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Background Median overall survival for patients with metastatic soft tissue sarcoma is 12 to 16 months. Olaratumab is a human anti–platelet-derived growth factor receptor α monoclonal antibody which has antitumour activity in human sarcoma xenografts. Methods We conducted an open-label phase 1b, randomised, phase 2 study of doxorubicin ± olaratumab in patients with unresectable/metastatic soft tissue sarcoma. The phase 1b primary endpoint was safety; the phase 2 primary endpoint was progression-free survival using a two-sided alpha level of 0·2 and statistical power of 0·8. This study was registered with ClinicalTrials.gov, number NCT01185964. Findings Fifteen patients were enrolled and treated with olaratumab+doxorubicin in the phase 1b portion; 133 patients were randomised (66 to olaratumab+doxorubicin; 67 to doxorubicin) in the phase 2 portion, 129 of whom (97%) received at least one dose of study treatment (64 olaratumab+doxorubicin; 65 doxorubicin). Median progression-free survival in phase 2 was 6·6 months (95% confidence interval [CI], 4·1–8·3) with olaratumab+doxorubicin and 4·1 months (95% CI, 2·8–5·4) with doxorubicin (stratified hazard ratio [HR], 0·672; 95% CI, 0·442–1·021; p=0·0615). Median overall survival was 26·5 months (95% CI, 20·9–31·7) with olaratumab+doxorubicin and 14·7 months (95% CI, 9·2–17·1) with doxorubicin (stratified HR, 0·463; 95% CI, 0·301–0·710; p=0·0003). Adverse events more frequent with olaratumab+doxorubicin vs doxorubicin alone included neutropenia (38 [59%] vs 25 [39%]), mucositis (34 [53%] vs 23 [35%]), nausea (47 [73%] vs 34 [52%]), vomiting (29 [45%] vs 12 [19%]), and diarrhea (22 [34%] vs 15 [23%]). Febrile neutropenia of grade ≥3 was similar in both groups (olaratumab plus doxorubicin 8 (13%) vs doxorubicin 9 (14%). Interpretation This study of olaratumab with doxorubicin in patients with advanced soft tissue sarcoma met its predefined primary endpoint for progression-free survival and achieved a highly significant improvement of 11·8 months in median overall survival (P=0·0003; HR 0·46). Funding Eli Lilly and Company.

R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.

A B S T R A C T PurposeOur goals were to evaluate the safety of adding rituximab to methotrexate (MTX)-based chemotherapy for primary CNS lymphoma, determine whether additional cycles of induction chemotherapy improve the complete response (CR) rate, and examine effectiveness and toxicity of reduced-dose whole-brain radiotherapy (WBRT) after CR. Patients and MethodsThirty patients (17 women; median age, 57 years; median Karnofsky performance score, 70) were treated with five to seven cycles of induction chemotherapy (rituximab, MTX, procarbazine, and vincristine [R-MPV]) as follows: day 1, rituximab 500 mg/m 2 ; day 2, MTX 3.5 gm/m 2 and vincristine 1.4 mg/m 2 . Procarbazine 100 mg/m 2 /d was administered for 7 days with odd-numbered cycles. Patients achieving CR received dose-reduced WBRT (23.4 Gy), and all others received standard WBRT (45 Gy). Two cycles of high-dose cytarabine were administered after WBRT. CSF levels of rituximab were assessed in selected patients, and prospective neurocognitive evaluations were performed. ResultsWith a median follow-up of 37 months, 2-year overall and progression-free survival was 67% and 57%, respectively. Forty-four percent of patients achieved a CR after five or fewer cycles, and 78% after seven cycles. The overall response rate was 93%. Nineteen of 21 CR patients received the planned 23.4 Gy WBRT. The most commonly observed grade 3 to 4 toxicities included neutropenia (43%), thrombocytopenia (36%), and leukopenia (23%). No treatment-related neurotoxicity has been observed. ConclusionThe addition of rituximab to MPV increased the risk of significant neutropenia requiring routine growth factor support. Additional cycles of R-MPV nearly doubled the CR rate. Reduced-dose WBRT was not associated with neurocognitive decline, and disease control to date is excellent. J Clin

The Response Evaluation Criteria in Solid Tumors, or RECIST criteria (one-dimensional [1D] measurement), are widely used to measure response in tumors, but there are few studies evaluating these criteria in brain tumors. We compared linear and volumetric measurements in adult high-grade supratentorial enhancing gliomas to determine the agreement between measurements, in defining responses and in their subsequent relation to survival. We hypothesized that the 1D RECIST criteria maybe suitable for response assessment in adult high-grade gliomas. Tumor size on MRI scans in 104 patients with high-grade enhancing gliomas treated on clinical trial protocols was measured by using 1D (greatest length), 2D (two-dimensional: product of the two longest perpendicular diameters), 3D (three dimensional: product of the longest perpendicular diameters in one plane and the longest orthogonal diameter to that plane), enhancing volume (EV), and total volume (TV). A total of 388 T1 postgadolinium MRI scans (104 baseline and 284 follow-up scans) were evaluated. Volumetric analysis (EV and TV) was performed with commercially available software. Intraobserver and interobserver correlations (rho) were high for all modalities (rho > 0.92 and rho > 0.71, respectively). Correlation was excellent (rho > 0.9) among all modalities except for 3D (rho < 0.6). Patient response rates ranged from 12% to 26%. Median progression-free survival (mPFS) and six-month progression-free survival (6mPFS) were not significantly different among the methods (range, 5.3 months to 5.9 months and 42% to 48%, respectively). Landmark analyses of response at two months using linear methods predicted overall survival with hazard ratios of 0.19 to 0.29 (P < 0.005). These results suggest high concordance among 1D, 2D, TV, and EV, but not 3D, methods in assessing enhancing tumor progression and in estimating mPFS and 6mPFS in adult brain tumor patients. The tumor response at two months assessed by linear methods correlated better with overall survival. Thus, linear methods are comparable to volumetric methods, but simpler to implement for routine clinical use and for designing clinical trials of brain tumors.

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A large body of evidence suggests that the platelet-derived growth factor (PDGF) family and associated receptors are potential targets in oncology therapeutic development because of their critical roles in the proliferation and survival of various cancers and in the regulation and growth of the tumor stroma and blood vessels. Several small molecules that nonspecifically target the PDGF signaling axis are in current use or development as anticancer therapies. However, for the majority of these agents, PDGF and its receptors are neither the primary targets nor the principal mediators of anticancer activity. IMC-3G3, a fully human monoclonal antibody of the immunoglobulin G subclass 1, specifically binds to the human PDGF receptor a (PDGFRa) with high affinity and blocks PDGF ligand binding and PDGFRa activation. The results of preclinical studies and the frequent expression of PDGFRa in many types of cancer and in cancer-associated stroma support a rationale for the clinical development of IMC-3G3. Currently, IMC-3G3 is being evaluated in early clinical development for patients with several types of solid malignancies. Cancer 2010;116(4 suppl):1018-26.