The melanoma differentiation-associated gene-7 (mda-7; approved gene symbol IL24) is a tumor suppressor gene whose expression induces selective apoptosis in tumor cells. To characterize the safety and biologic activity of mda-7 gene transfer, we conducted a phase I trial using intratumoral injections of an adenovirus containing the mda-7 construct (Ad-mda7; INGN 241; 2 x 10(10) to 2 x 10(12) vp) in 28 patients with resectable solid tumors. One hundred percent of injected lesions demonstrated INGN 241 vector transduction, transgenic mRNA, elevated MDA-7 protein, and apoptosis induction, with the highest levels near the injection site. Apoptosis of cells in injected tumors was consistently observed even in heavily pretreated patients. INGN 241 vector DNA and mRNA were detected more than 1 cm from the injection site, whereas MDA-7 protein and bioactivity were more widely distributed. Toxicity attributable to the injections was self-limiting and generally mild; however, one patient experienced a grade 3 SAE possibly related to the study drug. Evidence of clinical activity was found in 44% of lesions with the repeat injection schedule, including complete and partial responses in two melanoma patients. Thus intratumoral administration of INGN 241 is well tolerated, induces apoptosis in a large percentage of tumor cells, and demonstrates evidence of clinically significant activity.
A single injection of pegfilgrastim 100 microg/kg per cycle was as safe and effective as daily injections of filgrastim 5 microg/kg/d in reducing neutropenia and its complications in patients who received four cycles of doxorubicin 60 mg/m(2) and docetaxel 75 mg/m(2).
P-CAP showed promising clinical activity compared with CAP in previously treated patients with mCRC. A phase III trial is underway comparing P-CAP with CAP in patients with refractory mCRC.
A 67-year-old white man with human ehrlichiosis infection complicated by pancytopenia, hemophagocytic syndrome, disseminated intravascular coagulopathy and septic shock is presented. The patient had been on a three-week camping trip to California, Colorado, Utah, and New Mexico. The diagnosis of human ehrlichiosis was confirmed by sixteen-fold rise in antibody titer to Ehrlichia canis, and supported by the characteristic cytoplasmic inclusions. Human ehrlichiosis should be considered in the differential diagnosis in patients with fever and cytopenia associated with hemophagocytosis. Pancytopenia associated with ehrlichiosis is transient; however, it may be severe, and appears to be associated with destruction of normal blood elements.
Introduction
Dasatinib inhibits the protein tyrosine kinase, Src, which can support the development of bone metastases in patients with ER+ breast cancer. The primary objective of this study is to determine if letrozole plus dasatinib increases the clinical benefit rate (CBR) (CR+PR+SD ≥6mo) in first-line MBC patients compared with letrozole alone. Secondary objectives include overall response; progression-free survival; time to treatment failure (TTF); and toxicity.
Methods
This is a Phase II randomized, noncomparative study of postmenopausal women with locally recurrent or metastatic, measurable or nonmeasurable BC, ER+, HER2-. Patients are allowed to have had prior non-AI endocrine therapy for MBC; prior adjuvant AI therapy if completed at least 1 year prior to study entry; and up to 1 prior chemotherapy regimen for MBC. Patients are stratified by ≤2 yrs vs >2 years disease-free interval (DFI) from initial breast cancer diagnosis (date of definitive surgery) to first locally recurrent or MBC and by prior tamoxifen for MBC. Patients were randomly assigned to Arm 1 (letrozole 2.5mg PO QD + dasatinib 100mg PO QD) or Arm 2 (single-agent letrozole 2.5mg PO QD) on 28-day cycles. Arm 1 patients who experienced intolerable toxicity related to dasatinib discontinued dasatinib and continued single-agent letrozole. Arm 2 patients who developed progressive disease (PD) on letrozole had the option to receive dasatinib plus letrozole. The primary endpoint of CBR was assessed when patients developed progressive disease on their randomly assigned therapies before any crossover therapy.
Results
Patients with prior adjuvant AI/tamoxifen were 39%/32% Arm 1 and 44%/37% Arm 2; prior metastatic endocrine therapy Arm 1/Arm 2 was 9%/5%; and prior metastatic chemotherapy Arm 1/Arm 2 was 11%/6%. Median DFI Arm 1/Arm 2 was 27.5/21.2 months; patients presenting with de novo MBC Arm 1/Arm 2 was 42%/32%, respectively; measureable disease by RECIST Arm 1/Arm 2 was 58%/75%. The ITT population comprised 120 patients; 57 in Arm 1 and 63 in Arm 2. Clinical benefit rate (CBR) in 116 evaluable patients in Arm 1(55)/Arm 2(61), respectively, was 64% (95% CI, 50-76) and 61% (95% CI, 47-73). Median PFS time was 22 months with letrozole/dasatinib and 11 months with letrozole alone, p = .05. PFS at 6 and 12 months for Arms 1 and 2, respectively, was 78%/66% and 66%/43%. The most common toxicities observed with dasatinib on Arm 1 were fatigue (38%), nausea (38%), anemia (25%), rash (23%), pleural effusion (16%), and edema (13%). 27% of patients required dasatinib dose reduction.
Conclusion
The addition of dasatinib to letrozole in MBC patients receiving their first AI therapy for metastatic disease did not improve CBR compared with letrozole alone. Median PFS improved from 11 to 22 months (p = .05) with the addition of dasatinib, suggesting dasatinib improved duration of disease control combined with letrozole. Most patients tolerated full dose dasatinib until PD. 25% of patients remain on study therapy; final results will be available at SABCS 2013.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S3-07.
#33
Background
 Trastuzumab-DM1 (T-DM1), an antibody drug conjugate (ADC) designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent anti-microtubule agent (DM1) to HER2-expressing cells, has demonstrated activity in a Phase I study. The maximally tolerated dose (MTD) for T-DM1 given every 3 wks was 3.6 mg/kg.
 Methods
 This is a multi-institutional, open-label, single-arm, Phase II study of T-DM1, 3.6 mg/kg administered by IV infusion every 3 wks, to pts with HER2+ MBC; 100 efficacy-evaluable pts who have progressed on prior T and chemotherapy given in the metastatic setting will be enrolled. The primary objective is to assess objective response rate (ORR) and safety and tolerability in this patient population. Key secondary objectives include measurement of duration of objective response and progression-free survival; to characterize the pharmacokinetics of this T-DM1 regimen; and to assess the formation of antibodies to T-DM1. A preplanned, protocol specified interim analysis of efficacy data was performed after the first 30 efficacy evaluable pts had completed 4 cycles (12 wks) of treatment. A final analysis will be conducted 26 wks after the last patient has been enrolled.
 Results
 As of June 6, 2008, 92/100 pts have been enrolled. Demographic data from the first 31 enrolled pts include: median age 57 (range 38-79); PS 0-1, 29; PS 2, 2; median number prior metastatic chemo agents 2 (range 1-9); median duration of prior T is 76.1 wks (range 12-379); 13 pts (42%) received prior lapatinib. Of the 31 pts, 30 were evaluable for efficacy per protocol. Based on investigator assessments, 12/30 (40%) pts have had a partial (11) or complete (1) response reported. The IRF has reported a partial response in 9/30 (30%) pts to date. To date, these 31 pts have received a median of 4 T-DM1cycles (range 1-11). Gr2 adverse events (AEs) include thrombocytopenia (10%), fatigue (13%), nausea/vomiting (10%), infusion reaction/fever/chills (10%). Gr3 thrombocytopenia occurred in 10% of pts and Gr4 AEs occurred in 2 (6%) pts (thrombocytopenia and transaminase elevation). Sixteen (52%) pts have discontinued therapy, 11 for progressive disease.
 Conclusions
 T-DM1 has shown single-agent clinical activity in pts who have progressed on prior HER2-directed therapy. The safety profile of T-DM1 appears tolerable at the recommended dose. To date, preliminary data show a 40% investigator-determined response rate and a 30% IRF-reported response rate. Updated results for the entire study population will be presented.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 33.
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