Regorafenib plus nivolumab in patients with mismatch repair-proficient/microsatellite stable metastatic colorectal cancer: a single-arm, open-label, multicentre phase 2 study.

Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months' follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4-15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0-not evaluable) and 1.8 months (95% CI 1.8-2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Funding: Bayer/Bristol Myers Squibb.

Eribulin Plus Pembrolizumab in Patients with Metastatic Triple-Negative Breast Cancer (ENHANCE 1): A Phase Ib/II Study.

PURPOSE: As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings. PATIENTS AND METHODS: In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1-2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination. RESULTS: The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8-38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2-31.1) for stratum 2 (n = 101). Patients with PD-L1-positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1-negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9-54.3) vs 16.1% (95% CI: 5.5-33.7); stratum 2, 24.4% (95% CI: 12.9-39.5) vs 18.2% (95% CI: 8.2-32.7)]. CONCLUSIONS: Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.

Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours.

BACKGROUND: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). PATIENTS AND METHODS: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. RESULTS: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11). CONCLUSION: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib.

Eribulin versus dacarbazine in patients with leiomyosarcoma: subgroup analysis from a phase 3, open-label, randomised study.

BACKGROUND: This subgroup analysis of a phase 3 study compares outcomes for eribulin versus dacarbazine in patients with leiomyosarcoma. METHODS: Patients ≥18 years old with advanced liposarcoma or leiomyosarcoma, ECOG PS ≤2, and ≥2 prior treatment regimens were randomly assigned (1:1) to eribulin mesylate (1.4 mg/m² intravenously on day 1 and day 8) or dacarbazine (either 850, 1000, or 1200 mg/m² intravenously) every 21 days until disease progression. The primary end point was OS; additional end points were progression-free survival (PFS) and objective response rate (ORR). RESULTS: 309 Patients with leiomyosarcoma were included (eribulin, n = 157; dacarbazine, n = 152). Median age was 57 years; 42% of patients had uterine disease and 57% had nonuterine disease. Median OS was 12.7 versus 13.0 months for eribulin versus dacarbazine, respectively (hazard ratio [HR] = 0.93 [95% CI 0.71-1.20]; P = 0.57). Median PFS (2.2 vs 2.6 months, HR = 1.07 [95% CI 0.84-1.38]; P = 0.58) and ORR (5% vs 7%) were similar between eribulin- and dacarbazine-treated patients. Grade ≥3 TEAEs occurred in 69% of patients receiving eribulin and 59% of patients receiving dacarbazine. CONCLUSIONS: Efficacy of eribulin in patients with leiomyosarcoma was comparable to that of dacarbazine. Both agents had manageable safety profiles.

A Phase II Trial of Sorafenib and Dacarbazine for Leiomyosarcoma, Synovial Sarcoma, and Malignant Peripheral Nerve Sheath Tumors.

BACKGROUND: Sorafenib and dacarbazine have low single-agent response rates in metastatic sarcomas. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of sorafenib and dacarbazine in select sarcoma subtypes. MATERIALS AND METHODS: Patients with leiomyosarcoma (LMS), synovial sarcoma (SS), or malignant peripheral nerve sheath tumors (MPNST) with up to two previous lines of therapy and adequate hepatic, renal, and marrow function received 3-week cycles of sorafenib at 400 mg oral twice daily and dacarbazine 1,000 mg/m2 intravenously (later reduced to 850 mg/m2). Patients were evaluated for response every 6 weeks. The primary objective was to determine the disease control rate (DCR) of sorafenib plus dacarbazine in the selected sarcoma subtypes. RESULTS: The study included 37 patients (19 female); median age was 55 years (range 26-87); and histologies included LMS (22), SS (11), and MPNST (4). The DCR was 46% (17/37). Median progression-free survival was 13.4 weeks. The RECIST response rate was 14% (5/37). The Choi response rate was 51% (19/37). Median overall survival was 13.2 months. Of the first 25 patients, 15 (60%) required dacarbazine dose reductions for hematologic toxicity, with one episode of grade 5 neutropenic fever. After reducing the starting dose of dacarbazine to 850 mg/m2, only 3 of the final 12 (25%) patients required dose reduction. CONCLUSION: This phase II study met its primary endpoint with an 18-week DCR of 46%. The clinical activity of dacarbazine plus sorafenib in patients with these diagnoses is modest. IMPLICATIONS FOR PRACTICE: Metastatic soft tissue sarcomas are a heterogeneous group of relatively rare malignancies. Most patients are treated with cytotoxic chemotherapy or targeted therapy in the form of tyrosine kinase inhibitors. Response rates are relatively low, and there is a need for better therapies. This clinical trial demonstrates that combining a cytotoxic therapy (dacarbazine) with an antiangiogenic small molecule (sorafenib) is feasible and associated with favorable disease-control rates; however, it also increases the potential for significant toxicity.

A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314).

BACKGROUND: Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose-limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. METHODS: Eribulin was administered intravenously on days 1 and 8 in 21-day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m2 /dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. RESULTS: Twenty-three patients, ages 3-17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m2 /dose, respectively. One subject at the 1.4 mg/m2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m2 /dose, 2/5 subjects experienced dose-limiting (grade 4) neutropenia. Grade 3/4 non-DLTs included lymphopenia and hypokalemia, while low-grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half-life was 39.6 (range 24.2-96.4) hr. A partial response was observed in one patient (Ewing sarcoma). CONCLUSIONS: Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m2 /dose on days 1 and 8 of a 21-day cycle.

Treatment-refractory ALK-positive inflammatory myofibroblastic tumour of the oral cavity.

We present a challenging case of a previously healthy 23-year-old man who developed an inflammatory myofibroblastic tumour of the hard palate, harbouring a rearrangement of the anaplastic lymphoma kinase (ALK) locus. Despite surgical intervention, radiotherapy and ALK-inhibition therapy, the tumour recurred locally and metastasised to regional lymph nodes, and the patient passed away roughly 9 months after diagnosis from local progression. The rapid progression of this patient's disease and its resistance to treatment demonstrate the potentially aggressive clinical course of inflammatory myofibroblastic tumours. ALK-inhibition therapy was unsuccessful in this ALK-positive tumour, highlighting the need for further investigation of markers predictive of disease progression and treatment response.

Activity of Eribulin in Patients With Advanced Liposarcoma Demonstrated in a Subgroup Analysis From a Randomized Phase III Study of Eribulin Versus Dacarbazine.

Purpose A phase III study comparing eribulin with dacarbazine in patients with advanced liposarcoma (LPS) or leiomyosarcoma showed a significant improvement in overall survival (OS) for the eribulin arm, with a manageable toxicity profile. We now report the histology-specific subgroup analysis of the efficacy and safety of eribulin compared with dacarbazine in patients with LPS, an independently randomized stratified subgroup of this phase III trial. Methods Patients ≥ 18 years with advanced or metastatic dedifferentiated, myxoid/round cell, or pleomorphic LPS incurable by surgery or radiotherapy were included. Patients with Eastern Cooperative Oncology Group performance status ≤ 2 and two or more prior systemic treatment regimens, including one with anthracycline, were randomly assigned 1:1 to receive eribulin mesylate (1.4 mg/m2 intravenously on days 1 and 8) or dacarbazine (850, 1,000, or 1,200 mg/m2 intravenously on day 1) every 21 days. OS, progression-free survival (PFS), and safety were analyzed. Results In the LPS subgroup, OS was significantly improved: 15.6 versus 8.4 months (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P < .001) with eribulin versus dacarbazine, respectively. Longer OS with eribulin was observed in all LPS histologic subtypes and in all geographic regions evaluated. PFS was also improved with eribulin versus dacarbazine (2.9 v 1.7 months, respectively; hazard ratio, 0.52; 95% CI, 0.35 to 0.78; P = .0015). Adverse events were similar between arms. Conclusion In patients with previously treated LPS, eribulin was associated with significantly superior OS and PFS compared with dacarbazine. Eribulin represents an important treatment option for patients with LPS, a sarcoma subtype for which limited effective systemic treatments are available. Further studies are justified to explore the role of eribulin in earlier lines of therapy as well as in combination with other agents.

Evaluation of Quality of Life at Progression in Patients with Soft Tissue Sarcoma.

Introduction. Soft Tissue Sarcoma (STS) is a rare malignancy of mesodermal tissue, with international incidence estimates between 1.8 and 5 per 100,000 per year. Understanding quality of life (QoL) and the detrimental impact of disease progression is critical for long-term care and survival. Objectives. The primary objective was to explore the relationship between disease progression and health-related quality of life (HRQoL) using data from Eisai's study (E7389-G000-309). Methods. This was a 1 : 1 randomized, open-label, multicenter, Phase 3 study comparing the efficacy and safety of eribulin versus dacarbazine in patients with advanced STS. The QoL analysis was conducted for the baseline and progression populations using the European Organization for Research and Treatment of Cancer 30-item core QoL questionnaire (EORTC QLQ-C30). Results. There were no statistical differences between the two treatment arms at baseline for any domain (p > 0.05; n = 452). Of the 399 patients who experienced disease progression (unadjusted and adjusting for histology), dacarbazine patients had significantly lower Global Health Status, Physical Functioning scores, and significantly worse Nausea and Vomiting, Insomnia, and Appetite Loss (p < 0.05). Conclusions. These results indicate differences in HRQoL overall and at progression between dacarbazine and eribulin patients, with increases in symptom severity observed among dacarbazine patients.

Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: A non-randomised, phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma. In this phase 3 study, we aimed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine (an active control). METHODS: We did this randomised, open-label, phase 3 study across 110 study sites in 22 countries. We enrolled patients aged 18 years or older with intermediate-grade or high-grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease (including an anthracycline). Using an interactive voice and web response system, an independent statistician randomly assigned (1:1) patients to receive eribulin mesilate (1·4 mg/m(2) intravenously on days 1 and 8) or dacarbazine (850 mg/m(2), 1000 mg/m(2), or 1200 mg/m(2) [dose dependent on centre and clinician] intravenously on day 1) every 21 days until disease progression. Randomisation was stratified by disease type, geographical region, and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT01327885, and is closed to recruitment, but treatment and follow-up continue. FINDINGS: Between March 10, 2011 and May 22, 2013, we randomly assigned patients to eribulin (n=228) or dacarbazine (n=224). Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine (median 13·5 months [95% CI 10·9-15·6] vs 11·5 months [9·6-13·0]; hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·0169). Treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin and 218 (97%) of 224 who received dacarbazine. Grade 3 or higher adverse events were more common in patients who received eribulin (152 [67%]) than in those who received dacarbazine (126 [56%]), as were deaths (10 [4%] vs 3 [1%]); one death (in the eribulin group) was considered treatment-related by the investigators. INTERPRETATION: Overall survival was improved in patients assigned to eribulin compared with those assigned to an active control, suggesting that eribulin could be a treatment option for advanced soft-tissue sarcoma. FUNDING: Eisai.

Phase II Trial of Gemcitabine and Docetaxel with Bevacizumab in Soft Tissue Sarcoma.

Gemcitabine (G) and docetaxel (D) are commonly used to treat recurrent/metastatic soft tissue sarcoma. This study tested the hypothesis that outcomes would be improved by addition of bevacizumab (B). The initial design was randomized double-blind trial of G + D + B versus G + D + placebo. Due to slow accrual this was modified to single-arm open-label G + D + B. Eligible patients had diagnosis of leiomyosarcoma, pleomorphic undifferentiated sarcoma, pleomorphic liposarcoma, or angiosarcoma. Treatment was B 15 mg/kg on d1, G 900 mg/m(2) on d1 and d8, and D 75 mg/m(2) on d8, q21d. Primary endpoint was progression-free survival (PFS) at 6 months and would be met if ≥17 patients were progression-free at 6 m. Secondary endpoints are response rate, PFS at 3 m, overall survival, and toxicity. Of 44 patients enrolled, 35 were treated with GDB and evaluable for safety and efficacy. Median age was 55, 50% male, most ECOG 0. Toxicity is mostly myelosuppression with one deep vein thrombosis and one small bowel perforation possibly related to B. There were 17 partial responses (49%) by RECIST 1.1. Among 35 patients, the number who remained on study and progression-free was 24 at 3 m and 15 at 6 m. 9 withdrew prior to 6 m for reasons other than toxicity or progression. PFS at 6 m was 65% (95% CI: 51-85%). The primary endpoint of 6 m PFS was not met due to censoring of patients who withdrew. However PFS at 3 m (76%) was promising and response rate was higher than expected from G + D.

Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy.

BACKGROUND: Preclinical studies have documented antitumor activity of PARP inhibition both in vitro and in vivo, against Ewing sarcoma cells. This study aimed to translate that observation into a clinical trial to assess the efficacy and tolerability of olaparib, a PARP inhibitor, in patients with advanced Ewing sarcoma (EWS) progressing after prior chemotherapy. METHODS: In this nonrandomized phase II trial, adult participants with radiographically measureable metastatic EWS received olaparib tablets, 400 mg orally twice daily, until disease progression or drug intolerance. Tumor measurements were determined by CT or MRI at 6 and 12 weeks after starting olaparib administration, and then every 8 weeks thereafter. Tumor response determinations were made according to RECIST 1.1, and adverse event determinations were made according to CTCAE, version 4.0. A total of 22 participants were planned to be enrolled using a conventional 2-step phase II study design. If no objective responses were observed after 12 participants had been followed for at least 3 months, further accrual would be stopped. RESULTS: 12 participants were enrolled, and all were evaluable. There were no objective responses (PR/CR), 4 SD (duration 10.9, 11.4, 11.9, and 17.9 wks), and 8 PD as best response. Of the SD, 2 had minor responses (-9% and -11.7% by RECIST 1.1). The median time to disease progression was 5.7 weeks. Further enrollment was therefore discontinued. No significant or unexpected toxicities were observed with olaparib, with only a single case each of grade 3 anemia and grade 3 thrombocytopenia observed. CONCLUSIONS: This study is the first report of a prospective phase II trial to evaluate the safety and efficacy of a PARP inhibitor in patients with advanced Ewing sarcoma after failure of standard chemotherapy. Olaparib administration was safe and well tolerated when administered to this small heavily pre-treated cohort at the 400 mg BID dose, although the median duration of dosing was for only 5.7 weeks. No significant responses or durable disease control was seen, and the short average interval to disease progression underscores the aggressiveness of this disease. Other studies to combine cytotoxic chemotherapy with PARP inhibition in EWS are actively ongoing. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01583543.

A Pilot Study of Anti-CTLA4 Antibody Ipilimumab in Patients with Synovial Sarcoma.

Background. Patients with recurrent synovial sarcomas have few options for systemic therapy. Since they express large amounts of endogenous CT (cancer testis) antigens such as NY-ESO-1, we investigated the clinical activity of single agent anti-CTLA4 antibody ipilimumab in patients with advanced or metastatic synovial sarcoma. Methods. A Simon two-stage phase II design was used to determine if there was sufficient activity to pursue further. The primary endpoint was tumor response rate by RECIST 1.0. Patients were treated with ipilimumab 3 mg/kg intravenously every 3 weeks for three cycles and then restaged. Retreatment was possible for patients receiving an extra three-week break from therapy. Sera and peripheral blood mononuclear cells were collected before and during therapy to assess NY-ESO-1-specific immunity. Results. Six patients were enrolled and received 1-3 cycles of ipilimumab. All patients showed clinical or radiological evidence of disease progression after no more than three cycles of therapy, for a RECIST response rate of 0%. The study was stopped for slow accrual, lack of activity, and lack of immune response. There was no evidence of clinically significant either serologic or delayed type hypersensitivity responses to NY-ESO-1 before or after therapy. Conclusion. Despite high expression of CT antigens by synovial sarcomas of patients treated in this study, there was neither clinical benefit nor evidence of anti-CT antigen serological responses. Assessment of the ability of synovial sarcoma cell lines to present cancer-germ cell antigens may be useful in determining the reason for the observed lack of immunological or clinical activity.

The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial.

PURPOSE: Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas. EXPERIMENTAL DESIGN: Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion. RESULTS: Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m(2) bolus; 50 mg/m(2) bolus + 40 mg/m(2) infusion) both in combination with doxorubicin (60 mg/m(2)). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing C(max) with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks. CONCLUSIONS: The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified.

Comparison of doxorubicin and weekly paclitaxel efficacy in metastatic angiosarcomas.

BACKGROUND: Data regarding the role of anthracyclines and taxanes as first-line treatments of metastatic angiosarcoma are limited. METHODS: Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed. RESULTS: Seventy-five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single-agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression-free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9-6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4-10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS. CONCLUSIONS: First-line single-agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS.

Appraising the current role of chemotherapy for the treatment of sarcoma.

Sarcomas are a heterogeneous group of relatively rare mesenchymal neoplasms. They can be grouped into two general categories: soft tissue sarcoma (STS) and primary bone sarcoma, which are treated differently. Because sarcomas are relatively rare and complex with a wide variety of different histopathologic subtypes, evaluation by multidisciplinary teams who have expertise in the field is recommended. Treatment guidelines for the use of chemotherapy in patients with STS and bone sarcoma have been published by the National Comprehensive Cancer Network. The role of adjuvant chemotherapy in resected STS remains controversial. Although chemotherapy improves disease-free survival, the long-term overall survival benefit remains unproven. Chemotherapy is typically used as palliative treatment for most subtypes of metastatic STS. In contrast, chemotherapy has a proven role in the treatment of primary bone tumors and Ewing sarcoma, but it has not demonstrated efficacy in the treatment of chondrosarcoma. The standard chemotherapy regimens used in sarcoma are associated with significant toxicity, including long-term complications. Less intense and less toxic regimens are the focus of ongoing clinical research. Newer cytotoxic agents with an improved safety profile, such as trabectedin and palifosfamide, are currently in development. Future research needs to focus on identification of subpopulations of patients that are most likely to benefit from chemotherapy.

An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions.

BACKGROUND: BRCA1 and BRCA2 germline mutations are associated with an elevated risk for pancreas adenocarcinoma (PAC). Other BRCA-associated cancers have been shown to have greater sensitivity to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors with better clinical outcomes than in sporadic cases; however, outcomes in BRCA-associated PAC have not been reported. METHODS: Patients with a known BRCA1 or BRCA2 mutation and a diagnosis of PAC were identified from the Gastrointestinal Oncology Service, Familial Pancreas Cancer Registry, and Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center. RESULTS: Fifteen patients, five male, with a BRCA1 (n = 4) or BRCA2 (n = 11) mutation and PAC and one patient with a BRCA1 mutation and acinar cell carcinoma of the pancreas were identified. Seven female patients (70%) had a prior history of breast cancer. Four patients received a PARP inhibitor alone or in combination with chemotherapy; three demonstrated an initial radiographic partial response by Response Evaluation Criteria in Solid Tumors whereas one patient had stable disease for 6 months. Six patients received platinum-based chemotherapy first line for metastatic disease; five of those patients had a radiographic partial response. CONCLUSION: BRCA mutation-associated PAC represents an underidentified, but clinically important, subgroup of patients. This is of particular relevance given the ongoing development of therapeutic agents targeting DNA repair, which may potentially offer a significant benefit to a genetically selected population. We anticipate that further study and understanding of the clinical and biologic features of BRCA-mutant PAC will aid in the identification of tissue biomarkers indicating defective tumor DNA repair pathways in sporadic PAC.

Activity of Sorafenib against desmoid tumor/deep fibromatosis.

BACKGROUND: Desmoid tumors (deep fibromatoses) are clonal connective tissue malignancies that do not metastasize, but have a significant risk of local recurrence, and are associated with morbidity and occasionally mortality. Responses of desmoid patients to sorafenib on an expanded access program led us to review our experience. METHODS: After Institutional Review Board (IRB) approval, we reviewed data for 26 patients with desmoid tumors treated with sorafenib. Sorafenib was administered at 400 mg oral daily and adjusted for toxicity. RESULTS: Sorafenib was the first-line therapy in 11/26 patients and the remaining 15/26 had received a median of 2 prior lines of therapy. Twenty-three of 26 patients had shown evidence of progressive disease by imaging, whereas 3 patients had achieved maximum benefit or toxicity with chemotherapy. Sixteen of 22 (∼70%) patients reported significant improvement of symptoms. At a median of 6 months (2-29) of treatment, the best response evaluation criteria in solid tumors (RECIST) 1.1 response included 6/24 (25%) patients with partial response (PR), 17/24 (70%) with stable disease, and 1 with progression and death. Twelve of 13 (92%) patients evaluated by MRI had > 30% decrease in T2 signal intensity, an indirect metric for increased fibrosis and loss of cellularity. Eighty percent of patients with radiological benefit had extra-abdominal desmoids. DISCUSSION: Sorafenib is active against desmoid tumors. A prospective, randomized clinical trial of sorafenib against other active agents is warranted. Loss of MRI T2 signal may be a useful surrogate for defining responses, but requires validation by examination of tumor pathology.