bluuebunny/crossref_metadata_2025 huggingface dataset:
A retrospective study evaluating treatment patterns and outcomes in patients receiving trastuzumab for treatment of first-line and second-line metastatic breast cancer (mBC)
Authors: Lalla D. , Hess G. , Quach D. , Brammer M. , Hill J. W.
Published: August 2020

e12008

Background: Practice patterns for patients with MBC following 1st line therapy have often continued trastuzumab treatments while changing other chemotherapeutic agents in the regimen. We described treatment patterns, switching patterns and progression in mBC patients treated with a trastuzumab containing regimen for 1st and second line mBC. Methods: A retrospective, longitudinal, observational study of patients with mBC during 1/1/2003 up to 6/30/2008. The dataset comprised 304,654 cancer patients from 91practice sites across 23 states using Varian or Impac electronic medical records (EMRs). The start and end of a line of therapy was defined by a regimen change or a > 42 day gap in the regimen. In addition to the database analyses, a manual chart review was also conducted for 20% of the study sample to validate the source data and results. Patients were required to be observed for ≥ 9 months from index. Mean, median, standard deviation, and standard error for the duration in days by line and regimen was calculated as well as an overall weighted mean by line. Results: The study sample of 239 patients post-mBC was treated with the following regimens in the Table. Conclusion: Trastuzumab is most frequently given with taxanes in the first and second line settings. In the second line trastuzumab monotherapy, vinorelbine and gemcitabine were also frequently used. First line therapy may influence the selection of second line therapy. As EMRs often reflect care primarily at the practice site, prescribing of oral agents should be further researched.

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Trastuzumab (H) treatment in patients (pts) with metastatic breast cancer (MBC): An observational retrospective study in four hospitals from Bogotá, Colombia (ONCOLGroup study)
Authors: Carranza H. , Cardona A. F. , Vargas C. , Otero J. M. , Sánchez J. O. , Carrasco-Chaumel E. , Reveiz L. , Torres D. , Castro C. , González-Angulo A. M.
Published: August 2020

e12016

Background: Breast cancer is the second most common cancer diagnosed in Colombian women, and approximately 26% of MBC are HER-2-positive in our population. The purpose of this study was to assess the characteristics and outcome of pts with HER-2-positive MBC treated with H-based therapy in Bogotá. Methods: This retrospective study included 119 pts treated between 2000 and 2007. Overall response rates (ORR), clinical benefit (CB), time to progression (TTP), and overall survival (OS) were estimated. Most common grade 2/3 toxicities are reported as well as variables that influenced survival. Results: Median age was 62 years (range, 37 to 75). Eighty-seven (73%) pts had recurrent disease and the rest had de novo MBC. Performance status was ≥70% in 114 pts, 66% had ≤2 metastatic sites, and 58% had hormone receptor positive disease. Previous adjuvant therapy before H included antracyclines in 68% and taxanes in 39% of the pts. H was part of the first-line therapy for MBC in 86.5% of the pts, leading to a 54% ORR in 103 evaluable pts. CB was 81% and median TTP was 6.1 months. (range, 1.2 to 26 mo). The most common toxicities in this setting included neutropenia ≥G3 (9%) and neuropathy ≥G3 (7%). H was given as part of second line therapy to 54 (45%) pts, but only 41 had evaluable disease. A 56% ORR was found in this subgroup, 85% CB and 4.7-month median of TTP. Grade ≥G3 hand-foot syndrome was the main toxicity (14%). Median OS after the diagnosis of MBC was 23 months (range, 1.6–93 mo), being longer for pts with HR-positive disease (p = 0.036), in pts with loco-regional relapse (p = 0.029), and in those older than 50 (p = 0.0025). Only two variables independently predicted OS: age (HR: 0.4, 95% CI: 0.35–0.93, p = 0.046) and HR status (HR: 0.7, 95% CI: 0.60–0.86, p = 0.040). Two pts (1.7%) had H-induced heart failure. Conclusions: H in combination with chemotherapeutic agents has been proved to be an effective and safe treatment for HER-2-positive MBC. The results from our series agreed with those reported in the medical literature and guarantee the regular use of H in Colombia.

No significant financial relationships to disclose.
Comparison of serum levels of CEA and CA 15–3 in triple-negative breast cancer at the time of metastases and serum levels at the time of first diagnosis
Authors: Sener Dede D. , Aksoy S. , Bulut N. , Dizdar O. , Arik Z. , Gullu I. , Ozisik Y. , Altundag K.
Published: August 2020

e12017

Background: Cancer antigen 15–3 (CA 15–3) and carcinoembryonic antigen (CEA), are often used in follow up care of breast cancer and provide important clues to the clinicians for disease progression in metastatic and recurrent breast cancer. Triple-negative breast cancers are frequently defined as a single group identifiable using routine clinical tests. They are negative for estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), the so-called triple-negative breast cancers. In this study we compared the tumor markers of triple negative breast cancer and non-triple negative patients. Methods: We retrospectively analyzed serum CEA and CA 15–3 levels of both triple negative and non-triple negative breast cancer patients at the time of first diagnosis and when they developed metastatic disease. Results: 544 consecutive nonmetastatic breast cancer patients presenting at Hacettepe University Institute of Oncology, Ankara, Turkey, with a median age of 49 were evaluated. 15.1% of the patients were triple negative breast cancer. At the time of diagnosis triple negative group had lower serum CEA (2.5 ± 5.9 vs 4.0 ±16.4 p = 0.35) and CA 15–3 (23.7 ± 14.6 vs 37.1 ± 117; p = 0.021) levels compared to non-triple negative group. In patients who developed metastasis during follow up; the CEA (3.2 ± 3.8 vs 29.6 ± 106.4 p = 0.022) and CA15–3 (46.9 ± 46.3 vs 203.2 ± 534 p = 0.008) levels were also significantly lower in triple negative breast cancer group compared to non-triple negative group.In non-triple negative breast cancer patients who developed metastasis, mean serum levels of CEA and CA15–3 significantly increased compared to baseline, whereas in triple negative group who developed metastasis CEA and CA 15–3 levels did not differ significantly. Conclusions: While being a good laboratory parameter in the follow-up of patients with breast cancer metastases, tumor markers may not show the increased tumor burden in the triple-negative breast cancer patients.

No significant financial relationships to disclose.
An open-label study of sunitinib (SU) plus exemestane (E) in the first-line treatment of hormone receptor (HR)-positive metastatic breast cancer (MBC)
Authors: Ahlgren P. , Thirlwell M. , O’Regan R. , Mormont C. , Levesque L. , Gaspo R. , Woloj M. , Bello A. , Martell B. , Leyland-Jones B.
Published: August 2020

e12019

Background: SU, an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET has activity in heavily pretreated pts with MBC. The aromatase inhibitor (AI), E, has proven 1st-line activity that compares favorably with tamoxifen in pts with HR+ BC in the adjuvant setting (Jones et al. 2008). Combining agents that target different signaling pathways may have additive/synergistic activity; combining the AI letrozole with the anti-VEGF agent bevacizumab prolonged progression-free survival to >14 mos as 1st-line therapy for HR+ MBC (Dickler et al. 2008). An open-label, phase I, dose-finding study of first-line SU + E was conducted in HR+ MBC pts. Methods: Eligible pts (postmenopausal; female; ≥18 yrs) had an ECOG PS ≤1, LVEF ≥50% and locally recurrent (unresectable) or MBC. Exclusion criteria included HER2+ BC (unless pt had progressed after trastuzumab) and prior treatment in the metastatic setting. Pts received SU 37.5 mg/d + E 25 mg/d on a continuous daily dosing regimen; if dose-limiting toxicities (DLTs) were experienced by >1/6 pts in the first 8 wks then further pts would be enrolled at SU 25 mg/d + E 25 mg/d. Pharmacokinetic (PK) analyses were performed for each drug and the active SU metabolite SU12662. Results: As of December 2008, enrollment was completed (N=6; mean age 59 ± 11 yrs; 50% of pts had ≥3 metastatic sites). No DLTs were observed and no dose reductions were required throughout the treatment period. An overview of key data is shown below. One death occurred on study (non treatment-related Enterobacter sepsis). No treatment-related G4/5 AEs occurred. PK parameter values determined for SU and E suggested increases in the systemic exposure of both drugs when administered concurrently. Conclusions: These data indicate that SU + E was tolerable with manageable toxicities, with increases in PK parameters and a similar AE profile to that of either single agent alone. This combination should be considered in future clinical trials.

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Secondary malignancies developing during metastatic breast cancer treatment
Authors: Nikolic N. M. , Tomasevic Z. , Jelic S.
Published: August 2020

e12020

Background: Secondary malignancies (SM) developing during metastatic breast cancer (MBC) are obviously more complicated for diagnosis, potential surgery and for further MBC treatment. However, the frequency of SM during MBC is not well explored, in contrast to SM after nonmetastatic BC. The aim of this paper is to determine frequency of SM in MBC patients and to determine the percentage of surgically treated SM. Methods: Hospital charts of BC patients were retrospectively analyzed at the Institute for Oncology and Radiology of Serbia. Patients who developed SM at any time point after BC were included in this analysis. Patients with contra-lateral BC and acute leukemia were excluded. Patients with SM during MBC were separately analyzed. Results: A cohort of 50 BC patients with SM was identified. Median age was 50 (range 32–78 years) median time to SM was 65.3 months (range 1–276). Forty-six patients had histological confirmation of SM. In 30 patients SM developed during treatment for MBC. Four SM were not confirmed by biopsy due to SM site or high burden of MBC. Median age was 53.4 years (range 34–74), median time to SM development was 78.9 months, and median time to BC metastases was 60.1 months. The most frequent SM in MBC patient were lung (5), endometrial (4, all treated with tamoxifen), ovarian (3), thyroid (3), cervical (3), and colon carcinoma (2). Only 14 patients with SM (14/30: 46%) could be treated with radical surgery and SM did not influenced further MBC treatment. Conclusions: According to our experience, SM develops more frequently in MBC than in non MBC patients, representing 60% (30/50 patients) of all SM in BC patients; 46.6% (14/30) of SM diagnosed during MBC could be surgically resected, and does not influence further MBC treatment.

No significant financial relationships to disclose.
The combination of capecitabine and cyclophosphamide for metastatic breast cancer patients
Authors: Suzuki M. , Kimijima I. , Ishii M.
Published: August 2020

e12025

Background: Capecitabine (X) is converted into 5-FU by thymidine phospholylase (TP). Cyclophosphamide (C) has been shown to make TP higher in the preclinical study. Therefore, the combination of capecitabine and cyclophosphamide (XC) is thought to have a synergistic activity. We explored the efficacy of XC for metastatic breast cancer patients. Methods: 50 metastatic breast cancer patients were treated with XC in our medical center between April 2004 and December 2008. Median patient age was 58 years old (range: 34–79 years old). 36 patients were postmenopausal. X was 1675mg/m2 days 1–21 and C was 67mg/m2 days 1–14 on a 28-day cycle in all-oral combination. This therapy was continued until progression of disease or unacceptable toxicities occurring. Results: Median time to treatment failure was 28 weeks (range: 2–158 weeks). 9 patients were not evaluable for tumor response. Among 41 evaluable patients, complete response (CR) was observed in 2.4% (1 patient) and partial response (PR) was 29.2% (12 patients). Stable disease (SD) was 41.4% (17 patients) and progression of the disease (PD) was 26.8% (11 patients). The objective response rate (CR+PR) was 31.7% and the overall clinical benefit (CR+PR+SDÅÜ24 weeks) was 53.6%. Significant toxicities were uncommon: grade 3 toxicities were encountered for neutropenia in 1 patient, anorexia in 1 patient and hand-foot syndrome in 2 patients. Conclusions: XC is an effective regimen in metastatic breast cancer, and this therapy is of an easy administration and very well tolerated.

No significant financial relationships to disclose.
Brain metastases (BM) in breast (BC) and lung cancer (LC) patients
Authors: Braverman A. S. , Hengel K. , Choi J. , Nwokedi E. , Sidhu G. , Weedon J. , Axiotis C. , Song X.
Published: August 2020

e12029

Background: Most BM arise from BC or LC. Few studies compare their attributes and distribution, though BC BM have been reported to more often involve the cerebellum. Methods: Brain scanning was for clinical evidence of BM. Contrast-enhanced computer-automated tomograms (CT) or magnetic resonance images (MRI) of brains of all BC and LC patients irradiated for BM between 1996 and 2008 were reviewed. BC epidermoid growth factor receptor2 (HER-2) expression was determined. Results: Data was from 63 BC and 59 LC patients; 58% of the BC and 55% of the LC patients had MRIs. MRIs showed more cerebellar BM (p = 0.047). Primary to BM diagnosis intervals were shorter for LC than for BC patients (p = 0.001), but LC BM were more edematous (0.019). BC patients had more cerebellar BM (p = 0.004) than LC patients, and more BM in the cerebellum only (p = 0.017). LC patient gender and small cell histology did not correlate with cerebellar BM. Both cerebrums and cerebellums of BC patients had more BM than those with LC (p = 0.020; 0.013). Cerebellar BMs were more frequent in brains with more cerebral BM (p = 0.0020). Amongst BC over-expressing HER-2 was a trend to more cerebellar BM (p = 0.072). Conclusions: LC BM, which elicit more edema, produce symptoms earlier than BC BM. There are larger numbers of BC BM, perhaps due to BC's longer disease course and responsiveness to therapy. BC causes more cerebellar mets than LC, often without cerebral BM. This may be due both to the larger number of BC BM, and a predilection for the cerebellum. Periodic brain MRI, more sensitive than CT to posterior fossa lesions, may be indicated in some BC patients, and early radiation may control multiple small BM.

No significant financial relationships to disclose.
Dosimetry study of a phase II multiple-dose intracavitary administration of 131I-TM601 in adult patients with recurrent high-grade glioma
Authors: Shen S. , Nabors L. B. , Raizer J. J. , Fiveash J. B. , Spies S. , Costello R. , O’Neill A. M.
Published: August 2020

e13006

Background: Postoperative radiotherapy for glioma has been shown to improve survival with increased radiation doses. Dose escalation of external beam radiotherapy or brachytherapy is limited by normal brain radionecrosis. Radiolabeled targeting molecules can deliver localized radiation to tumor and reduce normal brain radionecrosis. TM601, or synthetic Chlorotoxin, is a peptide derived from scorpion venom that specifically binds to tumor cells. Here we report dosimetry results of an imaging sub-study of a phase II trial, in which weekly doses of 131I-TM601 were infused into surgically created tumor resection cavities for 3 or 6 weeks. Methods: Five out of 76 patients treated in a phase II trial were imaged after receiving 1, 3, or 6 doses of 40 mCi/0.8 mg 131I-TM601 intracavitarily. For each imaging study, 5 sequential SPECT images (1–168 hour) were registered with MRI to determine the 131I-TM601 radiation dose to the 2-cm tumor cavity margin. Five sequential body scans were also acquired to determine 131I-TM601 radiation dose to extra-cranial organs. Results: 131I-TM601 is a rapidly penetrating and clearing radiolabeled peptide. The median residual activity in the cavity at 7 days post injection was 8.4%. Median radiation dose to the cavity margin was 121 cGy/mCi and ranged 52- 338 cGy/mCi in 5 subjects. The median coefficient of variation (intra-patient inter-fraction) for the 2-cm margin dose was 14.7% and ranged 7.1–18.9%. Median tumor cavity volume was 11.4 mL, and ranged 5.2 - 35.5 mL. There was no observed correlation between the 2-cm margin dose and the cavity volume. Median radiation dose to thyroid, kidneys, red marrow, and body was 8.3, 1.3, 0.4, and 0.6 cGy/mCi, respectively. Conclusions: Radiation dose ratio for 2-cm cavity margin-to-normal tissues was quite high. While intra-patient reproducibility was relatively good, cumulative effect of the residual activity was only meaningful within a week. These results support the multi-dose fractionation scheme for 131I-TM601 to minimize normal tissue toxicity, including radiation necrosis, and extend continuous irradiation to clinical or sub-clinical residual tumor cells after surgery.

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Phase II study: WBRT ±temozolomide (TMZ) in patients with multiple brain metastases from non-small cell lung cancer (NSCLC)
Authors: Marosi C. , Elandt K. , Preusser M. , Dieckmann K. , Nevinny M. , Knocke-Abulesz T. , Pfeifer W. , Stockhammer G. , Hammer J. , Zielinski C. C.
Published: August 2020

e13008

Background: Brain metastases cause increasingly morbidity and mortality in patients with NSCLC. In a multicentric Austrian phase II study, we investigated feasibility and toxicity of the addition of temozolomide to whole brain radiotherapy (WBRT) in patients with multiple brain metastases of NSCLC. Methods: Consenting patients with previously untreated, multiple, and measurable brain metastases from histologically confirmed NSCLC were eligible if they were 18 years or older, were at least in RPA (recursive partitioning analysis class) class II and showed adequate organ function. Treatment consisted of WBRT (arm A) +TMZ 75mg/m2 during radiation, followed at day 28 by TMZ 100 mg/m2 day 1–14, q28 for six cycles (arm B). The primary endpoint was objective radiographic response in CNS 10 weeks after the end of WBRT. Results: 35 patients (14 women) aged 35 to 86 years, median 65 years were randomized. Eight patients were in RPA class I and 27 were in RPA class II. 13 patients were enrolled in arm A and 22 in arm B. Toxicity was mainly haematological with WHO grade 3 and 4 thrombocytopenia observed in 0/13 versus 3/22 patients, leucocytopenia in 0/13 versus 1/22 patients, and lymphocytepenia in 12/13 and 7/22 patients respectively. No severe nonhematologic toxicity occured in arm A, whereas two episodes of transient hepatic toxicity were reported in arm B. 10/13 patients of arm A and 13/22 patients of arm B showed progressive disease and dropped out of study before restaging 10 weeks after completion of WBRT. Two patients of arm A had progressive disease in CNS, all other progresses noted were systemic. At restaging there were 2 PR, 1 SD in arm A, and 1 CR, 3 PR, 6 SD in arm B. Median time to progression was 40 days in arm A and 74 days in arm B (p = 0.027). Conclusions: The addition of temozolomide to WBRT in patients with brain metastases of NSCLC yielded acceptable toxicity and promising activity, although systemic progression remained the main cause of morbidity and mortality.

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Case-control study of long-term survivors of glioblastoma
Authors: Quant E. C. , Silver M. , Yip S. , Ryg P. , Provencher K. , McCormack K. , Louis D. N. , Betensky R. , Nutt C. , Batchelor T. T.
Published: August 2020

e13021

Background: Survival of patients with glioblastoma (GBM) remains poor. However, a small percentage of GBM patients live ≥ 3 years. Relatively little is known about the patterns of care and outcomes of these long term survivors relative to GBM patients with standard or short-term survival. Methods: Nested case-control study of long term survivors (≥ 36 months), short term survivors (≤ 6 months) and standard survivors (> 6 months but < 36 months). Pathology was confirmed in all study subjects by a single neuropathologist. Each long term survivor (LTS) was matched to a short term survivor (STS) and 3 standard survivors (SS) by the well-established prognostic factors, age and postoperative Karnofsky Performance Status. Clinical characteristics, treatment regimens and outcomes were reviewed. Conditional logistic regression models were used to assess potential associations between baseline factors and the probability of long or short term survival. Results: Matching yielded 23 LTS with 23 STS and 69 SS. Patient characteristics are summarized in the table below. Conclusions: Controlling for the well-established prognostic factors of age and performance status, long-term GBM survivors differed significantly from short-term GBM survivors based on tumor location and extent of resection. However, there were no significant differences in baseline factors between long-term survivors versus standard survivors in this analysis. Short-term GBM survivors differed from standard survivors by tumor location and extent of resection. Molecular factors are being assessed in these groups as potential contributors to these survival differences.

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Temozolomide (TMZ) and bevacizumab (BV) as initial treatment for unresectable or multifocal glioblastoma multiforme (GBM)
Authors: Peters K. , Desjardins A. , Reardon D. A. , Perry S. , Herndon J. E. , Bailey L. , Friedman A. H. , Friedman H. S. , Bigner D. D. , Vredenburgh J. J.
Published: August 2020

e13025

Background: GBMs are vascular tumors and inherently resistant to therapy. The prognosis for patients is poor with a median survival of 9–15 months. Patients with unresectable or multifocal GBMs have an even poorer prognosis, with a median survival of 6–8 months. Given the angiogenic phenotype of GBM, we conducted a phase II trial of upfront BV and 5-day TMZ in newly diagnosed unresectable or multifocal GBMs. Methods: Patients had histologically documented newly diagnosed GBMs that were unresectable or multifocal. Patients received up to 4 cycles of temozolomide at 200 mg/m2/d days 1–5 and BV at 10 mg/kg on days 1 and 14 in a 28 day cycle. An MRI was performed after every cycle and patients continued on therapy as long as there was no tumor progression, grade 4 non-hematologic toxicity or recurrent grade 4 hematologic toxicity after a dose reduction to 150 mg/m2/d. The primary endpoint was tumor response using the modified MacDonald criteria plus FLAIR and T2 sequences to evaluate non-enhancing tumor. Results were evaluated by two independent reviewers. Results: 41 patients were enrolled between October 2007 and September 2008 and 31 patients were analyzed after completion of cycle 2. As the best response, there were 8 (25.8%) partial responses, 19 (61.3 %) patients with stable disease, and 4(12.9 %) had disease progression. 19 of the 41 patients enrolled completed four cycles without tumor progression. The regimen was tolerable, with 3 grade 4 hematologic toxicities including neutropenia and thrombocytopenia. There were 2 grade 4 non-hematologic toxicities, including pulmonary embolism. There were two CNS hemorrhages. The median PFS was 3.6 months (2.9 months, 4.4 months) and the median OS was 4.5 months (3.7 months, 5.3 months). Conclusions: Upfront temozolomide and bevacizumab was well tolerated, but synergistic chemotherapy or growth factor inhibitors need to be added to produce meaningful clinical benefit, particularly for unresectable or multifocal GBM.

No significant financial relationships to disclose.
The temozolomide O6-methylguanine-DNA methyltransferase (MGMT) study: A phase II trial to evaluate the effect of low-dose preoperative neoadjuvant temozolomide on brain tumour MGMT activity in glioma patients
Authors: Del Maestro R. F. , Siu V. , Seyed Sadr M. , Alshami J. , Sabau C. , Seyed Sadr E. , Samani A. , Assadian S. , Greaves K. , Pouliot J.
Published: August 2020

e13027

Background: Epigenetic methylation of the O6-methylguanine-DNA methyltransferase (MGMT) DNA repair gene promoter in tumor tissue from glioblastoma multiforme patients is associated with improved survival after treatment with radiotherapy plus concomitant and adjuvant temozolomide (TMZ). We hypothesized that MGMT promoter methylation mosaicism exists in glial tumors and would affect response to TMZ. Methods: This is a nonrandomized, prospective, open-label, two cohort, single-center phase II study. Twenty-three patients with brain tumors detected by MRI scan and suspected to be gliomas were evaluated. All eligible patients were treatment naive and were self-selected into a TMZ group or a control group. The primary goal of the study was to evaluate the effect of TMZ 75 mg/m2 daily prior to surgery on the brain tumor MGMT expression. Secondary endpoints included safety, tolerability, and MGMT promoter methylation mosaicism in glial tumors. Samples were obtained from multiple regions of each tumor intra-operatively and were analyzed by methylation specific PCR. Results: Our results on MGMT promoter methylation demonstrate that three groups of patients can be identified: Type I: all sites assessed in the tumor demonstrate no methylation of the MGMT promoter; Type II: all sites demonstrate high levels of MGMT promoter methylation; and Type III: a mixed promoter methylation pattern is observed. Conclusions: These results suggest that 1) preoperative neoadjuvant temozolomide is not associated with increased postoperative complications; 2) glial tumors can have very heterogeneous areas of MGMT promoter methylation; and 3) three patterns of MGMT promoter methylation can be discerned. This experimental paradigm may be a useful experimental platform for the assessment of the effect of new drugs at the tumor level.

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Enzastaurin (ENZ) before and concomitant with radiation therapy (RTX), followed by ENZ maintenance therapy in patients with newly diagnosed glioblastoma (GBM) without hypermethylation of the O6-methylguanyl DNA-methyltransferase (MGMT) promoter: A multicenter, open-label, uncontrolled phase II study
Authors: Wick Wolfgang W. , Combs S. E. , Platten M. , Weller M. , Ohnmacht U. , Stoffregen C. , Thornton D.
Published: August 2020

e13038

Background: There is an unmet need to improve efficacy outcome for GBM patients without hypermethylation of the MGMT promoter. Preclinical data indicated a potential benefit of ENZ, an oral serine/threonine kinase inhibitor, together with RTX (Tabatabai et al; Ann Neurol 61: 2007). In a run-in phase of this phase II study the feasibility of once or twice daily ENZ dosing was evaluated. The split dose results in higher exposure. The results of the run-in phase are presented. Methods: Patients (pts) with newly diagnosed supratentorial GBM were entered. The first regimen administered once daily ENZ (500 mg QD) before and concomitant with standard radiotherapy at a dose of 60 Gy (2 Gy, 5 days a week). As no dose-limiting toxicities occurred in the first 3 pts, another 6 pts were enrolled into the second regimen, twice daily ENZ (250 mg BID) with RTX. ENZ is given until progression afterward. Results: Between 10/07 and 07/08 a total of 9 pts were enrolled. Mean treatment duration was 9.3 weeks for ENZ, and 6.3 weeks for RTX. No drug-related grade 3/4 toxicity was reported. The only laboratory toxicity CTC grade 3 (low potassium) and 1 serious adverse event (erysipelas) were reported in the BID regimen. No pts discontinued in the first 9 weeks, no deaths in this period. Conclusions: Following the results of the run-in phase, the BID regimen was chosen for the ongoing study.

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A phase I study investigating the combination of orally bioavailable platinum and nanoparticle albumin-bound paclitaxel in advanced solid tumors
Authors: Deshpande H. A. , Gettinger S. , Rowen E. , Abu-Khalaf M. M. , Clarke J. , Burns A. J. , Kelly W. K.
Published: August 2020

e13501

Background: The combination of a taxane and a platinum agent is considered a standard chemotherapy regimen for many solid tumors. Adverse effects often limit the administration of these drugs. Satraplatin (S) is an orally bioavailable platinum agent with a similar spectrum of activity to other platinum analogs, but less renal or neurological side effects. The nanoparticle albumin-bound paclitaxel (A) has shown greater efficacy and less toxicity than Cremophor-based paclitaxel as a single agent in the treatment of breast cancer. The primary aim of this study was to determine a safe dose for the combination of S +A and to investigate if there were pharmacokinetic (PK) interactions between S + A in patients (pts) with advanced malignancies. Methods: Cohorts of 3–6 pts were enrolled and treated. Escalating oral doses of S (40–60- 80mg) were administered on days 1–5 in combination with intravenous fixed dose of A (100 mg/m2) on 1, 8, and 15 of a 28 day cycle. Prior to cycle 1 all patients received A day -14. Blood samples for PK studies were drawn with the day -14 and Day 1 treatments. Results: To date 15 pts (2 renal, 3 prostate, 2 bladder, 1 hypopharyngeal, 1 mesothelioma, 1 colorectal, 1 melanoma and 2 leiomyosarcomas) with a median age 51 (range 37 - 78 yrs) have been treated in 3 cohorts. Doses were escalated as follows; Cohort 1 (40 (S)/100(A), n = 4), Cohort 2 (60/100, n = 7), Cohort 3 (80/100, n = 3). 1 patient (testicular cancer) intended for cohort 1 was a screen failure. Two patients in cohort 3 had grade 3\/4 neutropenia (DLT). An additional 4 patients were treated in cohort 2 without DLT and this dose level was determined to be the MTD. Most common severe adverse events were Grade 3 anemia (5%), neutropenia (22%), fatigue (5%) and dehydration (5%). 3 patients had grade 4 neutropenia, 2 in cycle 1 of cohort 3 and 1 in cycle 2 of cohort 2. To date 6 patients had progressive disease, 4 had stable disease (3.8 months), 3 patients (2 with prostate cancer and 1 with hypopharyngeal cancer) had a partial response. Conclusions: The combination of A plus S was well tolerated and the recommended dose for phase 2 studies is paclitaxel 100 mg/m2 weekly for 3 weeks plus satraplatin 60 mg/m2 daily for 5 days every 28 days. PK analyses will be presented.

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Final results of phase I and pharmacokinetic study of SJG-136 administered on a daily x 5 schedule
Authors: Kadia T. M. , Faderl S. , Estrov Z. , Konopleva M. , George S. , Lee W. , Puzanov I. , Chen A. , Kantarjian H. , Ravandi F.
Published: August 2020

e13506

Background: SJG-136 is a pyrrolobenzodiazepine dimer that forms covalent DNA crosslinks in a sequence-specific manner in the minor groove. In vitro testing demonstrated a broad pattern of antitumor activity in sub-nmol concentrations. A phase I study in patients (pts) with solid tumors revealed clinical activity, defined MTD as 30 mg/m2/d administered on daily x 3 schedule, and confirmed manageable toxicity. Here we report the results of a CTEP-sponsored phase I trial of SJG-136 administered on a daily x 5 schedule in pts with relapsed or refractory (R/R) leukemias. Methods: Previously treated pts with R/R acute leukemias (AML, ALL, high risk MDS, CML blast phase) or R/R CLL with adequate organ function and ECOG performance status of ≤ 2 were eligible for the study. The starting dose level was 6 mcg/m2 given intravenously daily x 5 days on a 21 day cycle. Pts were sequentially enrolled in cohorts of 3 and the dose was escalated in a classic 3+3 schema at the dose levels: 6, 12, 24, and 36 mcg/m2. Repeat courses and intrapatient dose escalation were allowed. Results: Sixteen pts (11M, 5 F) were enrolled on the study. The median age of the patients was 53 (21–84). Thirteen (81%) pts had R/R AML, and 3 (19%) had R/R ALL of which 5 (31%) had diploid and 6 (38%) had adverse cytogenetics. Median number of prior therapies was 3 (2–6). Pts enrolled at each dose level (mcg/m2) were: 6 (3 pts), 12 (5 pts), 24 (4 pts), 36 (4 pts). The median number of cycles delivered was 1 (0–5). The dose of 36 mcg/m2 was found to be above the MTD, with the DLT being grade 3 soft tissue edema. Other manifestations of vascular leak including grade I, II hypoalbuminemia, edema, and pleural effusions were seen in a number of patients starting at dose level 24 mcg/m2 and above. Other non-dose limiting toxicities included nausea, dyspnea, fatigue, bloating, and insomnia. One pt had a PR, 8 pts had stable disease, and 6 had progression. Pharmacokinetic characteristics in this population will be reported. Conclusions: SJG-136 is safe and active in patients with advanced leukemias. Edema and other vascular leak syndromes are characteristic toxicities of the agent at higher dose levels. 24 mcg/m2 is the recommended phase II dose for the daily x 5 schedule.

No significant financial relationships to disclose.
Phase I study of E7389/gemcitabine combination in patients with advanced solid tumors
Authors: Goel R. , Chen E. , Welch S. , Laurie S. , Siu L. , Jonker D. , Srinivasan R. , Wang L. , Ivy P. , Oza A.
Published: August 2020

e13509

Background: E7389 (E) is a synthetic analogue of halichondrin B, an investigational tubulin-based antimitotic drug. Gemcitabine (G) is a nucleoside analogue clinically active in several human tumours. These two drugs exhibit synergistic cytotoxic effects against the H522 non-small cell lung cancer (NSCLC) xenografts. Methods: A phase I study of these two drugs in combination was initiated in patients with advanced solid tumours. Two prior chemotherapy regimens for metastatic disease were allowed. Results: Patient characteristics: male 11/female 10; median age 59 (range 28–84); performance status 0 /1/2: n=1/13/7; prior chemotherapy 21, prior radiotherapy 7, prior immunotherapy 1; tumour types: ovarian cancer 3, endometrial cancer 3, NSCLC 3, gastric/esophageal adenocarcinoma 3, miscellaneous 9. Total number of cycles given 52, median cycles/patient (range) 2 (1, 8). Cohort (CT) 1: E/G given days 1,8,15 q28 days. Due to DLT, regimen changed in CT 2 with E/G given days 1, 8 q21 days. Cycles (C) given: median 2 range 1–8, total 52. Response: partial response 1 (ovarian cancer), stable 8 [minor response 4 (NSCLC 2, endometrial cancer 1, head and neck cancer 1)], progression 8, inevaluable 4. Conclusions: Further phase II investigation of this regimen should be considered at a dose of E 1.0 g/m2/G 1000 mg/m2 q 3 weeks.

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No significant financial relationships to disclose.
A phase Ib dose-escalation study of orally administered MP-470, a multi-kinase inhibitor and supressor of Rad51, in combination with carboplatin doublet containing regimens shows activity in highly refractory solid tumor patients
Authors: Mita M. M. , Tolcher A. , Gordon M. S. , Rosen L. , Mita A. , Fine G. , Choy G. , Berk G.
Published: August 2020

e13511

Background: MP-470 (MP) is an oral multi-targeted tyrosine kinase inhibitor which inhibits a number of validated tumor targets including c-kit, flt3, and PDGFα. MP470 targets cancer cells by disrupting DNA repair, an important survival pathway in many human cancers. Results presented herein are from two arms of a phase-Ib five arm trial of MP combined with standard of care (SOC) anti- cancer therapies. Methods: MP is administered in combination with SOC in a 21-day cycle. Adults with ECOG PS of 0–2 and malignant disease appropriate for SOC regimens consisting of paclitaxel/carboplatin (PC), carboplatin/etoposide (CE), topotecan, docetaxel, and erlotinib were enrolled. Each arm follows a 3+3 design where MP is escalated based on the modified Fibonacci sequence until the MTD of MP in combination with SOC agents is reached. RECIST and CTCAE are utilized to assess response and safety, respectively. The primary objectives of the study are to determine the MTD, DLTs, and quantify the effects of MP on the PK of SOC agents. Results: Between Dec 2007 and Aug 2008, 26 subjects were enrolled in the PC and CE arms and received a total of 70 cycles (median 2; range, 0–8) of MP at 4 dose levels (100–500 mg/day). Median number of prior therapies was 2 (range, 0–19). Male/Female: 14/12. Median age, 56 years (range, 24–76). Subjects completing ≥ 6 and ≥ 4 cycles were 5 and 7, respectively. Six PRs (2 neuroendocrine, 2 SCLC, 1 NSCLC, 1 small cell of anal canal) and 3 SDs (≥ 4 cycles) was observed. The MTDs have not been reached and DLTs have not been identified. Adverse events occurring in ≥ 15% of patients were myelosuppression, diarrhea, constipation, nausea, reflux, fatigue, alopecia, rash, neuropathy, anorexia, hypokalemia, dyspnea, and myalgias. MP470 did not alter the kinetics of SOC agents. Dose escalation in the PC and CE arms is ongoing. Conclusions: MP470 combined with carboplatin-containing regimens may promote tumor regression and may also sensitize/resensitize tumors to the anticancer effects of such agents. An amendment will be issued to collect tumor tissue biopsy at baseline and during treatment to adequately evaluate DNA damage in tumor tissue.

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Phase I study of pemetrexed (P) and pegylated liposomal doxorubicin (PLD) in patients with refractory breast, ovarian, primary peritoneal, or fallopian tube cancer
Authors: Richards D. A. , Loesch D. , Vukelja S. J. , Wu H. H. , Hyman W. J. , Nieves J. , Wang Y. , Hu S. , Shonukan O. , Tai D.
Published: August 2020

e13515

Background: P and PLD are clinically active as single agents and synergistic in preclinical models. This phase I, open-label trial determined the maximum tolerated dose (MTD) and safety profile of P followed by PLD in patients (pts) with breast or gynecologic cancers. Methods: Using standard phase I (3+3 dose escalation) study design, cohorts of 3–9 pts received escalating doses of P followed by PLD in 28-day cycles: P 400–500 mg/m2 on Days 1 and 15 and PLD 30–45 mg/m2 on Day 1. All pts received folic acid (350–1000 μg daily) and vitamin B12 (1000 μg) until 21 days after last dose of P. Pts continued until dose-limiting toxicity (DLT) or disease progression (PD) occurred. Results: From 11/05 to 1/08, 29 pts were registered/treated. Median age: 60.6 years (range, 47.5–80.1); ECOG performance status 0/1: 28%/72%; primary disease sites: ovarian (55%), breast (35%), peritoneal (10%); prior therapies: chemotherapy (100%), surgery (72%), hormones/biologics (35%), radiation (21%). Dosing results are shown below. At dose level (L) 2 and L3, 1 pt/cohort had DLTs; L5 was added and 3/3 pts had DLTs; 4 more pts were treated at L4 (1 pt replaced). Most frequent drug-related Grade 3–4 hematologic toxicities: neutropenia (86%), leukopenia (59%), thrombocytopenia (48%), anemia (41%). Most frequent drug-related Grade 3–4 nonhematologic toxicities: hand-foot syndrome (14%), hypokalaemia (10%). Major reasons for discontinuation: PD (48%), toxicity (28%), pt request (14%). Overall best responses (n=24): 5 pts (21%) had partial response (PR), 14 pts (58%) had stable disease (SD), 2 pts (8%) had PD, 3 pts (13%) were not evaluable. All 5 PR and 8 SD pts were ovarian; 5 SD and both PD pts were breast. Conclusions: P followed by PLD was reasonably tolerated in this heavily-pretreated population. The MTD was P 500 mg/m2 and PLD 40 mg/m2. These dose levels may be carried forward to phase II studies in more specific patient populations.

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Phase I safety and pharmacokinetic (PK) study of sunitinib (S) in combination with ifosfamide (I) in patients (pts) with advanced solid tumors (STs)
Authors: Hamberg P. , Steeghs N. , Loos W. J. , van der Biessen D. J. , den Hollander M. A. , Tascilar M. , Verweij J. , Gelderblom H. , Sleijfer S.
Published: August 2020

e13520

Background: S is a tyrosine kinase inhibitor (TKI) of PDGFR, VEGFR and KIT. As combinations of VEGFR-TKI with cytotoxic therapy are promising, this phase I study aimed to determine the recommended phase II dose (RP2D) of S in combination with 2 different I schedules. Methods: Pts with progressive STs, good PS, organ function, and no standard therapy available, were eligible. I (3 g/m2/day, 72h CIV (I*3), every 3 wks) was combined with continuous S. S was started at 12.5 mg/day and to be escalated in serial cohorts of 3–6 pts. RP2D was exceeded if ≥ 1/3 pts experienced dose-limiting toxicity (DLT) within the 1st cycle. After establishing the RP2D of S with I*3, feasibility of this S dose with I at 1.2 g/m2/day for 5 days CIV (I*5) every 3 wks was assessed without further scheduled dose-escalation. At RP2D, additional patients were enrolled to assess PK. Circulating endothelial cells (CECs) were measured prior to the 1st, 3rd and 6th cycle. Results: 26 pts (36–68 yrs) were accrued. 12.5 mg S was not feasible with I*3 due to neutropenia > 7 days in 2/6 pts. After protocol amendment, pegfilgrastim 6 mg (P) was given to all subsequent patients after each I-cycle. Using P, the RP2D was I*3 plus 12.5 mg S (in 1/9 pts DLT: febrile neutropenia), while I*3 plus 25 mg S was not feasible due to febrile neutropenia in 2/5 pts and hypertension & cardiac chest pain in 1/5 pts. 12.5 mg S was also feasible using I*5 as 1/6 pts had a DLT: encephalopathy. Most frequent drug related adverse events (all grades/grade 3–4) were: neutropenia (77%/62%), thrombocytopenia (73%/31%), elevated transaminases (65%/0%), renal (42%/4%), nausea (77%/0%), vomiting (58%/0%) and alopecia (62%/0%). 4/22 pts evaluable for response had PR: 1 CUP, 1 small cell carcinoma (SCC) and 2 sarcoma pts. 7 pts had SD for ≥ 3 months: 1 CUP, 1 uveal melanoma, 1 SCC, and 4 sarcoma pts. The AUC ratio of I and its metabolites in cycles I*3 without versus with S ranged from 0.72 to 1.36. No consistent change in the number of CECs during treatment was observed. Conclusions: S at 12.5 mg/day with I*3 or I*5 every 3 weeks supported by P is tolerable in pts with advanced STs. S does not affect I-PK. Antitumor activity was observed in pts with diverse tumor entities including sarcoma.

No significant financial relationships to disclose.
Cancer-related TTP: Role of plasma exchange
Authors: Farhat M. H. , de Souza B. , Hanbali A.
Published: August 2020

e13527

Background: Thrombotic thrombocytopenic purpura (TTP) is a multisystemic disease classically described by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurologic manifestations and renal dysfunction. It is considered a hematologic emergency for which, the treatment of choice is plasma exchange therapy. However, its diagnosis and treatment can be particularly challenging in the setting of disseminated malignancy, as the misdiagnosis of TTP in a patient with cancer-associated thrombotic microangiopathy (TMA) will lead to ineffective use of plasma exchange and delay the timely delivery of chemotherapy. Moreover, patients with disseminated malignancy respond less often to plasma exchange and have a higher mortality rate. Methods: Three patients with disseminated malignancy who presented as TTP are discussed. Two of the three patients were given plasma exchange and had fatal outcomes, while the third patient received chemotherapy as the initial therapy and survived hospitalization. The three patients had prolonged PT with normal aPTT; LDH levels (>1,000 IU/L); and presence of schistocytes in the peripheral blood smear. Results: TMA associated with disseminated malignancy remains a challenging and underdiagnosed condition with very poor prognosis. Plasma exchange has no clinical use is potentially even life-threatening especially when it delays the administration of the appropriate chemotherapy which is the ultimate treatment for the underlying malignancy that resulted in TMA. We propose that the following criteria be used for diagnostic consideration of disseminated malignancy-associated TMA: evidence of hemolysis; leukoerythroblastic picture on the peripheral blood; coagulopathy consisting of elevated d-dimer, prolonged PT with normal aPTT; extreme elevations in the LDH levels (>1,000 IU/L); and presence of schistocytes in the peripheral blood smear. Such patients should be immediately considered for a bone marrow biopsy as chemotherapy should be initiated as soon as possible. Conclusions: See Table.

[Table: see text]

No significant financial relationships to disclose.
Reversion of physiological drug resistance of weakly basic drugs: The discovery of a new mechanism of PEG-PCL nanoparticles
Authors: Li R. , Xie L. , Li X. , Liu Q. , Qian X. , Jiang X. , Yu L. , Ding Y. , Liu B.
Published: August 2020

e13528

Background: A number of studies have reported the superior antitumor effect of nanoparticles loading chemotherapeutics than the free agents, yet the underlying mechanism has not attract enough attention. The extracellular pH of cancer cells is lower than that of the intracellular pH. Due to this pH gradient, weakly basic drug will protonated extracellularly and display decreased intracellular concentration. In this study, we aimed to reveal a new mechanism of PEG-PCL nanoparticles, namely the reversion of physiological drug resistance. Methods: Tetradrine (Tet), an alkaloid isolated from traditional Chinese medicine, was incorporated into the diblock copolymer methoxy poly(ethylene glycol)-polycaprolactone (mPEG-PCL). In vitro cytotoxicity of free Tet and Tet-loaded nanoparticles at pH7.4 and pH6.8 was compared on four different cancer cell lines. Fluorescent particle cellular uptake study was also used. To evaluate the antitumor effect of the nanoparticles in a more complex model rather than monolayer cell culture, we used Histoculture Drug Resistance Assay (HDRA). The in vivo antitumor effect of the nanoparticles was also studied in ICR mice bearing H22 tumor with different in vivo pH values. Results: In vitro cytotoxicity study in four tumor cell lines showed that the cytotoxicity of free Tet decreased significantly (P<0.05) when the extracellular pH decreased from 7.4 to 6.8, while the cytotoxicity of Tet-loaded nanoparticles increased or didn’t change significantly. The possible mechanism may mainly be the endocytosis of nanoparticles, which was proven by fluorescent particle cellular uptake study. HDRA indicated better tissue penetration of nanoparticles over free Tet. As to in vivo study, the mice with in vivo tumor pH 6.8 and treated with Tet-loaded nanoparticles exhibited best tumor inhibit rate and mildest side effect, suggesting that the use of nanoparticles was more preferable than the manipulation of tumor pH by the use of basic water. Conclusions: Our study clearly demonstrated that the mPEG-PCL nanoparticles could overcome the drug resistance caused by low extracellular pH and enhance drug penetration in the tumor tissue, thus increasing the antitumor efficacy of weakly basic agents.

No significant financial relationships to disclose.