Combination Of Carboplatin Research Articles

Targeting RAS-ERK pathway alterations with MEK inhibitors to improve chemosensitivity in high grade serous ovarian cancers

ObjectiveAssess if MEK inhibitor blockade of RAS-ERK pathway adaptive response in high grade serous ovarian cancers (HGSOC) improves platinum sensitivity. MethodsThree HGSOC cell lines and three patient derived organoid (PDOs) samples from ascites of platinum resistant HGSOC patients were collected. Cell lines and PDOs were exposed to carboplatin and MEK inhibitors cobimetinib or trametinib. Cytotoxic effects of MEK inhibitors alone or combined with carboplatin were established. Western blots demonstrated RAS-ERK pathway blockage after MEK inhibitor treatment. RNA sequencing assessed gene expression after MEK inhibitor treatment. Cell line NF1 gene knockdown was performed with corresponding chemosensitivity levels. ResultsHigh carboplatin IC50 levels indicated platinum resistance in cell lines and PDOs. Cobimetinib induced cytotoxicity in cell lines and PDOs, while trametinib was less effective. Western blot confirmed MEK-ERK pathway blockage at minimal concentrations of MEK inhibitors in cell lines and PDOs. Phosphorylated-ERK levels of untreated cells indicated higher levels of RAS-ERK pathway activation in OVSAHO and OVCAR7 compared to OVCAR3. OVSAHO harbors a NF1 mutation and had highest levels of RAS-ERK activation. Cotreatment with carboplatin and MEK inhibitors showed varying synergistic cytotoxic effects at different combinations. Synergistic effect was most prominent in the OVSAHO carboplatin and cobimetinib combination. RNA sequencing identified downregulation of c-MYC and FOXM1 gene expression after MEK inhibitor treatment. NF1 gene knockdown showed an acquired increased IC50 compared to parental cells. ConclusionMEK inhibitors block RAS-ERK pathways in platinum resistant HGSOC cells and PDOs. MEK inhibitors with carboplatin have select synergistic effects which may indicate a strategy to improve platinum sensitivity.

Cost-utility analysis of Pembrolizumab compared to other alternative immunotherapy and chemotherapy treatments for patients with advanced melanoma in Iran

ABSTRACT Objectives Immunotherapy drugs like Pembrolizumab have shown significant improvements in treatment outcomes of advanced melanoma. This study aimed to evaluate the cost-utility of Pembrolizumab compared to other immunotherapy and chemotherapy drugs in the first-line treatment of advanced melanoma in Iran. Methods A partitioned-survival model, based on data from a recent randomized phase 3 study (KEYNOTE-006) and recent meta-analysis, was used to divide Overall survival (OS) time into Progression-free survival (PFS) and post-progression survival for Pembrolizumab, Nivolumab, Ipilimumab, Dacarbazine, Temozolomide, Carboplatin, and Paclitaxel combination. Quality Life Years (QALY) and Incremental Cost-Effectiveness Ratio (ICER) were considered as the final outcome. Results The ICER of Ipilimumab, Nivolumab, Nivolumab & Ipilimumab, and Pembrolizumab compared to Temozolomide was calculated as $40,365.53, $19,591.13, $24,578, and $47,324.2 per QALY, respectively. Scenario analysis demonstrated if the price of one vial of Nivolumab 100 is $90.51, each vial of Pembrolizumab is $119.20, and each vial of Ipilimumab is $101.54, they will be cost-effective in Iran. Conclusion None of the immunotherapy drugs studied were found to be cost-effective when considering the cost-effectiveness threshold of $3,532. Therefore, a cost reduction of more than 90% in the prices of immunotherapy drugs would be necessary for them to be considered cost-effective in Iran.

Efficacy of first-line immunization combined with antiangiogenesis treatment and chemotherapy for the treatment of tongue cancer: A case report.

There is currently no uniform and effective treatment for patients with locally advanced oral cancer who cannot tolerate surgery or radiotherapy. The prognosis of oral cancer patients with lymph node metastasis is very poor, but the clinical treatment of such patients faces certain challenges. Case 1 was a 59-year-old patient with tongue cancer (cT 3 N x M 0 G 2) who refused radiotherapy because of a history of leukoderma. After evaluation of disease condition, a 4-drug combination therapy of toripalimab + anlotinib + nabpaclitaxel + carboplatin was administered. Case 2 was a 55-year-old patient with tongue cancer (cT 3 N 2 M 0 G 1) who could not receive radiotherapy because of a medical history of cervicofacial burns. After disease evaluation, toripalimab + anlotinib + docetaxel + carboplatin combination therapy was administered. Both patients did not experience any adverse reactions during treatment and achieved a complete response after 2 cycles of treatment. Their progression-free survival is currently 6 and 8 months, respectively, and they are in sustained remission. Currently, the efficacy of immune checkpoint inhibitors targeting programmed death-1 as a first-line treatment of inoperable and non-radiatable locally advanced oral cancer is unknown. Here, we describe 2 cases of locally advanced oral cancer treated with first-line immune checkpoint inhibitors in combination with targeted therapy and chemotherapy. This approach was successful in these patients, but a larger sample size is required to verify our findings.

Neuroendocrine prostate tumors: histologic features and therapy

Neuroendocrine (NE) tumors of the prostate are rare tumors, that can arise de novo but much more commonly occur after androgen deprivation therapy for prostate adenocarcinoma. NE tumors of the prostate are classified into: adenocarcinoma with NE differentiation, well-differentiated NE tumor/carcinoid, small-cell NE carcinoma, large cell NE carcinoma, adenocarcinoma with Paneth cell NE differentiation and mixed NE carcinoma—acinar adenocarcinoma. IHC plays a vital role and should be approached at two levels. For the issue of confirming NE differentiation, markers for NE differentiation include synaptophysin, chromogranin, and CD56. If there is any uncertainty about the histogenesis, that is, whether a tumor is primary to the prostate, markers for prostatic lineage—PSA, PSAP, PSMA, prostein (p501s), NKX3.1, ERG (by IHC or FISH)—may be used. Actually, platinum-based chemotherapy is commonly administered to patients with pure small cell carcinoma based on small cell lung cancer (SCLC) data and the accumulating data for aggressive variants of castration-resistant prostate cancer (AVPC). This may consist of a combination of carboplatin (or sometimes cisplatin) plus either etoposide (based on SCLC) or a taxane (especially if mixed histology or AVPC features). A combination regimen of cisplatin, etoposide, and doxorubicin has been also investigated but the benefit-risk ratio of the three-drug combination was considered unfavorable. Unfortunately, platinum-based chemotherapy often presents high toxicity and a short overall survival. Results of currently ongoing preclinical and clinical studies are expected to enhance our understanding of these tumors’ underlying biology and guide our efforts toward the development of personalized medicine through targeted diagnostic and therapeutic approaches.

Effect of the combination of trastuzumab, paclitaxel and carboplatin in the treatment of uterine serous carcinoma: A systematic review and meta-analysis

Purpose: To systematically review the efficacy of paclitaxel-carboplatin versus trastuzumab in combination with paclitaxel/carboplatin for the treatment of uterine serous carcinoma (USC) with high Her2/neu expression, in order to obtain an evidence-based reference for clinical treatment.Methods: Publications were obtained from China Knowledge Network (CNKI), VIP database (VIP), Wanfang database, PubMed, Embase, Cochrane Library, and Web of Science. The retrieval period was from the establishment of database to May 2022, and the efficacy of paclitaxel-carboplatin combination with trastuzumab (study group) versus paclitaxel-carboplatin (control group) for the treatment of Her2/neu high-expressing USC was collected. Two reviewers independently screened, extracted data, and evaluated the quality of evidence of included studies. RevMan 5.3 statistical software was used for meta-analysis. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events.Results: Meta-analysis showed that the study group had significantly longer OS than control group (p = 0.004), and PFS of study group was significantly longer than that of control group (p < 0.0001). In terms of ORR, there was no difference between the two groups (p = 0.42). However, in terms of total and high-risk adverse events, the number of patients with adverse events in study group was higher than in control group (p = 0.05), (p = 0.0001).Conclusion: Paclitaxel-carboplatin combination with trastuzumab significantly prolongs OS and PFS in USC patients with high Her2/neu expression, but it may increase the incidence of adverse events.

Induction of metallothionein expression by supplementation of zinc induces resistance against platinum-based treatment in malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Currently, multimodality treatment including chemotherapy with cisplatin or carboplatin in combination with pemetrexed offers the best options. Detoxification of heavy metals in the cell by metallothioneins (MT) is associated with early failure to platin-based chemotherapy. The induction of MTs gene expression or its enzyme results in saturation by exposure to metal ions such as zinc or cadmium. Its therapeutically effect is still not analyzed in depth. In our study, we investigated three MPM cell lines and one fibroblast cell line in the course of cisplatin treatment and supplementation of zinc. Cell state analyses via an enzyme-activity based assay were performed. With this, we were able to analyze apoptosis, necrosis and viability of cells. Additionally, we tested treated cells for changes in metallothionein IIA (MT2A) expression by using quantitative realtime polymerase chain reaction. Zinc supplementation induces gene expression of MT2A. Overall, a zinc dose-dependent induction of apoptosis under platin-based treatment could be observed. This effect could be verified in all analyzed cell lines in varying intensity. MT expression is induced by zinc in a dose-dependent manner and inhibits a successful cisplatin therapy. Therefore, heavy metal exposure during cisplatin therapy, e.g., via cigarette smoke, might be an important factor. This should be considered in further therapeutic approaches.

Weekly paclitaxel, carboplatin and cetuximab (PCC) combination followed by nivolumab in platinum-sensitive recurrent and /or metastatic squamous cell carcinoma of head and neck: a retrospective analysis from two institutions in India

Background: First line (1L) TP-Ex-like regimen followed by 2nd-line (2L) immunotherapy represents one of the standards of care in platinum-sensitive recurrent and/or metastatic squamous cell carcinoma of head and neck (R/M SCCHN). We report our experience from 2 tertiary care institutions of India. Methods: This is a retrospective analysis of consecutive patients of platinum-sensitive R/M SCCHN treated with 1L weekly paclitaxel, carboplatin, and cetuximab (PCC) regimen followed by cetuximab maintenance (if non-progressive) or 2L nivolumab or oral metronomic chemotherapy (OMCT) on progression. Overall response rates (ORR), progression-free survival after 1L and 2L (PFS-1 & PFS-2), overall survival (OS), and safety were evaluated. Results: The study included 54 patients; median age 56.5 years; 89% men; 11% had cardiac dysfunction; 13% had renal dysfunction. After 1L PCC, ORR was 59.3%; median PFS-1 was 7.031 months; 61% had progression; 35% were treated with nivolumab and 18% with OMCT. The ORR was 26.3% (nivolumab) and 10% (OMCT). Median PFS-2 was 6.5 months (nivolumab) and 2 months (OMCT). The median OS was 15.01 months (entire cohort), 20.6 months (nivolumab), and 7 months (OMCT). Grade III/IV adverse events on PCC included neutropenia (31.4%), anaemia (35.1%), thrombocytopenia (7.4%), febrile neutropenia (11.1%), and skin reaction (16.6%); no Grade-III/IV treatment-related toxicities on 2L. Conclusions: 1L weekly PCC is an effective regimen for palliative therapy of platinum- sensitive R/MSCCHN with an acceptable toxicity profile. The addition of 2L nivolumab on progression further improves the outcomes.

A localized hydrogel-mediated chemotherapy causes immunogenic cell death via activation of ceramide-mediated unfolded protein response.

Treatment of triple-negative breast cancer (TNBC) is challenging because of its "COLD" tumor immunosuppressive microenvironment (TIME). Here, we present a hydrogel-mediated localized delivery of a combination of docetaxel (DTX) and carboplatin (CPT) (called DTX-CPT-Gel therapy) that ensured enhanced anticancer effect and tumor regression on multiple murine syngeneic and xenograft tumor models. DTX-CPT-Gel therapy modulated the TIME by an increase of antitumorigenic M1 macrophages, attenuation of myeloid-derived suppressor cells, and increase of granzyme B+CD8+ T cells. DTX-CPT-Gel therapy elevated ceramide levels in tumor tissues that activated the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-mediated unfolded protein response (UPR). This UPR-mediated activation of apoptotic cell death led to release of damage-associated molecular patterns, thereby activating the immunogenic cell death that could even clear the metastatic tumors. This study provides a promising hydrogel-mediated platform for DTX-CPT therapy that induces tumor regression and effective immune modulation and, therefore, can be explored further for treatment of TNBC.

The combination of APR-246 and carboplatin in olaparib-resistant high grade serous ovarian cancer (HGSOC) and triple negative breast cancer (TNBC) cell lines.

e17504 Background: PARP inhibitors (PARPi), as Olaparib (OLA), have changed the therapeutic landscape in HGSOC and TNBC. However, most patients will develop resistance to PARPi. Although resistance mechanisms are poorly understood, it is suggested that BRCA mutations reversions or cell cycle alterations could be involved. APR-246 is a new targeted agent that restores p53 in TP53-mutated cells. The aim of our study was to assess the potential synergism of the combination of carboplatin (carbo) plus APR-246 in both OLA-sensitive and OLA-resistant HGSOC and TNBC cell lines. Methods: We selected two HGSOC (PEO1-S and Kuramochi-S) and one TNBC TP53 mutant cell lines (MDA-MB-231-S). Resistance to OLA was generated by pulse doses with IC75 OLA for 24 hours and recovered for two weeks during a period of 6 months (PEO1-R) and to increased concentrations of OLA for 72 hours during a period of 1 year (Kuramochi-R, MDA-MB-231-R). Next-generation sequencing was performed in order to assess mutations. IC50 of APR-246 and Carbo and the combination of both (combo) were calculated for Kura-S/R, PEO1-S/R and 231-S/R cell lines. Synergism between both drugs was assessed with Chou-Talalay method for combination index (CI) at Fa50. DNA damage was assessed by gamma-H2AX expression by western-blot (WB). Results: 231-S harboured a TP53 mutation (mut) (missense R280K) and BRCA wildtype (wt), in PEO1-S BRCA2 mut p.Y1655* and TP53 mut was detectable. Kuramochi-S was TP53 mut (missense D816Y) and BRCA2 mut. BRCA and p53 mutation remained unchanged in the resistant lines generated.The mutation profile of each line and the IC50 of APR-246, carbo and combo are shown in the table. IC50 of carboplatin is superior in all 3 resistant cell lines when compared to their sensitive parental line, suggesting a potential cross-resistance to platinum in OLA-resistance. The combination of carbo and APR-246 is synergistic even in OLA-resistant cell lines, in fact in those cross-resistant lines values of synergism by Chou-Talalay are improved by the combo suggesting a potential role of this combination in PARPi resistant cell lines. WB showed an increased DNA damage with the combo when compared to either single agent, with an increase in H2AX in all lines either sensitive or resistant. Conclusions: The combination of APR246 and carboplatin is synergistic in all 3 studied cell lines but also in the OLA resistant ones. The combo increased its synergistic effect suggesting a potential role of combo in OLA-resistant tumors. [Table: see text]

UPGRADE-A: Phase 1 expansion trial of the NaPi2b-directed antibody drug conjugate (ADC) upifitamab rilsodotin (UpRi) in combination with carboplatin in patients with high-grade serous ovarian cancer (HGSOC).

TPS5613 Background: UpRi is a first in class NaPi2b ADC with a novel scaffold-linker-payload that is designed to enable high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a sodium-dependent phosphate transporter protein broadly expressed in HGSOC, with limited expression in healthy tissues. Interim data from a previous phase 1b study of heavily pretreated HGSOC patients reported clinical activity and tolerability data for UpRi as a monotherapy, most notably in patients with NaPi2b positive tumors (TPS≥75). Based on these emerging single-agent safety and efficacy data, it is hypothesized that UpRi in combination with carboplatin may provide additional clinical benefit for patients in earlier lines of treatment. UPGRADE-A is a Phase 1 dose escalation (DES) and expansion (EXP) study to evaluate UpRi and carboplatin followed by UpRi maintenance in recurrent platinum-sensitive HGSOC. The DES portion of UPGRADE-A has completed enrollment, and the EXP portion is ongoing. Methods: The EXP cohort of UPGRADE-A is enrolling patients with recurrent or metastatic PSOC (defined as having achieved a PR or CR to 4+ cycles in their last platinum containing regimen) who have received 1-3 prior lines of therapy. Up to 1 non-platinum based prior chemotherapy regimen is allowed, provided it is not the most recent line of chemotherapy. The primary objective of EXP is feasibility of UpRi + carboplatin at the RP2D, defined as 60% of patients completing at least 4 cycles of UpRi + carboplatin without discontinuing treatment early for reasons other than disease progression. Secondary objectives include the safety/tolerability, pharmacokinetics, and preliminary anti-neoplastic activity of the UpRi + carboplatin combination. Tumor tissue must be provided (archival or fresh sample) for retrospective NaPi2b assessment. UpRi 30mg/m2 + carboplatin (AUC 5) will be administered IV every 28 days for up to 6 cycles, followed by UpRi maintenance monotherapy until disease progression or unacceptable toxicity. Up to 30 patients are expected to enroll in EXP, and the trial is currently open for enrollment. NCT04907968. Clinical trial information: NCT04907968 .

Final results of a pilot study of docetaxel and carboplatin for treatment of patients with mCRPC containing biallelic inactivation of genes in the homologous recombination DNA repair pathway.

5054 Background: Inactivating mutations in genes important in homologous recombination DNA repair (HRD) are present in the tumors of ~25% of patients with metastatic castration resistant prostate cancer (mCRPC). These alterations are associated with more aggressive disease but may also predict vulnerability to DNA damaging agents. We previously reported promising interim results from a single arm, Phase 1/2 trial studying the combination of the DNA damaging agent carboplatin with docetaxel for patients with mCRPC containing HRD mutations. Here we report final results after completing accrual and two additional years of follow up. Methods: We assessed response to the combination of docetaxel 60mg/m2 and carboplatin AUC 5 IV q21 days in patients with mCRPC whose tumors had evidence of biallelic inactivation of genes involved in HRD and who had progressed on any prior treatment, including docetaxel and/or PARP inhibitor (PARPi). The primary endpoint was the proportion of patients who achieved ≥50% PSA decline from baseline (PSA50). With H0 of PSA50 of 26%, 14 patients provided 80% power to conclude H1 of PSA50 of 60% based on Simon's 2-stage design with 1-sided α = 5%. The secondary endpoints included PSA30, response duration, progression-free survival (PFS), and overall survival (OS). Results: The trial opened in Jan 2016 and completed in Sep 2021. A total of 16 patients were treated on study, including 6 who had previously received PARPi and 5 who had received docetaxel. 11/16 patients (69%) achieved PSA50. 7/9 patients (78%) with biallelic inactivation of BRCA2 (7), BRCA1 (1), or PALB2 (1) achieved PSA50. Other biallelic inactivated HRD-related genes were ATM (1), CHD1 (1), CDK12 (3), MRE11A (1), and NBN (1). Of these patients, 4/7 (57%) achieved PSA50. Notably, 3/6 patients (50%) previously treated with PARPi therapy achieved PSA50. The median PFS was 8.4 months, and the median OS was 2 years. 6/16 patients (38%) had grade 3 AEs, most commonly thrombocytopenia (25%) and anemia (13%). One patient (6%) had a grade 4 AE (thrombocytopenia). Conclusions: The addition of carboplatin to docetaxel significantly improved response rates in patients with mCRPC with biallelic inactivation in genes involved in the HRD pathway. Responses were also seen in patients who had previously received PARPi. The combination was relatively safe and well-tolerated. The encouraging activity and favorable toxicity profile observed here merits further investigation. Additional work is ongoing to further refine biomarkers predictive of treatment response and resistance. Clinical trial information: NCT02598895 .

Neoadjuvant PARP inhibitors in patients with early HER2-negative breast cancer harboring BRCA 1/2 germline mutations: A systematic review and meta-analysis.

e12611 Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for the treatment of germline BRCA mutated (gBRCAm) breast cancer (BC) patients in the adjuvant and metastatic settings. Several studies have explored the role of PARPi in the neoadjuvant setting both with and without chemotherapy. Here, we explore the efficacy and safety of neoadjuvant PARPi in early HER2-negative BC patients. Methods: We searched PubMed, Scopus, and the Cochrane Library databases for randomized (RCT) and non-randomized clinical trials (non-RCT) that reported the proportion of patients with pathological complete response (pCR) after neoadjuvant PARPi and safety. Statistical analysis was performed using R software. Data were pooled using the random effects model. Results: Analysis included 3 RCTs and 4 non-RCTs, with 942 HER-2 negative breast cancer patients, 293 harboring a gBRCA 1/2 mutation. In a pooled analysis, gBRCAm carriers achieved a significantly higher rate of pCR than BRCA wild-type patients (56% versus 37%, p=0.04) with neoadjuvant PARPi. There was no difference in pCR when PARPi were combined with carboplatin (+/- chemotherapy) (40% versus 44%, p=0.69). Among RCTs (n=457) patients received PARPi in combination with either Paclitaxel plus Carboplatin (PCb) (85%) or with Paclitaxel alone (P) (15%). PARPi were associated with a higher pCR which approached, but did not meet statistical significance (51% vs 41%; Odds Ratio [OR]: 1.30, 95%CI 0.97 to 1.74, p=0.08). gBRCAm was associated with higher pCR compared to wild type in RCTs analysis (60% versus 48%; OR: 1.64, 95%CI 1.01 to 2.68, p=0.05). The most common adverse events (AEs) were cytopenias, nausea, fatigue, alopecia, and dizziness. Hematological toxicities were the most frequent serious AEs, including anemia (15%), neutropenia (22%), and thrombocytopenia (3%). The combination of PARPi and carboplatin was associated with higher hematological AEs (78% versus 46%; P=0.002). Conclusions: The addition of PARPi in the neoadjuvant setting improves pCR in early-stage HER2-negative breast cancer and germline BRCA 1/2 mutations, but not for unselected patients. Combination of PARPi with carboplatin does not improve pCR and leads to substantially worse toxicity. Further studies are warranted to identify the best neoadjuvant PARPi schema.[Table: see text]

A phase II study of weekly carboplatin and nab-paclitaxel with trastuzumab or bevacizumab as neoadjuvant therapy for patients with early-stage nonmetastatic breast cancer.

e12623 Background: Neo-Adjuvant chemotherapy (NAC) allows patients to undergo breast conserving surgery, treats micro metastatic disease and improves patient outcomes. Achieving a complete pathologic response to NACT has prognostic significance in HER2+ and triple negative breast cancer. Anthracyclines are commonly integrated to Neo-adjuvant regimens. Their use is limited by cardiac and hematologic toxicity. We proposed that weekly Carboplatin and Nab-Paclitaxel is a well-tolerated regimen and aim to demonstrate that this approach can be a selective anthracycline sparing regimen with comparable improvement in recurrence free survival (RFS) and pathologic complete response (pCR). Methods: We conducted a single institution, open label, prospective Phase II clinical trial for patients with non-metastatic breast cancer who were eligible to receive NACT. All Patients with stage I-III breast cancers were treated with weekly Nab-paclitaxel (90 mg/m2) and carboplatin (AUC 2) for 12 weeks. Patients with HER2+ breast cancer received trastuzumab (4 mg/kg induction, followed by 2 mg/kg/week) weekly for 12 weeks. Triple negative and HR + patients received bevacizumab (10 mg/kg) every other week for 5 doses. Results: We enrolled 125 patients from February 2008 to December 2015. 85 pts were HER2- and 42 pts were HER2+. The pCR rate was 17.6% (15 pts) in the HER2- cohort and 50% (21 pts) in the HER2+ cohort. In the subgroup analysis based on hormone receptor (HR) status, pts with HR- tumor had more favorable response with higher rate of pCR compared with pts with HR+ tumor. In the HER2- cohort, the total pCR rate was 34% in HR- tumors vs 8% in HR+ tumors, P = 0.0018. After a median follow up of 53 months, overall survival was 88.9% for pts who achieved pCR and 77.7% for those who did not. HR = 0.3664, CI = 0.06147 to 2.1843, P = 0.34.In the HER2+ cohort the pCR rate was 33% in pts with HR+ tumors vs 72% in pts with HR- tumor, P = 0.0137. After a median follow up of 53 months, overall survival was 100% for pts who achieved pCR vs 20% in those who did not. The relapse-free survival was 90% vs 25% respectively (HR = 0.0669, CI = 0.00454 to 0.9251 P = 0.0016). In the entire study population, 6 pts (4.7%) had treatment discontinuation and 12 pts (9.4%) had dose reduction due to side effects. The rate of treatment disruption was higher in the HER2- cohort. Nausea, vomiting, and neutropenia were the most common side effects in both cohorts (7.9%) followed by thrombocytopenia and anemia (4.7%). Hematologic toxicity was the most common toxicity grade 3 and 4. Conclusions: Combination of nab-paclitaxel and carboplatin plus targeted therapy as an anthracycline sparing neoadjuvant chemotherapy showed a good pCR rate in HER2+ subgroup and moderate activity in TNBC subset. High rate of pCR was associated with high survival outcomes in HER2+ cohort. The regimen was well tolerated among both cohorts. Clinical trial information: NCT00618657 .

Safety of locally administered large surface area microparticle paclitaxel and docetaxel in combination with standard of care cancer therapies.

e15187 Background: The safety of local delivery of large surface area microparticle paclitaxel (LSAM-PTX) or docetaxel (LSAM-DTX) to solid tumors has been evaluated in Phase 1/2 trials across 156 subjects with 43% (67/156) on various concurrent standard of care (SOC) therapies. Local administration of LSAM-PTX or LSAM-DTX leads to a reduction in systemic drug exposure and drug-related adverse events (AE) and may reduce toxicities encountered in combination systemic treatment regimens. This report summarizes safety findings in subjects co-administered LSAM-PTX or LSAM-DTX and common SOC therapies for treatment of carcinomas. Methods: During the study follow-up periods, AE and serious AE (SAE) were coded (MedDRA 16.1 -23.1) and assessed (NCI CTCAE 3 - 5). Results: In 7 studies (median age 69 years (range 37-96), 61% male, 88% white) (Table), LSAM-PTX administrations occurred as follows: intraperitoneal (n = 31 subjects), intraprostatic (n = 17), and intratumoral (n = 72). A median of 1 cycle (range 1-6) of LSAM-PTX was administered. LSAM-DTX was injected once into bladder tissue after tumor resection followed by a median of 10 cycles (range 7-10) of intravesical instillation in 36 subjects. 59 subjects (median age 65 (range 48-86), 53% male, 88% white) received local LSAM-PTX and concomitant chemotherapy, immunotherapy, or radiation. Rates of subjects who had Grade 3 SAE possibly related to LSAM-PTX were 29%, 24%, 16%, 6.7% and 5.0% in paclitaxel, carboplatin, 5-FU, nab-paclitaxel, and gemcitabine combinations, respectively. Grade 4 SAE possibly related to LSAM-PTX were found in 1 subject each co-administered pembrolizumab (13%), carboplatin (5.9%), and paclitaxel (7.1%). Subjects treated with 5-FU, gemcitabine, and nab-paclitaxel reported no related Grade 4 SAE. No Grade 5 SAE were deemed possibly related to LSAM-PTX. 8 subjects (median age 78 (range 54-89), 100% male, 88% white) received local LSAM-DTX therapy in combination with SOC therapies. No Grade 3-5 AE were reported with LSAM-DTX in combination with gemcitabine, carboplatin, pembrolizumab, avelumab or radiation. Conclusions: Local treatment of solid tumors with LSAM-PTX or LSAM-DTX has the potential to overcome some limitations of SOC therapies by increasing tumor dwell time and reducing systemic toxicities which are often exacerbated in combinatorial treatment regimens. Clinical trial information: NCT00666991 , NCT03636256 , NCT03077659 , NCT04221828 , NCT03029585 , NCT03077685 , NCT04314895 . [Table: see text]

WEE1 inhibitor adavosertib in combination with carboplatin in advanced TP53 mutated ovarian cancer: A biomarker-enriched phase II study

ObjectiveIn the first part of this phase II study (NCT01164995), the combination of carboplatin and adavosertib (AZD1775) was shown to be safe and effective in patients with TP53 mutated platinum-resistant ovarian cancer (PROC). Here, we present the results of an additional safety and efficacy cohort and explore predictive biomarkers for resistance and response to this combination treatment. MethodsThis is a phase II, open-label, non-randomized study. Patients with TP53 mutated PROC received carboplatin AUC 5 mg/ ml·min intravenously and adavosertib 225 mg BID orally for 2.5 days in a 21-day cycle. The primary objective is to determine the efficacy and safety of carboplatin and adavosertib. Secondary objectives include progression-free survival (PFS), changes in circulating tumor cells (CTC) and exploration of genomic alterations. ResultsThirty-two patients with a median age of 63 years (39–77 years) were enrolled and received treatment. Twenty-nine patients were evaluable for efficacy. Bone marrow toxicity, nausea and vomiting were the most common adverse events. Twelve patients showed partial response (PR) as best response, resulting in an objective ORR of 41% in the evaluable patients (95% CI: 23%–61%). The median PFS was 5.6 months (95% CI: 3.8–10.3). In patients with tumors harboring CCNE1 amplification, treatment efficacy was slightly but not significantly better. ConclusionsAdavosertib 225 mg BID for 2.5 days and carboplatin AUC 5 could be safely combined and showed anti-tumor efficacy in patients with PROC. However, bone marrow toxicity remains a point of concern, since this is the most common reason for dose reductions and dose delays.

Study Design and Rationale for Marble Study: A Phase II Trial of Atezolizumab (MPDL3280A) Plus Carboplatin and Paclitaxel in Patients With Advanced or Recurrent Thymic Carcinoma (JTD2101)

BackgroundThymic carcinoma (TC) is a rare thymic epithelial tumor, and advanced or recurrent TC has limited prognosis. Treatment for chemotherapy-naïve, advanced, or recurrent TC remains unchanged with the combination of carboplatin and paclitaxel; therefore, a new treatment strategy is warranted. Immune checkpoint blockades inhibiting the programmed cell death-1 (PD-1) pathway (PD-1 and its ligand, PD-L1) have shown potential as a monotherapy for TC, although the efficacy of monotherapy was moderate for previously treated TC. We hypothesized that the combination of an anti-PD-L1 antibody, atezolizumab, with carboplatin and paclitaxel, would be effective in inducing immunogenic cell death in patients with advanced or recurrent TC. MethodsWe initiated a multicenter, single-arm, open-label phase II study of atezolizumab combined with carboplatin and paclitaxel for metastatic or recurrent TC. Eligible patients will receive atezolizumab plus carboplatin and paclitaxel every 3 weeks for up to 6 cycles, followed by atezolizumab every 3 weeks for up to 2 years until progression or unacceptable toxicity. A total of 47 patients will be enrolled in this study, with a 24-month enrollment period and 12-month follow-up. The primary endpoint is the objective response rate (ORR), based on an independent central review. The secondary endpoints are the investigator-assessed ORR, disease control rate, progression-free survival, duration of response, overall survival, and safety. ResultsThis study aims to establish the safety and efficacy of atezolizumab combined with carboplatin and paclitaxel in patients with advanced or recurrent TC. Trial registrationJapan Registry of Clinical Trials (jRCT), jRCT2031220144. Registered on June 18, 2022, https://jrct.niph.go.jp/en-latest-detail/jRCT2031220144.

Advancements in super-selective catheterization and drug selection for intra-arterial chemotherapy for retinoblastoma: a 15-year evolution

BackgroundRetinoblastoma (Rb) is the most common primary ocular malignancy of childhood. Left untreated, it is 100% fatal and carries a substantial risk of impaired vision and removal of one or...

Phase II Randomized Trial of Carboplatin, Pemetrexed, and Bevacizumab With and Without Atezolizumab in Stage IV Nonsquamous Non–Small-Cell Lung Cancer Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked

IntroductionPatients with non–small-cell lung cancer (NSCLC) who have never smoked or have tumors with mutations in EGFR generally derive minimal benefit from single-agent PD-1/PD-L1 checkpoint inhibitors. Prior data indicate that adding PD-L1 inhibition to anti-VEGF and cytotoxic chemotherapy may be a promising approach to overcoming immunotherapy resistance in these patients, however prospective validation is needed. This trial in progress (NCT03786692) is evaluating patients with stage IV NSCLC who have never smoked or who have tumors with sensitizing EGFR alterations to determine if a 4-drug combination of atezolizumab, carboplatin, pemetrexed, and bevacizumab can improve outcomes compared to carboplatin, pemetrexed and bevacizumab without atezolizumab. MethodsThis is a randomized, phase II, multicenter study evaluating carboplatin, pemetrexed, bevacizumab with and without atezolizumab in 117 patients with stage IV nonsquamous NSCLC. Randomization is 2 to 1 favoring the atezolizumab containing arm. Eligible patients include: 1) those with tumors with sensitizing EGFR alterations in exons 19 or 21 or 2) patients who have never smoked and have wild-type tumors (ie, no EGFR, ALK or ROS1 alterations). Patients are defined as having never smoked if they have smoked less than 100 cigarettes in a lifetime. Patients with EGFR-mutated tumors must have disease progression or intolerance to prior tyrosine kinase inhibitor (TKI) therapy. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), response rate, duration of response, and time to response. ConclusionThis phase II trial is accruing patients at U.S. sites through the National Comprehensive Cancer Network (NCCN). The trial opened in August 2019 and accrual is expected to be completed in the Fall of 2024.

Abstract CT160: Phase 1b/2a clinical trial of the oral BET inhibitor PLX2853 as monotherapy for ARID1A mutated gynecologic cancers and in combination with carboplatin for platinum resistant ovarian cance

Abstract The Bromodomain and Extra-Terminal (BET) Domain proteins facilitate the development of many human cancers via epigenetic regulation. BET inhibitors may be effective in reversing platinum resistance in ovarian cancer (OC) and may generate synthetic lethality with ARID1A loss. PLX2853 is an orally active, small molecule inhibitor of BET bromodomain-mediated interactions that exhibits low nanomolar potency in blocking all 4 BET family members (BRD2, BRD3, BRD4, and BRDT). PLX2853 development is continuing at Opna Bio as OPN-2853. Clinical experience with PLX2853 monotherapy in subjects with heavily pretreated solid tumors and lymphoma showed signs of activity. The current study (NCT04493619) was designed as a multicenter, open-label trial with two parallel arms: (1) a phase 2a study of PLX2853 monotherapy in advanced gynecological malignancies with a known ARID1A mutation and (2) a phase Ib/2a combination study of PLX2853 plus carboplatin in platinum resistant OC. The primary objective of the Ib portion of the study was safety and tolerability, with the primary objective of both phase 2a portions being efficacy. In the monotherapy arm, up to 6 patients were treated at 80 mg PLX2853 daily in a safety lead-in, with progression to phase 2a using a Simon 2-stage design if dose limiting toxicities (DLTs) were observed in fewer than 33% subjects. In Stage 1, 6 additional subjects (N=12 total) were planned, with progression to stage 2 if two or more patients responded in stage 1. The combination arm included an escalation phase Ib. Three to six evaluable subjects were planned for each group, with dose escalation pending less than 33% DLT rate. The combination arm defined by the phase 1b portion of the study continued to a planned phase 2a Simon 2 stage design similar to that described for the monotherapy arm. 34 of 37 enrolled patients were evaluable with data from at least 1 post-baseline response (14 monotherapy, 20 combination therapy). Of the 14 evaluable patients on the monotherapy arm, 1 (7.1%) achieved a partial response (PR) with progression-free survival of 278 days, 5 (35.7%) had stable disease (SD) and 8 (57.1%) had progressive disease (PD). Of the 20 evaluable OC patients on the PLX2843 + carboplatin combination, 1 (5.0%) had PR, 9 (45.0%) had SD, and 10 (50%) had PD. This study in a larger cohort of gynecologic cancer patients confirmed the safety profile of the agent and demonstrated the feasibility of combination with carboplatin. While these results did not meet the pre-specified response criteria, evidence of clinical activity nevertheless highlights the rationale for further exploration of BRD4 inhibitors in patients with ARID1A-mutated gynecologic malignancies, possibly in combination with agents targeting potential feedback mechanisms such as the PI3K pathway, frequently activated in these cancers. Citation Format: Elizabeth M. Swisher, Linda R. Duska, Erika P. Hamilton, Amit M. Oza, Gini Fleming, Oladapo O. Yeku, Alexander I. Spira, Debra L. Richardson, Robin Guo, Jackie Walling, Kerry Inokuchi, Dmitriy Zamarin. Phase 1b/2a clinical trial of the oral BET inhibitor PLX2853 as monotherapy for ARID1A mutated gynecologic cancers and in combination with carboplatin for platinum resistant ovarian cance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT160.

Treatment outcomes and prognostic factors in children with hepatoblastoma using a risk‐stratified approach

Not all the significant progress made in the management of children with hepatoblastoma (HB) has translated into improved outcomes in limited-resource settings. There are limited data on outcomes in children with HB from India. All patients diagnosed with HB between July 2013 and December 2020 were risk-stratified and treated as per International Liver Tumor Strategy Group (SIOPEL). Patients with standard-risk HB received cisplatin monotherapy and those with high-risk HB received alternating cycles of cisplatin and the combination of carboplatin plus doxorubicin. Data regarding demographic details, chemotherapy, surgery, liver transplantation, outcomes, prognostic factors, and toxicity were collected. Of 157 patients with HB, 117 (74%) were high risk, 31 (20%) were standard risk, and nine (6%) unknown. Patients with standard-risk disease had excellent outcomes, with 3-year event-free survival (EFS) and overall survival (OS) of 96% and 100%, respectively. Among high-risk HB, six underwent orthotopic liver transplantation of which four were alive at last follow-up. The 3-year EFS and OS of patients with high-risk disease was 56% and 66%, respectively. Outcomes of patients with PRETEXT IV (3-year EFS: 42%, 3-year OS: 50%) and metastatic disease (3-year EFS: 30%, 3-year OS: 50%) were dismal. Patients with serum alpha-fetoprotein (AFP) reduction greater than 90% following two courses of chemotherapy had favorable outcomes; 3-year EFS: 80% versus 58% (p=.013) and 3-year OS: 95% vs. 68% (p<.01). Only two (6%) of 31 patients with relapse/refractory HB were alive at a median follow-up of 36months, and both had received salvage chemotherapy and surgery. While children with standard-risk HB had excellent outcomes, those with high-risk disease continue to do poorly. Serial monitoring of serum AFP values is a cost-effective and reliable predictor of outcomes. Orthotopic liver transplantation remains a viable option for inoperable disease in resource-limited settings as well.