Sami G. Diab

Phase I Pharmacologic and Biologic Study of Ramucirumab (IMC-1121B), a Fully Human Immunoglobulin G1 Monoclonal Antibody Targeting the Vascular Endothelial Growth Factor Receptor-2

PURPOSE To evaluate the safety, maximum-tolerated dose (MTD), pharmacokinetics (PKs), pharmacodynamics, and preliminary anticancer activity of ramucirumab (IMC-1121B), a fully human immunoglobulin G(1) monoclonal antibody targeting the vascular endothelial growth factor receptor (VEGFR)-2. PATIENTS AND METHODS Patients with advanced solid malignancies were treated once weekly with escalating doses of ramucirumab. Blood was sampled for PK studies throughout treatment. The effects of ramucirumab on circulating vascular endothelial growth factor-A (VEGF-A), soluble VEGFR-1 and VEGFR-2, tumor perfusion, and vascularity using dynamic contrast-enhanced magnetic resonance imaging were assessed. Results Thirty-seven patients were treated with 2 to 16 mg/kg of ramucirumab. After one patient each developed dose-limiting hypertension and deep venous thrombosis at 16 mg/kg, the next lower dose (13 mg/kg) was considered the MTD. Nausea, vomiting, headache, fatigue, and proteinuria were also noted. Four (15%) of 27 patients with measurable disease had a partial response (PR), and 11 (30%) of 37 patients had either a PR or stable disease lasting at least 6 months. PKs were characterized by dose-dependent elimination and nonlinear exposure consistent with saturable clearance. Mean trough concentrations exceeded biologically relevant target levels throughout treatment at all dose levels. Serum VEGF-A increased 1.5 to 3.5 times above pretreatment values and remained in this range throughout treatment at all dose levels. Tumor perfusion and vascularity decreased in 69% of evaluable patients. CONCLUSION Objective antitumor activity and antiangiogenic effects were observed over a wide range of dose levels, suggesting that ramucirumab may have a favorable therapeutic index in treating malignancies amenable to VEGFR-2 inhibition.

Tumor Characteristics and Clinical Outcome of Tubular and Mucinous Breast Carcinomas

PURPOSE To comprehensively characterize the clinical and biologic features of tubular and mucinous carcinomas in a large cohort of patients and to relate this to clinical outcome and management. PATIENTS AND METHODS The clinical and biologic features of 444 patients with tubular and 1,221 patients with mucinous carcinomas were compared with those of 43,587 patients with infiltrating ductal carcinoma, not otherwise specified (NOS). Disease-free survival (DFS) and overall survival (OS) for patients with tubular and mucinous carcinomas were compared with those of patients with NOS carcinomas and with age-matched sets from the general population. RESULTS Tubular and mucinous carcinomas were more likely to occur in older patients, be smaller in size (tubular only), have substantially less nodal involvement, be estrogen receptor- and progesterone receptor-positive, have a lower S-phase fraction, be diploid, and be c-erbB-2- and epidermal growth factor receptor-negative compared with NOS carcinomas. Axillary node involvement was a poor prognostic feature in mucinous but not tubular carcinomas. Mucinous carcinomas < or = 1 cm had a < or = 5% incidence of node involvement. The 5-year DFS and OS were 94% and 88% for tubular, 90% and 80% for mucinous, and 80% and 77% for NOS carcinoma, respectively (P < .001 for differences among all three types for both DFS and OS). The 5-year OS of females from the general population age-matched to the patients with tubular and mucinous carcinomas was 89% and 82%, respectively, which is not different from the OS of patients with tubular or mucinous carcinomas. CONCLUSION The biologic phenotype of tubular and mucinous carcinomas is quite favorable. Consistent with this observation, the survival of patients with tubular and mucinous carcinomas is similar to that of the general population. Systemic adjuvant therapy and node dissection may be avoided in many patients with these special types of carcinoma.

Mapatumumab, an Antibody Targeting TRAIL-R1, in Combination With Paclitaxel and Carboplatin in Patients With Advanced Solid Malignancies: Results of a Phase I and Pharmacokinetic Study

PURPOSE A phase I study assessed the safety, tolerability, pharmacokinetics, and preliminary antitumor effect of mapatumumab, a fully-human agonist monoclonal antibody to the tumor necrosis factor-related apoptosis-inducing ligand receptor 1 (TRAIL-R1, DR4), in combination with paclitaxel and carboplatin. PATIENTS AND METHODS Patients with advanced solid malignancies received 3, 10, or 20 mg/kg of mapatumumab with standard doses of paclitaxel and carboplatin every 21 days for up to six cycles in the absence of disease progression. Additional cycles of paclitaxel and/or mapatumumab were permissible in selected cases. RESULTS Twenty-seven patients (21 males), with a median age of 54 years, received mapatumumab in the following three cohorts: 3 mg/kg (n = 4), 10 mg/kg (n = 11), and 20 mg/kg (n = 12). The median number of cycles was four. Dose-limiting toxicities (DLTs) were grade 3 hypersensitivity reaction (n = 1) and neutropenic fever (n = 1), both at 10 mg/kg. Non-DLT treatment-related adverse events occurring in more than 10% of administered doses included alopecia, neutropenia, fatigue, nausea, anemia, thrombocytopenia, anorexia, and neuropathy. Paclitaxel and carboplatin exposures were similar in the presence or absence of mapatumumab. Plasma mapatumumab concentrations seemed similar to data from previous phase I monotherapy studies. Five patients (19%) achieved a confirmed radiologic partial response (including one pathologic complete response), and 12 patients (44%) had stable disease as their best response. CONCLUSION Mapatumumab is well-tolerated up to 20 mg/kg in combination with paclitaxel and carboplatin. There are no apparent pharmacokinetic interactions among the drugs. Preliminary anticancer activity demonstrated clinical benefit for the majority of these patients.

Radiation therapy and survival in breast cancer patients with 10 or more positive axillary lymph nodes treated with mastectomy.

PURPOSE Adjuvant loco-regional radiation (XRT) frequently is recommended after mastectomy and adjuvant systemic therapy in patients with 10 or more positive axillary lymph nodes (ALN) to reduce the high loco-regional failure rate observed in this subset. In this study, we explored the possibility that adjuvant loco-regional radiation therapy (LR-XRT) also could decrease distant failure and improve overall survival (OS) in this subset of poor-prognosis patients. PATIENTS AND METHODS Retrospectively, 618 breast patients with 10 or more positive ALN were studied. The median follow-up time was 7.5 years. All patients received systemic adjuvant therapy and 35% also received adjuvant radiation therapy. Loco-regional failure, distant failure, and OS analyses were adjusted for age, tumor size, number of positive ALN, and estrogen receptor (ER) status using Cox regression model. RESULTS As expected, patients had a very high risk of loco-regional and distant failure. At 5 years, 30% of patients had loco-regional failure as a first event and 54% had distant failure. Radiation dramatically reduced loco-regional failure (hazards rate ratios [RR]=0.29; 95% confidence interval [CI], 0.19 to 0.45). The adjusted 5-year loco-regional failure rate was 13% with radiation and 38% without radiation (P=.0001). Radiation also was associated with improved distant control (RR=0.75; 95% CI, 0.58 to 0.96). The adjusted 5-year distant failure rate was 48% with radiation and 58% without radiation (P=.02). OS also improved with radiation (RR=0.68; 95% CI, 0.53 to 0.85). The adjusted 5-year OS was 56% with radiation and 42% without radiation (P=.001). CONCLUSION In this cohort of high-risk breast cancer patients, XRT was associated with less loco-regional and distant failure and improved OS. This suggests that improved loco-regional control might decrease secondary systemic spread and improve survival.

WAF1/CIP1 protein expression in human breast tumors

WAF1/CIP1 is a cyclin-dependent kinase inhibitor which isdirectly induced by p53 and negatively controls cellproliferation. To test the hypothesis that increased levelsof WAF1 would be associated with a lowerS-phase fraction and better prognosis, WAF1 protein wasassessed by immunohistochemistry (IHC) in 115 node-negative humanbreast tumors, and results were correlated with establishedprognostic factors and clinical outcome. Nuclear staining wasobserved in malignant cells in 43% of tumors.In most (90%) of the positive tumors, theproportion of cells staining for WAF1 was low(< 10%). WAF1 was not detected in thecytoplasm, or in non-malignant epithelium. Contrary to expectations,the accumulation of p53 protein, a surrogate markerof p53 inactivation, was weakly but positively associatedwith WAF1 expression (p=0.05). Surprisingly, therewas no significant correlation with S-phase fraction, ERor PgR status, tumor size, age, ploidy, nucleargrade, or survival.Conclusion: WAF1 expression is found inthe nuclei of a small fraction of cellsin human breast tumors. WAF1 status is notsignificantly associated with cell proliferation, other established prognosticfactors, or clinical outcome.

Phase I and Pharmacologic Study of PN401 and Fluorouracil in Patients With Advanced Solid Malignancies

PURPOSE To assess the feasibility of administering PN401, an oral uridine prodrug, as a rescue agent for the toxic effects of fluorouracil (5-FU), and to determine the maximum-tolerated dose of 5-FU when given with PN401, with an 8-hour treatment interval between these agents. PATIENTS AND METHODS Patients with advanced solid malignancies were treated with escalating doses of 5-FU, given as a rapid intravenous infusion weekly for 3 consecutive weeks every 4 weeks. PN401 was administered orally 8 hours after 5-FU administration, to achieve sustained plasma uridine concentrations of at least 50 micromol/L. Initially, patients received 6 g of PN401 orally every 8 hours for eight doses (schedule 1). When dose-limiting toxicity (DLT) was consistently noted, patients then received 6 g of PN401 every 2 hours for three doses and every 6 hours thereafter for 15 doses (schedule 2). RESULTS Twenty-three patients received 50 courses of 5-FU and PN401. Among patients on schedule 1, DLT (grade 4 neutropenia complicated by fever and diarrhea) occurred in those receiving 5-FU 1,250 mg/m(2)/wk. Among patients on schedule 2, 5-FU 1,250 mg/m(2)/wk was well tolerated, but grade 4, protracted (> 5 days) neutropenia was consistently noted in those treated with higher doses of the drugs. Nonhematologic effects were uncommon and rarely severe. The pharmacokinetics of 5-FU, assessed in 12 patients on schedule 2, were nonlinear, with the mean area under the time-versus-concentration curve (AUC) increasing from 298 +/- 44 to 962 +/- 23 micromol/L and mean clearance decreasing from 34 +/- 4 to 15.6 +/- 0.38 L/h/m(2) as the dose of 5-FU was increased from 1,250 to 1,950 mg/m(2)/wk. 5-FU AUCs achieved with 5-FU 1,250 mg/m(2)/wk for 6 weeks along with the intensified PN401 dose schedule were approximately five-fold higher than those achieved with 5-FU alone. Plasma uridine concentrations increased with each of the three PN401 doses given every 2 hours, and uridine steady-state concentrations were greater than 50 micromol/L. CONCLUSION Treatment with oral PN401 beginning 8 hours after 5-FU administration is well tolerated and results in sustained plasma uridine concentrations above therapeutic-relevant levels. The recommended 5-FU dosage for phase II evaluations is 1,250 mg/m(2)/wk for 3 weeks every 4 weeks with the intensified PN401 dose schedule (schedule 2). At this dose, systemic exposure to 5-FU as measured by AUC was five-fold higher than that observed after administration of a conventional 5-FU bolus.

Significant activity of a novel cytotoxic agent, LY295501, against a wide range of tumors in the human tumor cloning system.

The diarylsulfonylureas (DSUs) are a novel class of cytotoxic agents with high potential for activity. LY295501 is one of the most active DSUs. In this study, we evaluated the cytotoxicity of LY295501 utilizing the human tumor cloning assay. LY295501 was tested at 10, 50 and 100 microg/ml using either 1 h or continuous exposure schedules. The majority of common solid tumors were evaluated including breast, colorectal, non-small cell lung and ovarian carcinomas. LY295501 demonstrated significant activity against all tumor types tested. Antitumor activity was noted after either 1 h or continuous exposure schedules at all concentrations tested. A concentration-response relationship was noted, with increasing concentrations of LY295501 leading to more cytotoxicity. Cytotoxicity, on the continuous exposure schedule, was noted in 38% of tumors exposed to LY295501 at 10 microg/ml, 58% of tumors exposed at 50 microg/ml (p=0.002 for 10 versus 50 microg/ml) and 72% of tumors exposed at 100 microg/ml (p=0.008 for 50 versus 100 microg/ml). In addition, more cytotoxicity was observed on the continuous exposure schedule compared to the 1 h schedule at all concentrations tested (p<0.01). The substantial activity of LY295501 in the human tumor cloning assay coupled with its clinical activity in phase I studies supports further clinical development of this agent.

Role of Altered Estrogen Receptors in Breast Cancer

Breast cancer is the most common malignancy in women in the United States, and is predicted to account for about 32% of new cancer cases in 1995 (Wingo et al., 1995). One of the first pieces of evidence to suggest that breast tumors depend on estrogen for growth comes from the observation, made more than a century ago, that oophorectomy can cause tumor shrinkage in women with metastatic breast cancer (Beatson, 1896). The discovery of the estrogen receptor (ER) as a mediator of estrogen’s biological effects revolutionized our understanding of breast cancer biology and eventually led to the classification of breast cancer into two major groups: those tumors that express the ER (ER-positive), and those tumors with undetectable levels of the ER (ER-negative). We now appreciate that each of these groups has its own distinct biological and clinical features.

Abstract B238: A phase 1 study of belinostat (PXD101) in combination with bortezomib in patients with advanced solid tumors or lymphoma

Background: Belinostat (B) is a low molecular weight, synthetic hydroxamic acid derivative that inhibits class I and II histone deacetylases. Bortezomib (Bz) is a potent, selective inhibitor of the 26S proteasome. In preclinical studies, synergistic antiproliferative and pro‐apoptotic effects were observed with the combination, providing the rationale for this study. Methods: This phase 1 study is designed to determine the maximum tolerated dose (MTD) and to evaluate the safety and pharmacokinetic (PK) behavior of the combination of B and Bz. Each 21‐day treatment cycle consists of B (600–1000 mg/m2) IV daily over 30 minutes on days 1–5 and Bz (0.7–1.5 mg/m2) IVP over 3–5 seconds on days 1, 4, 8, and 11 (days 2, 5, 8 and 11, cycle 1 only). Results: To date, 26 patients have been enrolled (median age 59 [range 27–72]; median PS 1 [range 0–1]). Twenty‐two patients were evaluable for toxicity and received a total of 58 treatment cycles (median 2 [range 1–6]). Four patients, 2 at dose level (DL) 3 (B: 600 mg/m2)/Bz: 1.3 mg/m2) and 2 at DL 5 (B: 1000 mg/m2)/Bz: 1.5 mg/m2) experienced a dose limiting toxicity (DLT). At DL 3, the DLTs were grade (gr) 3 dehydration and gr 4 thrombocytopenia. The exact relationship of the gr 3 dehydration and study combination is unclear as the patient had uncontrolled constipation and decreased oral intake as a result of a change in pain medications on cycle 1 day 1. This cohort was expanded to 9 pts to further determine tolerability of the study combination. No other DLTs were identified and dose escalation continued. At DL 5, DLTs included gr 4 thrombocytopenia and gr 4 fatigue. Most adverse events (AEs) have been mild to moderate. Gr 1–2 AEs (number of cycles) include anorexia (8), acute infusion reaction (5), fatigue (14), nausea (19), neutropenia (1), pain (12), phlebitis (6), thrombocyctopenia (11), and vomiting (12). Gr 3 AEs (occurring after course 1) include anorexia, dehydration, fatigue, nausea, vomiting, hypoalbuminemia, and elevation of alkaline phosphatase. Analysis of B PK demonstrates no statistical differences in the parameters between days 1 (B only) and 2 (B + Bz) for AUC, Cmax, clearance, or t1/2. Likewise, increasing Bz doses have no effect on B PK, whereas doses of B from 600 to 1000 mg/m2 result in dose‐proportional increases in drug exposure. Four patients have maintained stable disease for 4–6 cycles of therapy. Conclusions: Belinostat and bortezomib is a reasonable combination with a tolerable toxicity profile and no evidence of pharmacological interactions. Accrual is ongoing at the MTD, DL 4 (B: 1000 mg/m2)/Bz: 1.3 mg/m2). Additional biological assessments are planned in an expanded cohort of patients. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B238.

Abstract P1-09-02: Higher incidence of second cancers in African American (AA) patients compared to Caucasian patients with a primary breast cancer:

Background: AA women with breast cancer have lower survival rates compared to Caucasian women. Since this lower survival rate may be related to genetic mutations, and environmental/socioeconomically factors, we hypothesize that the same factors may lead to a higher risk of secondary cancers after an initial diagnosis of breast cancer. Method: Analysis of the Surveillance, Epidemiology, and End Results (SEER) Program data using Multiple Primary - Standardized Incidence Ratio parameters. The incidence of second cancer diagnoses in AA and Caucasian women previously diagnosed with breast was compared to the incidence of cancer in the general population matched by age, race, and year of diagnosis. Results are reported as the observed risk divided by the expected risk (O/E). Results: For the 43,688 AA pts, the overall O/E and excess risks were 1.48 and 51.2 compared to 1.11 and 14.7 for the 428,103 Caucasian patients. The mean ages of diagnoses of initial breast cancer diagnosis and second cancer were 57.2 and 65 years for AA patients compared to 61.8 and 70.2 years for Caucasian patients. The following is a summary of statically significant (p This higher risk of second cancers occurred despite the lower relative survival rate for AA compared to Caucasian patients with a 5-year relative survival rate of 68.6% for AA and 78.3% for Caucasian patients. Conclusions: To our knowledge, this is the first report of the incidence of second cancers in AA patients with breast cancer compared to caucasian. More research to understand the biological, genetic, therapeutic, and environmental factors leading to this higher risk of second cancers is warranted. Citation Format: Diab N, Clark G, Hamlington B, Brzeskiewicz L, Langer L, Diab S. Higher incidence of second cancers in African American (AA) patients compared to Caucasian patients with a primary breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-09-02.