Paclitaxel poliglumex (PPX), cisplatin and concurrent radiation for esophageal and gastric cancer: A phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15130-15130
Author(s):  
T. Dipetrillo ◽  
D. Evans ◽  
P. Akerman ◽  
T. Miner ◽  
R. Millis ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Neoadjuvant Treatment ◽  
Hematologic Toxicity ◽  
Radiation Enhancement ◽  
Esophagogastric Cancer ◽  
Grade 3 ◽  
Level 2

15130 Background: PPX is a conjugate of paclitaxel to a polyglutamate polymer. Preclinically, PPX demonstrated a radiation enhancement factor (REF) >7.0, versus 1.5–2.0 for paclitaxel. (Milas et al Int J Rad Onc 55:2003, Li et al. Clin Cancer Res 6:2000). The maximally tolerated dose (MTD) of PPX was determined previously to be 70 mg/m2 /week with concurrent radiation. We initiated a phase I study of PPX, cisplatin, and concurrent radiation with patients with esophageal and gastric cancer. Methods: Patients with esophageal or gastric cancer receiving chemoradiation for locoregional control, adjuvant, or neoadjuvant treatment were eligible. All patients received radiation at a dose of 50.4 Gy delivered in 28 fractions (5 fractions per week for 5 1/2 weeks), and cisplatin (25 mg/m2) on days 1, 8, 15, 22, 29, and 36. PPX was given as a 10 minute infusion in escalating dosages prior to each cisplatin dose. Dose limiting toxicities (DLTs) were defined as grade 4 hematologic toxicity, esophagitis, nausea/vomiting, or dehydration, or any other grade 3/4 non-hematologic toxicity. Patients were enrolled in successive cohorts of three. The MTD was defined as the dose level at which no more than 2 of 6 patients have DLTs. Results: Eleven patients have been entered over 2 dose levels of PPX: 50 mg/m2 (six patients, dose level 1), and 60mg/m2 (5 patients, dose level 2). Five patients had esophageal cancer and six had gastric cancer. All histologies were adenocarcinomas. One of six patients treated at dose level had a DLT (esophagitis). Three of five patients had DLTs at dose level 2, including esophagitis, nausea, vomiting, and dehydration. Conclusions: PPX is a novel radiation sensitizer for patients with esophageal and gastric cancer. The MTD for PPX is 50 mg/m2 /week in combination with cisplatin 25mg/ m2 /week for 6 weeks, and 50.4 Gy concurrent radiation for patients with esophagogastric cancer. A phase II study of PPX/cisplatin and radiation will be initiated. No significant financial relationships to disclose.

Phase I study of biweekly intravenous paclitaxel plus intraperitoneal cisplatin and paclitaxel for gastric cancer with peritoneal metastasis.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 139-139
Author(s):  
H. Ishigami ◽  
J. Kitayama ◽  
S. Kaisaki ◽  
H. Yamaguchi ◽  
H. Yamashita ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Cancer Patients ◽  
Dose Level ◽  
Peritoneal Metastasis ◽  
Phase I Study ◽  
Level 1 ◽  
Grade 3 ◽  
Gastric Cancer Patients ◽  
Experienced Grade

139 Background: Intraperitoneal (IP) chemotherapy is promising for the treatment of gastric cancer with peritoneal metastasis. We previously verified the safety and efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous (IV) PTX in phase I and phase II studies (Oncology. 2009; Ann Oncol. 2010). Secondly, we developed a new IP-containing chemotherapy regimen, IV PTX plus IP cisplatin (CDDP) and PTX, for patients who have failed S-1-based chemotherapy. We performed a phase I study to determine the maximum-tolerated dose (MTD) and recommended dose (RD) in gastric cancer patients. Methods: A total of 9 gastric cancer patients were enrolled who had shown progression of peritoneal metastasis after S-1-based chemotherapy. PTX was administered intravenously at a dose of 100 mg/m2 and intraperitoneally over 1 hour with an initial dose of 20 mg/m2 (level 1), stepped up to 30 or 40 mg/m2 depending on observed toxicity. CDDP was subsequently administered intraperitoneally at a dose of 30 mg/m2 over 24 hours after PTX infusion. PTX and CDDP were administered on days 1 and 15 in 4-week cycles. Results: At dose level 1, dose-limiting toxicities (DLTs) were observed in 2 of 3 patients. One patient experienced grade 4 leukopenia, and the other grade 3 vomiting. Because of higher toxicities than anticipated, the initial dose-escalation schedule was abandoned, and the doses of IV PTX and IP CDDP were reduced to 80 mg/m2 and 25 mg/m2, respectively, while keeping the dose of IP PTX at 20 mg/m2 (level 0). At dose level 0, one of the first 3 patients experienced grade 3 nausea, and an additional 3 patients experienced no DLTs. Consequently, the MTD and RD were determined to be dose level 1 and dose level 0, respectively. No patients experienced complications related to the peritoneal access device or IP infusion. Conclusions: Combination chemotherapy of IV PTX plus IP CDDP and PTX was shown to be a safe regimen that should be further explored in clinical trials. No significant financial relationships to disclose.

A dose-finding study for irinotecan, cisplatin, and S-1 (IPS) in patients with advanced gastric cancer (OGSG 1106).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 144-144
Author(s):  
Hiroki Yukami ◽  
Masahiro Goto ◽  
Takayuki Kii ◽  
Tetsuji Terazawa ◽  
Toshifumi Yamaguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Activity ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Advanced Gastric Cancer ◽  
Phase I Study ◽  
Fixed Dose ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

144 Background: In Japan, S-1 plus cisplatin is regarded as one of the standard first line treatment of advanced gastric cancer (AGC). However, the prognosis of AGC remains dismal. The development of more effective chemotherapeutic regimen is thus warranted. A combination of irinotecan, cisplatin, and S-1 (IPS) can be a promising triplet therapy for advanced gastric cancer. We conducted a phase I study of IPS to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and recommended dose (RD), and to assess its safety and antitumor activity in patients with AGC. Methods: This phase I study was designed and conducted in a 3 + 3 manner to determine the recommended dose (RD) of IPS for the subsequent phase II study. Patients received an escalating dose of intravenous irinotecan (level 1: 100/level 2: 125/level 3: 150 mg/m²) on day 1, a fixed dose of intravenous cisplatin (60 mg/m²) on day 1, a fixed dose of S-1 (80 mg/m² b.i.d.) orally on days 1-14, every 4 weeks. Results: Twelve patients were enrolled between June 2013 and February 2017. During the first cycle, one of the six patients in level 1 and two of six patients in level 2 developed the DLT (grade 4 leucocytopenia and grade 3 febrile neutropenia). The MTD of irinotecan was 125 mg/m 2 (level 2) and the RD of irinotecan was considered to be 100 mg/m² (level 1). The most common grade 3 or 4 adverse events included neutropenia 75 % (9/12), anemia 25% (3/12), anorexia 8% (1/12), and febrile neutropenia 17% (2/12). Among six patients with measurable lesions, the response rate was 66.7% (4/6) [95% CI, 33.3-90.7%]. Two patients were performed R0 resection after IPS, with one patient achieved pathological complete response. The median survival time is under analysis. Conclusions: RD of IPS was determined to be 100 mg/m² of irinotecan, 60 mg/m² of cisplatin, and 80 mg/m² of S-1. Our data showed that this regimen provided acceptable antitumor activity and a favorable toxicity profile. Further evaluation of this regimen is warranted. Clinical trial information: UMIN000006864.

Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4559-4559
Author(s):  
C. Kim ◽  
J. Lee ◽  
Y. Choi ◽  
B. Kang ◽  
M. Ryu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Dose Finding ◽  
Finding Study ◽  
Level 3 ◽  
Dose Finding Study ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

4559 Background: We conducted a phase I dose-finding study of sorafenib (S) in combination with capecitabine (X) and cisplatin (P) in patients with previously untreated metastatic or inoperable advanced gastric cancer. Methods: Four dose levels of S, X, and P combination were tested. The doses of S (p.o. daily), X (p.o. on days 1–14), and P (i.v. on day 1) were escalated at the following schedule; level 1: S 400 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 2: S 800 mg/d, X 1,600 mg/m2/d, P 80 mg/m2; level 3: S 800 mg/d, X 2,000 mg/m2/d, P 80 mg/m2; level 1A: S 800 mg/d, X 1,600 mg/m2/d, P 60 mg/m2. The cycle was repeated every 3 weeks. Dose limiting toxicities (DLTs) were evaluated only in the first cycles and a standard 3+3 dose escalation design was implemented. Results: A total 21 pts were enrolled in the study. No DLTs were observed at dose level 1 (n=3). One DLT (grade 3 diarrhea) was noted at dose level 2 (n=6), and 2 DLTs (two grade 4 neutropenias longer than 5 days in duration) were observed at dose level 3 (n=6), which made the level 3 dose the maximum tolerated dose (MTD). However, at cycle 2 and thereafter at dose level 2, the relative dose intensity (RDI) of S and X could not be maintained (mostly below 80%) due to the frequent dose reductions and cycle delays. So, we explored a new dose level (1A) between dose level 1 and 2. Since no DLTs were found in 6 patients at level 1A with RDI mostly above 80% throughout the treatment period, level 1A was determined as recommended dose (RD). Most frequent grade 3 and 4 hematologic toxicities were neutropenia (25.0% of cycles), and most frequent grade 2 and 3 non-hematologic toxicities were hand-foot syndrome (9.4%), asthenia (7.0%), and anorexia (5.5%). The objective responses were confirmed in 10 out of 16 patients with measurable lesions (62.5%; 95% CI, 38.8–86.2%). With a median follow-up of 8.1 months, estimated median progression-free survival was 10.0 months (95% CI, 1.6–18.4 months) and median overall survival has not been reached. Conclusions: Diarrhea and neutropenia were DLTs in this S, X, and P combination. The dose schedule of sorafenib 400 mg po bid daily with capecitabine 800 mg/m2 po bid on days 1–14, and cisplatin 60 mg/m2 iv on day 1 in every 3 weeks is recommended for further development in AGC. [Table: see text]

scholarly journals Phase I study of the 177Lu-DOTA0-Tyr3-Octreotate (lutathera) in combination with nivolumab in patients with neuroendocrine tumors of the lung

2020 ◽  
Vol 8 (2) ◽  
pp. e000980
Author(s):  
Chul Kim ◽  
Stephen V Liu ◽  
Deepa S Subramaniam ◽  
Tisdrey Torres ◽  
Massimo Loda ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Neuroendocrine Tumors ◽  
Phase I Study ◽  
Somatostatin Receptors ◽  
Atypical Carcinoid ◽  
Platinum Based Chemotherapy ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

BackgroundLutathera is a 177Lutetium-labeled somatostatin analog approved for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). Somatostatin receptors are expressed in small cell lung cancer (SCLC). Nivolumab, an anti-PD-1 antibody, may act synergistically with lutathera to generate antitumor immunity. We conducted a phase I study of lutathera plus nivolumab in patients with advanced NETs of the lung.MethodsPatients with relapsed/refractory extensive-stage SCLC (ES-SCLC), non-progressing ES-SCLC after first-line platinum-based chemotherapy, or advanced grade I-II pulmonary NETs were eligible. The primary objective was to determine the recommended phase 2 dose (RP2D). The phase I portion followed a standard 3+3 design, assessing two dose levels (dose level 1: lutathera 3.7 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks; dose level 2: lutathera 7.4 GBq every 8 weeks for four doses with nivolumab 240 mg every 2 weeks).ResultsNine patients were enrolled (six ES-SCLC, two pulmonary atypical carcinoid, one high-grade pulmonary neuroendocrine carcinoma). No dose-limiting toxicities (DLTs) were observed at dose level 1. At dose level 2, one patient with refractory ES-SCLC developed a DLT (grade 3 rash). The most common treatment-related adverse events (TRAEs) were lymphopenia (n=7), thrombocytopenia (n=4), anemia (n=3), and nausea (n=3). The most common grade 3 TRAE was lymphopenia (n=4). Among the seven patients with measurable disease, one patient with ES-SCLC had a partial response. Two patients with pulmonary atypical carcinoid had stable disease lasting 6 months. The RP2D was dose level 2.ConclusionsLutathera plus nivolumab was well tolerated and showed signs of antitumor activity. This combination warrants further exploration.Trial registration numberNCT03325816

scholarly journals Updated Results of a Phase I Study of Ibrutinib and Lenalidomide in Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3983-3983 ◽  
Author(s):  
Beth A Christian ◽  
John G. Kuruvilla ◽  
Sonali M. Smith ◽  
Pierluigi Porcu ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Disease Progression ◽  
Dose Level ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Off Label ◽  
Grade 3

Abstract Introduction: Lenalidomide, an immunomodulatory agent, and ibrutinib, a selective and covalent inhibitor of Bruton's tyrosine kinase, are orally bioavailable agents with single-agent activity in several histologic subtypes of relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). We are conducting a phase I study of the combination of ibrutinib and lenalidomide to determine the maximum tolerated dose, dose limiting toxicities (DLT), and preliminary efficacy in pts with relapsed/refractory NHL and updated results are presented. Methods: Patients (pts) with relapsed/refractory B-cell NHL including diffuse large B-cell (DLBCL), transformed, mantle cell (MCL), marginal zone (MZL), lymphoplasmacytic (LPL), and follicular (FL) lymphoma who have received at least one prior therapy were eligible. Prior autologous but not allogeneic stem cell transplant and prior lenalidomide were permitted. Prior ibrutinib, CNS involvement, and pts requiring anticoagulation were not permitted. ANC > 1000/mm3, platelets > 50,000/mm3, and creatinine < 2.0 mg/dL, ALT/AST ≤ 2.5 x ULN, bilirubin ≤ 1.5 x ULN, and ECOG PS 0-2 were required at study entry. Treatment consisted of escalating doses of lenalidomide days 1-21 and ibrutinib days 1-28 of a 28 day cycle. A standard 3+3 dose escalation schema was followed. DLTs included: treatment delays > 14 days for toxicity; grade 5 toxicity; tumor lysis syndrome requiring dialysis; tumor flare reaction nonresponsive to corticosteroids; ANC < 500/mm3 or platelets <25, 000/mm3 persisting > 7 days; grade 3 or 4 febrile neutropenia or infection; and any grade 3 or 4 non-hematologic toxicity with the following exceptions: DVT, diarrhea, nausea or vomiting amenable to medical therapy, correctable electrolyte abnormalities; grade 3 fatigue, or grade 3 maculopapular rash that resolved within 7 days. Pts without significant toxicity could continue treatment until disease progression. Response was assessed every 3 months for 12 months and then every 6 months until disease progression. Results: Twenty-five pts have been treated. Median age is 67 years (range 45-85) with 16 males. Histologies include DLBCL/transformed lymphoma (n=9), MCL (n=7), FL (n=4), MZL (n=2), and LPL (n=3). Four pts were treated at dose level (DL) 1 (lenalidomide 15 mg/ibrutinib 420 mg). One pt was replaced for rapid disease progression and 1 pt experienced DLT consisting of a grade 2 ischemic stroke. As a result of this DLT, DL 1 was expanded to 6 evaluable pts. A second DLT was observed, a grade 3 rash that resolved within 7 days but recurred on day 22. A total of 6 pts were then treated at DL-1 (lenalidomide 10 mg/ibrutinib 280 mg), and no DLTs were encountered. The protocol was amended to include additional dose levels. Pts enrolled on dose level -1A with lenalidomide 10 mg and ibrutinib 420 mg. One DLT occurred at this dose level, a grade 3 rash that failed to resolve within 7 days. The dose level was expanded to 6 pts without further DLT. DL-1B includes an intra-pt dose escalation of the lenalidomide from 10 mg in cycle 1 to 15 mg in cycle 2 with ibrutinib 420 mg. Six pts have been enrolled on this dose level. Three pts have been replaced including 2 with cytopenias not meeting DLT criteria but precluding dose escalation and one with progressive disease. Three pts at DL-1B remain on treatment. Related grade 3-4 toxicities occurred in 16/24 currently evaluated pts (67%), including primarily hematologic toxicity, rash, increased LFTs, pneumonia, hypokalemia, and syncope. Pts have received a median of 3 cycles of therapy to date (range 1-19) and 9 remain on therapy. At DL 1, a pt with DLBCL achieved a complete response (CR) and a pt with transformed follicular achieved a partial response (PR). At DL-1, a pt with DLBCL achieved a CR and 1 pt each with MCL and FL achieved PR. At DL -1A, 1 pt each with MCL and MZL achieved a PR. Overall response rate for 18 assessable pts is 39%. Five pts had best response of stable disease. Sixteen pts have discontinued the study including 3 pts with DLTs, 2 for alternative treatment, 2 for toxicity, and 9 pts with progression. Conclusions: Combined therapy with lenalidomide and ibrutinib in pts with relapsed NHL is well-tolerated, although DLTs of recurrent rash and stroke were encountered. Lenalidomide 10 mg and ibrutinib 420 mg was tolerated and pts are currently enrolling in an intra-pt dose escalation cohort. Preliminary efficacy has been observed in pts with relapsed/refractory DLBCL, MCL, FL, MZL, and transformed NHL. Disclosures Christian: Pharmacyclics: Research Funding; Acerta: Research Funding; Immunomedics: Research Funding; Celgene: Consultancy; Novartis: Other: IDSM; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding. Off Label Use: The use of ibrutnib and lenalidomide in combination in relapsed/refractory non-Hodgkin's lymphoma is off-label. Kuruvilla:Karyopharm: Honoraria, Research Funding; Roche Canada: Honoraria; Seattle Genetics: Honoraria, Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy. Porcu:Cell Medica: Research Funding; Infinity: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Shape: Research Funding. Maddocks:Acerta: Research Funding; Pharamcyclics: Research Funding; Novartis: Research Funding. Byrd:Pharmacyclics: Research Funding. Blum:Celgene: Research Funding; cephalon: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding.

A Phase I Trial of Oblimersen Sodium (G3139) for Relapsed or Refractory Waldenstrom Macroglobulinemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2407-2407
Author(s):  
Morie Abraham Gertz ◽  
Susan M. Geyer ◽  
Brad S. Kahl ◽  
Ashraf Badros ◽  
Craig Reeder ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase I Study ◽  
Protein Translation ◽  
Hematologic Toxicity ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Grade 3 ◽  
Dose Reductions

Abstract Introduction Antisense oligonucleotides are used to inhibit messenger RNA function and inhibit protein translation. Bcl-2 expression proteins have been implicated in mediating resistance to apoptotic cell death in Waldenstrom Macroglobulinemia (WM). Oblimersen sodium is a specific inhibitor of Bcl-2 expression and has shown activity in multiple myeloma and in Waldenstrom cell lines. The in vitro data led to the development of a phase I study for WM patients with relapsed or refractory disease. Materials and Methods Eligible patients had symptomatic WM who had failed prior cytotoxic chemotherapy. All patients had to have one of the following: a hemoglobin &lt;11 g/dL, a platelet count &lt;100,000/uL, bulky lymphadenopathy, or hyperviscosity syndrome. As a phase I study, the primary end point was toxicity assessment, but all patients were assessed for response, using monoclonal protein levels. Patients were enrolled and evaluated in cohorts of three. Drug was administered as a 24-hour continuous infusion for 7 days every 21 days, with intrapatient dose escalation each subsequent cycle beginning at 3 mg/kg/day up to a maximum of 7 mg/kg/day days 1–7 for a maximum of 8 cycles. Results To date 9 patients have been accrued, six at dose level one and three patients at dose level two. Data is available for the first six entered. Five women and 1 man have been accrued with a median age of 74.5 years, ranging from 58 to 81. Four patients had relapsed from prior therapy, 2 were refractory. Three had a history of transfusions. The median number of prior regimens was 4 (range 2–7). One patient had a dose-limiting toxicity on the first cycle of therapy, which was grade 3 fatigue and anorexia, and the dose for this patient was reduced. Two patients had non-hematologic grade 3 toxicity, possibly related to therapy. Five out of six patients on dose level one had grade 3 or greater hematologic toxicity. These toxicities occurred after cycle 1 was completed, during the toxicity observation period and were not considered dose limiting toxicities influencing dose escalation. Three patients required dose reductions in subsequent cycles. To date one patient has had a partial response with her serum M spike falling from 3.6 to 1.1 g/dL. Her quantitative IgM fell from 6,000 mg/dL to 1,000 mg/dL(figure). Conclusion Oblimersen was well tolerated at the first dose level in patients with WM. Hematologic toxicity is frequent in this cohort with heavily involved bone marrows when the dose was escalated during successive cycles. Dose reductions with subsequent cycles were frequently required. Evaluation of the maximum tolerated dose continues. Data on response for this dose level is promising, where efficacy will be fully evaluated in the phase II portion of this trial. Figure Figure

A Phase I Study of Lenalidomide in Combination with Fludarabine-Rituximab in Previously Untreated CLL/SLL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3426-3426
Author(s):  
Jennifer R Brown ◽  
Jeremy S. Abramson ◽  
Ephraim P. Hochberg ◽  
Evgeny Mikler ◽  
Virginia Dalton ◽  
...  
Keyword(s):  
Phase I ◽  
Immune Function ◽  
Dose Level ◽  
Phase I Study ◽  
Objective Response ◽  
Study Entry ◽  
Hematologic Toxicity ◽  
Significant Difference ◽  
Level 1 ◽  
Grade 3

Abstract Abstract 3426 Poster Board III-314 Lenalidomide is an immunomodulatory drug recently reported to have an objective response rate (ORR) of 35-53% in relapsed/refractory CLL, even with poor risk features. Initial therapy of CLL currently includes chemoimmunotherapy combinations like FCR, which have high response rates and improved PFS, but at the cost of myelosuppression and infection. Given the high ORR reported with lenalidomide and its potential to spare immune function, we undertook this Phase I study to explore the safety and tolerability of lenalidomide in combination with fludarabine and rituximab. Eligibility criteria included a confirmed diagnosis of CLL/SLL, previously untreated with systemic therapy with an indication for therapy by NCI-WG 1996 criteria; ANC > 1000, platelets > 50K, and adequate organ function. Six dose levels were planned, beginning with fludarabine 25 mg/m2 days 1-3, rituximab 375 mg/m2 day 1, and lenalidomide 2.5 mg administered on days 1-21 of a 28-day cycle. The study used a standard 3+3 dose escalation design, with dose limiting toxicity (DLT) assessed in the first 28 days and defined as grade 3 or greater non-hematologic toxicity, grade 4 neutropenia or thrombocytopenia, grade 3 febrile neutropenia, or a >2-week delay in initiating the second cycle. Nine patients were enrolled on this study, 7 males and 2 females, with a median age of 59 yrs (range 37-66). The median time from diagnosis to study entry was 66.1 months (range 11.7-82.8 months). The median WBC at study entry was 99.6 (range 11.1-325.7). Six patients had Rai 3-4 disease, and three patients had bulky lymphadenopathy (>5 cm) on physical exam. Median beta-2 microglobulin level at study entry was 3.8 mg/L (range 2.5-7.7). The first cohort enrolled four patients, of whom two developed DLTs (grade 4 neutropenia persisting through day 50; febrile syndrome with grade 3 rash, myalgias and grade 4 CPK elevation). The study then proceeded to enroll five patients at dose level -1, with the same dosing of rituximab and fludarabine, but reduced lenalidomide dosing of 2.5 mg every other day for 21 of 28 days. Only two of five patients on dose level -1 completed the planned six cycles of therapy. The other three patients discontinued after 3 cycles due to toxicity: persistent grade 2 thrombocytopenia preventing further therapy; recurrent grade 3-4 neutropenia and thrombocytopenia, despite growth factor support, dose reduction and holding lenalidomide; and intermittent recurrent grade 3 tumor flare, rash and hand-foot syndrome, along with recurrent grade 3 neutropenia despite similar measures as above. At that point the study was closed to enrollment due to the significant myelotoxicity and idiosyncratic tumor flare, resulting in only two of nine patients completing the planned therapy. The median number of cycles completed for all patients was three. Six of the nine enrolled patients were evaluable for response, with five of nine having objective responses (56%, 90% CI 25-83%). No significant difference was observed in IgG and IgM levels between baseline and two months on study, although a trend toward a decrease in IgA levels (p=0.05) was observed. Baseline CD4 counts were variable (median 1139, range 529-2687), but showed significant declines of 574 cells by week 4 (p=0.003) and 707 cells by post-treatment (p=0.002). Analysis of alterations in serum cytokines is ongoing. We conclude that administering lenalidomide concurrently with fludarabine and rituximab is difficult, does not appear to preserve immune function, and limits the ability to deliver adequate therapy with either drug. Other trials currently in progress are exploring alternative schedules of lenalidomide administration with fludarabine and other standard CLL chemotherapy regimens; our data would favor a sequential schedule. Disclosures Brown: Celgene: Honoraria, Provided funding for this investigator-initiated study; Genzyme: Research Funding; Genentech: Consultancy; Calistoga: Consultancy. Off Label Use: Lenalidomide for CLL. Hochberg:Enzon: Speakers Bureau; Biogen-Idec: Speakers Bureau; Genentech: Speakers Bureau; Amgen: Speakers Bureau.

Phase I study of the combination of everolimus (RAD001) with 5FU/LV in patients with refractory solid malignancies.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 512-512
Author(s):  
J. M. Davies ◽  
A. J. McRee ◽  
H. K. Sanoff ◽  
T. Triglianos ◽  
K. Keller ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Cellular Growth ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Oncogenic Pathways ◽  
Solid Malignancies ◽  
Level 3 ◽  
Grade 3

512 Background: mTOR is a controller of cellular growth and other processes that is activated by several oncogenic pathways in cancer. Everolimus is an oral inhibitor of mTOR activation. The mTOR inhibitor, temsirolimus, when combined with high dose 5FU, was limited by significant mucosal toxicity. Purpose: Phase I study to determine the maximum tolerated doses (MTD) and the safety of everolimus combined with 5FU/LV in patients with refractory solid tumors. Methods: Using a standard 3+3 design, starting doses were everolimus 15mg weekly, and q2 weekly 5FU 400mg/m2 bolus and 1800mg/m2 infusion (over 46 hours) and LV 400mg/m2. Daily dosing of everolimus was instituted during level 3 as data emerged about improved target inhibition and adverse event profile with daily dosing. Dose escalation to the maximum planned levels was achieved: everolimus 10mg daily, 5FU 400mg/m2 bolus and 2400mg/m2 infusion, and LV 400mg/m2. Dose limiting toxicities (DLT) were assessed in cycle 1 (4 weeks), defined as any grade 3/4 non-hematologic toxicity (except grade 3 skin rash, nausea and diarrhea), or complicated grade 3-4 heme toxicity. Tumors were measured every 8 weeks. Results: From 03/2008 and 11/2009, 21 patients were treated. Median age 58 (range 35-77), male/female 13/8, PS 0/1 10/11. One DLT was seen at dose level 1 (grade 3 hypersensitivity/angioedema); two at dose level 6 (grade 3 diarrhea, grade 3 hypophosphatemia). As such, dose level 5 is the MTD. Dose reductions were required in 4 patients for mouth sores (2), nasal sores (1), and grade 3 transaminitis (1). Responses are as follows: 11 stable disease and 8 progressive disease; 2 patients were not evaluable. Conclusions: MTD is everolimus 5mg daily, with q2 weekly 5FU 400mg/m2 bolus and 2400mg/m2 infusion and LV 400mg/m2. We are currently expanding the study to evaluate the addition of oxaliplatin and panitumumab to the 5-FU/LV and everolimus base. [Table: see text] [Table: see text]

Phase I study of imatinib, cisplatin, and fluoruracil in patients with advanced gastric cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 115-115
Author(s):  
Martina Mayr ◽  
Barbara Alberter ◽  
Karin Becker ◽  
Roland M. Schmid ◽  
Matthias Philip Ebert
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Gastroesophageal Junction ◽  
Maximum Tolerated Dose ◽  
Gastric Body ◽  
Grade 3 ◽  
Immediate Surgery ◽  
Dose Escalating

115 Background: Combination chemotherapies are established as standard treatment in gastric cancer, but prognosis remains poor. Integration of targeted therapies may provide an additional benefit. Imatinib may inhibit platelet derived growth factor (PDGF) mediated tumor growth and amplify effects of chemotherapy. This Phase I study evaluated dose limiting toxicity (DLT) of imatinib in combination with cisplatin and fluoruracil/ capecitabine therapy in gastric cancer. Methods: The study was designed as a 3-patient cohort dose-escalating trial. Patients (pts) received cisplatin (60 mg/m2 d1 q 21) and capecitabine (1250 mg/m2 bid d1-14 q 21) or cisplatin (50 mg/m2 d1, 15, 29 q 50) and leucovorin (500 mg/m2), followed by a 24-hour 5-fluoruracil infusion (2000 mg/m2 d1,8,15,22,29,36 q 50). Imatinib was started d - 4 and continuously administered with the dose being escalated from 300 to 700 mg QD in 100 mg steps. Results: Characteristics of the 35 enrolled pts: Median age= 61 years (range 39-76). Male: female= 27:8. ECOG 0: 21 pts (60%), ECOG 1: 13 pts (37%), ECOG 2: 1 pt (3%). Localization: carcinoma of the gastroesophageal junction 17 pts (48%), gastric body 18 pts (52%). Histology: intestinal 8 (23%), diffuse 10 (28%), not specified 17 (49%). Metastatic disease: 21 pts (60%). At imatinib dose level 1 (300mg) one DLT was observed and three more pts were enrolled without further DLT. No DLT was encountered up to dose level 4. At dose level 5 (700 mg) two gastric perforations occurred, so 600 mg imatinib emerged as the maximum tolerated dose. Immediate surgery was performed on both with good clinical outcome. Therapy was delivered 14 weeks (range 1- 59) on average. Major grade 3/4 toxicities were nausea (6%), anemia (4%), fatigue (6%) and upper GI hemorrhage (3%). Response evaluation at 6 weeks revealed partial response (PR) in 27%, stable disease (SD) in 43% and progressive disease in 13% of the assessable pts. Conclusions: Combination of imatinib and chemotherapy is a well tolerated therapeutic approach with promising activity. A relationship between study medication and the occurred gastric perforations remains disputable. Further investigations are required to confirm the assumed amplification of chemotherapy effects by imatinib.

MK-0457, a Novel Multikinase Inhibitor, Has Activity in Refractory AML, Including Transformed JAK2 Positive Myeloproliferative Disease (MPD), and in Philadelphia-Positive ALL.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1967-1967 ◽  
Author(s):  
Francis Giles ◽  
Steven J. Freedman ◽  
Alan Xiao ◽  
Gautam Borthakur ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Standard Dose ◽  
Performance Status ◽  
Resistance Mutation ◽  
Hematologic Toxicity ◽  
Grade 3 ◽  
Dose Limiting Toxicity ◽  
Refractory Aml

Abstract Background. MK-0457 (VX-680) is a small-molecule inhibitor of aurora kinases A, B, and C, FLT3, BCR-ABL, and JAK2. MK-0457 exhibits nanomolar level broad-spectrum preclinical anti-tumor activity. Specifically, MK-0457 inhibits proliferation of patient-derived AML cells in vitro, and improves survival of a Ba/F3 FLT3 ITD murine model of systemic AML. A Phase I study of MK-0457 is being conducted in patients with a broad range of hematological malignancies, including acute myeloid and lymphoid leukemias. Methods. After IRB approval, 15 consenting patients with relapsed/refractory AML and ALL, ECOG performance status ≤ 2, and adequate organ function were enrolled using a standard dose escalation scheme with 3 patients/dose level until dose-limiting toxicity (DLT), followed by 6 patients/level. MK-0457 was administered by continuous 5-day intravenous infusion every 2 to 3 weeks. DLT was defined as grade 3 or higher non-hematologic toxicity during cycle 1. Pharmacokinetics (PKs) were collected pre-dose through 168 h and analyzed for MK-0457 by HPLC/mass spec. Results. Thirteen patients with AML and 2 patients with ALL were enrolled at 8, 12, 20, 24, and 28 mg/m2/hr. Among AML patients, two had a diploid karyotype and the remainder had complex unfavorable cytogenetic abnormalities. Two AML patients had a prior JAK2-positive MPD, transformed to AML, and then received MK-0457 as their 1st AML treatment. One AML patient received MK-0457 as first salvage, three as second salvage, and the remainder as salvage attempt three or higher. Both ALL patients failed prior multiagent chemotherapy; one of these patients had Philadelphia (Ph)-positive ALL and progressed after prior BCR-ABL inhibitor therapy, including dasatinib. The latter patient carried the BCR-ABL inhibitor resistance mutation, T315I. Four of 5 AML patients without baseline grade 3/4 myelosuppression in one cell line developed grade 4 neutropenia, including both JAK2-positive AML patients. Normalization of the platelet count during cycle one occurred in one MPD patient with thrombocytosis at baseline (~800 x 103/mL); Grade 3 thrombocytopenia occurred during cycle one in the other MPD patient with a normal baseline. The Ph+-ALL patient had eradication of peripheral blood blasts at the end of 2 cycles of therapy. No MK-0457 attributable extramedullary grade 2 or above adverse events were seen. Mild hair thinning was seen in some patients at dose levels 20 mg/m2/hr and above. Preliminary PK analysis showed dose-dependent linearity at steady state, with a biexponential decay at the end of infusion characterized by a rapid a decay followed by a slower b decay (t1/2 10–20 hrs). Conclusions. MK-0457 at well tolerated doses achieves myelosuppression in refractory AML and ALL patients. Its activity in JAK2+ transformed AML patients may be partially attributable to JAK2 inhibitory activity. The role of aurora kinase inhibition in the above responses is not yet established. As neither maximum tolerated dose nor dose limiting toxicity has been defined to date, dose finding on this Phase I study of MK-0457 is on-going in the acute leukemia population with 36 mg/m2/hr as the current dose level under investigation.

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