Phase I/II study of weekly topotecan and gefitinib in patients with platinum-resistant ovarian, peritoneal, or fallopian tube cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6059-6059
Author(s):  
Anca Chelariu- Raicu ◽  
Charles F. Levenback ◽  
Brian M. Slomovitz ◽  
Diane C. Bodurka ◽  
David Marc Gershenson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Phase I ◽  
Dose Level ◽  
Fallopian Tube ◽  
Phase Ii ◽  
Response To Therapy ◽  
Clinical Activity ◽  
Study Results ◽  
Level 3

6059 Background: The epidermal growth factor receptor (EGFR) is expressed in many types of cancer. Fifty to 70% of epithelial ovarian can overexpress EGFR, and its expression has been correlated with poor prognosis features in many cases. While these tumors are chemosensitive to platinum-based therapy, chemoresistance often develops. We conducted a phase I/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with EGFR receptor positivity (1+ or greater). Methods: Patients with measurable, recurrent or persistent cancer after treatment with a platinum and paclitaxel-containing regimen were eligible for this study (n = 19). We first used “run-in” dose escalation, in which a conventional 3+3 algorithm was used. Initial treatment was gefitinib 250 mg oral dose daily and topotecan at a dose of 2.0 mg/m2 on days 1, 8, and 15, with cycles repeated every 28 days. Dose escalations were planned for topotecan (Dose Levels 1–3: 2, 3, 4 mg/m2) until the MTD was reached. Next, an additional 10 patients with refractory or progressive ovarian cancer were enrolled in the phase II study. Results: 19 patients received a total of 61 cycles. Median age was 60 years. Histological types of treated patients included 73% serous (n = 14), 12.5% mixed (n = 2), 12.5% transitional (n = 2) and 6.3% clear cell (n = 1). There were 3 patients treated at dose level 1, 3 patients at dose level 2, and 3 patients treated at dose level 3. The maximum tolerated dose was topotecan 4.0mg/m2 IV days 1, 8 and 15, and gefitinib 250mg p.o. QD x28 days. Therefore, dose level 3 was used for the Phase II portion of the trial. Of the 19 patients included in the phase I/II, 3 patients were inevaluable for response to therapy due to toxicity, missed therapy or decline in performance status. Of the 16 patients, 81% patients (n = 13) had progressive disease, 12.5% stable disease (n = 2), and 6% partial response (n = 1). We assessed all 19 patients for adverse events; 60% had treatment-related grade 3 events, primarily blood disorders such as anemia (n = 3, 16%), neutrophil count decrease (n = 4, 21%). Conclusions: This prospective phase I/II clinical trial failed to show sufficient clinical activity of topotecan in combination with gefitinib in patients with EGFR-positive recurrent ovarian, fallopian tube, or peritoneal cancers. The drug combination was relatively well-tolerated in this cohort. As such, the study did not proceed to the next accrual goal secondary to the lack of response. Clinical trial information: NCT00317772.

Oxaliplatin, Fludarabine, Cytarabine, and Rituximab Combination Therapy Induces High Response Rates in Agressive Chronic Lymphocytic Leukemia (CLL) and Richter's Syndrome (RS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3443-3443 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
William Wierda ◽  
William Plunkett ◽  
Susan O'Brien ◽  
Thomas J. Kipps ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rates ◽  
Off Label ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 3443 Poster Board III-331 Introduction The first Phase I-II clinical trial of oxaliplatin, fluradabine, cytarabine (Ara-C), and rituximab (OFAR1) demonstrated significant activity in refractory CLL and RS (Tsimberidou et al, J Clin Oncol, 2008;26:196). To enhance the response rate and decrease myelosuppression, the dose of oxaliplatin was increased to 30mg daily, the dose of Ara-C was decreased to 0.5g/m2 daily and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods In a Phase I-II study of OFAR2, patients were treated with oxaliplatin 30mg/m2, D1-4; fludarabine 30mg/m2, Ara-C 0.5g/m2; rituximab 375mg/m2, D3; and pelfigrastim 6mg, D6. Fludarabine and Ara-C were given on D2-3 (dose level 1) D2-4 (dose level 2) or D2-5 (dose level 3); courses were repeated every 4 weeks. Patients received prophylaxis for tumor lysis, DNA viruses, and PCP. A “3+3” design was used and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results Ninety-one patients (CLL, 67; RS, 24) have been treated to date: Phase I, 12 patients (by dose level: 1, n=3; 2, n=6; and 3, n=3). DLTs were noted in 2 of 3 patients on dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1); thus, dose level 2 was the MTD. Seventy-nine patients (relapsed CLL, 58; RS, 19) have been treated in the Phase II portion of the study. Patient characteristics were as follows: age > 60 years, 65%; 17p deletion, 38%; 11q deletion, 13%; 13q deletion, 16%; trisomy 12, 21%; no findings, 12%; unmutated IgVH, 80%; ZAP70-positive, 75%; and CD38 ≥30%, 58%. Response in patients treated in the Phase II recommended dose is shown in Table (evaluable, 67). The overall response rates in patients with 17p and 11q deletions were 48% and 55%, respectively. The median survival duration was 21 months (CLL, 21 months; RS, 9.5 months). At 18 months, the survival rates in patients with 17p and 11q deletions were 66% and 76%, respectively. Twelve patients underwent stem cell transplantation after OFAR2 (as post-remission therapy, n=10; as salvage, n=2). Overall, 196 cycles were administered. Grade 3-4 neutropenia, thrombocytopenia, and anemia were noted in 63%, 72%, and 39% of patients and in 57%, 70%, and 25% of cycles and Grade 3-4 infections in 19% of patients. Conclusion Preliminary results demonstrated that OFAR2 induced response in 40% of patients with RS and 63% of patients with relapsed/refractory CLL. OFAR2 had antileukemic activity in patients with 17p deletion. Clinical outcomes appeared to be superior to those of OFAR1 in refractory CLL, whereas results of OFAR1 appeared to be superior to those of OFAR2 in RS. Accrual is ongoing. Disclosures Tsimberidou: ASCO: ASCO Career Development Award; Sanofi: Research Funding. Off Label Use: Oxaliplatin is used off-label. Wierda:Genentech: Honoraria; Bayer, Sanofi-Aventis, Abbott, GSK: Research Funding; GSK, Trubion, Ligand, Genentech, Medimmune, Abbot: Consultancy; Celgene: Speakers Bureau. Plunkett:Sanofi-Aventis: Research Funding. O'Brien:Genentech: Research Funding; Sanofi: Consultancy. Kipps:NCI: Grant P01CA-81534.

Clinical activity of imatinib mesylate in combination with docetaxel in patients with advanced, platinum-resistant ovarian cancer—Hoosier Oncology Group GYN03–62

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5091-5091 ◽  
Author(s):  
D. Matei ◽  
R. E. Emerson ◽  
N. Menning ◽  
J. Schilder ◽  
J. McClean ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Response Rate ◽  
Advanced Ovarian Cancer ◽  
Ovarian Tumors ◽  
Phase Ii Clinical Trial ◽  
Ovarian Cancer Cells ◽  
Clinical Activity ◽  
Platinum Resistant

5091 Background: Ovarian tumors harborc-Kit and PDGF receptors. We showed in an in-vitro model that Imatinib (G) inhibits the growth of ovarian cancer cells. We hypothesized that G in combination with chemotherapy inhibits the growth of ovarian tumors. Data from a phase II clinical trial utilizing G in combination with Docetaxel (D) in patients with advanced ovarian cancer (OC) are presented. Methods: This was an open label, one stage, multi-center phase II clinical trial. Planned sample size was 23. Patients with relapsed, platinum-resistant or refractory OC expressing PDGFR or c-kit were eligible. PDGFR and c-kit expression was assessed prior to enrollment by IHC using archival tumor tissue. G was administered at 600mg/d continuously and D was given weekly (30mg/m2) for 4 weeks, with 2 weeks break. Each cycle was 6 weeks, with a maximum of 6 cycles allowed. Tumor assessments were obtained after 2, 4 and 6 cycles. Response rate by RECIST was the primary endpoint. Results: 34 patients were screened. 17 tumors were c-kit + and 25 were PDGFRα +. 23 patients were enrolled. Of those, 4 patients had c-kit+/PDGFR- tumors, 12 were PDGFR+/c-kit- and 7 were c-kit+/PDGFR+. Median age was 55 (range 33–76) and median PS was 0 (range 0–2). Median number of prior treatments was 3 (range 1–9). Efficacy and toxicity data are available for 20 and 14 patients, respectively. Based on RECIST, there were 3 patients with PR and 3 patients with SD lasting at least 12 weeks. Of these 6 patients, 2 pts were c-kit+, 2 were PDGFR+ and 2 were PDGFR and c-kit+. All 6 patients had carboplatin and taxane resistant disease. Grade 3–4 toxicities were: neutropenia (2), thrombocytopenia (1), fatigue (1), dehydration (1), constipation (1), cardiac ischemia (1), nausea/vomiting (2), urinary frequency (1). Other G1–2 toxicities were: N/V (9), diarrhea (7), fatigue (8), mucositis (4), anemia (4), hypocalcemia (5), rash (6), anorexia (7), edema (5), hemolysis (1), non-neutropenic infections (7). Additional data will be available in May 2006. Conclusions: The combination G+D is tolerated well. Clinical activity consisted of 3 PRs (15% response rate) and 3 SD > 3 months in pts with heavily pre-treated, platinum resistant OC expressing c-kit or PDGFRα. [Table: see text]

Phase I trial of liposomal doxorubicin and ZD 1839 in patients with refractory gynecological malignancies or metastatic breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5085-5085
Author(s):  
S. M. Campos ◽  
L. Parker ◽  
W. Chen ◽  
C. A. Bunnell ◽  
T. Atkinson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Liposomal Doxorubicin ◽  
Response To Therapy ◽  
Cross Resistance ◽  
Ovarian Cancer Cells ◽  
Breast And Ovarian Cancer ◽  
Level 2

5085 Background: Liposomal Doxorubicin has activity in both breast and ovarian cancer. Preclinical data reported by several investigators have suggested that ZD1839 acts synergistically with chemotherapy in ovarian cancer cells expressing high levels of EGFR. Given the lack of cross resistance and the different targets for these agents a Phase I trial was initiated examining the safety and the efficacy of the combination of Liposomal Doxorubicin and ZD1839. Methods: Dose limiting toxicity was defined within the first two cycles of treatment. The dose escalation schema was described as such: Results: As of January 2006, 23 patients have been enrolled in this study (GYN = 6; Breast 17). Six patients were enrolled in dose level 1 and no DLTs were observed. Dose level 2 enrolled six patients. One DLT was observed (febrile neutropenia). As defined by protocol an additional 6 patients were accrued to dose level 2. Accrual to dose level 3 began on 11/2005. One patient has completed 2 cycles and no additional DLTs have been noted. MTD has not yet been reached. SAEs have included mental status changes, and two CNS bleeds (believed most likely to be unrelated to study drug combination). Toxicities noted in cycle 3 and above have been mild with the exception of 2 grade 3 and 2 grade 4 toxicities related to skin and GI toxicity. No cardiac toxicity was observed. Doxil dose modifications (cycle 3 +) occurred in 7 patients. Best response to therapy has included 2 PRs and 10 patients with SD. Eleven patients to date have had progressive disease. The trial continues to accrue. Correlative studies including EGFR expression and CECs and PKs (at MTD) are planned. Conclusion: Liposomal Doxorubicin in conjunction with ZD1839 is tolerable regimen in patients with advanced breast and ovarian cancer. To date MTD has not been reached. [Table: see text] [Table: see text]

Phase I/II study of oral TS-1 and gemcitabine in elderly patients with advanced non-small cell lung cancer (NSCLC): Thoracic Oncology Research Group 0502

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18137-18137
Author(s):  
T. Seto ◽  
T. Yamanaka ◽  
K. Eguchi ◽  
H. Okamoto ◽  
M. Shibuya ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Skin Toxicity ◽  
Combination Regimen ◽  
Oncology Research ◽  
Level 3 ◽  
Level 2

18137 Background: Optimal treatment for elderly patients with NSCLC has been under active investigation. This study evaluated the safety and initial efficacy of a novel combination regimen of oral fluoropyrimidine TS-1 plus gemcitabine (GEM) for elderly patients (pts) with advanced NSCLC. Methods: A phase I/II trial in 11 centers examined TS-1 and GEM in pts with age = 70, stage IIIB/IV previously untreated NSCLC. The starting dose was 60 mg/m2day (day 1–14) for TS-1 and 800 mg/m2 for GEM (day 8, 15). GEM was increased to 1,000 mg/m2 at dose level 2 and TS-1 was increased to 80 mg/mg2/day at dose level 3. Phase II portion of the study assessed the efficacy and tolerability of the combination regimen at the dose determined in the phase I portion. The primary endpoint was objective response rate. Results: Twenty two pts were enrolled in the phase I portion: 6 pts on dose level 1, 10 on dose level 2 and 6 on dose level 3. Median age of this group was 75 yrs (range 70–85). Dose limiting toxicities included Gr. 4 neutropenia (2 pts) and Gr.3 skin toxicity (4 pts). The recommended dose (RD) was TS-1 60 mg/day and GEM 1,000 mg/m2, with which 20 pts were subsequently treated in the phase II portion. The median age of 30 pts treated with the RD was 76 yrs (range 70–85). Grade (Gr) 3/4 toxicities include neutropenia (12 pts; 7 with Gr 4), thrombocytopenia (4 pts; 0 with Gr 4), skin toxicity (8 pts), thrombus (1 pt) and peumonitis (2 pts). Nine patients (30%, 95% confidence interval [CI] = 14 to 46%) had partial responses and 16 (53%, 95% CI = 35 to 71%) had stable disease. Conclusions: Encouraging antitumor activity and safety of TS-1 plus gemcitabine support further development of this combination therapy for elderly patients with advanced NSCLC. No significant financial relationships to disclose.

Phase I study of weekly intraperitoneal paclitaxel combined with S-1 and oxaliplatin for gastric cancer with peritoneal metastasis.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 146-146 ◽  
Author(s):  
Hironori Ishigami ◽  
Shoichi Kaisaki ◽  
Hironori Yamaguchi ◽  
Hiroharu Yamashita ◽  
Shigenobu Emoto ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Peritoneal Metastasis ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Level 3 ◽  
Grade 3 ◽  
Dose Levels

146 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer with peritoneal metastasis. We previously verified the safety and efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous PTX in phase I and phase II studies. S-1 plus oxaliplatin (SOX) demonstrated efficacy in a phase II study, and is regarded as a candidate for the next-generation standard regimen for gastric cancer. We designed a new regimen combining weekly IP PTX with SOX in order to maximize systemic effects as well as local effects in the peritoneal cavity. A dose-escalation study of IP PTX in combination with fixed doses of SOX was carried out to determine the maximum-tolerated dose (MTD) and recommended dose (RD). Methods: PTX was administered intraperitoneally on days 1 and 8 with an initial dose of 20 mg/m2 (level 1), stepped up to 30 mg/m2 (level 2) or 40 mg/m2 (level 3) depending on observed toxicity. S-1 was administered orally at a dose of 80 mg/m2/day (b.i.d.) for 14 days followed by a 7-day rest. Oxaliplatin was administered intravenously at a dose of 100 mg/m2 on day 1. This treatment was repeated every 3 weeks. Toxicity was graded according to CTCAE v4.0. Dose-limiting toxicities (DLTs) were defined as grade 4 leukopenia, grade 3 febrile neutropenia, grade 3 thrombocytopenia, and grade 3 non-hematological toxicity. The MTD was defined as the dose level at which 2 or more of 3 or 6 patients developed DLTs during two courses of treatment. The RD was defined as one dose level under the MTD. Results: A total of 12 gastric cancer patients with peritoneal metastasis were enrolled. No DLTs were observed at all dose levels. Neutropenia in one patient at dose level 3 was the only grade 3 toxicity observed. Grade 2/3 leukopenia, neutropenia and thrombocytopenia were observed only in 2 patients at dose level 3. Regarding grade 2 non-hematological toxicities, anorexia, fatigue and nausea were observed in 6, 4 and 2 patients, respectively, independent of dose levels. Consequently, the MTD was not reached, and the RD of IP PTX was determined to be 40 mg/m2 (level 3). Conclusions: Combination chemotherapy of IP PTX with SOX was shown to be a safe regimen that should be further explored in clinical trials.

Phase I/II Clinical Trial of Lenalidomide in Combination with AT101 for the Treatment of Relapsed B-Cell Chronic Lymphocytic Leukemia (B-CLL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5299-5299 ◽  
Author(s):  
Aneel Paulus ◽  
Pooja Advani ◽  
Betsy R. Laplant ◽  
Sharoon Akhtar ◽  
Taimur Sher ◽  
...  
Keyword(s):  
Clinical Trial ◽  
British Journal ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Hematologic Toxicity ◽  
Combination Regimen ◽  
Starting Dose ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Abstract Background: Lenalidomide (Len) is clinically active in CLL patients (pts). Robust anti-leukemic immune response from Len is truncated by dysfunctional immune system in CLL and anti-apoptotic bcl-2 protein. We hypothesized that therapeutic downregulation of Bcl-2 may help enhance the killing potential of immune effector cells that are activated by Len. AT-101 is a novel, orally active BH3-mimetic that binds to antiapoptotic Bcl-2 family proteins (Bcl-2, Mcl-1 and Bcl-xL) and induces CLL cell death ex vivo (Masood et al British Journal of Haematology 2012). Encouraging efficacy and safety results of AT-101 alone or in combination with rituximab in CLL have been reported in Phase I/II studies. We have previously demonstrated that bcl-2 downregulation in CLL cells enhanced the killing potential of Len-activated immune cells. Conversely, pretreatment of CLL cells with Len enhanced AT-101 cytotoxicity in an immune cell independent manner (Masood et al British Journal of Haematology 2012). These preclinical findings formed the basis of a phase I/II clinical trial testing the combination of AT-101 and lenalidomide in relapsed B-CLL patients. Methods: The phase I portion of this study (NCT 01003769) utilizes a standard cohort of three design to determine the maximum tolerated dose (MTD) of the combination regimen. The MTD is defined as the dose level below the lowest dose that induces dose-limiting toxicity (DLT) in at least one-third of patients. Following the MTD determination, the phase 2 portion will assess the efficacy of this combination using a one-stage design with an interim analysis. Key inclusion criteria include adult CLL pts with relapsed disease who have received 1-4 prior lines of treatment (Rx) (phase I) or 1-2 lines of Rx (phase II), last dose > 4 weeks from enrollment, ECOG performance status 0-2, good renal/liver function, acceptable blood counts. Patients with known hypersensitivity to thalidomide/Len or prior use of gossypol/AT-101 were excluded. Cycle 1 Rx includes Len alone and cycles 2-12 includes Len and AT-101. Starting doses of Len and AT-101 are 5mg oral daily on days 1-21 and 40 mg oral twice daily (b.i.d) on days 1-3 of a 28-day cycle. Planned dose escalation is shown in Table 1. Three pts will be treated at each dose level and observed during the first cycle of the combination Rx. Dose limiting toxicity is defined as grade 4 anemia unrelated to disease, thrombocytopenia-grade 4 or grade 3 with bleeding/requiring platelets, ANC <500 for >14 days, febrile neutropenia , Grade 3/4 non-hematologic toxicity. Dose from Phase II will be based on MTD from phase I. Peripheral blood and bone marrow will be collected and analyzed for immune cellular microenvironment and effect of Len and AT-101 on molecular targets. Optional lymph node biopsy will be done at baseline and if tumor-flare reaction occurs. This study is expected to accrue a maximum of 26 pts in phase I and 34 pts in phase II, overall maximum sample size of 60 pts. Five pts in phase I have been accrued to date. Table 1 (* starting dose level) Table 1. (* starting dose level) Disclosures No relevant conflicts of interest to declare.

Comparison Of Intermittent and Continuous Dosing Regimens Of Pomalidomide In Relapsed/Refractory Myeloma: Results Of A Phase II Randomized Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3205-3205
Author(s):  
Kartik Sehgal ◽  
Mehmet H. Kocoglu ◽  
Yanhong Deng ◽  
Rakesh Verma ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Response To Therapy ◽  
Phase Iii ◽  
Clinical Activity ◽  
Measurable Disease ◽  
Dosing Regimens ◽  
Grade 3 ◽  
Maximal Reduction ◽  
Continuous Dosing

Abstract Pomalidomide (POM) is a novel IMiD(r) immunomodulatory agent with clinical activity in relapsed / resistant myeloma (RRMM) refractory to both lenalidomide and bortezomib. In prior phase II studies, the clinical activity of POM has been demonstrated using both continuous and intermittent dosing schedules. However the optimal dosing regimen for POM remains to be clarified and prospective data comparing these dosing schedules is limited. Herein we report the results of a randomized phase II clinical trial comparing the two POM dosing schedules. The primary objective was to compare clinical response to therapy (greater than or equal to partial response (PR) according to International Myeloma Working Group (IMWG) criteria). Patients (n=39) with RRMM documented to be refractory to lenalidomide were randomized to therapy with POM 2 mg/day for 28/28 days (Arm A, n=19) or POM 4 mg/day for 21/28 days (Arm B, n=20) of a 28 day cycle. All patients (pts) received POM alone at 2 or 4 mg for cycle 1, followed by the addition of dexamethasone at 40 mg weekly in subsequent cycles in both arms. Aspirin was utilized for thromboprophylaxis in both arms. Toxicity consisted primarily of myelosuppression which was manageable and similar in both cohorts. The incidence of serious adverse events (SAEs) was 36% in arm A and 55% in arm B. Grade 3 or 4 neutropenia (common toxicity criteria v4.0) was the most common toxicity and was observed in 42% and 45% of patients in arm A and arm B respectively. There was no treatment-emergent grade 3 or 4 neuropathy observed in either arm. Only one patient (in arm B) experienced grade 3 / 4 thromboembolic complication. Overall, objective response to therapy (greater than or equal to PR by IMWG criteria) was observed in 21% (4/19 patients) in arm A and 45% (9/20 patients) in arm B (p=0.18). There were no complete remissions in either cohort. Patients in arm B did have greater maximal reduction in measurable disease compared to arm A (percent maximal reduction mean (+ SD) 54% (+ 34%) in arm B versus 28% (+ 35%) in arm A, p=0.02). However both cohorts had comparable event-free survival (EFS) and overall survival (OS). The mean EFS in arm A and arm B was 4.4 months (95% confidence intervals (CI) 2.21 months, 7.67 months) and 5.1 months (95% CI 3.4 months, 9.2 months) respectively (p=0.56). Similarly the median OS in the arm A (17.7 months, 95% CI 10.02, not reached) was similar to that in arm B (17.7 months, 95% CI 9.98, not reached)(p=0.73). These data demonstrate in the context of a prospective randomized controlled clinical trial that both continuous (28/28) and intermittent (21/28) dosing regimens of POM with dexamethasone have remarkable clinical activity in this heavily pretreated MM population. These data provide further support towards the choice of POM at 4 mg/day for 21/28 days for phase III testing. The finding that intermittent dosing at 4 mg/day led to greater maximal cytoreduction of measurable disease compared to continuous dosing at 2 mg/day, without any differences in survival suggests that understanding the biology of residual disease will be essential to further improving outcome in these patients. Disclosures: No relevant conflicts of interest to declare.

Phase I study of weekly topotecan and gefitinib in patients with platinum-resistant ovarian, peritoneal, or fallopian tube cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5090-5090 ◽  
Author(s):  
B. M. Slomovitz ◽  
R. L. Coleman ◽  
C. Levenback ◽  
M. Jung ◽  
D. M. Gershenson ◽  
...  
Keyword(s):  
Dose Level ◽  
Fallopian Tube ◽  
Phase Ii ◽  
Standard Dose ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Fallopian Tube Cancer ◽  
Prior Chemotherapy ◽  
Platinum Resistant ◽  
Level 3

5090 Background: To determine the dose limiting toxicity and the maximum tolerated dose (MTD) of weekly topotecan in combination with standard dose gefitinib in patients with relapsed, platinum-resistant, ovarian, peritoneal or fallopian tube cancers that are EGF-R positive (>/= 1+). Methods: Patients with measurable, recurrent or persistent cancer after treatment with a platinum and paclitaxel-containing regimen were eligible for this study. Initial treatment was gefitinib at a dose of 250 mg oral dose daily and topotecan at a dose of 2.0 mg/m2 on days 1, 8, and 15, with cycles repeated every 28 days. Dose escalations were planned for topotecan (Dose Levels 1–3: 2, 3, 4 mg/m2) until the MTD was reached. A conventional 3+3 algorithm was used. The 2mg/m2 dose of topotecan was chosen as a starting dose because there are reported responses to this level when it has been used as a single agent on this schedule. Results: Thirteen patients received a total of 45 cycles. Twelve patients were evaluated for toxicity and 11 patients for response. Median age range was 63 years. At the time of initial diagnosis, all twelve patients underwent tumor debulking surgery. One patient had one prior chemotherapy regimen, 6 patients had 2, 4 patients had 3 and 1 patient had more than 3 prior chemotherapy regimens. There were 3 patients treated at dose level 1, 3 patients at dose level 2 and 7 patients treated at dose level 3 (1 patient was inevaluable). One of 6 evaluable patients in the dose level 3 group had a grade 4 thrombocytopenia. Therefore, dose level 3 will used for the Phase II portion of the trial. There were no treatment related deaths. Of the 11 patients evaluated for response, there were 4 patients with stable disease (mean number of cycles 6.5, range 3–12) and 7 had progressive disease. Conclusions: Gefitinib with weekly topotecan infusion is a well-tolerated regimen and suitable for study in platinum-resistant or refractory ovarian or tubal cancers. The phase II component of this study is ongoing. No significant financial relationships to disclose.

scholarly journals Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Allylamino, 17-Demethoxygeldanamycin in Patients With Advanced Malignancies

2005 ◽  
Vol 23 (18) ◽  
pp. 4152-4161 ◽  
Author(s):  
Udai Banerji ◽  
Anne O'Donnell ◽  
Michelle Scurr ◽  
Simon Pacey ◽  
Sarah Stapleton ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Clinical Activity ◽  
Phase Ii Trials ◽  
Pharmacodynamic Profile ◽  
Advanced Malignancies ◽  
Grade 3

Purpose To study the toxicity and pharmacokinetic-pharmacodynamic profile of 17-allylamino, 17- demethoxygeldanamycin (17-AAG) and to recommend a dose for phase II trials. Patients and Methods This was a phase I study examining a once-weekly dosing schedule of 17-AAG. Thirty patients with advanced malignancies were treated. Results The highest dose level reached was 450 mg/m2/week. The dose-limiting toxicities (DLTs) encountered were grade 3 diarrhea in three patients (one at 320 mg/m2/week and two at 450 mg/m2/week) and grade 3 to 4 hepatotoxicity (AST/ALT) in one patient at 450 mg/m2/week. Two of nine DLTs were at the highest dose level. Two patients with metastatic melanoma had stable disease and were treated for 15 and 41 months, respectively. The dose versus area under the curve-relationship for 17-AAG was linear (r2 = .71) over the dose range 10 to 450 mg/m2/week, with peak plasma concentrations of 8,998 μg/L (standard deviation, 2,881) at the highest dose level. After the demonstration of pharmacodynamic changes in peripheral blood leukocytes, pre- and 24 hours post-treatment, tumor biopsies were performed and demonstrated target inhibition (c-RAF-1 inhibition in four of six patients, CDK4 depletion in eight of nine patients and HSP70 induction in eight of nine patients) at the dose levels 320 and 450 mg/m2/week. It was not possible to reproducibly demonstrate these changes in biopsies taken 5 days after treatment. Conclusion It has been possible to demonstrate that 17-AAG exhibits a tolerable toxicity profile with therapeutic plasma concentrations and target inhibition for 24 hours after treatment and some indications of clinical activity at the dose level 450 mg/m2/week. We recommend this dose for phase II clinical trials.

Results of a Phase I/II Study of the Combination of 5-aza-2′-Deoxycytidine (DAC) and Valproic Acid (VPA) in Patients (pts) with Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 263-263 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hagop Kantarjian ◽  
Blanca Sanchez-Gonzalez ◽  
Stefan Faderl ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Antiepileptic Agent ◽  
Level 3 ◽  
Level 1 ◽  
Dose Levels ◽  
Level 2 ◽  
Grade Iii

Abstract DAC is a potent hypomethylating agent with clinical activity in patients with myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). VPA is a histone deacetylase inhibitor used as an antiepileptic agent. In vitro, the combination of DAC with VPA results in synergistic antileukemia activity at doses of VPA above 1mM. Based on this data, we have developed a phase I/II study of this combination for pts with leukemia. The phase I of the study followed a classic 3+3 design. The dose of DAC was fixed: 15 mg/m2 iv daily for 10 days. This was based on a previous phase I study (Blood2004;103:1635) that indicated that this schedule had an optimal toxicity-response profile in this population. Three dose levels of VPA were selected: 20, 35 and 50 mg/kg. VPA was given orally for 10 days concomitantly with DAC. 22 pts have completed the phase I portion of the study (median age 56 years, range 4–78, 20 pts AML, 2 MDS). At dose level 1 (20 mg/kg of VPA) no grade III-IV toxicity was observed. At dose level 2 (VPA 35 mg/kg), 2 out 6 pts developed grade III neurotoxicity. Both pts were receiving high doses of other neurotropic agents. After IRB approval, 3 mores pts were treated at this dose level with no significant toxicity. Subsequently, 3 pts were treated at the highest planned dose level (50 mg/kg) with no toxicity observed. This cohort was then expanded to a total of 10 pts. One pt developed grade III neurotoxicity. No other severe drug-related toxicities were observed, but 5 patients at all dose levels developed grade II sedation/somnolence. Pancytopenia was induced in all pts. At dose level 1, one pt with refractory AML achieved complete remission (CR) after the second course of therapy. This is now maintained for 5 courses. At dose level 2, a patient with HIV disease and relapsed AML achieved CR after the third course of therapy, and 2 pts with relapsed AML achieved complete marrow responses (marrow blasts less then 5%, no recovery of peripheral counts). Of 3 pts evaluable for response at dose level 3, 1 pt with MDS has achieved CR after 1 course, and 1 with relapsed AML a complete marrow response. Median free VPA levels pretreatment were 0, and 25 mg/L on both days 5 and 10 and returned to 0 prior to next course. Histone acetylation measured by Western blot was observed in 3 pts (25%), all at doses above 20 mg/kg of VPA. Reactivation of p21 expression was induced in 4 out 11 pts analyzed. Global hypomethylation measured using a bisulfite PCR LINE assay was induced in 1 out 3 pts so far studied. Based on the toxicity observed, the phase II portion of the study was initiated. This is restricted to pts with AML/MDS. Seven pts have been accrued to this phase, and 8 out the 10 pts at dose level 3 of the phase I are also evaluable. The response data of this pts will be updated at the meeting. In summary, the combination of low dose DAC and VPA up to doses of 50 mg/kg can be safely administered to pts with leukemia although it may be complicated by neurotoxicity. Clinical and biological activity was observed at all dose levels.

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