First-in-human Study of AZD5153, A Small-molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma.

AZD5153, a reversible, bivalent inhibitor of the bromodomain and extraterminal family protein BRD4, has preclinical activity in multiple tumors. This first-in-human, phase I study investigated AZD5153 alone or with olaparib in patients with relapsed/refractory solid tumors or lymphoma. Adults with relapsed tumors intolerant of, or refractory to, prior therapies received escalating doses of oral AZD5153 once daily or twice daily continuously (21-day cycles), or AZD5153 once daily/twice daily continuously or intermittently plus olaparib 300 mg twice daily, until disease progression or unacceptable toxicity. Between June 30, 2017 and April 19, 2021, 34 patients received monotherapy and 15 received combination therapy. Dose-limiting toxicities were thrombocytopenia/platelet count decreased (n = 4/n = 2) and diarrhea (n = 1). The recommended phase II doses (RP2D) were AZD5153 30 mg once daily or 15 mg twice daily (monotherapy) and 10 mg once daily (intermittent schedule) with olaparib. With AZD5153 monotherapy, common treatment-emergent adverse events (TEAE) included fatigue (38.2%), thrombocytopenia, and diarrhea (each 32.4%); common grade ≥ 3 TEAEs were thrombocytopenia (14.7%) and anemia (8.8%). With the combination, common TEAEs included nausea (66.7%) and fatigue (53.3%); the most common grade ≥ 3 TEAE was thrombocytopenia (26.7%). AZD5153 had dose-dependent pharmacokinetics, with minimal accumulation, and demonstrated dose-dependent modulation of peripheral biomarkers, including upregulation of HEXIM1. One patient with metastatic pancreatic cancer receiving combination treatment had a partial response lasting 4.2 months. These results show AZD5153 was tolerable as monotherapy and in combination at the RP2Ds; common toxicities were fatigue, hematologic AEs, and gastrointestinal AEs. Strong evidence of peripheral target engagement was observed.

Toxicity of a Modified PEG-Asparaginase-Based SMILE Regimen Is Comparable to L-Asparaginase-Based SMILE in a Non-Asian Population.

INTRODUCTION: L-asparaginase-based chemotherapy regimens are effective for treating chemotherapy-resistant natural killer- (NK-) cell neoplasms. To treat these lymphoma subtypes in Asia, where NK/T-cell lymphomas are more prevalent, the NK-Cell Tumor Study Group developed the SMILE regimen, which includes a steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide. In the US however, the only commercially available form of asparaginase is the pegylated form (PEG-asparaginase) which has been incorporated into a modified SMILE (mSMILE). We sought to study the toxicity associated with replacing L-asparaginase with PEG-asparaginase in mSMILE. PATIENTS AND METHODS: We retrospectively identified all adult patients treated with the mSMILE chemotherapy regimen in our database at Moffitt Cancer Center (MCC) between December 1, 2009, and July 30, 2021. Patients were included if they were treated with mSMILE irrespective of their underlying diagnosis. Toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5. The rate of toxicity in our mSMILE treatment group was numerically compared to data published in a metanalysis of the SMILE regimen's toxicity (Pokrovsky et al., 2019). RESULTS: A total of 21 patients were treated with mSMILE at MCC during the 12-year analysis window. Compared to patients receiving the L-asparaginase-based SMILE, patients receiving mSMILE experienced grade 3 or 4 leukopenia less often, with a toxicity rate of 62% (median with SMILE, 85% [95% CI, 74%-95%]); thrombocytopenia, however, was more common, with a toxicity rate of 57% (median with SMILE, 48% [95% CI, 40%-55%]). Other hematological, hepatic and coagulation related toxicities were also reported. CONCLUSION: In a non-Asian population, the mSMILE regimen with PEG-asparaginase is a safe alternative to the L-asparaginase-based SMILE regimen. There is a comparable risk of hematological toxicity, and no treatment-related mortality was seen in our population.

A randomized phase II trial of bevacizumab vs. bevacizumab and erlotinib as first-line consolidation after carboplatin, paclitaxel, and bevacizumab in newly diagnosed patients with mullerian tumors.

BACKGROUND: The combination of paclitaxel to platinum remains the backbone of therapy in patients with advanced Mullerian tumors. In patients with newly diagnosed Mullerian tumors, we investigated the progression-free survival benefit of bevacizumab and bevacizumab and erlotinib as consolidation therapy post-induction therapy. METHODS: Sixty patients were enrolled in a phase II trial of carboplatin, paclitaxel, and bevacizumab (induction therapy). After the completion induction therapy, patients were stratified by response (≥ SD) and then randomized (1:1) to either bevacizumab (A) or bevacizumab and erlotinib (AE.) The primary endpoint was PFS. Secondary endpoints included the response rate of induction and consolidation therapy and toxicity profile of each consolidative arm. Each consolidative arm was compared to the historical control GOG 111. RESULTS: Forty-eight patients advanced to the consolidative phase of the trial. Twelve patients were removed in the induction phase, the majority for toxicity. The most common toxicity (grade ≥ 3) was diarrhea (20%: arm AE; 0%: arm A). One patient in the AE arm had a fatal cardiac arrest deemed unrelated to the study treatment. No gastrointestinal perforations were reported. The median PFS in the AE and A arm was 18.9 months (p < 0.0001) and 13.3 months (p: ns), respectively. The overall rate of grade 3/4 toxicities in the AE arm was 72% and in the A arm 30%. Six patients remain free of disease 10 years after enrollment. CONCLUSION: Combinatorial consolidation therapy with AE was associated with an improved progression-free survival in patients with Mullerian tumors.

Grading Evaluation of Cardiotoxicity in Patients with Breast Cancer Treated with Adjuvant Paclitaxel Anthracycline/Cyclophosphamide Chemotherapy: A Meta-Analysis.

Objective: The cardiac safety of concurrent treatment with anthracycline (A), cyclophosphamide (C), and paclitaxel (T) in an adjuvant BC treatment regimen is still under debate. In this study, we aimed to determine cardiotoxicity events following ACT chemotherapy among operable breast cancer patients without HER2-positive. Methods: We searched PubMed and the Cochrane Library for RCTs prior to July 2019 evaluating the cardiac impairment of ACT chemotherapy regimens in BC patients. The search terms were "BC," "chemotherapy," "docetaxel or "doxorubicin," "paclitaxel," and "cyclophosphamide." Cardiotoxic events included LVEF decline ≥ 10 points, congestive heart failure (CHF), and cardiac death. Results: In total, 12 studies with 4032 subjects were included in this meta-analysis, and all patients received ACT regimen. The analysis results indicated that LVEF decrease ≥ 10 points was the most common cardiotoxic event (16%; (95% CI (8%-24%)) with χ 2 = 95.75, P < 0.001, I 2 = 95.8%). CHF showed the lowest rate (1%; (95% CI (0%-1%)) with χ 2 = 8.00, P = 0.433, I 2 = 0.0%). Subgroup analysis demonstrated that the incidence of CHF due to A → C → T chemotherapy regimen was lower than that of other events, however, without significance. No significant difference was observed in the occurrence of cardiac death. Conclusion: The ACT regimen in patients with HER2-negative BC was associated with an increased risk of adverse cardiactoxic events.

Phase 2 study of anti-disialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma: A report from the Children's Oncology Group.

PURPOSE: Novel effective therapies are urgently needed in recurrent osteosarcoma. GD2 is expressed in human osteosarcoma tumours and cell lines. This study evaluated the disease control rate (DCR) in patients with recurrent osteosarcoma treated with the anti-GD2 antibody dinutuximab plus cytokine therapy as compared to historical outcomes. METHODS: AOST1421 was a single-arm Phase 2 study for patients with recurrent pulmonary osteosarcoma in complete surgical remission. Patients received up to five cycles of dinutuximab (70 mg/m2/cycle) with granulocyte-macrophage colony-stimulating factor (GM-CSF). Two different dinutuximab infusion schedules were studied: 35 mg/m2/day over 20 h (2 days) and 17.5 mg/m2/day over 10 h (4 days). Primary end point was DCR, defined as a proportion of patients event free at 12 months from enrolment. The historical benchmark was 12-month DCR of 20% (95% CI 10-34%). Dinutuximab would be considered effective if ≥ 16/39 patients remained event free. Secondary objectives included toxicity evaluation and pharmacokinetics. RESULTS: Thirty-nine eligible patients were included in the outcome analysis. Dinutuximab did not demonstrate evidence of efficacy as 11/39 patients remained event free for a DCR of 28.2% (95% CI 15-44.9%). One of 136 administered therapy cycles met criteria for unacceptable toxicity when a patient experienced sudden death of unknown cause. Other ≥ Grade 3 toxicities included pain, diarrhoea, hypoxia, and hypotension. Pharmacokinetic parameters were similar in the two schedules. CONCLUSIONS: The combination of dinutuximab with GM-CSF did not significantly improve DCR in recurrent osteosarcoma. Dinutuximab toxicity and pharmacokinetics in adolescent and young adult osteosarcoma patients were similar to younger patients. Other strategies for targeting GD2 in osteosarcoma are being developed.

Neoadjuvant Trastuzumab and Pertuzumab for Early HER2-Positive Breast Cancer: A Real World Experience.

Background: Randomized studies of neoadjuvant (NA) trastuzumab and pertuzumab combined with chemotherapy for HER2-positive breast cancers (BC) have reported pathological complete response (pCR) rates of 39 to 61%. This study aimed to determine the real-world efficacy and toxicity of NA trastuzumab and pertuzumab combined with chemotherapy in a UK tertiary referral cancer centre. Methods: HER2-positive early BC patients given neoadjuvant chemotherapy with trastuzumab and pertuzumab between October 2016 and February 2018 at our tertiary referral cancer centre were identified via pharmacy records. Clinico-pathological information, treatment regimens, treatment-emergent toxicities, operative details, and pathological responses and outcomes were recorded. Results: 78 female patients were identified; 2 had bilateral diseases and 48 of 78 (62%) were node positive at presentation. 55 of 80 (71%) tumours were ER-positive. PCR occurred in 37 of 78 (46.3%; 95% CI: 35.3-57.2%) patients. 14 of 23 (60.8%) patients with ER-negative tumours achieved pCR; 23 of 55 (41.8%) were ER-positive and 6 of 19 (31.6%) were ER-positive and PgR-positive. No cardiac toxicity was documented. Diarrhoea occurred in 53 of 72 (74%) patients. Grade 3-4 toxicity occurred in ≥2% patients. These were diarrhoea, fatigue, and infection. The Median follow up period was 45.2 months (95% CI 43.8-46.3) with 71 of 78 (91.0%) remaining disease-free and 72 of 78 (92.3%) alive. Estimated OS at 2 years 86% (95% CI: 75-99%). Conclusion: This data confirms the efficacy of neoadjuvant chemotherapy combined with dual HER2 directed therapy. While no cardiac toxicity was observed, diarrhoea occurred frequently. The low pCR rate observed in ER and PgR-positive BCs warrants further investigation and consideration of strategies to increase the pCR rate.

Phase I study of aflibercept in combination with docetaxel in Japanese patients with advanced solid malignancies.

Angiogenesis is a hallmark of cancer development. This study sought to determine the recommended dose of aflibercept, a recombinant fusion protein targeting VEGF-A, VEGF-B and placental growth factor (PlGF), combined with docetaxel in Japanese patients with advanced solid malignancies. This phase I study was planned to include 12 patients following a 3 + 3 algorithm to determine the maximum tolerated dose of aflibercept combined with docetaxel in patients with metastatic or unresectable solid tumors (trial registration: NCT00545246). Docetaxel (75 mg/m2 every 3 weeks or 60 mg/m2 after protocol amendment) was combined with escalating doses of aflibercept (2, 4 and 6 mg/kg every 4 weeks). Free and VEGF-bound aflibercept were measured to assess free aflibercept in excess of the VEGF-bound form. At the starting dose of the combination, 3 of 6 patients treated experienced febrile neutropenia. After reducing the docetaxel dose to 60 mg/m2 in step 2 and permitting therapeutic granulocyte colony-stimulating factor (G-CSF) use, 2 of 3 patients in both cohorts experienced febrile neutropenia. Five patients (42%) had a partial response and 4 patients had stable disease (33%). Free aflibercept in excess of the VEGF-bound form was not maintained at this dose level. The dose limiting toxicity (DLT) of aflibercept combined with docetaxel was febrile neutropenia, which occurred in 2 of 3 Japanese patients at the lowest aflibercept dose level (2 mg/kg) combined with docetaxel (60 mg/m2) and therapeutic G-CSF use. A recommended dose for further studies was not determined because of the DLT at the starting dose.

Phase II study of Disulfiram and Cisplatin in Refractory Germ Cell Tumors. The GCT-SK-006 phase II trial.

BACKGROUND: Multiple relapsed/refractory germ cell tumor (GCT) patients have extremely poor prognosis. Cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory GCTs. METHODS: Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m2 day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in this report. RESULTS: Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. Median number of treatment cycles was 2 (range 1-6). None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival was 1.4 months, 95% CI (0.7-1.5 months), and median overall survival was 2.9 months 95% CI (1.5-4.7 months). Disease stabilization for at least 3 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection. CONCLUSIONS: This study failed to achieve its primary endpoint and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory GCTs.

Bendamustine in combination with pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: A phase II trial.

Treatment of patients with resistant/refractory multiple myeloma (MM) is an unmet need. In this phase II study, we evaluated the role of bendamustine, pomalidomide and dexamethasone combination in this setting. Between February 2020 and December 2021, 28 patients were recruited. Patients received bendamustine 120 mg/m2 day 1, pomalidomide 3 mg days 1-21, and dexamethasone 40 mg days 1, 8, 11, 22, regimen given for a maximum of six cycles. The median (range) age of the patients was 54 (30-76) years and 15 (53.6%) were males. Patients had received a median (range) of three (two-six) prior lines and 85.7% were refractory to both lenalidomide and bortezomib. The primary end-point was the overall response rate (ORR) defined as ≥partial response after at least three cycles. Secondary objectives were toxicity, progression-free survival (PFS), time to progression and overall survival (OS). An intent-to-treat analysis was done. An ORR of 57.6% was achieved. Patients with extramedullary myeloma had a better response rate. At a median follow-up of 8.6 months, the median PFS and OS were 6.2 and 9.7 months respectively. Toxicity was manageable; mainly haematological (neutropenia, 46.4%; anaemia, 42.8%; and thrombocytopenia, 7.1%). Bendamustine, pomalidomide and dexamethasone could be a novel combination for the heavily pretreated, lenalidomide-refractory myeloma population.

Efficacy of ixazomib-lenalidomide-dexamethasone in high-molecular-risk relapsed/refractory multiple myeloma - case series and literature review.

INTRODUCTION AND OBJECTIVE: Multiple myeloma (MM) is an incurable condition with variable clinical course. The study included a group of patients with especially poor-prognosis, individuals with relapsed/refractory multiple myeloma (RRMM) and specific cytogenetic disorders. Among the currently used therapies the ixazomib-lenalidomid-dexamethasone (IRd) is considered as a candidate to improve outcomes. The aim of the study was to evaluate the safety and efficacy of IRd regimen in the treatment of patients with RMMM. MATERIAL AND METHODS: Nine patients aged 52-82 years who received ixazomib in the early access programme, were included in the study. All patients met the criteria for recurrent/relapsed MM and had high (t(4:14), t(14:16), del17p or +1q21) risk aberrations. Previous chemotherapy regimens included thalidomide and bortezomib. Median duration of exposure to ixazomib was 12 months. RESULTS: One patient with multiple cytogenetic aberrations and extramedullary plasmocytoma died because of progression after two months of treatment. In the remaining patients, the objective response to treatment was reached, and in four cases it was qualified as a very good partial response (VGPR). Observed adverse effects included neutropenia, infections, and oedema (in three cases Grade 3). Eight patients continue treatment, in two cases the decision was made to reduce lenalidomide doses. CONCLUSIONS: Preliminary results suggest potentially high efficacy and good safety profile of IRd therapy in patients with RRMM and unfavourable cytogenetics.

Pembrolizumab plus azacitidine in patients with chemotherapy refractory metastatic colorectal cancer: a single-arm phase 2 trial and correlative biomarker analysis.

BACKGROUND: DNA mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is not responsive to pembrolizumab monotherapy. DNA methyltransferase inhibitors can promote antitumor immune responses. This clinical trial investigated whether concurrent treatment with azacitidine enhances the antitumor activity of pembrolizumab in mCRC. METHODS: We conducted a phase 2 single-arm trial evaluating activity and tolerability of pembrolizumab plus azacitidine in patients with chemotherapy-refractory mCRC (NCT02260440). Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg SQ on days 1-5, every 3 weeks. A low fixed dose of azacitidine was chosen in order to reduce the possibility of a direct cytotoxic effect of the drug, since the main focus of this study was to investigate its potential immunomodulatory effect. The primary endpoint of this study was overall response rate (ORR) using RECIST v1.1., and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Tumor tissue was collected pre- and on-treatment for correlative studies. RESULTS: Thirty chemotherapy-refractory patients received a median of three cycles of therapy. One patient achieved partial response (PR), and one patient had stable disease (SD) as best confirmed response. The ORR was 3%, median PFS was 1.9 months, and median OS was 6.3 months. The combination regimen was well-tolerated, and 96% of treatment-related adverse events (TRAEs) were grade 1/2. This trial was terminated prior to the accrual target of 40 patients due to lack of clinical efficacy. DNA methylation on-treatment as compared to pre-treatment decreased genome wide in 10 of 15 patients with paired biopsies and was significantly lower in gene promoter regions after treatment. These promoter demethylated genes represented a higher proportion of upregulated genes, including several immune gene sets, endogenous retroviral elements, and cancer-testis antigens. CD8+ TIL density trended higher on-treatment compared to pre-treatment. Higher CD8+ TIL density at baseline was associated with greater likelihood of benefit from treatment. On-treatment tumor demethylation correlated with the increases in tumor CD8+ TIL density. CONCLUSIONS: The combination of pembrolizumab and azacitidine is safe and tolerable with modest clinical activity in the treatment for chemotherapy-refractory mCRC. Correlative studies suggest that tumor DNA demethylation and immunomodulation occurs. An association between tumor DNA demethylation and tumor-immune modulation suggests immune modulation and may result from treatment with azacitidine. Trial registration ClinicalTrials.gov, NCT02260440. Registered 9 October 2014, https://clinicaltrials.gov/ct2/show/NCT02260440 .

FV-429 enhances the efficacy of paclitaxel in NSCLC by reprogramming HIF-1α-modulated FattyAcid metabolism.

Solid tumors often exhibit hypoxia in their centers, which has been associated with a marked reduction in the sensitivity of the tumor cells to anti-tumor and chemotherapeutic interventions. Here, we found that the occurrence and progress of hypoxic insensitivity to paclitaxel in non-small cell lung cancer (NSCLC) are closely associated with the HIF-1α pathway. The HIF-1α protein upregulated the expression of adipose differentiation-related protein (ADRP), fatty acid synthase (FASN), and sterol regulatory element binding protein 1(SREBP1), while simultaneously downregulating carnitine palmitoyltransferase 1 (CPT1), thereby leading to a more pronounced uptake of lipids and reduced oxidation of fatty acids. Diminished levels of fatty acids led to reduced Wnt pathway activation and ß-catenin nuclear translocation, leading to G2/M cell cycle arrest. In this study, FV-429, a derivative of the natural flavonoid wogonin, reprogrammed metabolism of cancer cells and decreased fatty acid levels. Moreover, paclitaxel-induced G2/M phase arrest in hypoxia-resistant NSCLC was hampered but FV-429 improved the sensitivity of these cancer cells to paclitaxel. FV-429 activated and modulated fatty acid metabolism in NSCLC cells, significantly reduced levels of fatty acids within cells and increased the oxidation of these fatty acids. The results of our study demonstrated that FV-429 could reshape fatty acid metabolism in hypoxia-induced paclitaxel-resistant NSCLC and enhance the sensitivity of NSCLC cells to paclitaxel through G2/M phase arrest deterioration, by inactivating the Wnt pathway, and suggested the possibility of using FV-429 as a promising candidate therapeutic agent for advanced NSCLC.

Preclinical toxicological study of long-circulating and fusogenic liposomes co-encapsulating paclitaxel and doxorubicin in synergic ratio.

Combination therapy between paclitaxel (PTX) and doxorubicin (DXR) is applied as the first-line treatment of breast cancer. Co-administration of drugs at synergistic ratio for treatment is facilitated with the use of nanocarriers, such as liposomes. However, despite the high response rate of solid tumors to this combination, a synergism of cardiotoxicity may limit the use. Thus, the objective of this work was to investigate the toxicity of long-circulating and fusogenic liposomes co-encapsulating PTX and DXR at the synergistic molar ratio (1:10) (LCFL-PTX/DXR). For this, clinical chemistry, histopathological analysis and electrocardiographic exams were performed on female Balb/c mice that received a single intravenous dose of LCFL-PTX/DXR. The results of the study indicated that the LD50 dose range (lethal dose for 50% of animals) of the LCFL-PTX/DXR treatment (28.9-34.7 mg/kg) is much higher than that found for free PTX/DXR treatment (20.8-23.1 mg/kg). In addition, liposomes promoted cardiac protection by not raising CK-MB levels in animals, keeping cardiomyocytes without injury or electrocardiographic changes. After 14 days of treatment, free PTX/DXR caused prolongation of the QRS interval when compared to LCFL-PTX/DXR treatment at the same dose (37.0 ± 5.01 ms and 30.83 ± 2.62 ms, respectively, with p = 0.017). The survival rate of animals treated with LCFL-PTX/DXR was three times higher than that of those treated with free drugs. Thus, it was established that the toxicity of LCFL-PTX/DXR is reduced compared to the combination of free PTX/DXR and this platform has advantages for the clinical treatment of breast cancer.

Combination Therapy of Metastatic Castration-Recurrent Prostate Cancer: Hyaluronic Acid Decorated, Cabazitaxel-Prodrug and Orlistat Co-Loaded Nano-System.

PURPOSE: Prostate cancer (PCa) is the second leading cause of cancer-related death among men in developed countries. Cabazitaxel (CBZ) is recommended as one of the most active chemotherapy agents for PCa. This study aimed to develop a hyaluronic acid (HA) decorated, cabazitaxel-prodrug (HA-CBZ) and orlistat (ORL) co-loaded nano-system against the prostate cancer in vitro and in vivo. METHODS: Cabazitaxel-prodrug was firstly synthesized by conjugating HA with CBZ through the formation of ester bonds. HA contained ORL and CBZ prodrug co-loaded lipid-polymer hybrid nanoparticles (ORL/HA-CBZ/LPNs) were constructed and characterized in terms of particle size, zeta potential, drug loading capacity and stability. The antitumor efficiency and systemic toxicity of LPNs were evaluated in vitro and in vivo. RESULTS: The resulting ORL/HA-CBZ/LPNs were 150.9 nm in particle size with narrow distribution and high entrapment efficiency. The minimum combination index of 0.57 was found at a drug ratio of 1:2 (ORL:HA-CBZ, w/w) in the drug co-loaded formulations, indicating the strongest synergism effect. ORL/HA-CBZ/LPNs demonstrated an enhanced in vitro and in vivo antitumor effect compared with single drug loaded LPNs and free drug formulations. CONCLUSION: ORL/HA-CBZ/LPNs showed remarkable synergism cytotoxicity and the best tumor inhibition efficiency in mice with negligible systemic toxicity. ORL/HA-CBZ/LPNs can be highly useful for targeted prostate cancer therapy.

Tumor-suppressing effect of bartogenic acid in ovarian (SKOV-3) xenograft mouse model.

Bartogenic acid (BA), a natural pentacyclic triterpenoid, proved to have chemomodulatory, anticancer, antidiabetic, anti-arthritic, and anti-inflammatory activity. Based on structure-activity relationship (SAR) approaches, BA has close structural resemblance to oleanolic acid and ursolic acid. These two pentacyclic triterpenoids are well accepted with respect to their therapeutic value in various ailments including anti-cancer activity. The aim of this study is to evaluate the efficacy of BA as a possible antitumor agent, along with its safety in SKOV-3 ovarian cancer. In vitro cytotoxicity of BA and paclitaxel on human ovarian cancer cells (SKOV-3) was assessed using MTT assay. Antitumor potential of BA alone, standard anticancer drug (paclitaxel) alone, and BA in combination with paclitaxel were evaluated in SKOV-3 xenografted SCID mice. Immunohistochemical analysis of NF-κB was performed and analyzed in SKOV-3 tumors. BA alone and BA in combination with paclitaxel significantly inhibited the tumor growth. IC50 of BA was found to be 15.72 µM. Similarly, paclitaxel showed significant antitumor effect with IC50 of 3.234 µM. Treatments of paclitaxel, BA, and combination of BA with paclitaxel were well tolerated during treatment period. Immunohistochemical analysis of NF-κB in SKOV-3 tumors treated with BA in combination with paclitaxel revealed antitumor effect in terms of inhibition of NF-κB. Our results suggested that BA exhibits promising antitumor effect in the restriction of SKOV-3 cells and tumors with considerable safety.

A Phase I dose-escalation study of third-line regorafenib with trifluridine/tipiracil in metastatic colorectal cancer.

Aim: To determine a recommended Phase II dose of the oral fluoropyrimidine trifluridine/tipiracil (FTD/TPI) combined with the multi-kinase inhibitor regorafenib (REG) in refractory metastatic colorectal cancer patients. Materials & methods: A conventional 3 + 3 dose finding design was used. FTD/TPI was administered on days 1-5 and 8-12 of a 28-day cycle, REG on days 2-22. Two dose levels were used: FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d, then escalated to FTD/TPI 35 mg/m2 b.i.d. + REG 120 mg/d. Results: In total, 12 patients were treated at two dose levels. Three dose-limiting toxicities were observed; all were grade 3 hypertension causally attributed to REG. Recommended Phase II dose is FTD/TPI 25 mg/m2 b.i.d. + REG 120 mg/d. Median progression-free survival was 3.81 months (95% CI: 1.51-5.29), median OS 11.1 months (95% CI: 2.3-18.2). Conclusion: The combination of REG and FTD/TPI is feasible and safe. Efficacy signals exceed that of the single agents at acceptable toxicity levels and are clinically meaningful.

Lay abstract Many patients with metastatic colorectal cancer need a sequence of different treatments over time. Regorafenib and trifluridine/tipiracil (also called TAS-102) are two drugs which are both used late in this sequence of treatments, but there is no rule as to which should be used first. Both drugs have very different mechanisms of action, and it might be beneficial to patients to administer them both at the same time as a combination treatment, instead of sequential treatment. We therefore conducted a Phase Ib study with a small number of patients to investigate whether this combined treatment would be feasible and safe. The study was designed to test the drug combination at different doses, and we found that treatment with trifluridine/tipiracil at 25 mg/m² twice daily combined with regorafenib at 120 mg daily had acceptable side effects and is likely to be safe for use in future clinical trials. Efficacy results suggest that combined treatment with both drugs may extend patient's life span. However, these observations are preliminary and need testing in further clinical trials. Clinical trial registration: EudraCT 2016-001968-11; NCT03305913 (ClinicalTrials.gov).

T cell ALL in a child with Ataxia telangiectasia; diagnosis and management challenges.

Ataxia telangiectasia (A-T) is a rare childhood autosomal recessive neurodegenerative chromosomalin stability disorder. It is characterized by high risk of hematological malignancies with T-cell phenotype being the most common, which can present first before the diagnosis of A-T made. The chromosomalin stability in A-T increases the toxicity to radio-chemotherapeutic agents, creating the treatment modification challenges and the deviation from the optimal management protocols. In this case report, we present a 14-month-old boy diagnosed as T cell -ALL. Based on his early presentation, family history of childhood lymphoma, and high AFP, inherited predisposition was suspected, and genetic testing confirms A-T. This report represents the crucial part of clinical suspicion of A-T in similar cases as well as highlighting the importance of an early A-T diagnosis that prevents toxic death due to the extensive regimen of radio- chemotherapeutic agents. The report summarizes the toxicity and modification challenges during management with literature review for the chemotherapy modification experience in such cases.

Combination immunotherapy with ipilimumab and nivolumab in patients with advanced adrenocortical carcinoma: a subgroup analysis of CA209-538.

Background: Adrenocortical carcinoma is a rare malignancy, with poor prognosis and limited treatment options for patients with advanced disease. Chemotherapy is the current standard first-line treatment, providing only a modest survival benefit. There is only limited treatment experience with immunotherapy using single-agent anti-PD-1/PD-L1 therapy. To date no clinical trials have been reported using combination immunotherapy with anti-CTLA-4 and anti-PD-1 blockade in this patient population. Methods: CA209-538 is a prospective multicentre clinical trial in patients with advanced rare cancers. Participants received the anti-PD-1 antibody nivolumab (3 mg/kg IV) and the anti-CTLA-4 antibody ipilimumab (1 mg/kg IV) every three weeks for four doses, followed by nivolumab (3 mg/kg IV) every two weeks and continued for up to 96 weeks, until disease progression or unacceptable toxicity. Response was assessed every 12 weeks by RECIST version 1.1. Primary endpoint was clinical benefit rate (complete response, partial response, stable disease at 12 weeks). Results: Six patients with adrenocortical carcinoma were enrolled and received treatment. Two patients (33%) have an ongoing partial response (10 and 25 months +) and two patients (33%) stable disease leading to a disease control rate of 66%. Both responders had tumors with a microsatellite instable phenotype. One patient rapidly progressed shortly after enrollment into the trial and did not undergo restaging. Immunotherapy-related toxicity was reported in all patients, with four patients (67%) experiencing grade 3/4 hepatitis leading to discontinuation of treatment. Conclusions: This is the first treatment experience using ipilimumab and nivolumab combination immunotherapy in patients with advanced adrenocortical carcinoma. Durable responses have been observed in a subset of patients suggesting that this treatment regimen should be further investigated in this patient population.

The efficacy and safety of gemcitabine-based induction chemotherapy for locally advanced nasopharyngeal carcinoma treated with concurrent chemoradiation: A meta-analysis.

OBJECTIVES: To assess the efficacy and toxicity of gemcitabine-based induction chemotherapy followed by concurrent chemoradiotherapy (CCRT) in locally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: Both observational studies (OBS) and randomized controlled trials (RCT) were included in the meta-analysis. Systematic online searches were conducted in Web of Sciences, PubMed, Embase, meeting proceedings and ClinicalTrials.gov from the inception to May 25, 2020. The primary endpoint of interest was overall survival. RESULTS: five OBSs and 2 RCTs including 1680 patients were incorporated in the analysis. The evidence from the RCTs showed that adding gemcitabine-based induction chemotherapy to CCRT significantly improved progression free survival (hazard ratio (HR): 0.60, 95% confidence interval (CI): 0.40-0.88; P = .010; chi square P = .25; I2 = 24%) and overall survival (HR: 0.47; 95% CI: 0.28-0.80; P = 0.005; chi square P = .49, I2 = 0%) and was related to a higher risk of hematological toxicities. Furthermore, based on the data of OBSs, overall survival (HR: 0.52; 95% CI: 0.31-0.88; P = .02; chi square P = .37, I2 = 6%) was significantly improved in patients treated with gemcitabine-based induction chemotherapy compared to those treated with taxane-based induction chemotherapy. However, the progression free survival (HR: 0.67; 95% CI: 0.45-1.01; P = .06; chi square P = .74; I2 = 0%) showed no significant difference. CONCLUSIONS: For LA-NPC patients, adding gemcitabine-based induction chemotherapy to CCRT significantly improved overall survival and progression free survival with a higher risk of hematological toxicities when compared to CCRT alone. Also, gemcitabine-based regimen could be used as an alternative induction chemotherapy regimen to taxane-based regimen in the treatment of LA-NPC.

Combined delivery of salinomycin and docetaxel by dual-targeting gelatinase nanoparticles effectively inhibits cervical cancer cells and cancer stem cells.

Intra-tumor heterogeneity is widely accepted as one of the key factors, which hinders cancer patients from achieving full recovery. Especially, cancer stem cells (CSCs) may exhibit self-renewal capacity, which makes it harder for complete elimination of tumor. Therefore, simultaneously inhibiting CSCs and non-CSCs in tumors becomes a promising strategy to obtain sustainable anticancer efficacy. Salinomycin (Sal) was reported to be critical to inhibit CSCs. However, the poor bioavailability and catastrophic side effects brought about limitations to clinical practice. To solve this problem, we previously constructed gelatinase-stimuli nanoparticles composed of nontoxic, biocompatible polyethylene glycol-polycaprolactone (PEG-PCL) copolymer with a gelatinase-cleavable peptide Pro-Val-Gly-Leu-Iso-Gly (PVGLIG) inserted between the two blocks of the copolymer. By applying our "smart" gelatinase-responsive nanoparticles for Sal delivery, we have demonstrated specific accumulation in tumor, anti-CSCs ability and reduced toxicity of Sal-NPs in our previous study. In the present study, we synthesized Sal-Docetaxel-loaded gelatinase-stimuli nanoparticles (Sal-Doc NP) and confirmed single emulsion as the optimal method of producing Sal-Doc NPs (Sal-Doc SE-NP) in comparison with nanoprecipitation. Sal-Doc SE-NPs inhibited both CSCs and non-CSCs in mice transplanted with cervical cancer, and might be associated with enhanced restriction of epithelial-mesenchymal transition (EMT) pathway. Besides, the tumorigenic capacity and growing speed were obviously suppressed in Sal-Doc-SE-NPs-treated group in rechallenge experiment. Our results suggest that Sal-Doc-loaded gelatinase-stimuli nanoparticles could be a promising strategy to enhance antitumor efficacy and reduce side effects by simultaneously suppressing CSCs and non-CSCs.