:1,000, 1:100, 1:10, and 1:1 dilutions and concomitant fluid administration were compared for the 4-step 2-bag (bags A, B) and 4-step 4-bag (bags 1, 2, 3, 4) methods. Pharmacy preparation of bags A and B is described. A succinct overview of the desensitization procedure is provided. Important considerations germane to pharmacy practice are presented. Chart review of patients who underwent carboplatin desensitization with the 4-step 2-bag method between 7/13/2021 and 11/22/2023 was performed to demonstrate institutional use. The 4-step 2-bag method delivers similar rates of drug intensity from start of desensitization to completion of the planned dose as the previously published 4-step 4-bag method. Accuracy of regimen-based dose administration is assured by infusion of bag B contents irrespective of infusion interruptions or rate changes necessitated by patient tolerance. Bag A provides the 1:1000 dilution in a pharmaceutically elegant manner using administration rates and volumes compatible with clinical practice. The 4-step 2-bag method for carboplatin desensitization administers controlled drug titration corresponding to 1:1000, 1:100, 1:10, and 1:1 dilutions for dose administration using two compounded admixture bags. Inaugural clinical use of the 4-step 2-bag method for carboplatin desensitization at our healthcare facility has proceeded with expected patient tolerance.

Repeated blood–brain barrier opening with a nine-emitter implantable ultrasound device in combination with carboplatin in recurrent glioblastoma: a phase I/II clinical trial

Here, the results of a phase 1/2 single-arm trial (NCT03744026) assessing the safety and efficacy of blood-brain barrier (BBB) disruption with an implantable ultrasound system in recurrent glioblastoma patients receiving carboplatin are reported. A nine-emitter ultrasound implant was placed at the end of tumor resection replacing the bone flap. After surgery, activation to disrupt the BBB was performed every four weeks either before or after carboplatin infusion. The primary objective of the Phase 1 was to evaluate the safety of escalating numbers of ultrasound emitters using a standard 3 + 3 dose escalation. The primary objective of the Phase 2 was to evaluate the efficacy of BBB opening using magnetic resonance imaging (MRI). The secondary objectives included safety and clinical efficacy. Thirty-three patients received a total of 90 monthly sonications with carboplatin administration and up to nine emitters activated without observed DLT. Grade 3 procedure-related adverse events consisted of pre syncope (n = 3), fatigue (n = 1), wound infection (n = 2), and pain at time of device connection (n = 7). BBB opening endpoint was met with 90% of emitters showing BBB disruption on MRI after sonication. In the 12 patients who received carboplatin just prior to sonication, the progression-free survival was 3.1 months, the 1-year overall survival rate was 58% and median overall survival was 14.0 months from surgery.

Effectiveness of Carboplatin-Prescreening Intradermal Skin Tests to Reduce Unanticipated Immediate Hypersensitivity Reactions: A Comparative Study

BackgroundCarboplatin administration poses a risk of immediate hypersensitivity reactions (IHRs) that tend to increase with repeated administration and are mostly IgE-mediated. ObjectiveThis study evaluated the usefulness of carboplatin-prescreening intradermal skin tests (IDTs). MethodsCarboplatin-prescreening IDTs were routinely conducted in patients with a history of receiving six or more carboplatin cycles from January 2021. The primary objective was to assess disparities in the incidence of unanticipated IHRs to carboplatin administration. Comparisons were made between patients in the intervention group (period: 2021–2022) and those who did not undergo prescreening IDTs under the same conditions (pre-intervention group; period: 2019–2020). The secondary objectives included evaluating the sensitivity and specificity of the prescreening IDT and the incidence of carboplatin IHR according to the number of infusion cycles. ResultsThe intervention group comprised 67 patients who were administered 347 carboplatin cycles, whereas the pre-intervention group included 96 patients who were administered 464 carboplatin cycles. The risk of unanticipated carboplatin IHRs decreased by 83.2% in the intervention group compared to the pre-intervention group (pre-intervention group: 3.45%, N=16 vs. intervention group: 0.58%, N=2; p=0.005). The prescreening IDT showed a sensitivity and specificity of 77.78% and 99.41%, respectively. The risk of newly developed IHRs based on the number of carboplatin cycles was <1% (cycle 1-5), 2.11% (cycle 6), 3.90% (cycle 7-12), 2.90% (cycle 13-18), and 0.74% (cycle ≥ 19), respectively. ConclusionsInitiating carboplatin-prescreening IDTs from the seventh cycle significantly reduced the risk of unanticipated IHRs.

Remarkable Breakthrough: Unleashing the Power of Paclitaxel and Carboplatin in Defeating Squamous Cell Carcinoma (SCC) of the Lungs - A Compelling Case Report

Background: This case report focuses on the evaluation of treatment efficacy in a 64-year-old male patient diagnosed with stage IVA lung squamous cell carcinoma (SCC) in the right upper lobe. The patient underwent chemotherapy using paclitaxel and carboplatin, administered in measured doses over six cycles. Close monitoring of patients was conducted throughout the treatment period, taking into account their clinical condition. Case: The patient underwent a computerized tomography (CT) examination before starting treatment, followed by a comparison in the third month of treatment. Encouragingly, significant clinical improvement was observed with respect to the initial complaint. The patient achieved an excellent response, the tumor appearance disappeared and the previous size was assessed by Partial Response (PR) based on RECIST criteria. Discussions: The administration of paclitaxel and carboplatin in patients with SCC gave positive results. Metered doses and scheduled administration allow for effective disease management, leading to substantial clinical improvement. The case studies highlight the potential of this treatment regimen in treating SCC, emphasizing the importance of close monitoring during therapy. Conclusion: This case report underscores the promising results obtained with paclitaxel and carboplatin in the treatment of lung SCC. The patient's notable response, marked by clinical improvement and achieving a partial response based on RECIST criteria, exemplifies the potential of this therapeutic approach. Further investigations and clinical trials are warranted to explore the broader applicability and efficacy of this regimen.

From in silico to in Vitro to In Vivo: Increasing Megakaryocytes to Treat Thrombocytopenia

Hematopoietic stem cells undergo a multi-step differentiation program through several precursor stages to give rise to megakaryocytes (Mk), which ultimately release platelets. Thrombocytopenia can manifest in various clinical settings and can adversely affect a patient's quality of life through easy bruising and risk of bleeding. An example is chemotherapy-induced thrombocytopenia (CIT) which occurs when myelosuppressive chemotherapy is given, especially with certain agents such as platinum analogs and cyclophosphamide. We used a single-cell RNA-sequencing approach to study the differentiation of hematopoietic stem cells to Mk progenitors (MkP) and delineated the trajectory that defines the transition of cells to the megakaryocytic lineage. Using our proprietary platform which pairs new approaches in computation and machine learning in drug discovery, we predicted small molecule interventions that could modulate the hematopoietic lineage direction to increase the differentiation towards MkP and subsequent increases in platelet counts. Using an in vitro 5-day CD34-based Mk differentiation assay we demonstrated that some of our predicted interventions increased generation of MkP from stem cells. Analysis of early MkP (CD34-CD235a-CD71+CD41b+CD42b-) and late MkP (CD34-CD235a-CD71-CD41b+CD42b+) by flow cytometry elucidated differential mechanisms of action such as induction of early or late MKP or both. We performed an 8-day study in healthy mice, which revealed that a selected set of compounds increased MkPs in vivo, consistent with our predicted cell behavior and in vitro findings. To evaluate a possible application for this MkP and platelet increases we tested the efficacy of one of our hit compounds CP3 in a CIT mouse model using Carboplatin. In this model, we recorded a &amp;gt;70 % reduction in platelet counts on day 9 post carboplatin administration, with platelet numbers recovering on day 13 and return to basal levels by day 21. To assess the efficacy of CP3, mice dosed first with this compound were challenged with carboplatin. The primary endpoint of this study was the ability of the compound to rescue mice from nadir of thrombocytopenia and accelerate recovery to baseline. Prior to carboplatin dosing, 7 days of CP3 dosing showed a dose dependent increase in platelet counts confirming our initial studies. However, CP3 dosing did not rescue platelet nadir or accelerate recovery to baseline in the CIT model. This study demonstrated the capacity of CP3 to increase platelets in a healthy BM environment but not under conditions of myelosuppression as seen in the CIT mouse model. Taken together, these findings highlight the benefits of our platform to predict compounds that modulate lineage differentiation towards MkP, and a resultant increase in platelet numbers in an animal model.

Evaluation of Retinal Nerve Fiber Layer and Macular Thickness Pre- and Post-Chemotherapy With Carboplatin and Paclitaxel in Patients With Endometrial and Ovarian Cancer.

Background Carboplatin and paclitaxel are two standard chemotherapeutic agents known to cause neurotoxicity. In this study, we aim to evaluate the toxicity of these agents by measuring the peripapillary retinal nerve fiber layer (RNFL) and macular thickness in patients with endometrial and ovarian cancers who are receiving them. Methods A one-year prospective cohort study involving 28 patients who were treated intravenously with carboplatin (200-400 mg/m2) and paclitaxel (175 mg/m2) three-weekly for six cycles was conducted. RNFL and macula thickness were measured using optical coherence tomography (OCT) before the commencement of chemotherapy, after the third cycle, and one month after the sixth cycle. The main outcome measurements were the average RNFL thickness and central subfield thickness of the macula. Results The mean age of the 28 participants was 54.68 years old (standard deviation [SD] 9.03). Eleven had endometrial cancer, while 17 had ovarian cancer. The mean of the average RNFL thickness during baseline pre-chemotherapy was 96.43 µm (SD 11.39). One month after cessation of treatment, the mean RNFL thickness increased to 101.57 µm (SD 13.54). Statistical analysis showed a significant increment in the mean RNFL thickness (p≤ 0.001), from baseline to after three cycles, and baseline to one month after six cycles of chemotherapy, except the nasal quadrant. The increment of all macular quadrants was statistically significant (p < 0.05) except for central subfield thickness. Conclusion Systemic administration of carboplatin and paclitaxel affected both the peripapillary RNFL and macula thickness. This represents early evidence of subacute subclinical retinal toxicity. OCT can be used as a screening tool to assess peri-chemotherapeutic retinal alterations.

Carboplatin beyond 4 cycles during therapy with carboplatin, pemetrexed, and pembrolizumab for advanced non-small cell lung cancer (NSCLC).

e13509 Background: Since the publication of KEYNOTE-189 study , carboplatin/pemetrexed/pembrolizumab (carbo/pem/pembro) has become a common frontline regimen for advanced non-small cell lung cancer (NSCLC). In KEYNOTE-189, carboplatin was administered for a maximum of 4 cycles. To date, the number of carboplatin cycles administered in the real-world setting remains unclear. We analyzed factors predicting the receipt of carboplatin beyond 4 cycles (CB4). Methods: We interrogated a population-based, real-world database by Flatiron for NSCLC patients with no actionable EGFR/ALK who received carbo/pem/pembro from March to July 2019 (pre-pandemic period) and from March to July 2020 (pandemic period). Patients were included if they completed the regimen as shown by transitioning to maintenance pem, pembro, or pem/pembro. Primary endpoint was CB4. Secondary endpoint was overall survival. Multivariable logistic regression analyses were performed to identify independent predictors of receiving CB4. Results: Among 2090 patients treated during the study period, 966 patients (46%) started on carbo/pem/pembro and subsequently proceeded to maintenance therapy. Among them, 134 patients (14%) received CB4. Multivariable analysis revealed the following statistically significant predictors of receiving CB4, along with respective odds ratios (95% CI) and p-values: Non-white race 1.67 (1.09-2.57) (p=0.017), ECOG ≥1 1.66 (1.07-2.59) (p= 0.024), pandemic year 2020 1.68 (1.11- 2.52) (p=0.013), and ever-smoking status 0.51 (0.30-0.87) (p=0.013). Survival analysis is ongoing. Conclusions: A significant number of patients received CB4. Since this practice is not considered a standard practice, the benefits and risks of CB4 is unknown. Predictors of receiving CB4 included year of treatment, race, ECOG, and smoking status. Further investigation is needed to understand patient-physician decision making process with regards to the length of carboplatin administration. [Table: see text]

Survey of carboplatin desensitization therapy: JCOG Gynecologic Cancer Study Group multicenter retrospective study.

e17631 Background: The purpose of the present study was to investigate the real-world experience with carboplatin desensitization (CD) therapy in Japan, along with its safety, and establish a strategy to address carboplatin-induced hypersensitive reactions (HSRs). Methods: The present study included patients diagnosed with gynecologic cancer (ovarian, endometrial, or cervical cancer, i.e., OC, EC, and CC, respectively) who underwent CD therapy between 2016 and 2020 at Japan Clinical Oncology Group Gynecologic Cancer Study Group (JCOG-GCSG) participating centers. CD therapy was performed at each institution, and cases of implementation were registered in online case report forms. We examined patient information, treatment regimens, frequency and dose of carboplatin administration, administration rates, and CD practices. This study was approved by the Ethics Committee of the Tottori University. Results: Overall, 20 of 51 JCOG-GCSC-participating facilities performed CD therapy. The present study enrolled 136 patients (OC, 108; EC, 17; CC, 11). Of these, 37 (27.2%) patients had pre-existing allergies, and 29 (20.5%) exhibited prodromal symptoms at the time of treatment prior to the onset of HSRs. The most common symptoms were erythema and itching. At the onset of HSRs, erythema was the most common symptom, occurring in 93 (68.4%) patients, followed by itching in 72 (52.9%), reduced oxygen saturation in 43 (31.6%), and loss of consciousness in 3 (2.2%). The onset of HSRs was most common during treatment of the first recurrence (47%). The mean total carboplatin dose until the appearance of HSRs was 7331 (2620–18282) mg, and the mean number of doses was 14 (4–63). Six centers discontinued CD therapy owing to the appearance of breakthrough HSRs. CD therapy was completed in 75% of patients, with 25% (34/136) experiencing breakthrough HSRs. HSR-related mortality was not observed. The associated risk factors with HSR were not selected in the present study. Conclusions: Although patients who undergo CD therapy in Japan have a high probability of safely completing planned therapy, erythema and pruritus are important signs of breakthrough HSRs. Breakthrough HSRs were most frequent during the first cycle of desensitization. [Table: see text]

Abstract P4-07-60: Identification of Optimal Carboplatin Containing Regimen for Triple Negative Breast Cancer

Abstract Background: Current management for triple negative breast cancer (TNBC) involves chemotherapy and immunotherapy systemic treatments. TNBC treatment remains a challenge, with up to 40% of those treated using standard methods for stage I to III TNBC experiencing recurrence. Currently, the optimal carboplatin regimen for TNBC is yet to be defined. In our previous study, we identified an optimal carboplatin containing chemotherapy regimen that improved patient outcomes. In this study, we expanded the cohort as an extension of the previous prospective study to further verify these promising results. Patients and Methods: We performed a retrospective review of 37 TNBC patients who had &amp;lt; 10% estrogen and progesterone receptor positivity and were human epidermal growth factor receptor-2 (HER2) negative. This study was originally done in an adjuvant setting, but patients with locally advanced tumors received neoadjuvant chemotherapy. Patients received dose-dense Adriamycin, cyclophosphamide, and paclitaxel every two weeks for sixteen weeks. Adriamycin (60 mg/m^2) and cyclophosphamide (600 mg/m^2) were given intravenously every two weeks for four cycles, followed by paclitaxel (175 mg/m^2) every two weeks for four cycles. Carboplatin with an area under the curve of 6 was added to cycles two and four of paclitaxel. Last, we changed the parameters of continuing chemotherapy to allow platelet counts &amp;gt; 70,000 × 10^9. Only paclitaxel could be modified for neuropathy. Results: Of 37 patients enrolled in this trial, 35 patients survived without recurrence, one required a dose reduction in paclitaxel, and one has incomplete staging as grade is still pending. The two patients that did experience recurrence died. Of these two patients, the first had American Joint Committee on Cancer (AJCC) 7 stage IIIC cancer, and the second had two separate TNBCs at presentation – AJCC-7 IIB cancer of the right breast and AJCC-7 IIA cancer of the left breast. Under the AJCC-8 system, the first patient had AJCC-8 IIIB cancer, while the second patient had AJCC-8 IIIB cancer of the right and left breasts. These data suggest a completion rate of 97%, overall survival (OS) rates of 95% (AJCC-7 &amp; 8), and progression free survival (PFS) rates of 95% and 94% (AJCC-7 &amp; 8, respectively; Table 1). Additional stage-specific survival metrics and patient staging information are available in Table 1. Median follow-up in this study was 3.14 years. This is consistent with data from our previous study with significant PFS benefit over historic chemotherapy. All patients completed this regimen with no dose reductions of carboplatin and a 32% dose reduction in paclitaxel due to neuropathy. Toxicity was established in our previous study. The favourable toxicity profiling of the regimen allowed maximal tolerance for patients. Conclusion: Although administration of carboplatin with chemotherapy for TNBC is known to be beneficial, the ideal carboplatin containing regimen has not been identified because of concerns regarding toxicity and low completion rates. Here, an optimal carboplatin-containing regimen identified in our previous clinical trial led to 95% overall survival rates (AJCC-7 &amp; 8), 95% and 94% progression free survival rates (AJCC-7 &amp; 8, respectively), and a 97% completion rate for 37 TNBC patients. A limitation is that this is a small single center trial, and plans are underway to test this regimen with immunotherapy in a larger randomized control trial. Table 1: Patient Staging and Survival Metrics. Citation Format: Geoffrey J. Rempel, Claire S. Rim, Abdulkadir Hussein, Alina Bocicariu, Swati Kulkarni, Rasna Gupta, John Matthews, Amin Kay, Lisa Porter, Caroline Hamm. Identification of Optimal Carboplatin Containing Regimen for Triple Negative Breast Cancer [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 P4-07-60.

Magnesium Supplementation May Not Be Protective against Carboplatin-Induced Nephrotoxicity But May Be Beneficial for Children Suffering Malignancies: A Randomized Clinical Trial.

Magnesium oxide may be effective in renal insufficiency prevention after carboplatin therapy. We have evaluated magnesium oxide impression on the serum creatinine (Cr) and blood urea nitrogen (BUN) levels plus glomerular filtration rate (GFR) in cancerous children. A group of children with different cancers (n = 18) was treated with 250 mg/day magnesium oxide supplementation (MOS) and compared with a matched placebo-treated group (n = 18). After 2 weeks, carboplatin chemotherapy started. We compared serum Cr, BUN, and GFR values before and 3 and 7 days post intervention. Serum Cr and BUN were increased significantly 3 and 7 days after intervention in both the groups. Serum Cr and BUN were not statistically different between the MOS and placebo groups before the intervention and 3 or 7 days after carboplatin administration (P > 0.05). Three days after the intervention, the GFR reduced from 101.38 ± 14.67 to 90.11 ± 10.52 mL/min/1.73 m2 in the MOS group. Furthermore, in the placebo group, 3 days after the intervention, the GFR was reduced from 97.5 ± 9.71 to 92.33 ± 10.61 mL/min/1.73 m2. Further, in the MOS group, after 7 days of the intervention, the GFR was reduced to 84.11 ± 12.47 mL/min/1.73 m2. In the placebo group, after 7 days of the intervention, the GFR was diminished to 85.38 ± 10.66 mL/min/1.73 m2 (P = 0.371). The current study suggests that magnesium supplementation does not prevent carboplatin-induced nephrotoxicity in children with malignancies. Anyway, we propose magnesium oxide supplementation for this group of pediatrics because magnesium is an essential element for cell and tissue growth, maintenance, and metabolism.

CTNI-20. RESULTS OF A PHASE 1/2 CLINICAL TRIAL OF BLOOD-BRAIN BARRIER (BBB) OPENING WITH THE SONOCLOUD-9 IMPLANTABLE ULTRASOUND DEVICE IN RECURRENT GLIOBLASTOMA PATIENTS RECEIVING IV CARBOPLATIN

Abstract Low intensity pulsed ultrasound in combination with microbubbles can be used to temporarily disrupt the blood-brain barrier (BBB). A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of BBB disruption using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy. The SonoCloud-9 device, which contains nine, 1-MHz, 10-mm diameter ultrasound emitters (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every four weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 ml/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n = 3), 6 (n = 3), then 9 (n = 3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first two weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with nine emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium (&amp;lt; 1 hr after sonication). All patients received carboplatin either after (n = 21) or before (n = 12) device activation to disrupt the BBB. In addition, a sub-study was performed to investigate carboplatin concentration enhancement in the peritumoral region with sonication at time of device implantation. Study accrual is complete with 33 patients having been implanted and received at least one sonication. A total of 101 sonications were performed (range = 1-10 sonication sessions/patient). No DLTs were observed. Five serious adverse events (all resolved) were considered as possibly related to the study procedure. BBB disruption was confirmed by gadolinium enhancement after sonication. In three patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated survival results will be presented.

Toxicity management and efficacy of carboplatin desensitization therapy for recurrent epithelial ovarian carcinoma: A real-world study.

Epithelial Ovarian cancer (EOC) is the most lethal gynecologic cancer worldwide. Carboplatin (CP) is the main chemotherapeutic agent in the treatment of ovarian cancer. However, the development of a hypersensitivity reaction (HSR) in 10% to 15% of patients with EOC is an important limiting factor for the clinical use of CP. Herein, we aimed to investigate the efficacy and safety of CP-desensitization (CP-D) therapy in the treatment of recurrent patients with EOC. Forty-seven ovarian cancer cases treated with CP-desensitization at the Istanbul University Oncology Institute were retrospectively analyzed between 01.01.2017 and 01.01.2022. The decision for CP-D was based on the patients' history of HSR and/or a positive skin test. For all patients, a 6-hour 12-step rapid drug desensitization protocol with a 30-minutes premedication regimen was used. Forty-seven patients were included in this study, and the median age at diagnosis was 53 years (range; 27-80). Twenty-one (43.7%) patients had 1 or more comorbid diseases, and 12.7% had a previous history of drug allergy. On average, HSR due to carboplatin was identified after 9 (7-16) cycles, and carboplatin was administered n = 11 (range, 3-36) times to patients. The overall survival from the first desensitization procedure (0S2) was 42.2 months (range: 25.3-59.1), and the 1-, 2-, and 5-years survival rates were 92.6%, 75.6%, and 47.2%, respectively. The objective response rate (ORR) was 78.5%. Cumulatively, 496 CP-D procedures were performed, of which 478 (96.3%) were successfully completed. None of the patients included in this study developed severe (grade 3-4) HSR during CP administration (no adrenaline was used, no need for intensive care). No deaths due to CP-D were noted. CP-D is a beneficial and safe method in treating platinum-sensitive recurrent EOC patients with CP-induced HSR.

OS07.3.A Phase 1/2 clinical trial of blood-brain barrier opening with the SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin

Abstract Background Low intensity pulsed ultrasound (LIPU) in combination with microbubbles is a promising approach for brain drug delivery. A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of blood-brain barrier (BBB) disruption over a large volume using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy. Material and Methods The SonoCloud-9 device (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every 4 weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 μl/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n=3), 6 (n=3), then 9 (n=3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first 2 weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with 9 emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium (&amp;lt;1 hr after sonication). All patients received carboplatin either after (n=21) or before (n=12) device activation to disrupt the BBB. In addition, a sub-study was performed to investigate carboplatin concentration enhancement in the peritumoral region with sonication at time of device implantation. Results Study accrual is complete with 38 patients enrolled and 33 patients having been implanted and received at least one sonication+carboplatin. A total of 101 sonications were performed (range=1-10 sonication sessions/patient). No DLTs were observed. A total of 14 SAEs were observed including five events considered as possibly treatment related. BBB disruption was confirmed by gadolinium enhancement after sonication. In an analysis of 60 treatments in 27 patients that had all nine emitters active, 90% of activated emitters led to BBB opening in gray and/or white matter with good repeatability of BBB opening. In 3 patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated and mature outcome results will be presented. Conclusion These results confirm the safety and feasibility of repeated BBB disruption using an implantable ultrasound system. LIPU substantially increases drug levels in the peritumoral brain.

A randomized phase 3 trial of intraperitoneal versus intravenous carboplatin with dose-dense weekly paclitaxel in patients with ovarian, fallopian tube, or primary peritoneal carcinoma (a GOTIC-001/JGOG-3019/GCIG, iPocc Trial) (LBA 3)

<b>Objectives:</b> Traditionally, the target of intraperitoneal (IP) chemotherapy for ovarian cancer was patients with minimal residual disease after debulking surgery. However, our pharmacological study suggested that IP carboplatin therapy should also be feasible for patients with larger size residual disease, and our previous phase 2 study demonstrated a satisfactory response rate of IP carboplatin plus dose-dense paclitaxel (ddTCip) regimen in patients with macroscopic residual disease after initial surgery for ovarian (OV), fallopian tube (FT), and primary peritoneal (PP) carcinoma. The purpose of this study is to assess whether IP administration of carboplatin is superior to intravenous (IV) administration of carboplatin (ddTCiv regimen) in OV, FT, and PP carcinoma patients with either minimal or macroscopic residual disease. <b>Methods:</b> Eligible patients were those with newly diagnosed stages II-IV disease. All patients were to undergo an initial laparotomy or laparoscopy with primary debulking surgery if possible. Before abdomen was closed, patients were randomized to either IV or IP arm. An IP port and catheter was placed if the patient was assigned to IP arm. Chemotherapy regimen was either IV paclitaxel plus IV carboplatin (IV arm) or IV paclitaxel plus IP carboplatin (IP arm). Dose of paclitaxel was 80 mg/m² Q1W and dose of carboplatin was at an area under the curve (AUC) of 6 Q3W. Each patient was to receive 6 to 8 cycles of chemotherapy. Patients with bulky residual disease were allowed to undergo interval debulking surgery followed by assigned arm regimen up to 8 cycles total. Primary endpoint was PFS, and secondary endpoints included OS, safety, QOL, and cost/benefit. <b>Results:</b> Total of 655 patients were randomized between 2010 and 2016 from Japan, Singapore, Korea, New Zealand, USA, and Hong Kong. Stage distribution was II (n= 88), III (n=448), and IV (n=119). Size of residual disease at randomization was either 0 cm (n=163), < 1 cm (n=97), 1-2 cm (n=33), or >2 cm (n=362). Histological types were serous (n=420), endometrioid (n=61), clear cell (n=74), and others (n=100). Median follow-up was 55.7 months. IP chemotherapy significantly improved PFS in the ITT population (HR=0.83, 95%CI:0.69-0.99, p=.041) and in the 602 eligible patients (HR=0.78, 95%CI:0.65-0.94, p=.009). Median PFS for ITT population was 20.7 (95%CI: 18.1-22.8) months in the IV arm and 23.5 (95%CI: 20.5-26.9) months in the IP arm. Median PFS for eligible patients was 20.0 (95%CI: 18.0-22.2) months in the IV arm and 22.9 (95%CI:19.6-26.9) months in the IP arm. Subset analysis showed that the survival benefit was greater in patients with larger size residual disease. Toxicity profile was essentially equivalent in both arms except for catheter-related toxicities (11.8%). <b>Conclusions:</b> ddTCip chemotherapy improved the PFS over ddTCiv regimen in patients with OV, FT, and PP carcinoma regardless of the residual tumor size after initial surgery.

Mir-451a-5p Modulates Breast Cancer Cell Apoptosis, Migration, and Chemosensitivity to Carboplatin through the PTEN Pathway

Background: MicroRNAs (miRNAs) can play essential roles in the modulation of cancer cell growth, survival, and resistance to chemotherapy. Thus, we hypothesized that restoration of miR-451a-5p (a tumor suppressor) might affect sensitivity to chemotherapeutics in breast cancer cells. Methods: For this purpose, malignant breast cancer cells (MDA-MB-231) were transfected with miR-451a-5p mimic and exposed with carboplatin. Then, the apoptotic rate was evaluated by flow cytometry and DAPI staining (apoptosis), q-RT-PCR (expression levels of caspase-3, caspase-8, MMP9, ROCK, vimentin, c-Myc genes). Moreover, the proliferation and migration of cancer cells were assessed by MTT (cell viability) and wound healing assay. The western blot assay was used for protein expression of PTEN, AKT, and P-AKT. Results: Our findings demonstrated that a combination of miR-451a-5p restoration with carboplatin administration could additionally induce apoptosis, repress the proliferation and migration, and also increase PTEN protein expression with no significant alteration on the AKT/P-AKT protein expressions in the breast cancer cells. The present data was analyzed using GraphPad Prism 6 software by non-parametric one-way ANOVA and t-test. Conclusion: In conclusion, it seems that overexpression of miR-451a can enhance the chemosensitivity of breast cancer cells to carboplatin therapy. Thus, it may shed new light on miR-451a management of breast cancer chemoresistance and may be a beneficial strategy for future cancer therapy. However, further studies, particularly in other signaling pathways, should be required.

P70-2 A study of carboplatin-related hypersensitivity reactions in our hospital

Carboplatin is used for many types of cancer, sometimes at very high dosing rates. It has been reported that the risk of hypersensitivity reactions (HSRs) increases as the frequency of carboplatin administration increases, but the relationship between frequency of administration and risk is not clear. We investigated the relationship between the number of times carboplatin was administered to cancer patients and the frequency of HSRs in our hospital. We also investigated the frequency of HSRs to other platinum drugs in patients who had developed HSRs.

Abstract 2306: BLU-222, an investigational, potent, and selective CDK2 inhibitor, demonstrated robust antitumor activity in CCNE1-amplified ovarian cancer models

Abstract Background: Cyclin-dependent kinases (CDK) are a class of enzymes that, along with their regulatory cyclin binding partners, drive cell cycle progression. Cell cycle dysregulation is a hallmark of cancer and targeting its genetic drivers can confer therapeutic benefits. Cyclin E1 (CCNE1) gene alterations are common in patients with ovarian cancer and can be found in ~20% of high-grade serous ovarian cancer cases, which tend to be platinum therapy resistant and therefore represent a high medical need. Cyclin E1 is the canonical binding partner of CDK2, which becomes constitutively active when CCNE1 is amplified and overexpressed. Selectively inhibiting CDK2 is an attractive therapeutic option for CCNE1-amplified tumors and may limit off-target CDK-driven toxicities. Here we report preclinical validation studies leading to the development of an orally available CDK2 inhibitor, BLU-222, for the treatment of ovarian cancer harboring a CCNE1 amplification. Methods: BLU-222 selectivity was measured by enzyme assays, cellular target engagement assays (NanoBRET), and proliferation assays in a panel of ovarian cancer cell lines. In vitro cellular potency was assessed by phospho-Rb levels. In vivo antitumor activity of BLU-222 as a single agent or in combination with carboplatin was measured in an OVCAR-3 cell line-derived xenograft (CDX) tumor model harboring a CCNE1 amplification. Results: BLU-222 demonstrated selectivity, both biochemically and in cells, with low nanomolar potency for CDK2 vs other CDK family members (CDK1, -4, -6, -7, and -9). In a panel of ovarian cancer cell lines, those with CCNE1 amplifications were highly sensitive to BLU-222. Consistent with the in vitro profiling, BLU-222 exhibited significant antitumor activity in the OVCAR-3 CDX model. While administration of single-agent carboplatin led to stasis in vivo, the combination of BLU-222 + carboplatin induced durable tumor regression even after treatment cessation. Conclusions: These data provide a strong rationale for advancing BLU-222 towards clinical development in patients with CCNE1-amplified ovarian cancer. Citation Format: Victoria Brown, Phil Ramsden, Nealia House, Richard Vargas, Jian Guo, Ruduan Wang, Riadh Lobbardi, Maxine Chen, Douglas Wilson, Joseph Kim, Neil Bifulco, Michelle Maynard, Emanuele Perola, Dean Zhang, Steve Wenglowsky, Yoon Jong Choi. BLU-222, an investigational, potent, and selective CDK2 inhibitor, demonstrated robust antitumor activity in CCNE1-amplified ovarian cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2306.

Efficacy and Adverse Events of Carboplatin Desensitisation Therapy for Gynaecological Cancer: A Retrospective Study.

Background: Carboplatin, the key drug used in treating gynaecological cancer, has an approximately 12–16% risk of hypersensitivity reactions. We aimed to investigate the efficacy and adverse effects of carboplatin desensitisation therapy for gynaecological cancer. Methods: The desensitisation protocol was standardised as a four-step, 4-h, carboplatin administration in the hospital. A retrospective medical record review was conducted on 15 patients who underwent carboplatin desensitisation for gynaecological malignancies at our hospital. Patients’ data were analysed to evaluate the treatment success rate, therapeutic effect of desensitisation, adverse events, and treatment. Results: Of 91 carboplatin desensitisation cycles scheduled; the completion rate was 93.4% (85/91). Adverse events occurred in 23 of these 91 (25.3%). In four (4.4%) of the 23 cycles, hypersensitivity reactions could be treated only by discontinuing the infusion and slowing the administration, while in the remaining 19 (20.9%), medication was administered intravenously after discontinuing the infusion to manage hypersensitivity reactions. No treatment-related deaths occurred. Overall, 23 series of anti-cancer agent regimens, including carboplatin desensitisation, were administered to the 15 patients. The therapeutic response rate was 82.6% and the disease control rate was 95.7%. Conclusions: Carboplatin desensitisation was beneficial in patients with a history of carboplatin-induced hypersensitivity reactions.

Synergistic Antitumor Interaction of Risedronate Sodium and Standard Anticancer Agents in Canine (D-17) and Human Osteosarcoma (U-2 OS) Cell Lines.

Simple SummaryThe study investigated canine (D-17) and human (U-2 OS) osteosarcoma exposition to risedronate sodium and chosen standard anticancer drugs concurrently used in vitro. Risedronate sodium is frequently used in the therapy of bone tissue disorders. Our study demonstrated increased efficiency of cytostatic drugs in the presence of risedronate. During the incubation, testing and evaluation the standard protocols were used. MTT and TUNEL assays were employed to estimate changes in cell viability and percentage of apoptosis. We found that a combination of doxorubicin and cisplatin with risedronate sodium produced the strongest cytotoxic effects in both cell cultures. The cytotoxicity against both types of osteosarcoma was concentration-dependent and the cytostatic drugs and risedronate sodium were found to act synergistically.The study discusses in vitro cytotoxicity of a combination of cytostatic drugs (doxorubicin, cisplatin, carboplatin, etoposide) and risedronate sodium against canine and human osteosarcoma (D-17 and U-2 OS). Standard protocols were used for the preparation of cell cultures and evaluation of their viability and apoptosis. MTT assay assessed the culture viability and EC50, while the apoptotic effect of the drugs was checked with a TUNEL assay. Doxorubicin alone showed the strongest cytotoxicity against D-17 (0.056 ± 0.019 µg/mL) and U-2 OS (0.051 ± 0.003 µg/mL), while the lowest cytotoxicity was observed for carboplatin (D-17, 6.45 ± 0.2 µg/mL and U2-OS, 27.5 ± 2.3 µg/mL). Risedronate sodium at 100, 10 and 1 µg/mL lowered viability in OS cell lines by 53.38 ± 1.46 and 49.56 ± 0.7%, 97.08 ± 3.32 and 74.92 ± 4.01%, and 102.67 ± 3.56 and 94.56 ± 3.52%, respectively. In all analyzed drug combinations, risedronate sodium significantly (* p < 0.05) increased the cytotoxicity against tested osteosarcoma cell lines. The decrease in cell viability caused by the studied compound combinations was weaker in canine than in human cell cultures. A combination of doxorubicin (all concentrations), cisplatin (1 µg/mL) and etoposide (1 µg/mL) with 100 µg/mL of risedronate sodium significantly improved the cytotoxicity of the drugs against canine and human osteosarcoma. Administration of carboplatin (1 µg/mL) and risedronate sodium (100 µg/mL), compared to carboplatin per se, produced no significant differences in cytotoxicity against the D-17 cell culture but significantly enhanced cytotoxicity in the U-2 OS line. The strongest apoptosis in both lines was detected for 0.01 µg/mL doxorubicin combined with 100 µg/mL risedronate sodium or 1 µg/mL cisplatin and 100 µg/mL risedronate sodium. In all combinations, the tested compounds revealed a synergistic mechanism of action.