Incurable Solid Tumors Research Articles

Electronic monitoring of symptoms and syndromes associated with cancer: methods of a randomized controlled trial SAKK 95/06 E-MOSAIC

BackgroundIn patients with advanced, incurable cancer, anticancer treatment may be used to alleviate cancer-related symptoms, but monitoring of them in daily practice is rarely done. We aim to test the effectiveness of a real-time symptom and syndrome assessment using the E-MOSAIC software installed in handheld computer generating a longitudinal monitoring sheet (LoMoS) provided to the oncologists in a phase III setting.MethodsIn this prospective multicentre cluster randomized phase-III trial patients with any incurable solid tumor and having defined cancer related symptoms, who receive new outpatient chemotherapy in palliative intention (expected tumor-size response rate ≤20%) are eligible. Immediately before the weekly visit to oncologists, all patients complete with nurse assistance the E-MOSAIC Assessment: Edmonton Symptom Assessment Scale, ≤3 additional symptoms, estimated nutritional intake, body weight, Karnofsky and medications for pain and cachexia. Experienced oncologists will be randomized to receive the LoMoS or not. To minimize contamination, LoMoS are removed from the medical charts after visits. Primary endpoint is the difference in global quality of life (items 29 & 30 of EORTC-QlQ-C30) between baseline and last study visit at week 6, with a 10 point between-arm difference considered to be clinically relevant. 20 clusters (=oncologists) per treatment arm with 4–8 patients each are aimed for to achieve a significance level of 5% and a power of 80% in a mixed model approach. Selected co- variables are included in the model for adjustment. Secondary endpoints include patient-perceived patient-physician communication symptom burden over time, and oncologists’ symptom management performance (predefined thresholds of symptoms compared to oncologists’ pharmacological, diagnostic or counselling actions [structured chart review]).DiscussionThis trial will contribute to the research question, whether structured, longitudinal monitoring of patients’ multidimensional symptoms, indicators for symptom management, and clinical benefit outcomes can influence patients’ quality of life and symptom distress, in a setting of routine oncology practice.Trial registrationCurrent Controlled Trials NCT00477919

Phase I trial of pomalidomide given for patients with advanced solid tumors

To determine the safety, the maximal tolerated dose, and to assess for any clinical activity of pomalidomide given to patients with advanced solid tumors. Patients with incurable solid tumors were enrolled. Two different dosing schedules were explored. In Cohort A patients were given pomalidomide once daily for 21days followed by a 7day rest. For Cohort B additional patients were recruited to receive pomalidomide given once daily for 28 consecutive days. Dose-limiting toxicity was defined as ≥grade 3 non-hematological toxicity that occurs during cycle 1 and that does not resolve to ≤grade 1 by day 35. Subjects must have received optimal symptomatic treatment for ≥grade 3 nausea, vomiting, or diarrhea to be considered a DLT. Grade 4 transaminitis was considered to be a DLT while grade 3 transaminitis must be present >7days to be a DLT. Grade 3 febrile neutropenia was considered a DLT. Grade 4 neutropenia, without a fever, was a DLT if the neutropenia did not improve to ≤grade 1 by day 35 of cycle one. Platelet count ≤25,000/mm(3) must improve to ≥75,000/mm(3) by day 35 of cycle one in order not to be considered a DLT. If a patient did not complete one cycle of therapy, for reasons other than a DLT, a replacement subject was added to the same cohort level. A total of 40 patients were enrolled. In Cohort A, three patients received pomalidomide at 5mg daily without any significant toxicity. Two patients in the 10mg cohort experienced dose-limiting toxicities of two episodes of grade 3 dyspnea and one grade 4 neutropenia. Six patients were then enrolled at the 7mg daily of pomalidomide, and no dose-limiting events were observed. In Cohort B, 29 patients were enrolled and the maximal tolerated dose was 4mg once daily. Stable disease in a variety of tumors was observed. Pomalidomide was well tolerated and the recommended phase II dosing schedules are 7mg daily given for 21days followed by a 7-day rest or pomalidomide 4mg given on an uninterrupted daily schedule.

Phase I study of sequential sapacitabine and seliciclib in patients with advanced solid tumors.

3053 Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite CNDAC generates ss DNA breaks that are converted to ds DNA breaks (DSB) during subsequent replication, resulting in cell death if unrepaired. CNDAC-induced DSB repair is dependent on homologous recombination (HR). Seliciclib is a potent orally bioavailable inhibitor of CDK2, 7 and 9, and sensitizes cells to CNDAC by decreasing DSB repair via compromise of HR protein activation and transcriptional inhibition of HR components. This phase I study evaluates sequential sapacitabine and seliciclib. Methods: Dose escalation was conducted in patients with incurable solid tumors and adequate organ function with sapacitabine b.i.d. x 7 consecutive days (d1-7), seliciclib b.i.d. x 3 consecutive days (d8-10) followed by 11 days of rest. At least 3 patients were evaluated per dose level. MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine (d8 vs pre-treatment) and further augmentation of DNA damage after seliciclib (d11 vs d8). Results: 27 patients were treated. The MTD and RP2D is sapacitabine 50 mg b.i.d./seliciclib 1200 mg b.i.d. DLTs were reversible transaminase elevations and neutropenia. The most frequent adverse events (all cycles, regardless of causality) included anorexia, fatigue, abdominal pain, dizziness, nausea, anemia, neutropenia, creatinine elevation, hyperglycemia, hyperbilirubinemia, hypophosphatemia, hypokalemia and hypomagnesemia, the majority mild to moderate in intensity. Skin biopsies showed a 2.3-fold increase in H2AX staining post-sapacitabine (n=16; p=0.007) and a further 0.58-fold increase post-seliciclib (n=12; p=0.069). Two confirmed PRs occurred in patients with pancreatic and breast cancer, both BRCA mutation carriers. SD as best response >/= 12 weeks was observed in 6 additional patients, including one BRCA mutation carrier with ovarian cancer (ongoing at 24 weeks). Conclusions: Sequential sapacitabine and seliciclib is safe with preliminary antitumor activity. BRCA mutation carrier status may be a potential biomarker for response across multiple tumor types.

Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial

Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases. We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours, including those with non-Val600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and non-melanoma solid tumours. This study is registered with ClinicalTrials.gov, number NCT00880321. We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9-83·7) and confirmed responses in 18 (50%, 32·9-67·1). 21 (78%, 57·7-91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3-74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer. Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours. GlaxoSmithKline.

P1-12-20: The Safety and Tolerability of Vorinostat in Combination with Lapatinib in Advanced Solid Tumors.

Abstract Background: Lapatinib has been previously shown to markedly decrease cancer stem cells (CSC) in HER2−positive breast cancer. In preclinical models, we have demonstrated that histone deacetylase inhibitors (HDACi) such as vorinostat can induce differentiation and decrease CSC. The combination of vorinostat and lapatinib is synergistic with a combination index of 0.32 (synergism if CI <1). We therefore undertook a pilot study to evaluate the combination of these two drugs in advanced solid tumors. Method: Patients were eligible if they were: age ≥ 18 years with incurable solid tumors, ECOG PS 0–2, adequate organ function, and no prior exposure to HDACi. The first 3 patients received lapatinib at the dose of 1,250 mg continuous daily and vorinostat 300 mg 4 days on 3 days off. The second dose level with lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off were administered in 6 patients. Cycles were repeated every 21 days until disease progression. Echocardiogram and radiologic evaluation were performed every 12 weeks. During the first cycle, pharmacokinetic (PK) evaluation was performed on days 18 and 21. Results: Nine consented patients (7 with metastatic breast cancer, 1 with non-small cell lung cancer, and 1 with thyroid cancer) have been enrolled with the median age of 52 (range 25–66). Patients received an average of 6 prior treatments (range 2–10). No dose limiting toxicity or drug related death have been observed. Grade 1–2 toxicities including diarrhea, fatigue, muscle cramps and stomatitis were observed. No grade 3 or 4 hepatic, renal or cardiac toxicity were observed (including no QTc prolongation and no significant reduction in the left ventricular ejection fraction). Patients have received the maximum of 7 cycles (median 3 cycles, range 2–7). Response: as of June 2011, 2 patients are still on treatment. Two patients achieved stable disease (triple negative metastatic breast cancer and HER2−positive breast cancer), 6 patients with progressive disease, and 1 patient is too early to evaluate for response. PK analysis will be presented at the time of the meeting. Conclusions: The combination of vorinostat and lapatinib is tolerable and has some antitumor activity in heavily pretreated advanced solid tumors. A phase II study in HER2−positive metastatic breast cancer is underway with lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-20.

Abstract A89: A phase I study of the novel DNA topoisomerase-1 inhibitor, TLC388 (Lipotecan®), administered intravenously to patients with advanced solid tumors.

Abstract Introduction: TLC388 (Lipotecan) is a potent Topoisomerase-1 inhibitor and it can disrupt both Sonic Hedgehog and HIF1-α pathways to overcome cancer drug resistance and inhibit angiogenesis induced by tumor hypoxia. This phase I first-in-human study of Lipotecan examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles of TLC388 in patients with advanced incurable solid tumors. Methods: Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle. Patients underwent safety assessments regularly and tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2 for all treated patients. Results: The enrollment for this study has been concluded and 54 previously-treated patients with advanced or metastatic solid tumors received Lipotecan. The dose was escalated from 1.5 mg/m2 to 60 mg/m2 over 12 patient cohorts (11 dose levels). MTD was reached at 50 mg/m2, following the emergence of two DLTs at 60 mg/m2: one grade 3 febrile neutropenia and one toxicity that precluded treatment within the 14 days specified by the protocol. Other DLTs occurred in other dose levels include hyponatremia (grade 3 and 4; 40 mg/m2) and thrombocytopenia (grade 4; 40 mg/m2). To date, all the subjects except one have completed the study. Lipotecan given at this dosing schedule was well-tolerated and no cumulative toxicity was observed. Non-hematological toxicity was generally mild, including fatigue (41%), nausea (37%), diarrhea (28%), vomiting (14%) and constipation (14%). Anemia was the most frequently reported hematological toxicity (67.0%). Neutropenia (30%), thrombocytopenia (28%), and leukopenia (26%) were also reported. Grade 3 or grade 4 hematological toxicity included neutropenia (28%), anemia (22%), leucopenia (17%), and thrombocytopenia (13%). Other G3/4 non-hematological side effects included hyponatremia (11%), abdominal pain (7%), fatigue (6%), and hypokalaemia (6%). Twenty one of 35 evaluable patients (60%) continued therapy beyond cycle 2, received a median of 5 cycles (range of 2–18 cycles), and experienced stable disease or minor tumor regression. Prolonged (≥ 6 months) stable disease was noted in 9 patients (26%), including renal (chromophobe and clear cell types), docetaxel refractory prostate, salivary gland, sorafenib refractory hepatic, and vaginal cancers. One minor response occurred in a heavily pretreated 70-year-old male with stage II B thymoma cancer metastatic to lung, liver and lymph nodes who was treated for 18 courses and remains on the study. PET-CT scan revealed reduction in his tumor size by 27% at the end of cycle 16. His disease had progressed through prior treatment with cyclophosphamide, cisplatin and doxorubicin. Pharmacokinetics of TLC388 were dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m2 for S,R-TLC388 and 996 (1333) L/m2 for S,S-TLC388, and 7420 (8151) L/h-m2 for S,R-TLC388 and 4949 (5678) L/h-m2 for S,S-TLC388, respectively. The half-life values averaged 0.76 (1.15) hours for S,R-TLC388 and 0.75 (1.13) hours for S,S-TLC388. Conclusions: Lipotecan administered doses up to 50 mg/m2 on current treatment schedule is safe, well tolerated, and demonstrates broad antitumor activity to support Phase 2 disease-specific investigations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A89.

Modulation of angiogenic biomarkers in patients treated on a phase I study of TRC105 (anti-CD105 antibody) monotherapy for advanced solid tumors.

10565 Background: CD105 (endoglin) is an important mediator of tumor angiogenesis that is upregulated by hypoxia and VEGF inhibitors. TRC105 is an anti-CD105 monoclonal antibody currently being evaluated in clinical trials as an anti-angiogenic cancer therapy. Methods: In this first-in-human phase I study, pts with advanced, incurable solid tumors were treated with escalating doses of TRC105, iv every 2 wks, until disease progression. Serial plasma samples were analyzed via a novel multiplex ELISA platform optimized for cancer patients. 39 candidate biomarkers related to tumor growth, angiogenesis, and inflammation were assayed at baseline (BL), after 1 month, and at end of study (EOS). Results: 19 pts treated with TRC105 at 0.01-1 mg/kg were evaluable for biomarker analysis. Spearman’s rank correlation coefficients were calculated for pairs of analytes with known interactions. Wilcoxon signed rank tests indicated that the following analytes were significantly down-regulated at one month when compared with baseline: IGFBP-3 (p=0.001), VEGF-C (p=0.002), VEGF-D (p=0.003), FGFb (p=0.008), PDGF-AA (p=0.011), PDGF-BB (p=0.039), and PIGF (p=0.045). By EOS, significant increases from the 1 month nadir were observed for the following analytes: VEGF-C (p=0.027), VEGF-D (p=0.034), and IGFBP-3 (p=0.043). Conclusions: This is the first systematic investigation of the effect(s) of TRC105 on angiogenic biomarkers in the clinical setting. Multiplex analyses indicate that TRC105 therapy is associated with down-regulation of key modulators of angiogenesis that later increase at the time of disease progression. Based on these preliminary findings, additional analyses are planned for pts treated at higher TRC105 doses as well as pts treated on phase Ib and phase II studies of TRC105 in combination with VEGF inhibitors and other standard-of-care cancer therapies.

A phase I study of the novel DNA topoisomerase-1 inhibitor, TLC388, administered intravenously to patients with advanced solid tumors.

e13618 Background: The phase I first-in-human study of TLC388 (Lipotecan) examined the MTD, safety, anti-tumor activity and pharmacokinetic profiles in patients with advanced incurable solid tumors. Methods: Lipotecan was administered intravenously on day 1, 8 and 15 of a 28-day cycle. Patients underwent tumor assessments every other cycle. Pharmacokinetic samples were drawn on days 1, 8 and 15 of cycles 1 and 2. Results: Fifty four previously treated patients with advanced or metastatic solid tumors were enrolled The dose was escalated from 1.5 mg/m2 to 60 mg/m2 over 12 patient cohorts. MTD was reached at 50 mg/m2. DLTs above that dose were thrombocytopenia and febrile neutropenia. Treatment was well-tolerated and no accumulated toxicity seen. Treatment related G3/4 hematological toxicity include neutropenia (19%), leucopenia (15%), anemia (9%), and thrombocytopenia (7%). G3/4 non-hematological side effects were diarrhea (2%) and hyponatremia (4%). Twenty one of 35 evaluable patients (60%) continued therapy beyond cycle 2, received a median of 4.5 cycles (2-12 cycles), and had stable disease or minor tumor regression. Prolonged (≥ 6 months) stable disease was noted in 8 patients (23%), including renal (chromophobe and clear cell types), docetaxel refractory prostate, salivary gland, sorafenib refractory hepatic, and vaginal cancers. One minor response occurred in a heavily pretreated 70-year-old male with stage II B thymoma cancer metastatic to lung, liver and lymph nodes who was treated for 12 courses and remains on the study. PET-CT scan revealed tumor size reduction of 22% at cycle 10. Pharmacokinetics of TLC388 was dose-independent; mean (SD) values for the volume of distribution at steady-state and clearance were 857 (1122) L/m2 for S,R-TLC388 and 996 (1333) L/m2 for S,S-TLC388, and 2174 (2526) L/h-m2 for S,R-TLC388 and 2670 (2988) L/h-m2 for S,S-TLC388, respectively. The half-life values averaged 0.67 (1.15) hours for S,R-TLC388 and 0.64 (1.11) hours for S,S-TLC388. Conclusions: Lipotecan at dose of 50 mg/m2 on current treatment schedule is safe, well tolerated, and demonstrates broad antitumor activity to support phase II disease-specific investigations.

IL-4R Drives Dedifferentiation, Mitogenesis, and Metastasis in Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. The alveolar subtype of rhabdomyosarcoma (ARMS) is a paradigm for refractory and incurable solid tumors because more than half of the children at diagnosis have either regional lymph node or distant metastases. These studies follow our previous observation that Interleukin-4 receptor α (IL-4Rα) is upregulated in both human and murine ARMS, and that the IL-4R signaling pathway may be a target for abrogating tumor progression. By in vitro biochemical and cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of IL-4 and IL-13 in IL-4R-mediated mitogenesis, myodifferentiation, and tumor progression. IL-4 and IL-13 ligands accelerated tumor cell growth and activated STAT6, Akt, or MAPK signaling pathways in the human RMS cell lines, RD and Rh30, as well as in mouse primary ARMS cell cultures. IL-4 and IL-13 treatment also decreased protein expression of myogenic differentiation factors MyoD and Myogenin, indicating a loss of muscle differentiation. Using a genetically engineered mouse model of ARMS, we have shown that inhibition of IL-4R signaling pathway with a neutralizing antibody has a profound effect on the frequency of lymph node and pulmonary metastases, resulting in significant survival extension in vivo. Our results indicate that an IL-4R-dependent signaling pathway regulates tumor cell progression in RMS, and inhibition of this pathway could be a promising adjuvant therapeutic approach.

Phase I trial of dasatinib (D) and lapatinib (L).

2610 Background: Src transduces HER tyrosine kinase activation and phosphorylates HER to further increase its activity. Src also promotes osteoclast differentiation. We performed a phase I trial of D+L to: 1) determine the maximally tolerated dose (MTD) of D+L; 2) describe the toxicities; 3) assess the pharmacokinetic (PK) interaction of L+D; 4) assess the effect of D+L on circulating osteoclast/macrophage precursor (COMP) activation; 5) correlate the clinical endpoints with the PK parameters, and/or biologic results; and 6) describe the responses of this treatment. Methods: Eligibility criteria included ≥ 18 years of age, incurable solid tumors not amenable to other therapies, adequate organ function, normal K+ and Mg++, life expectancy ≥ 12 weeks, ejection fraction > 50%, ECOG PS 0-2, and able to swallow pills whole. Each agent was administered once daily on a 28-day schedule. At the MTD patients were treated with D day 1, and day 9-28 and L day 2-28. Dose levels (mg) were 1) D 70, L 1,000, 2) D 100, L 1,000, 3) D 140, L 1,000. Results: 12 patients were entered on the dose escalation part of the trial and 15 were entered at the MTD. Characteristics of evaluable patients were: median age, 61; 44% female; PS 0 (8%) 1 (65%), 2 (27%). DLT was seen in 2 patients at dose 3. One patient had grade 3 hypermagnesemia and 1 patient had grade 3 rash. The MTD was 100 mg of D and 1,000 mg of L once daily. Despite large variability in the PK data, it appeared that systemic exposure to D and L were increased by concomitant use in a concentration dependent manner. However, in most patients, the magnitude of this effect was small. No grade 4 or 5 events have been observed. One RCC and 2 CRC patients were stable for 6 months, 1 leiomyosarcoma was stable for 5 months and 1 CRC and 1 esophageal ca were stable for 3 months. COMP levels either increased and persisted or increased initially and then returned to baseline at day 28. Conclusions: D+L are tolerable at clinically relevant doses so the possible PK interaction of L and D may have little clinical significance. D+L affects levels of COMP. Studies of D+L in breast, esophageal, and CRC are warranted. Funded by a grant from GlaxoSmithKline and Bristol-Myers Squibb. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline

Phase I study of AV-412, a novel, irreversible EGFR inhibitor, administered intermittently in patients with advanced solid tumors.

3103 Background: AV-412, an irreversible EGFR TKI, has demonstrated activity in chimeric mouse models bearing the L858R/T790M mutation. A daily dosing study identified a maximally tolerated dose (MTD) of 150 mg/day [AACR-NCI-EORTC 2009]. The goals of this study were to determine the MTD, safety, dose limiting toxicity (DLT), pharmacokinetics (PK), and activity of AV-412 administered on two intermittent dosing schedules. Methods: Patients (pts) with incurable solid tumors were enrolled and administered AV-412 orally three times a week (TIW). Once the MTD was identified, a once weekly (OW) schedule was evaluated. Doses ranged from 100-200 mg TIW to 200-500 mg OW. Results: 36 patients were treated: 26 males/10 females, median age 60 years (range 27-80). ECOG PS 0/1 (21/15 pts). Tumor types were colorectal (17), pancreatic (4), appendiceal (3), esophageal (2), NSCLC (2), and other (8). Median number of prior treatments were 4 (range 0-14). Twenty-four pts (66.7%) received a prior EGFR inhibitor. The median duration of treatment was 49 days (range 1- 99). Two pts experienced DLT in cycle 1 at 200 mg TIW (grade 3 nausea and vomiting, and grade 3 diarrhea), therefore the MTD was 100 mg. In the OW schedule, two pts experienced DLT in cycle 1 at 500 mg (grade 3 acute renal failure, and grade 3 diarrhea) and 400 mg OW was declared the MTD. Common treatment-related adverse events (all grades) were nausea (69.4%), diarrhea (55.6%), vomiting (41.7%), and fatigue (27.8%). Treatment-related skin rash was rare (2.7%). Preliminary PK data showed less than dose proportional exposure and high interpatient variability. Preliminary efficacy data revealed 8 pts had stable disease with a median duration of 7.7 weeks. Conclusions: AV-412 is well tolerated at 400 mg once weekly. The OW schedule was able to achieve a higher MTD and Cmax when compared to daily dosing. Additional studies are under discussion. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AVEO AVEO

Phase II Study of Cediranib, an Oral Pan–Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma

Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma. Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points. Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell-derived factor-1alpha, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival. Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.

Phase I Trial of Bortezomib and Concurrent External Beam Radiation in Patients With Advanced Solid Malignancies

To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy. An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0 mg/m(2), 1.3 mg/m(2), and 1.6 mg/m(2)/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, defined as any grade 4 hematologic toxicity, any grade ≥3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for ≥2 weeks. A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6 mg/m(2). One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients). The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6 mg/m(2) is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6 mg/m(2).

Abstract C31: Phase 1 study of AV-412, a novel irreversible EGFR inhibitor, administered daily in patients with advanced solid tumors

Abstract Background: Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib is a frequent clinical phenomenon in non-small cell lung cancer (NSCLC). Approximately 50% patients (pts) with acquired resistance to EGFR TKIs demonstrate the T790M mutation in EGFR gene. AV-412, an irreversible EGFR TKI, has demonstrated activity in chimeric mouse models with acquired resistance to EGFR TKIs (bearing the T790M mutation), and is being developed for treatment of NSCLC. Methods: Pts with advanced, incurable solid tumors were enrolled in a phase 1 study and administered AV-412 orally once-a-day. Doses evaluated were: 50mg, 100mg, 150mg and 200mg. The goals of the study were to determine the maximum tolerated dose (MTD), safety, dose limiting toxicity (DLT), pharmacokinetics (PK) and activity of AV-412. Results: 24 pts were treated: 13 males/11 females, median age 61 yrs (range 32–73). ECOG PS 0 (17 pts) or 1 (7 pts). Tumor types (No. of pts) were colorectal (5), NSCLC (3), pancreatic (3), uterine (3), melanoma (2), ovarian (2), hepatocellular (1), breast (1), head and neck (1) and other (3). Mean number of prior treatments were 6 (range 1–15). Five (20.8%) pts had received prior therapy with an EGFR inhibitor. The median duration of treatment was 32.5 days (range 7 – 214 days). Two pts experienced DLT at 200mg (grade 3 nausea and vomiting, and grade 3 diarrhea), following which anti-emetic premedications were instituted in the study. The MTD of AV-412 was 150mg; 11 pts were treated at this dose. The most common treatment-related adverse events (all grades) were nausea (54.2%), diarrhea (45.8%), and vomiting (41.7%); hematologic abnormalities included lymphopenia, increased INR, anemia, and leucopenia (12.5% each), hepatic and renal abnormalities included increased ALT, increased AST, and proteinuria (12.5% each). Drug-related laboratory abnormalities were generally mild to moderate in severity. Preliminary PK data indicate dose proportional exposure. Three patients had disease stabilization > 16 weeks: 2 pts with colorectal cancer (116 days, 170 days) and a pt with ovarian cancer (172 days). Conclusions: AV-412 is well tolerated at a dose of 150 mg/day. The most frequent toxicities were nausea and diarrhea, which could be controlled with standard medications. This study is currently enrolling a cohort of patients with NSCLC to evaluate clinical activity of AV-412 in patients with EGFR mutations, and updated results will be available for presentation. A phase 1 study of intermittent dosing of AV-412 is also being conducted. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C31.

Abstract B56: A phase I trial of the combination of dasatinib and lapatinib

Abstract Src transduces activated HER tyrosine kinase and phosphorylates HER to further increase its activity. Src also is involved in osteoclast differentiation. We hypothesized that combining a HER tyrosine kinase inhibitor with a Src inhibitor would result in increased therapeutic activity. To address this hypothesis we performed a phase I trial of D and L to: 1)determine the maximally tolerated dose (MTD) of D combined with L; 2)describe the toxicities associated with this combination; 3)assess the pharmacokinetic (PK) interaction of L and D; 4) assess the effect of the L and D combination on circulating tumor cells (CTC) and on osteoclast precursor activation; 5)study the association of toxicity and/or tumor response with PK, and/or pharmacodynamic parameters; and 6)describe the responses of this combination. Eligibility criteria included ≥ 18 years of age, incurable solid tumors not amenable to other therapies, ANC ≥ 1500/ L, PLT ≥ 100,000/ L, total bilirubin ≤ ULN, AST ≤ 3 × ULN or AST ≤5 × ULN if liver involvement, creatinine ≤ 1.5 × ULN, Hgb ≥ 9.0 g/dL, K+ and Mg++ WNL, life expectancy ≥ 12 weeks, ejection fraction > 50%, ECOG PS 0–2, and able to swallow pills whole. In addition to standard phase I exclusion criteria patients could not have received erlotinib, sunitinib, sorafenib, gefitinib, imatinib ≤ 4 weeks prior to registration. Each agent was administered once daily on a 28 day schedule. At the MTD patients were treated with D day 1, and day 9–28 and L day 2–28 to assess PK interaction. Dose levels (mg) were #1 D 70, L 1000, #2 D 100, L 1000, #3 D 140, L 1000. 12 patients were entered on the dose escalation portion of the trial and 15 were entered at the MTD. 5 patients entered at the MTD are too early to be fully evaluable. Characteristics of evaluable patients were: median age, 63; 46% female; PS 0 (64%) 1 (27%), 1 (9%); ≥ 3 prior chemotherapies (59%). DLT was seen in 2 patients at # 3 (1 patient, grade 3 hypermagnesemia, 1, grade 3 rash) and 1 patient at # 2 (grade 3 dyspnea). The MTD was determined to be # 2. No grade 4 or 5 events have been observed in this study. 6 patients had stable disease in the dose escalation cohort. 1 (RCC) was stable disease for 6 cycles, 2 (colorectal) were stable for 5 cycles, 1 (esophagus) was stable for 3 cycles, and 2 (GIST & leiomyosarcoma) were stable for 2 cycles. Analysis of drug levels, CTCs and circulating osteoclast precursors is ongoing. There was a consistent increase in the percentage of CD11b (monocyte/macrophage/osteoclast lineage marker) positive cells in circulation as treatment progressed. However, the late osteoclast lineage marker c-Fms was not similarly increased, suggesting that the elevated CD11b reflects an inflammatory response and not activation of osteoclastogenesis. D and L is a tolerable combination at nearly full doses of each drug. Funded by a grant from Glaxo Smith Kline and Bristol Myers Squibb. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B56.

Abstract A184: A phase I study of 5-azacytidine (AZA) and erlotinib (E) for patients (pt) with advanced solid tumors

Abstract Background: Erlotinib (E), a tyrosine kinase inhibitor of EGFR, is approved for non-small cell lung cancer. 5-Azacytidine (AZA) is approved for leukemia. AZA traps DNA methyltransferase (DMT) in a covalent complex with DNA resulting in a progressive loss of DNA methylation, at concentrations that do not cause major suppression of DNA synthesis. Hypomethylation reactivates previously quiescent genes and may restore the function of genes that control cell proliferation and differentiation, such as EGFR. Methods: A standard 3+3 phase I study of the combination of E and AZA was planned in patients with incurable solid tumors. E was given at full dose (150 mg/day continuously). Vidaza was given intravenously every 2 weeks at a starting dose of 75 mg/m2/day ×1 day. Increments were by number of AZA days: The second cohort received 2 consecutive days of Vidaza, the third, 3 days, the fourth, 4 days. One course was 4 weeks. Standard grade 3 and 4 DLTs (CTCAE version 3) were recorded on the first course of treatment. RECIST criteria were used to determine response. Results: 18 adult patients (pt) have been enrolled. Cohort 1: 6 pt; cohort 2, 3 pt; cohort 3, 6 pt; cohort 4, 3 pt. DLTs included eye infection (1 pt in cohort 1) and a neutropenic sepsis in cohort 3. Both cohorts were expanded. Overall AEs were: grade 3 rash, diarrhea, and hypokalemia (1 each (5%)); grade 1–2 rash (60%), nausea/vomiting (38%), diarrhea (38%), fatigue (33%), mouth sores and dysgeusia (22% each), hypokalemia (16%), transaminase increase (11%), neutropenia (5%), pneumonitis (5%), urticaria (5%). The maximum tolerated dose has not been reached at 75 mg/m2/day × 4 days every 2 weeks. Enrollment will continue until AZA 100 mg/m2/day × 4 days is reached. ORR is 5% with a clinical benefit rate of 40%, and the median number of courses given is 2 (range 1–6). Conclusions: The combination of E and AZA is well tolerated with no synergistic toxicities. The main AEs are rash and gastrointestinal. E+AZA has modest but definite activity in patients with refractory tumors, and long disease stabilization are observed in selected patients. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A184.

A phase II randomized study of oral seliciclib in patients with previously treated nasopharyngeal carcinoma

6026 Background: Seliciclib is a selective inhibitor of cyclin dependent kinases (CDKs) 2, 7 and 9. In a phase I study of 2 weeks of oral administration, clinical antitumor activity was observed in patients with treatment-naive nasopharyngeal carcinoma (NPC) and biological effects consistent with CDK inhibition were detected in tumor biopsy samples. We are conducting a multicenter, randomized phase 2 study to evaluate the safety and efficacy of prolonged administration of seliciclib in patients with previously treated NPC. The study has a lead-in phase where the safety and tolerability of 2 dosing schedules of seliciclib are to be confirmed in patients with advanced solid tumors (including NPC) before being used in the randomized phase of the study where only NPC patients are eligible to participate. The primary efficacy endpoint is 6-month progression free survival. Here we report interim findings from the lead-in phase. Methods: Eligible patients must be ≥18 years with previously treated NPC or other incurable solid tumors; must have measurable disease according to RECIST, ECOG 0–1, and adequate bone marrow, hepatic and renal function. The planned sample size is 6 to 12 patients per dosing schedule. A dosing schedule is considered tolerable for proceeding to the randomized phase if <33% patients experienced dose-limiting toxicities (DLT) during the first treatment cycle. Results: Twenty-three patients (age 38 - 74) were enrolled and treated. DLTs were observed in 4 patients: grade 3 increase in ALT or AST (n=3), and treatment delay > 2 weeks for grade 1 creatinine (n=1). Common adverse events (all grades, regardless of causality) included fatigue, nausea/vomiting, constipation, cough, fever, hypokalemia, hyponatremia, and elevation in ALT/AST, most of which were mild to moderate in intensity. Conclusions: These interim data confirm that both dosing schedules are tolerable for proceeding to the randomized phase. Majority of stable disease occurred in NPC patients. Updated data will be presented at the meeting. [Table: see text] No significant financial relationships to disclose.

A phase I study of nab-paclitaxel in patients (pts) with advanced solid tumors and hepatic dysfunction

13503 Background: 130-Nanometer albumin-bound paclitaxel (nab-pac, nab-paclitaxel) 260 mg/m2 produced an increased objective response rate (ORR) in comparison with solvent-based paclitaxel (sb-pac) 175 mg/m2 (33% vs. 19%, p = .001) and a favorable safety profile in pts with metastatic breast cancer. [Gradishar et al, JCO, 2005] To address concerns about potential life-threatening toxicities in pts with hepatic impairment, we studied nab-paclitaxel in pts with incurable solid tumors using the same percentage dose reductions recommended for sb-pac according to degree of hepatic dysfunction (Taxol Package Insert). The safety profile was the primary objective secondary objective is assess antitumor activity in those pts with measurable disease. Methods: In this open-label, parallel design study, nab-pac was administered IV over 30 minutes every 3 weeks to pts with advanced solid tumors. Pts with AST > upper limit of normal (ULN) and < 10×ULN and bilirubin ≤ 5.0×ULN were included. nab-pac dosing was determined...

Treatment of otherwise incurable tumor diseases in childhood using whole-body hyperthermia and chemotherapy

Conventional methods of treatment having failed in 17 children (aged 9/12 to 16 5/12 years) with incurable solid malignant tumours underwent whole-body hyperthermia (41.8-42.0 degrees C, for 2-3 h), hyperglycaemia (20-25 mmol/l) and polychemotherapy. Five children had neuroblastoma (stage 4), three Wilm's tumour (stage 4 or 5, unfavourable histology), five skeletal sarcoma with metastases, three inoperable malignant liver tumour, and one brainstem tumour of unknown histology. Whole-body hyperthermia was induced by extracorporeal blood warming in an haemodialysis apparatus under neuroleptic analgesia, thermistors measuring the temperature in the oesophagus, rectum, trachea and skin. There were on average four treatment sessions (between one and ten, total 58), a week apart. The result could be assessed in 12 children: one persisting complete remission (19 months-metastasising renal rhabdoid tumour), eight partial or incomplete remissions, and three nonresponders (osteogenic sarcoma; Ewing sarcoma; brainstem tumour). If the risk can be satisfactorily judged the method is useful and of bearable toxicity. The results point to a high antitumour effectiveness of combined hyperthermia and chemotherapy.

A phase I study of oxaliplatin in combination with gemcitabine: correlation of clinical outcome with gene expression

Oxaliplatin has in vitro activity similar to or higher than other platinum agents. Preclinically, gemcitabine has demonstrated synergy when combined with platinum compounds. These facts formed the rationale for determining the maximum tolerated dose (MTD) of gemcitabine in combination with oxaliplatin. Eligible patients with advanced incurable solid tumors were given oxaliplatin 130 mg/m2 as a 2-h infusion on day 1 followed by escalating doses of gemcitabine given over 30 min on day 1 and 8 of a 21-day cycle. A total of 43 patients were enrolled, including 30 patients at the MTD in an expanded cohort. At a gemcitabine dose of 800 mg/m2, 1/6 patients had a dose limiting toxicity (DLT) (grade 3 blurred vision and memory loss). At 1,000 mg/m2, 1/6 patients had a DLT (grade 3 increase in AST). At 1,200 mg/m2, 2/3 patients had a DLT (grade 4 thrombocytopenia and grade 3 confusion). The MTD of gemcitabine with 130 mg/m2 of oxaliplatin was therefore 1,000 mg/m2. The clearances of gemcitabine and ultrafilterable platinum are within the ranges previously reported for single agents. A patient with colon cancer had a partial response, and 21 patients had a best response of stable disease. In patients with tumor biopsies treated at the MTD, decreased ribonucleotide reductase M2 expression correlated with response. Treatment with gemcitabine and oxaliplatin was well tolerated with primarily hematologic toxicity at the MTD. Study of biochemical correlates of response remain of interest thought current results remain exploratory.