Therapy for high-risk neuroblastoma (HR NBL) is comprised of multimodal therapy including chemoth... more Therapy for high-risk neuroblastoma (HR NBL) is comprised of multimodal therapy including chemotherapy, surgery, radiation therapy, myeloablative therapy followed by autologous hematopoietic stem cell transplant, and immunotherapy. GD2 is a disialoganglioside that is highly expressed on the surface of neuroblastoma cells, with limited expression on normal tissues, which makes it an attractive target for immunologic therapy. The combination of immunotherapy with murine and chimeric anti-GD2 antibody formulations has improved outcomes compared with standard therapy in HR NBL patients. Naxitamab (Danyelza), a fully humanized anti-GD2 antibody, was developed at Memorial Sloan Kettering Cancer Center (MSKCC) to mitigate adverse reactions related to intolerance of foreign murine and chimeric antigens. Phase I and II studies demonstrating the tolerability and efficacy of naxitamab in patients with relapsed/refractory (r/r) HR NBL prompted its approval by the U.S. Food and Drug Administrati...
9547 Background: Irinotecan has shown antitumor activity in a number of pediatric tumors. In adul... more 9547 Background: Irinotecan has shown antitumor activity in a number of pediatric tumors. In adults with colorectal cancer, combining irinotecan with cetuximab enhances clinical activity as compared to treatment with irinotecan alone. We implemented this first-in- pediatrics phase I study to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of cetuximab and irinotecan in pediatric patients. Methods: 35 heavily pre-treated pts with refractory solid tumors were enrolled: brainstem glioma/astrocytoma (16), hepatoblastoma (4), neuroblastoma (2), other (13). Weekly cetuximab was escalated in 3 sequential dose levels: 75, 150 or 250mg/m2; Irinotecan was given at 16 or 20 mg/m2/day over 1 hour [daily × 5] for two weeks, every 21 days. Correlative EGFR expression (immunohistochemistry and FISH) and/or mutations, pharmacokinetics (PK) of and immune response to cetuximab were performed. Results: Pts were treated in two age cohorts (ages 1–12 yrs = Group A, and 13...
Classical Hodgkin lymphoma treatment is evolving rapidly with high responses from antibody-drug c... more Classical Hodgkin lymphoma treatment is evolving rapidly with high responses from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response therefore development of novel therapies is warranted to improve patient outcomes. In this phase 2 study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled; 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week), 16 patients on Schedule B (15 mg oral entinostat once weekly in three of four weeks). Patients received a median of 3 prior treatments (range 1-10) with 80% of the patients receiving a prior stem-cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention to treat analysis, the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease be...
D. DeRyckere, M. E. Macy, K. M. Hasebroock, L. A. Gardner, P. Jedlicka, E. L. Bradshaw-Pierce, A.... more D. DeRyckere, M. E. Macy, K. M. Hasebroock, L. A. Gardner, P. Jedlicka, E. L. Bradshaw-Pierce, A. L. Merz, L. Gore, and N. J. Serkova Medical Oncology, University of Colorado Health Sci, Aurora, CO, United States, Anesthesiology, University of Colorado Health Sci, Aurora, CO, United States, Pediatrics, University of Colorado Health Sci, Aurora, CO, United States, Pathology, University of Colorado Health Sci, Aurora, CO, United States
3159 Background: Angiogenesis is essential for tumor growth and metastasis. Distinct pro-angiogen... more 3159 Background: Angiogenesis is essential for tumor growth and metastasis. Distinct pro-angiogenic pathways are targeted by Cel (a cyclooxygenase-2 inhibitor), Z (an epidermal growth factor receptor tyrosine kinase inhibitor that results in reduced vascular endothelial growth factor expression), and Cp (a prodrug of 5-fluorouracil (5FU) activated by thymidine phosphorylase, a tumor-associated pro-angiogenic molecule). This abstract reports the results of an amended treatment schedule based on preclinical data suggesting that antitumor effects are sequence dependent. In vitro synergistic effects were observed when ZD1839 was administered prior to 5FU, additive effects with concomitant administration, and antagonistic effects when administered after 5FU. METHODS This phase I trial assesses the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic interactions, and biologic effects of the combination of Z (250-500 mg/day days 1-14), Cp (1000 mg/m2- 2000 mg/m2/day days 8-21), and Cel (400 mg twice daily days 1-28) given in 28-day cycles. RESULTS Eleven patients (pts) have been enrolled and completed 29 treatment courses (crs). Median age was 66 (range 52-77) and median performance status was 1 (range 0-1). Dose-limiting toxicity (DLT) occurred in 1of 6 pts treated with ZD1839 250mg, Cp 1500mg/m2, and Cel 400mg and 1 of 1 pt treated with ZD1839 250mg, Cp 2000mg/m2, and Cel 400mg. DLT consisted of Gr 3-4 diarrhea and Gr 3 fatigue Additional Gr 3 toxicities considered to be possibly related to treatment include Gr3 hand-and-foot syndrome (HFS) in 2 courses. Grade 1-2 toxicities include fatigue (10 crs), acneiform rash (9 crs), diarrhea (8 crs), HFS (7 crs), and mucositis (5 crs). Three patients maintained stable disease for ≥ 5 cycles (adenocarcinoma unknown primary, gallbladder, and rectal cancer). CONCLUSIONS Accrual is ongoing to determine the MTD. Tumor biopsies will then be obtained to assess effects on tumor metabolism and gene expression. No significant financial relationships to disclose.
3014 Background: Anti-NRP1 specifically targets neuropilin-1 (NRP1), a multi-domain receptor know... more 3014 Background: Anti-NRP1 specifically targets neuropilin-1 (NRP1), a multi-domain receptor known to bind a variety of ligands, including VEGF family members. NRP1 is expressed by endothelial cell...
TPS281 Background: Dasatinib, a highly potent BCR-ABL inhibitor, is safe and effective in adults ... more TPS281 Background: Dasatinib, a highly potent BCR-ABL inhibitor, is safe and effective in adults with Ph+ leukemias. In response to an unmet need for novel agents in childhood diseases with poor outcomes, a comprehensive pediatric drug development program for dasatinib has been initiated. Pediatric studies include one completed phase I study (Aplenc et al. ASCO 2008; 26;3591) in patients (pts) with refractory solid tumors and Ph+ leukemia, and three ongoing studies (one phase I [Zwaan et al. Blood 2008;112:3241] and two phase II) in pts with Ph+ leukemias (1st-line or refractory setting). Although no efficacy was observed in solid tumors, preliminary data show dasatinib is active and tolerable in pts with Ph+ leukemia. In a phase I study in relapsed/refractory Ph+ leukemias resistant/intolerant to imatinib, among 41 evaluable pts, a complete hematologic response (CHR) of 75% was seen in CP-CML, and a major cytogenetic response rate (MCyR) of 88% in CP-CML and 50% in Ph+ CML and ALL/AML2. A phase II study ...
Introduction: Vorinostat has been shown to potentiate DNA damage induced by topoisomerase II inhi... more Introduction: Vorinostat has been shown to potentiate DNA damage induced by topoisomerase II inhibitors in a sequence dependent fashion. A multi-center, open label phase I study with escalating doses of vorinostat in combination with etoposide was conducted to establish the safety of the combination in pediatric patients with refractory solid tumors to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and recommended phase II dose (RP2D) of this regimen. Methods: Eligible patients were ≤21 years of age with relapsed/refractory solid tumors including central nervous system tumors. Study design consisted of a standard 3+3 dose escalation schema. Vorinostat was administered once daily for days 1-4 of the treatment cycle in escalating doses (125 mg/m2, 160 mg/m2, 210 mg/m2, and 270 mg/m2). Etoposide was administered at a fixed dose of 100 mg/m2/day on days 3-5 of the treatment cycle. Etoposide was administered 4 hours after administration of vorinostat. Each treatment cycle was 21 days. Intrapatient dose escalation was not permitted. The maximum tolerated dose (MTD) was defined as the highest dose level with an observed incidence of dose-limiting toxicity (DLT) in no more than one of six patients within the first treatment cycle. Histone acetylation, histone phosphorylation, and gene expression profiling were performed as correlative studies. Exploratory studies included assessment of symptom distress by self report in children between the ages of 10 and 18 with the MSAS (10-18) instrument. Results: Twenty-one patients (CNS 12, neuroblastoma 6, Wilms’ tumor 1, rhabdomyosarcoma 1, hepatoblastoma 1) were enrolled on study and 19 patients were treated. Median age was 12 years (range 4-20 years); 11 males and 10 females with a median performance status 90% were included. One patient experienced a DLT (Gr 4 platelet count decreased) at the 1stdose level (125 mg/m2 vorinostat,100 mg/m2 etoposide). The predominant Grade 3 and 4 toxicities attributed to the combination included white blood cell count decreased (45%), neutrophil count decreased (55%), lymphocyte count decreased (30%), and platelet count decreased (25%). Grade 3-4 events in ≤10% of patients included anemia (10%), hypophosphatemia (5%), and infection (5%). Stable disease was reported in 4 patients (CNS 3, sarcoma 1). Biologic correlative studies and symptom distress data will be presented. Conclusion: Vorinostat followed in combination with etoposide was found to be safe and well tolerated in children with refractory solid tumors. The recommended phase II dose was established at vorinostat 270 mg/m2 and etoposide 100 mg/m2 and will be evaluated in an ongoing phase II study in pediatric patients with sarcoma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B81. Citation Format: Tanya M. Trippett, Amy Smith, Kathleen Neville, Susan Chi, Aru Narendran, Robert Arceci, Jennifer Direnzo, Lia Gore. Phase I/II trial of vorinostat in combination with etoposide in pediatric patients with relapsed/refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B81.
Manifestation of the malignant potential of the neoplastic cell requires metabolic transformation... more Manifestation of the malignant potential of the neoplastic cell requires metabolic transformation to support the bioenergetic, synthetic, and catabolic requirements of malignancy. Metabolic phenotypes have been associated with every type of cancer and have been used as indicators of disease status, prognosis, and response to therapy. However, few studies investigating changes in metabolism associated with acute leukemia have been reported. We used ex vivo magnetic resonance spectroscopy to investigate changes in metabolite levels in the bone marrow, spleen, and/or blood of leukemic MLL‐AF9 transgenic (Tg) mice relative to wild‐type littermates. These studies identified differences in more than 20 cellular metabolites and metabolic pathways in leukemic tissues. Significant differences in the levels of metabolites related to glucose metabolism and in flux through glucose metabolic pathways (theWarburg effect) were observed in all tissues examined. Decreased levels of glutamine and glutamate suggest increased utilization of glutaminolysis as an alternative carbon source for macromolecular synthesis. Significant changes in the levels of phospholipid precursors and increased levels of lipids and phospholipids were observed in the bone marrow, suggesting increased flux through lipid biosynthetic pathways and/or decreased lipid breakdown. These changes may allow for increased macromolecular and membrane synthesis to support the hyperproliferative phenotype of leukemic blasts. A switch from high levels of GPC and low levels of PCho to low levels of GPC and high levels of PCho, as we observed here, has also been observed in patients with breast (Aboagye and Bhujwalla, 1999, Cancer Res 59:80) or ovarian cancers (Iorio et al., 2005, Cancer Res 65:9369). Thus, changes in lipid metabolism in leukemic MLL‐AF9 Tg mice reflect similar changes in patients with leukemias and other tumors and suggest mechanisms by which metabolic changes may contribute to leukemogenesis in a physiologically relevant context. In contrast to the wide‐spread changes in lipid metabolism observed in blood and bone marrow, only a small subset of lipid metabolites were significantly different in the spleens of leukemic mice. The vast majority of metabolic differences in leukemic mice were tissue‐specific, being restricted to either the bone marrow or spleen with the largest number and broadest spectrum of metabolic changes detected in the spleen. These data indicate that leukemia cell metabolism is critically dependent on cellular environment, underscoring the importance of development of robust animal models for metabolic studies, as we have described here. Many of the metabolic changes observed in tissues are also reflected in the blood, which may allow for ex vivo assessment of these markers using samples that can be routinely obtained with minimal discomfort to patients. Because this is the first comprehensive study of the “metabolomic” profile associated with leukemia, several markers that have not been previously associated with leukemogenesis and/or that have not been previously associated with any tumor type were identified in this study, revealing novel insights into leukemia cell biology and leukemogenesis. These studies also identify metabolic changes that may be clinically relevant for prognostication, as indicators of therapeutic efficacy, and/or as novel therapeutic targets. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B38.
Background: A, a water soluble Hsp90 inhibitor, is currently under clinical development using int... more Background: A, a water soluble Hsp90 inhibitor, is currently under clinical development using intravenous and oral (PO) dosing. Objectives of this study were to determine the DLT, MTD, recommended phase II dose (RP2D), PK and PD of A using 2 schedules of ...
Results: AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum t... more Results: AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum tolerated dose was not reached. Treatment-related adverse events were generally mild and included fatigue (13%), constipation (8%), nausea (8%), vomiting (5%), anorexia ...
14059 Background: A is ∼3–5 fold more potent compared to 17-AAG (the first Hsp90 inhibitor to ent... more 14059 Background: A is ∼3–5 fold more potent compared to 17-AAG (the first Hsp90 inhibitor to enter clinical testing), based on in vitro cytotoxicity or the MTD in toxicology studies; it is water-soluble; and oral bioavailability in dogs is estimated at 40%. Toxicity in the dog included kidney, intestinal and liver findings. This study was conducted to determine the toxicity, MTD, recommended phase 2 dose (RP2D), PK and PD of A in pts with solid tumors. Methods: Escalating doses of A were given PO on 2 different schedules: every other day or daily for 4 out of 6 weeks. An initial IV dose was given to calculate absolute bioavailability. PK was evaluated after the IV dose, Day 1 and 21 of oral dosing. PBLs were collected to investigate changes in intracellular signaling proteins by immunoblot (Days 1 and 21 at 1, 3, 24 and 48 hours post-dose). Results: 28 pts were enrolled: 24 on the QOD schedule at doses of 5 (n=4), 10 (n=4), 20 (n=8), 30 (n=5) and 40 mg (n=3); 4 pts received 10mg on the QD schedule. 50% were male, median age/ECOG PS 55 and 0; median prior regimen 3. DLT has not yet been observed. Common drug-related toxicities (n=23): fatigue 43%, nausea 24%, anorexia 19%, proteinuria 19%, and peripheral edema 14%. Of these, fatigue and peripheral edema appear to be possibly dose-related. Drug-related Grade 3–4 toxicity (one patient each) included anemia, neutropenia, peripheral edema, hypokalemia, pain in extremity and hypoxia. For pts with full PK data (n=14), bioavailability equaled 51% and 49% on Day 1 and 21, and was not dose-dependent. Mean Day 21 AUCinf for the 5 to 30 mg/m2 levels equaled 91, 166, 542 and 1889 ng*h/mL. One pt with 3-fold increase in AUCinf comparing Day 1 and 21 dose had been started on dronabinol, a CYP2C9 inhibitor. One pt with fibrosarcoma (4 prior regimens) had necrotic changes in the tumor in the axilla with improved symptoms (active at 5+ months). Additional pts with SD include hemangioendothelioma (7 months), melanoma (6+ months), and renal cell (5 months). Induction in Hsp70 at the 30 mg dose level was seen pre-dose on Day 21 with maximal induction at 24 hours post-dose. Conclusions: Dose escalation continues on both schedules in order to define a RP2D. Toxicity is acceptable. Early signs of activity have been observed. [Table: see text]
TPS9594 Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in adult patients (pt... more TPS9594 Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in adult patients (pts) with newly diagnosed Ph+ CML-CP; CML resistant/intolerant to prior therapy, including imatinib; and Ph+ acute lymphoblastic leukemia (ALL). There are no established dasatinib treatment regimens for children/adolescents with relapsed/refractory leukemia, but pediatric trials are underway. A phase I dose-escalation study of dasatinib in pediatric pts with refractory solid tumors (n=28) and imatinib-refractory, Ph+ leukemia (n=11) reported a maximum tolerated dose of 85 mg/m2 twice daily in solid-tumor pts and at least a partial cytogenetic response (CyR) in all evaluable CML pts (n=9) (Aplenc, J Clin Oncol 2011). Preliminary results from a phase I dose-escalation study in pediatric pts with subtypes of relapsed/refractory leukemia (NCT00306202) indicate that dasatinib was well tolerated up to 120 mg/m2 (Zwaan, Blood 2010 [abstr 2265]). Further study of dasatinib in pediatric pts is warr...
3551 Background: AMG102 is a fully human IgG2 monoclonal antibody against HGF that prevents tumor... more 3551 Background: AMG102 is a fully human IgG2 monoclonal antibody against HGF that prevents tumorigenesis in preclinical models through blockade of the HGF/c-Met receptor tyrosine kinase pathway. We describe interim results from the first-in-human study of AMG102. Methods: This ongoing phase 1, open-label, dose-escalation study is evaluating safety, pharmacokinetics (PK), and preliminary pharmacodynamics (PD) of AMG102 after single and multiple intravenous doses in pts with advanced solid tumors. Sequential dose cohorts of 4–6 pts were administered AMG102 at 0.5, 1, 3, 5, 10, or 20 mg/kg. Pts received a single dose, followed by a 4-wk treatment- free period during which safety and PK were assessed. If no dose-limiting toxicity (DLT) was observed, treatment was resumed every 2 wks at the same dose until pts exhibited drug intolerance or disease progression. Results: As of 10 August 2006, 31 pts have been treated with AMG102 at doses up to 20 mg/kg ( Table ). AMG102 appears to be well...
3032 Background: Anti-VEGFR2 antibodies are effective in a variety of preclinical leukemia and so... more 3032 Background: Anti-VEGFR2 antibodies are effective in a variety of preclinical leukemia and solid tumor models. IMC-1121B is a fully human anti-VEGFR2 IgG1 Mab. Methods: Cohorts of 3–6 pts (ECOG PS ≤ 2) with advanced cancer and no significant cardiovascular, thrombotic or bleeding disorders received escalating doses of IMC-1121B. A single initial dose with extended PK sampling was followed by 4 x weekly infusions per treatment cycle starting at 2mg/kg. 7 dose levels up to a maximum of 16 mg/kg are planned. Human anti-human antibodies (HAHA) directed against IMC-1121B were assessed at baseline and before each Week 4 dose. Tumor response was assessed every 2 cycles. PD analyses include DCE-MRI, serum VEGF and sVEGFR1/2 levels, and peripheral blood mononucleocyte gene expression profiling at baseline and post-dosing. Results: 12 pts (8 M; 4 F), median age 58 years (range: 36–76), have entered the study: cohort 1 (2mg/kg) n=6, cohort 2 (4mg/kg) n=4 and cohort 3 (6mg/kg) n=2. No toxic...
Therapy for high-risk neuroblastoma (HR NBL) is comprised of multimodal therapy including chemoth... more Therapy for high-risk neuroblastoma (HR NBL) is comprised of multimodal therapy including chemotherapy, surgery, radiation therapy, myeloablative therapy followed by autologous hematopoietic stem cell transplant, and immunotherapy. GD2 is a disialoganglioside that is highly expressed on the surface of neuroblastoma cells, with limited expression on normal tissues, which makes it an attractive target for immunologic therapy. The combination of immunotherapy with murine and chimeric anti-GD2 antibody formulations has improved outcomes compared with standard therapy in HR NBL patients. Naxitamab (Danyelza), a fully humanized anti-GD2 antibody, was developed at Memorial Sloan Kettering Cancer Center (MSKCC) to mitigate adverse reactions related to intolerance of foreign murine and chimeric antigens. Phase I and II studies demonstrating the tolerability and efficacy of naxitamab in patients with relapsed/refractory (r/r) HR NBL prompted its approval by the U.S. Food and Drug Administrati...
9547 Background: Irinotecan has shown antitumor activity in a number of pediatric tumors. In adul... more 9547 Background: Irinotecan has shown antitumor activity in a number of pediatric tumors. In adults with colorectal cancer, combining irinotecan with cetuximab enhances clinical activity as compared to treatment with irinotecan alone. We implemented this first-in- pediatrics phase I study to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of cetuximab and irinotecan in pediatric patients. Methods: 35 heavily pre-treated pts with refractory solid tumors were enrolled: brainstem glioma/astrocytoma (16), hepatoblastoma (4), neuroblastoma (2), other (13). Weekly cetuximab was escalated in 3 sequential dose levels: 75, 150 or 250mg/m2; Irinotecan was given at 16 or 20 mg/m2/day over 1 hour [daily × 5] for two weeks, every 21 days. Correlative EGFR expression (immunohistochemistry and FISH) and/or mutations, pharmacokinetics (PK) of and immune response to cetuximab were performed. Results: Pts were treated in two age cohorts (ages 1–12 yrs = Group A, and 13...
Classical Hodgkin lymphoma treatment is evolving rapidly with high responses from antibody-drug c... more Classical Hodgkin lymphoma treatment is evolving rapidly with high responses from antibody-drug conjugates targeting CD30 and immune checkpoint antibodies. However, most patients do not achieve a complete response therefore development of novel therapies is warranted to improve patient outcomes. In this phase 2 study, patients with relapsed or refractory Hodgkin lymphoma were treated with entinostat an isoform selective histone deacetylase inhibitor. Forty-nine patients were enrolled; 33 patients on Schedule A (10 or 15 mg oral entinostat once every other week), 16 patients on Schedule B (15 mg oral entinostat once weekly in three of four weeks). Patients received a median of 3 prior treatments (range 1-10) with 80% of the patients receiving a prior stem-cell transplant and 8% of patients receiving prior brentuximab vedotin. In the intention to treat analysis, the overall response rate was 12% while the disease control rate (complete response, partial response, and stable disease be...
D. DeRyckere, M. E. Macy, K. M. Hasebroock, L. A. Gardner, P. Jedlicka, E. L. Bradshaw-Pierce, A.... more D. DeRyckere, M. E. Macy, K. M. Hasebroock, L. A. Gardner, P. Jedlicka, E. L. Bradshaw-Pierce, A. L. Merz, L. Gore, and N. J. Serkova Medical Oncology, University of Colorado Health Sci, Aurora, CO, United States, Anesthesiology, University of Colorado Health Sci, Aurora, CO, United States, Pediatrics, University of Colorado Health Sci, Aurora, CO, United States, Pathology, University of Colorado Health Sci, Aurora, CO, United States
3159 Background: Angiogenesis is essential for tumor growth and metastasis. Distinct pro-angiogen... more 3159 Background: Angiogenesis is essential for tumor growth and metastasis. Distinct pro-angiogenic pathways are targeted by Cel (a cyclooxygenase-2 inhibitor), Z (an epidermal growth factor receptor tyrosine kinase inhibitor that results in reduced vascular endothelial growth factor expression), and Cp (a prodrug of 5-fluorouracil (5FU) activated by thymidine phosphorylase, a tumor-associated pro-angiogenic molecule). This abstract reports the results of an amended treatment schedule based on preclinical data suggesting that antitumor effects are sequence dependent. In vitro synergistic effects were observed when ZD1839 was administered prior to 5FU, additive effects with concomitant administration, and antagonistic effects when administered after 5FU. METHODS This phase I trial assesses the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic interactions, and biologic effects of the combination of Z (250-500 mg/day days 1-14), Cp (1000 mg/m2- 2000 mg/m2/day days 8-21), and Cel (400 mg twice daily days 1-28) given in 28-day cycles. RESULTS Eleven patients (pts) have been enrolled and completed 29 treatment courses (crs). Median age was 66 (range 52-77) and median performance status was 1 (range 0-1). Dose-limiting toxicity (DLT) occurred in 1of 6 pts treated with ZD1839 250mg, Cp 1500mg/m2, and Cel 400mg and 1 of 1 pt treated with ZD1839 250mg, Cp 2000mg/m2, and Cel 400mg. DLT consisted of Gr 3-4 diarrhea and Gr 3 fatigue Additional Gr 3 toxicities considered to be possibly related to treatment include Gr3 hand-and-foot syndrome (HFS) in 2 courses. Grade 1-2 toxicities include fatigue (10 crs), acneiform rash (9 crs), diarrhea (8 crs), HFS (7 crs), and mucositis (5 crs). Three patients maintained stable disease for ≥ 5 cycles (adenocarcinoma unknown primary, gallbladder, and rectal cancer). CONCLUSIONS Accrual is ongoing to determine the MTD. Tumor biopsies will then be obtained to assess effects on tumor metabolism and gene expression. No significant financial relationships to disclose.
3014 Background: Anti-NRP1 specifically targets neuropilin-1 (NRP1), a multi-domain receptor know... more 3014 Background: Anti-NRP1 specifically targets neuropilin-1 (NRP1), a multi-domain receptor known to bind a variety of ligands, including VEGF family members. NRP1 is expressed by endothelial cell...
TPS281 Background: Dasatinib, a highly potent BCR-ABL inhibitor, is safe and effective in adults ... more TPS281 Background: Dasatinib, a highly potent BCR-ABL inhibitor, is safe and effective in adults with Ph+ leukemias. In response to an unmet need for novel agents in childhood diseases with poor outcomes, a comprehensive pediatric drug development program for dasatinib has been initiated. Pediatric studies include one completed phase I study (Aplenc et al. ASCO 2008; 26;3591) in patients (pts) with refractory solid tumors and Ph+ leukemia, and three ongoing studies (one phase I [Zwaan et al. Blood 2008;112:3241] and two phase II) in pts with Ph+ leukemias (1st-line or refractory setting). Although no efficacy was observed in solid tumors, preliminary data show dasatinib is active and tolerable in pts with Ph+ leukemia. In a phase I study in relapsed/refractory Ph+ leukemias resistant/intolerant to imatinib, among 41 evaluable pts, a complete hematologic response (CHR) of 75% was seen in CP-CML, and a major cytogenetic response rate (MCyR) of 88% in CP-CML and 50% in Ph+ CML and ALL/AML2. A phase II study ...
Introduction: Vorinostat has been shown to potentiate DNA damage induced by topoisomerase II inhi... more Introduction: Vorinostat has been shown to potentiate DNA damage induced by topoisomerase II inhibitors in a sequence dependent fashion. A multi-center, open label phase I study with escalating doses of vorinostat in combination with etoposide was conducted to establish the safety of the combination in pediatric patients with refractory solid tumors to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and recommended phase II dose (RP2D) of this regimen. Methods: Eligible patients were ≤21 years of age with relapsed/refractory solid tumors including central nervous system tumors. Study design consisted of a standard 3+3 dose escalation schema. Vorinostat was administered once daily for days 1-4 of the treatment cycle in escalating doses (125 mg/m2, 160 mg/m2, 210 mg/m2, and 270 mg/m2). Etoposide was administered at a fixed dose of 100 mg/m2/day on days 3-5 of the treatment cycle. Etoposide was administered 4 hours after administration of vorinostat. Each treatment cycle was 21 days. Intrapatient dose escalation was not permitted. The maximum tolerated dose (MTD) was defined as the highest dose level with an observed incidence of dose-limiting toxicity (DLT) in no more than one of six patients within the first treatment cycle. Histone acetylation, histone phosphorylation, and gene expression profiling were performed as correlative studies. Exploratory studies included assessment of symptom distress by self report in children between the ages of 10 and 18 with the MSAS (10-18) instrument. Results: Twenty-one patients (CNS 12, neuroblastoma 6, Wilms’ tumor 1, rhabdomyosarcoma 1, hepatoblastoma 1) were enrolled on study and 19 patients were treated. Median age was 12 years (range 4-20 years); 11 males and 10 females with a median performance status 90% were included. One patient experienced a DLT (Gr 4 platelet count decreased) at the 1stdose level (125 mg/m2 vorinostat,100 mg/m2 etoposide). The predominant Grade 3 and 4 toxicities attributed to the combination included white blood cell count decreased (45%), neutrophil count decreased (55%), lymphocyte count decreased (30%), and platelet count decreased (25%). Grade 3-4 events in ≤10% of patients included anemia (10%), hypophosphatemia (5%), and infection (5%). Stable disease was reported in 4 patients (CNS 3, sarcoma 1). Biologic correlative studies and symptom distress data will be presented. Conclusion: Vorinostat followed in combination with etoposide was found to be safe and well tolerated in children with refractory solid tumors. The recommended phase II dose was established at vorinostat 270 mg/m2 and etoposide 100 mg/m2 and will be evaluated in an ongoing phase II study in pediatric patients with sarcoma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B81. Citation Format: Tanya M. Trippett, Amy Smith, Kathleen Neville, Susan Chi, Aru Narendran, Robert Arceci, Jennifer Direnzo, Lia Gore. Phase I/II trial of vorinostat in combination with etoposide in pediatric patients with relapsed/refractory solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B81.
Manifestation of the malignant potential of the neoplastic cell requires metabolic transformation... more Manifestation of the malignant potential of the neoplastic cell requires metabolic transformation to support the bioenergetic, synthetic, and catabolic requirements of malignancy. Metabolic phenotypes have been associated with every type of cancer and have been used as indicators of disease status, prognosis, and response to therapy. However, few studies investigating changes in metabolism associated with acute leukemia have been reported. We used ex vivo magnetic resonance spectroscopy to investigate changes in metabolite levels in the bone marrow, spleen, and/or blood of leukemic MLL‐AF9 transgenic (Tg) mice relative to wild‐type littermates. These studies identified differences in more than 20 cellular metabolites and metabolic pathways in leukemic tissues. Significant differences in the levels of metabolites related to glucose metabolism and in flux through glucose metabolic pathways (theWarburg effect) were observed in all tissues examined. Decreased levels of glutamine and glutamate suggest increased utilization of glutaminolysis as an alternative carbon source for macromolecular synthesis. Significant changes in the levels of phospholipid precursors and increased levels of lipids and phospholipids were observed in the bone marrow, suggesting increased flux through lipid biosynthetic pathways and/or decreased lipid breakdown. These changes may allow for increased macromolecular and membrane synthesis to support the hyperproliferative phenotype of leukemic blasts. A switch from high levels of GPC and low levels of PCho to low levels of GPC and high levels of PCho, as we observed here, has also been observed in patients with breast (Aboagye and Bhujwalla, 1999, Cancer Res 59:80) or ovarian cancers (Iorio et al., 2005, Cancer Res 65:9369). Thus, changes in lipid metabolism in leukemic MLL‐AF9 Tg mice reflect similar changes in patients with leukemias and other tumors and suggest mechanisms by which metabolic changes may contribute to leukemogenesis in a physiologically relevant context. In contrast to the wide‐spread changes in lipid metabolism observed in blood and bone marrow, only a small subset of lipid metabolites were significantly different in the spleens of leukemic mice. The vast majority of metabolic differences in leukemic mice were tissue‐specific, being restricted to either the bone marrow or spleen with the largest number and broadest spectrum of metabolic changes detected in the spleen. These data indicate that leukemia cell metabolism is critically dependent on cellular environment, underscoring the importance of development of robust animal models for metabolic studies, as we have described here. Many of the metabolic changes observed in tissues are also reflected in the blood, which may allow for ex vivo assessment of these markers using samples that can be routinely obtained with minimal discomfort to patients. Because this is the first comprehensive study of the “metabolomic” profile associated with leukemia, several markers that have not been previously associated with leukemogenesis and/or that have not been previously associated with any tumor type were identified in this study, revealing novel insights into leukemia cell biology and leukemogenesis. These studies also identify metabolic changes that may be clinically relevant for prognostication, as indicators of therapeutic efficacy, and/or as novel therapeutic targets. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B38.
Background: A, a water soluble Hsp90 inhibitor, is currently under clinical development using int... more Background: A, a water soluble Hsp90 inhibitor, is currently under clinical development using intravenous and oral (PO) dosing. Objectives of this study were to determine the DLT, MTD, recommended phase II dose (RP2D), PK and PD of A using 2 schedules of ...
Results: AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum t... more Results: AMG 102 was well tolerated up to the planned maximum dose of 20 mg/kg, and the maximum tolerated dose was not reached. Treatment-related adverse events were generally mild and included fatigue (13%), constipation (8%), nausea (8%), vomiting (5%), anorexia ...
14059 Background: A is ∼3–5 fold more potent compared to 17-AAG (the first Hsp90 inhibitor to ent... more 14059 Background: A is ∼3–5 fold more potent compared to 17-AAG (the first Hsp90 inhibitor to enter clinical testing), based on in vitro cytotoxicity or the MTD in toxicology studies; it is water-soluble; and oral bioavailability in dogs is estimated at 40%. Toxicity in the dog included kidney, intestinal and liver findings. This study was conducted to determine the toxicity, MTD, recommended phase 2 dose (RP2D), PK and PD of A in pts with solid tumors. Methods: Escalating doses of A were given PO on 2 different schedules: every other day or daily for 4 out of 6 weeks. An initial IV dose was given to calculate absolute bioavailability. PK was evaluated after the IV dose, Day 1 and 21 of oral dosing. PBLs were collected to investigate changes in intracellular signaling proteins by immunoblot (Days 1 and 21 at 1, 3, 24 and 48 hours post-dose). Results: 28 pts were enrolled: 24 on the QOD schedule at doses of 5 (n=4), 10 (n=4), 20 (n=8), 30 (n=5) and 40 mg (n=3); 4 pts received 10mg on the QD schedule. 50% were male, median age/ECOG PS 55 and 0; median prior regimen 3. DLT has not yet been observed. Common drug-related toxicities (n=23): fatigue 43%, nausea 24%, anorexia 19%, proteinuria 19%, and peripheral edema 14%. Of these, fatigue and peripheral edema appear to be possibly dose-related. Drug-related Grade 3–4 toxicity (one patient each) included anemia, neutropenia, peripheral edema, hypokalemia, pain in extremity and hypoxia. For pts with full PK data (n=14), bioavailability equaled 51% and 49% on Day 1 and 21, and was not dose-dependent. Mean Day 21 AUCinf for the 5 to 30 mg/m2 levels equaled 91, 166, 542 and 1889 ng*h/mL. One pt with 3-fold increase in AUCinf comparing Day 1 and 21 dose had been started on dronabinol, a CYP2C9 inhibitor. One pt with fibrosarcoma (4 prior regimens) had necrotic changes in the tumor in the axilla with improved symptoms (active at 5+ months). Additional pts with SD include hemangioendothelioma (7 months), melanoma (6+ months), and renal cell (5 months). Induction in Hsp70 at the 30 mg dose level was seen pre-dose on Day 21 with maximal induction at 24 hours post-dose. Conclusions: Dose escalation continues on both schedules in order to define a RP2D. Toxicity is acceptable. Early signs of activity have been observed. [Table: see text]
TPS9594 Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in adult patients (pt... more TPS9594 Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in adult patients (pts) with newly diagnosed Ph+ CML-CP; CML resistant/intolerant to prior therapy, including imatinib; and Ph+ acute lymphoblastic leukemia (ALL). There are no established dasatinib treatment regimens for children/adolescents with relapsed/refractory leukemia, but pediatric trials are underway. A phase I dose-escalation study of dasatinib in pediatric pts with refractory solid tumors (n=28) and imatinib-refractory, Ph+ leukemia (n=11) reported a maximum tolerated dose of 85 mg/m2 twice daily in solid-tumor pts and at least a partial cytogenetic response (CyR) in all evaluable CML pts (n=9) (Aplenc, J Clin Oncol 2011). Preliminary results from a phase I dose-escalation study in pediatric pts with subtypes of relapsed/refractory leukemia (NCT00306202) indicate that dasatinib was well tolerated up to 120 mg/m2 (Zwaan, Blood 2010 [abstr 2265]). Further study of dasatinib in pediatric pts is warr...
3551 Background: AMG102 is a fully human IgG2 monoclonal antibody against HGF that prevents tumor... more 3551 Background: AMG102 is a fully human IgG2 monoclonal antibody against HGF that prevents tumorigenesis in preclinical models through blockade of the HGF/c-Met receptor tyrosine kinase pathway. We describe interim results from the first-in-human study of AMG102. Methods: This ongoing phase 1, open-label, dose-escalation study is evaluating safety, pharmacokinetics (PK), and preliminary pharmacodynamics (PD) of AMG102 after single and multiple intravenous doses in pts with advanced solid tumors. Sequential dose cohorts of 4–6 pts were administered AMG102 at 0.5, 1, 3, 5, 10, or 20 mg/kg. Pts received a single dose, followed by a 4-wk treatment- free period during which safety and PK were assessed. If no dose-limiting toxicity (DLT) was observed, treatment was resumed every 2 wks at the same dose until pts exhibited drug intolerance or disease progression. Results: As of 10 August 2006, 31 pts have been treated with AMG102 at doses up to 20 mg/kg ( Table ). AMG102 appears to be well...
3032 Background: Anti-VEGFR2 antibodies are effective in a variety of preclinical leukemia and so... more 3032 Background: Anti-VEGFR2 antibodies are effective in a variety of preclinical leukemia and solid tumor models. IMC-1121B is a fully human anti-VEGFR2 IgG1 Mab. Methods: Cohorts of 3–6 pts (ECOG PS ≤ 2) with advanced cancer and no significant cardiovascular, thrombotic or bleeding disorders received escalating doses of IMC-1121B. A single initial dose with extended PK sampling was followed by 4 x weekly infusions per treatment cycle starting at 2mg/kg. 7 dose levels up to a maximum of 16 mg/kg are planned. Human anti-human antibodies (HAHA) directed against IMC-1121B were assessed at baseline and before each Week 4 dose. Tumor response was assessed every 2 cycles. PD analyses include DCE-MRI, serum VEGF and sVEGFR1/2 levels, and peripheral blood mononucleocyte gene expression profiling at baseline and post-dosing. Results: 12 pts (8 M; 4 F), median age 58 years (range: 36–76), have entered the study: cohort 1 (2mg/kg) n=6, cohort 2 (4mg/kg) n=4 and cohort 3 (6mg/kg) n=2. No toxic...
Uploads