Phase I/II study of the combination of sorafenib and temsirolimus in patients with metastatic melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9026-9026 ◽  
Author(s):  
K. B. Kim ◽  
M. A. Davies ◽  
N. E. Papadopoulos ◽  
A. Y. Bedikian ◽  
W. Hwu ◽  
...  
Keyword(s):  
Phase I ◽  
Performance Status ◽  
Single Agent ◽  
Stage Iv ◽  
Pharmacokinetic Data ◽  
Advanced Cancer Patients ◽  
Ecog Performance Status ◽  
Multikinase Inhibitor ◽  
Taste Alteration

9026 Background: Inhibition of Signal transduction pathways at multiple levels may be a more effective therapeutic cancer strategy for advanced cancer patients. Sorafenib, a multikinase inhibitor and temsirolimus, an inhibitor of critical survival pathways, are targeted compounds with single agent anti-tumor activity in several solid tumors. Inhibition of mutant B-Raf and the AKT signaling pathway has been effective in vitro with melanoma cell lines. Therefore, we designed a phase I/II study of the combination of sorafenib and temsirolimus to inhibit multiple pathways for greater clinical efficacy.Methods: Patients (pts) with stage IV or unresectable or recurrent stage III melanoma and ECOG performance status of 0 to 1 were eligible. Pts with treated brain metastases were eligible if they had not progressed for 3 months. Sorafenib was given orally twice daily and temsirolimus was given intravenously once a week, both starting on day 1, with a 4-week cycle. Responses were assessed every 2 cycles per RECIST. Results: To date, 22 pts have been enrolled and treated. Median age was 56.5, and 17 were male. Median ECOG PS was 1. The MTD doses were sorafenib 400 mg in AM / 200 mg in PM daily and temsirolimus 25 mg IV weekly. The dose-limiting toxicity (DLT) included thrombocytopenia, hand-foot syndrome (HFS), serum transaminase elevation and hypertriglyceridemia. Other common adverse events were dry skin, fatigue, taste alteration, anorexia, flatulence, diarrhea, skin rash, insomnia, neuropathy, myalgia, and headaches, anemia, hypercholesterolemia, hyperglycemia and hypophosphatemia. There were 9 pts with stable disease among 21 evaluable pts for response. Conclusions: Sorafenib and temsirolimus can be administered concomitantly although with significant toxicity at higher dose levels. Currently, pts are enrolled in a dose expansion cohort. Pharmacokinetic data will be presented. Supported in part by NCI grant UO1 CA062461 and N01 CM17003. [Table: see text] No significant financial relationships to disclose.

Pemetrexed and carboplatin plus bevacizumab as first-line therapy for advanced non-squamous non-small cell lung cancer: preliminary safety results of a phase II trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17111-17111
Author(s):  
J. D. Patel ◽  
T. A. Hensing ◽  
P. O’Keeffe ◽  
K. Frantonius ◽  
E. Hart ◽  
...  
Keyword(s):  
Treated Patient ◽  
Performance Status ◽  
Single Agent ◽  
Stage Iv ◽  
Patient Characteristics ◽  
Median Number ◽  
Stage Iiib ◽  
Ecog Performance Status ◽  
Minor Response ◽  
First Line Therapy

17111 Background: Bevacizumab is a novel antiangiogenic agent that has been shown to improve response rates and survival of patients with advanced non-squamous NSCLC when added to paclitaxel and carboplatin. Pemetrexed is a multitargeted antimetabolite that has shown activity in NSCLC as a single agent and when combined with carboplatin. Because the combination of pemetrexed and carboplatin has activity comparable to that of other standard platinum doublets and promising toxicity profile (Zinner, 2005), the addition of bevacizumab to this regimen is investigated. Methods: This single cohort, phase 2 study evaluates the safety and efficacy of the combination of pemetrexed and carboplatin plus bevacizumab in patients with untreated non-squamous NSCLC. Eligibility requires ECOG performance status 0–1, Stage IIIB (malignant effusion) or Stage IV non- squamous NSCLC, no evidence of CNS metastases, no anticoagulation. Treatment consists of pemetrexed 500 mg/m2 over 10 minutes, carboplatin AUC 6 over 30 minutes, and bevacizumab 15 mg/kg over 30–90 minutes. Treatment is repeated every 21 days for 6 cycles. For patients who have either stable disease or partial response, pemetrexed 500 mg/m2 and bevacizumab 15 mg/kg are continued every 21 days until progression of disease or toxicity. All patients receive folic acid, vitamin B12 and steroid prophylaxis. Tumor response is assessed using RECIST every 2 cycles during treatment with carboplatin and then every 3 cycles during treatment with pemetrexed and bevacizumab alone. Results: From 8/2005 to 12/2005, 10 (of planned 50) patients with Stage IIIB and IV non-squamous NSCLC have been enrolled and treated. Patient characteristics are: median age: 65 (48–71), 20% female, 80% male, 30% stage IIIB, 70% stage IV. Median number of cycles delivered is 5 (range 1–9). No patient has discontinued therapy secondary to progressive disease or toxicity to date. 6 patients are evaluable for response: 1 PR, 1 minor response (24% reduction), 4 SD. No grade 3/4 toxicities have been experienced. Conclusions: This is a highly tolerable and active regimen with little toxicity to date. Updated response and toxicity data will be forthcoming. Supported by Genentech Inc and Lilly Pharmaceuticals. [Table: see text]

Phase II single institution study of sequential biochemotherapy (BCT) for patients (pts) with stage IV melanoma (M)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8580-8580
Author(s):  
P. R. Bojanapally ◽  
D. T. Alexandrescu ◽  
V. Rusciano ◽  
P. H. Wiernik ◽  
J. P. Dutcher
Keyword(s):  
Median Survival ◽  
Phase Ii ◽  
Performance Status ◽  
Single Agent ◽  
Stage Iv ◽  
Experimental Therapy ◽  
Ecog Performance Status ◽  
Maximum Benefit ◽  
Prospective Phase ◽  
Metastatic Sites

8580 Background: The utility of BCT for M remains controversial. A prospective phase II study was conducted to assess the clinical benefit of BCT in patients with stage IV M. Methods: Between March 2005 and March 2006 11 pts (6 Male and 5 Female with a median age of 54 (range 36 - 82)) with metastatic M were treated with paclitaxel 225 mg/m2 via continuous 24 hour IV infusion every 3 wks for 4 cycles or maximum benefit followed by HD IL2, 1.33 mg/m2 every 8 hours for 5 days of wk1 and wk3 based on pts tolerance to a maximum of 12 doses per wk. 2 Male pts received IL2 followed by paclitaxel. Pts had a ECOG performance status of 0 - 2, with a median time of 60 months since diagnosis of disease (range 7 to 240 months). 11 pts (92%) had multiple metastatic sites (50% had lung mets, 58% had liver mets) and 4 pts (33%) had prior chemotherapy or immunotherapy. Results: Of the 13 assessable pts one achieved a PR after paclitaxel and CR after IL2 continuing at 20+ months. One had SD for 1 year after receiving HD IL2 and SD for 6 months while on paclitaxel independently, One had PR for 6 months on paclitaxel and one had MR with paclitaxel for 3 months. 9 pts (69%) had PD on paclitaxel and again on IL2, with a median survival from treatment of 7 months, 2 of these got no IL2 due to rapid PD. An overall response rate of 30% (1 CR on paclitaxel + IL2 , 1 PR on paclitaxel, 2 SD (including MR) on paclitaxel) was seen with a median survival from treatment of 15 months. Conclusions: In this study there may be prolonged survival among responders, which may be due to synergy of sequential BCT, or may reflect single agent activity of each drug. BCT should still be considered as an experimental therapy and further evaluated. No significant financial relationships to disclose.

Phase I experience with c-MET inhibitor XL880 administered orally to patients (pts) with solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3526-3526 ◽  
Author(s):  
J. P. Eder ◽  
E. Heath ◽  
L. Appleman ◽  
G. Shapiro ◽  
D. Wang ◽  
...  
Keyword(s):  
Phase I ◽  
Phase 1 ◽  
Performance Status ◽  
Vegf Receptor ◽  
Significant Activity ◽  
Phase Ii Trials ◽  
Ecog Performance Status ◽  
Correlative Studies ◽  
Tumor Biopsies

3526 Background: XL880 is a sub-nM inhibitor of the hepatocyte growth factor receptor (Met) and VEGF receptor family with low in vitro nM inhibition of PDGFRβ, KIT, FLT3, Tie-2 and Ron. Methods: The safety of XL880 was evaluated in two phase 1 studies. XL880 was administered mass-based on a 5 days on / 9 days off schedule (study 1) or as a fixed daily dose (study 2). Inclusion criteria include ECOG performance status = 2, adequate liver, cardiac, and renal function and no brain metastases. Tumor response is assessed every 8 wks by RECIST criteria. Pharmacokinetics, pre and post treatment tumor biopsies and plasma markers of angiogenesis (VEGF, sVEGFR and Ang2) were collected. Results: To date, 51 pts have been dosed in studies 1 & 2. In study 1, dose limiting toxicities (DLT) included reversible Gr3 elevations of lipase, hepatic transaminases and proteinuria. The maximum tolerated dose (MTD) was 3.6 mg/kg. In study 2, the MTD has not been defined. Common adverse events include hypertension and fatigue with loss of concentration. In study 1, 5 of 40 pts had partial responses (2+ -12+ months[m]), 3 pts had minimal responses and 8 pts had stable disease (SD) > 3 m. In study 2, 5 of 8 evaluable pts had SD > 3 m (4 ongoing) and 3 are too early to evaluate. Correlative studies in tumor biopsies show marked inhibition of phospho (p)-met, p-RON, p- ERK, p-AKT and increased apoptosis at less than the MTD. Patients in study 2 pts showed lower XL880 Cmax values with consistent mean concentrations (Css)compared with study 1 MTD pts. Css levels are reached in 15 d. Conclusions: XL880 as daily oral or 5 day on / 9 day off administration is generally well tolerated for > 1 year, although hypertension is nearly universal but manageable. XL880 has demonstrated substantial phase I antitumor activity with both dosing regimens. Correlative studies indicate significant activity against Met and Ron signaling. Enrollment continues on study 2. Phase II trials in gastric cancer and head and neck cancer will begin soon. No significant financial relationships to disclose.

Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of intravenous dimethane sulfonate (DMS612, NSC 281612) in advanced malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2553-2553
Author(s):  
Susan Elaine Bates ◽  
Sanjeeve Balasubramaniam ◽  
Robert A Parise ◽  
Christina Bryla ◽  
William Bonner ◽  
...  
Keyword(s):  
Dna Damage ◽  
Phase I ◽  
Intravenous Infusion ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Lymphocytes ◽  
Ecog Performance Status ◽  
Alkylating Activity

2553 Background: DMS612 is a dimethane sulfonate compound that was identified as preferentially cytotoxic to renal cell carcinoma (RCC) cell lines in a chemical screen of the NCI-60 panel. DMS612 has bifunctional alkylating activity in vitro. Objectives of this first-in-human phase I study included determining the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), PK and PD of DMS612 administered by 10 minute intravenous infusion on day 1, 8 and 15 of a 28 day cycle. Methods: Eligibility criteria included adults with advanced solid malignancies or lymphoma with ECOG performance status 0-2, life expectancy > 3 months and adequate organ and marrow function. Patients were enrolled using a standard “3+3” dose escalation scheme. Plasma PK of DMS612 and metabolites was assessed by LC-MS/MS. DNA damage PD was assessed by γ-H2AX immunofluorescence. Results: 35 subjects were enrolled (22 male, 13 female) with median age 59 years (41-75). Tumor types included colorectal (8), RCC (4), cervix (2), and urothelial (2). Doses administered were 1.5, 3, 5, 7, 9 and 12 mg/m2. The MTD was determined to be 9 mg/m2, with only one DLT of grade 4 thrombocytopenia in 12 subjects enrolled. The maximum administered dose of 12 mg/m2 was considered to be intolerable after 1 of 3 subjects had grade 4 neutropenia and 1 had prolonged grade 3 thrombocytopenia. Prolonged thrombocytopenia in later cycles was observed in other subjects, including one patient naïve to prior cytotoxic chemotherapy. One subject with RCC had a confirmed partial response at 7 mg/m2. DMS612 was rapidly converted into carboxy, chloroethyl and hydroxyethyl analogues and their glucuronides, some of which retained alkylating activity in vitro. Dose-dependent pharmacodynamic evidence of DNA damage induced by DMS612 in vivo was observed by γ-H2AX immunofluorescance in both peripheral blood lymphocytes and plucked scalp hairs. Conclusions: The MTD of DMS12 administered by intravenous infusion on day 1, 8 and 15 of a 28-day cycle was 9 mg/m2. Pre-clinical and clinical observations suggest that further study of DMS612 in RCC is warranted.

Dasatinib in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma: Preliminary Results of a Phase I Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1876-1876 ◽  
Author(s):  
Thierry Facon ◽  
Xavier Leleu ◽  
A. Keith Stewart ◽  
Andrew Spencer ◽  
Philip Rowlings ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Performance Status ◽  
Randomized Study ◽  
Single Agent ◽  
Open Label ◽  
Ecog Performance Status ◽  
Advisory Committees ◽  
Minor Response

Abstract Abstract 1876 Poster Board I-901 Background: Multiple Myeloma (MM) remains incurable in spite of new effective agents and combination regimens. SRC family kinases (SFK) are potential targets for therapy in MM: Hck, Fyn and Lyn are implicated in IL6-induced proliferation. Dasatinib is a potent inhibitor of not only BCR-ABL, but also SFK, c-KIT, PDGFRb, and EPHA. In myeloma and endothelial cells (ECs) isolated from MM patients (pts), dasatinib blocked proliferation, survival, adhesion, migration, and angiogenic potential, through a combined targeting of PDGFRβ as well as VEGF-triggered phosphorylation of SRC. Lenalidomide has clinical efficacy in the treatment of multiple myeloma (MM) as a single agent and in combination with dexamethasone. The combination of dasatinib, lenalidomide and dexamethasone exhibits synergistic inhibition of MMIS cells. Methods: The primary objective of this Phase I, multicenter, open-label, non-randomized study was to determine the maximum tolerated dose (MTD) of the combination of dasatinib, with lenalidomide and dexamethasone in pts with relapsed or refractory (RR) MM. Secondary objectives were to assess the tolerability of the combination, to establish the dose for future clinical investigations, and to assess the efficacy by International Uniform Response and EBMT Criteria. Pts ≥18 years with confirmed RR MM, measurable disease (at least 1 g/dL for IgG or 0.5 g/dL for IgA in serum or urinary excretion of 200 mg monoclonal light chain/24 hours), and at least one prior treatment were enrolled sequentially into increasing dose cohorts (using a 3+3 design). Pts received oral dasatinib daily on a continuous schedule, oral lenalidomide daily for 21 days, and oral dexamethasone 40 mg/day (Days 1, 8, 15, and 22). Cycles were repeated every 28 days. Dose-limiting toxicities (DLTs) were assessed in the first cycle. If there was no DLT, dose escalation continued to MTD, followed by an expansion phase of the established dose. Results: Enrollment is ongoing. 16 pts (6 M, 10 F; median age 70.5 years, range 51–80) were treated in cohorts 1, 2, 3 and 4; MTD has not been established (as by July 2009). The median number of prior lines of therapy was 3 (range 1–6). Seven pts had prior autologous stem cell transplantation; 8 pts had prior thalidomide, 4 prior lenalidomide and 3 pts both. Baseline β2 microglobulin levels of >3.5mg/L were reported in 4 pts. The most common (310%) treatment related adverse events (AEs) diarrhea 6 (38%); nausea 4 (25%); constipation 2 (13%); stomatitis 2 (13%); asthenia 3 (19%); weight decrease 5 (31%); dyspnea 2 (13%); rash 2 (13%); vertigo 2 (13%); insomnia 2 (13%). The most common grade 3 / 4 hematologic AEs included neutropenia 6 (38%), anemia 4 (25%) and thrombocytopenia 3 (19%). Two DLTs were identified in cohorts 1 and 4: 1 pt had 2 point decline in ECOG Performance Status and other pt had a drug interruption > 15 days due to nausea and vomiting, respectively. Six out of 16 pts discontinued treatment: 1 due to death in first cycle (D19); 3 for AEs (2 study drug related and 1 unrelated), 1 withdrawal of consent, 1 following maximal clinical benefit (minor response) after 12+ cycles. As of July 2009, 10 pts remain on treatment, with a median duration of treatment of 4.2 months (range 0.6–12). Responses were observed in 13 pts: 8 partial responses (PR), and 5 minor responses (MR). 1 pt had stable disease (SD) and 2 pts were not evaluable (1 pts died before completion of cycle 1 and other pt was too early for assessment). Conclusion: Dasatinib in combination with lenalidomide and dexamethasone is well tolerated and preliminary activity has been observed. Disclosures: Facon: Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Stewart:Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy; Takeda, Millenium: Research Funding; Genzyme, Celgene, Millenium, Proteolix: Honoraria. Garzon:BMS: Employment. Bleickardt:BMS: Employment. Gialelis:BMS: Employment. Tuozzoli:BMS: Employment. Derreumaux:BMS: Employment. Sonneveld:Janssen-Cilag: Honoraria.

A randomized phase II study of EMD 121974 in patients (pts) with metastatic melanoma (MM)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8548-8548 ◽  
Author(s):  
K. B. Kim ◽  
A. H. Diwan ◽  
N. E. Papadopoulos ◽  
A. Y. Bedikian ◽  
L. H. Camacho ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Efficacy ◽  
Performance Status ◽  
Single Agent ◽  
Stage Iv ◽  
Melanoma Cells ◽  
Serum Lactate Dehydrogenase ◽  
Ecog Performance Status ◽  
Randomized Phase Ii ◽  
Grade 3

8548 Background: EMD 121974 is a selective antagonist of avβ3 integrin, which promotes the proliferation of tumor-associated endothelial cells and potentially the survival of melanoma cells expressing avβ3 integrin. We conducted a randomized phase II trial of cilengitide in pts with MM to evaluate the clinical efficacy at 2 different doses. Methods: Pts with stage IV or unresectable stage III non-choroidal melanoma who had no more than 1 prior systemic therapy were enrolled. Pts at least 18 years of age and with ECOG performance status of 0 to 2 were eligible. All pts underwent baseline tumor biopsy and were randomly assigned to either 500 mg or 2,000 mg intravenous (IV) EMD 121974 twice weekly, using the following stratification factors: 1) prior systemic treatment; 2) visceral metastases; 3) serum lactate dehydrogenase level; 4) tumor avβ3 overexpression, where overexpression is defined as > 25% of melanoma cells staining positive. The primary objective of this study was to determine the progression-free survival rate at 8 weeks. Results: Twenty-nine pts were enrolled, and 26 pts (14 at 500 mg; 12 at 2,000 mg dose) were treated. Patient characteristics for 500 mg and 2,000 mg arm, respectively, are as follows: median age, 57 and 61; percentage (% age) of male, 50% and 50%; % age of ECOG performance status of 0, 79% and 58%; % age of stage IV, 79% and 75%; % age of tumor avβ3 overexpression, 21% and 25%. Three of 26 pts were progression-free at 8 weeks (2 at 500 mg; 1 at 2,000 mg dose). One pt at 2,000 mg had a prolonged partial response after initial 28% enlargement of target lesions. There were no grade 3 or 4 adverse events (AEs) except one pt with grade 3 lymphopenia at 2,000 mg. Although both doses of EMD 121974 were well tolerated, the 2,000 mg was associated with higher incidences of grade 2 fatigue, arthralgia, lymphopenia, peripheral neuropathy, and GI AEs. Optional tumor biopsies were performed on day 8, and the correlative studies to examine the molecular changes in the tumor are currently in progress. Conclusions: IV EMD 121974, 500 or 2,000 mg twice weekly, was well tolerated but had minimal clinical efficacy as a single-agent for MM. Supported by NCI grant N01 CM-17003 and CA16672 No significant financial relationships to disclose.

A phase I trial of the proteosome inhibitor PS-341 in combination with carboplatin in platinum and taxane resistant ovarian cancer patinets

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5558-5558
Author(s):  
C. N. Landen ◽  
R. Coleman ◽  
M. R. Milam ◽  
T. Johnston ◽  
R. Iyer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Stable Disease ◽  
Performance Status ◽  
Single Agent ◽  
Optimal Dose ◽  
Recurrent Ovarian Cancer ◽  
Cytotoxic Agents ◽  
Pharmacokinetic Data ◽  
Resistant Disease

5558 Background. PS-341 (Millenium Pharmaceuticals, Inc.), a proteosome inhibitor, affects p53, NFκB, cell adhesion molecules, and sensitivity to cytotoxic agents to promote apoptosis and inhibit metastasis in cancer cells. PS-341 alone rarely causes myelosupression or renal toxicity, and therefore is an attractive agent to use in combination with cytotoxic chemotherapy. This phase I study evaluates the safety, dose-limiting toxicities (DLTs), and optimal dose of PS-341 when combined with carboplatin in ovarian cancer patients with recurrent, platinum- and taxane-resistant disease. Methods: After IRB approval, patients with recurrent ovarian cancer, platinum and taxane resistant (progression on platinum and/or taxane therapy or recurrence within 6 months of completing platinum and/or taxane therapy), measurable disease, and performance status 0–2 were eligible and enrolled after giving informed consent. As guided by toxicity and pharmacokinetic data from single-agent phase I trials, PS-341 was administered on days 1, 4, 8, and 11 by IV push every 28 days with carboplatin (AUC 5) on day 1. Four dose levels were evaluated: 0.8, 1.0, 1.3, and 1.5 mg/m2. Dose was escalated if 0 of 3 or 1 of 6 patients had a DLT. The MTD was defined as 2 or more patients out of 6 with a DLT. Results: 21 women (median age 63, range 43–83), were treated with carboplatin and PS-341 at 0.8mg/ m2 (n=6), 1.0 mg/m2 (n=3), 1.3 mg/m2 (n=6), or 1.5 mg/m2. (n=6). At each level, respectively, there were 1, 0, 1, and 3 DLT’s attributable to PS- 341; all were grade 3, consisting of fatigue (n=3), nausea/vomiting/dehydration (n=1), and anorexia/dehydration/syncope (n=1). There were no Grade 4 toxicities. Common grade 2 toxicities included fatigue (n=12), nausea (n=10), anorexia, anemia, and dyspnea (n=7 each). 18 patients evaluable for response had stable disease (SD) or progression of disease (PD): at 0.8 mg/m2, SD=2, PD=3; at 1.0 mg/m2, PD=3; at 1.3 mg/m2, SD=3, PD=3; at 1.5 mg/m2, SD=3, PD=1. Median duration of stable disease was 4 months (range 3–10). Conclusions: The recommended dose of PS-341 in combination is 1.3 mg/m2. Treatment was well-tolerated with reversible side effects and no grade 4 toxicities, and at the optimal dose, there was a 50% rate of stable disease. No significant financial relationships to disclose.

Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Combination with Bortezomib in Patients with Advanced Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1172-1172 ◽  
Author(s):  
Donna M. Weber ◽  
Sundar Jagannath ◽  
Amitabha Mazumder ◽  
Ronald Sobecks ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Phase I ◽  
Stable Disease ◽  
Phase I Trial ◽  
Performance Status ◽  
Single Agent ◽  
Primary Objective ◽  
Combination Regimen ◽  
Ecog Performance Status

Abstract Background: Vorinostat is a histone deacetylase inhibitor that has demonstrated antiproliferative and proapoptotic activity alone and in combination with the proteasome inhibitor bortezomib in preclinical multiple myeloma (MM) models. In a Phase I study, vorinostat also demonstrated modest single agent activity in patients (pts) with relapsed or refractory MM. Patients and Methods: We conducted a Phase I trial of oral vorinostat (200 mg bid or 400 mg daily × 14 days (d1–14) in combination with bortezomib 0.7 or 0.9 mg/m2 i.v. on d 4, 8, 11 and 15 or 0.9, 1.1, or 1.3 mg/m2 i.v. on d 1, 4, 8 and 11. Cycles were repeated every 21 d for a maximum of 8 cycles until progressive disease (PD) or intolerable toxicity. Pts with active relapsed or refractory MM who had not received bortezomib in the preceding 3 months and with adequate hematologic, hepatic, and renal function, and ECOG performance status of 0–2 were eligible. The primary objective was to determine the maximum tolerated dose (MTD). Activity (utilizing EBMT criteria) and safety of the combination regimen were also assessed. Results: Twenty pts have been enrolled: median age, 61 years (range 52–76), median number prior systemic therapies, 3 (range 1–14), prior therapy with bortezomib (4 pts). Eighteen pts have received ≥ 1 dose and were evaluable for safety as of 7/1/07. One pt (cohort 3) experienced a dose-limiting toxicity (DLT, Table). The MTD has not been reached. The most common drug-related toxicities of any grade were nausea (56%), thrombocytopenia (50%), diarrhea (39%), vomiting (39%), fatigue (39%), and anemia (22%). Grade ≥ 3 drug-related adverse events were thrombocytopenia (33%, none associated with bleeding), peripheral neuropathy (11%), neutropenia (11%, none associated with fever), diarrhea (6%), diverticulitis (6%), fatigue (6%), increased AST (6%), memory changes (6%), nausea (6%), vomiting (6%), and upper respiratory infection (6%). Eight pts discontinued treatment, 3 due to PD and 5 due to adverse experiences [fatigue (2), nausea (2), diverticulitis (1)]. Of 17 evaluable pts for efficacy, all had measurable response or stable disease; 4 had a partial response, 2 had a minimal response, and 11 stable disease. Among 3 evaluable pts previously treated with bortezomib, 1 achieved a partial response and 1, minimal response. Pts at the highest dose level were not yet evaluable for response. Conclusion: Although accrual continues to determine the MTD, the combination of vorinostat and bortezomib is well tolerated and effective in this group of heavily pretreated pts with refractory/relapsed MM. Table Cohort Vorinostat Dose (mg) Bortezomib Dose (mg/m2) N # of Cycles DLTs Best Response MR = minimal response; NE = not evaluable; PR = partial response; SD = stable disease. *Days 4, 8, 11 and 15. †Days 1, 4, 8 and 11. ‡Treatment cycle in progress. 1 200 0.7* 3 3, 3, 14 - SD (2), PR 2 200 0.9* 3 4, 5, 6 - SD (2), PR 3 400 0.9† 6 2, 3, 5, 6, 6, 6 Transient AST elevation SD (3), MR, PR (2) 4 400 1.1† 5 3, 3, 4, 5, 11 - SD (4), MR 5 400 1.3† 3 1‡, 1‡, 2 - NE (3)

Dasatinib plus capecitabine (Cap) for progressive advanced breast cancer (ABC): Phase I study CA180004

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1012-1012
Author(s):  
G. Somlo ◽  
F. Atzori ◽  
L. Strauss ◽  
A. Rybicki ◽  
X. Wu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Combined Treatment ◽  
Breast Cancer Cell Lines ◽  
Ecog Performance Status ◽  
Grade 3 ◽  
Study Laboratory

1012 Background: SRC family kinases (SFK) mediate numerous signal-transduction pathways relevant to breast cancer as well as osteoclast function. Dasatinib, a potent oral inhibitor of SFK and other kinases has preclinical activity in breast models and in vitro synergy with Cap in some breast cancer cell lines (KPL-4 and HCC-70). A phase I trial of dasatinib plus Cap was conducted to define dose-limiting toxicities (DLT), maximum tolerated (MTD), and recommended phase II (RP2D) doses. Methods: Sequential cohorts of pts with ABC were treated with Cap twice daily (BID) on days 1–14 and dasatinib daily in 21-day cycles using dose levels (DL) for Cap (mg/m2) and dasatinib (mg): DL1: Cap 825 + dasatinib 50 BID; DL2: Cap 825 + dasatinib 70 BID; DL3: Cap 1000 + dasatinib 70 BID; DL3a: Cap 1000 + dasatinib 100 once daily (QD). All pts had ECOG performance status 0–1, had prior anthracycline and/or taxane, and received ≤2 regimens in advanced setting. MTD was based on DLT in first cycle and RP2D also based on tolerability of additional cycles. Results: 31 pts with ABC, median age 53 years (range 36–78) were treated. Number of pts treated/evaluable for DLT/reported DLT (event) were DL1: 7/6/1 (headache, grade 3); DL2: 9/7/0; DL3: 6/6/1 (diarrhea, grade 3), and DL3a: 9/9/1 (pneumonia, grade 3). Most frequent AEs related to either drug and occurring at any time on study (n pts) were nausea (12), vomiting (7), diarrhea (6), abdominal pain (2), fatigue (8), headache (7), musculoskeletal pain (1), and pleural effusion (4); hand-foot syndrome (5) was as expected for Cap alone. 11 patients experienced a Grade 3–4 non-hematologic AE at some point during the study. Laboratory abnormalities were uncommon. To date, 20 pts have continued treatment for ≥6 weeks and 9 pts for ≥12 weeks. Number of pts who (at any time) reduced dasatinib/reduced Cap/discontinued for toxicity were DL1: 2/2/1; DL2 2/2/3; DL3: 2/1/2; DL3a: 0/1/1. Updated safety and efficacy data will be presented. Conclusions: Dasatinib + Cap was tolerated without unexpected combined-treatment toxicity; few pts required dose reduction in later cycles. The recommended phase II dose, Cap 1000 plus dasatinib 100 QD, is well tolerated and will be studied for efficacy in an expanded patient cohort. [Table: see text]

A phase II study (NCI9775) of sapanisertib (MLN0128/TAK-228) in relapsed and/or refractory acute lymphoblastic leukemia (ALL): Interim analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18506-e18506 ◽  
Author(s):  
Aref Al-Kali ◽  
Ibrahim Aldoss ◽  
Carrie Strand ◽  
Bijal D. Shah ◽  
Jonathan Allen Webster ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Lymphoblastic Leukemia ◽  
Performance Status ◽  
Single Agent ◽  
Median Number ◽  
Lymphoid Cells ◽  
Ecog Performance Status ◽  
Drug Concentrations ◽  
Treatment Naïve

e18506 Background: Sapanisertib (SAP) is an oral small molecule dual mTOR complex 1 and 2 (TORC1/2) inhibitor that showed activity in lymphoid neoplasms. It blocks a feedback loop involving mTORC2 activation when TORC1 is selectively inhibited (Yun S et al, Blood 2016). SAP induces apoptosis of malignant lymphoid cells in vitro and in xenografts, with greatest effects in ALL cell lines. We aim to assess potential efficacy of SAP when used as a single agent in relapsed/refractory ALL. Methods: Adults (age ≥18) with ECOG performance status 0-2 and normal organ function (creatinine/total bilirubin <1.5 upper limit of normal) with relapsed and/or refractory ALL (B- or T-cell) were enrolled. Newly diagnosed patients (pts) unfit for aggressive treatments and BCR-ABL+ ALL were allowed if there was no suitable standard treatment. SAP was given at 3 mg orally daily for 21 days every 28 days. Dose escalation was allowed after 2 cycles. Hydroxyurea and corticosteroids were not allowed after starting SAP. The primary end point was complete remission (CR) or CR with incomplete count recovery (CRi). This is a one stage Simon design study with interim analysis after 11 pts completed treatment. Enrollment was continued until interim analysis was done. Results: A total of 16 pts were enrolled on the study with a median age of 46 years old, 56% being males. 1/16 (6%) was treatment naïve. Median number of prior therapies is 3 (range, 1-9). The mean duration on SAP was 14.7 days (range 1-22). Three pts were able to start cycle 2. Safety was evaluable in 14 pts. All 14 pts had at least one G3 AE, while 10 pts had at least one G4 AE. G3/4 related non-hematological adverse events (AE) included 3 mucositis, 1 hepatic failure, 1 sepsis, 3 hyperglycemia, 1 anorexia, 1 seizure, 1 confusion, and 1 pneumonitis. One pt had G5 AE with malignancy. G3/4 hematological AEs included 2 with lymphopenia, 1 thrombocytopenia, 3 with leukopenia, and 1 with neutropenia. No pt achieved a CR/CRi. Best response was stable disease in 2 (12.5%) pts. Five pts had progressive disease while 9 were not evaluable because of early removal. Conclusions: SAP exhibited the expected safety profile. Although several pts developed cytopenias on drug, there was no evidence of clinically meaningful single-agent activity against ALL. Analysis of paired bone marrow aspirates from this trial is being performed to assess whether mTOR was substantially inhibited at therapeutically achievable drug concentrations. Clinical trial information: NCT02484430.

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