Docetaxel and capecitabine for previously treated metastatic colorectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13579-13579
Author(s):  
T. E. O’Brien ◽  
E. Newton ◽  
J. Trey ◽  
E. Crum
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Low Dose ◽  
Metastatic Breast ◽  
Human Colon Cancer ◽  
Level 3 ◽  
Previously Treated ◽  
Level 1 ◽  
Level 2

13579 Background: Docetaxel (D) induces human colon cancer cell lines to upregulate thymidine phosphorylase, an enzyme which activates capecitabine (C) to its cytotoxic form. This provided rationale for adding low dose D to C in patients with colorectal cancer (CRC). Although this combination has been established in metastatic breast cancer, it has not been evaluated in CRC. Because of concerns of toxicity in a pretreated population, we performed a phase I trial in patients with previously treated CRC. Methods: Eligibility: At least 1 prior treatment for metastatic disease; ECOG PS 0–1; adequate organ function. Design: Phase I, dose escalation. D, IV, days 1 & 8, and C, PO BID days 5–18, repeated q21days. Dose Level 1: D=15mg/m2, C=1000mg/m2; Level 2: D= 15 mg/m2, C= 1100 mg/m2; Level 3: D= 20 mg/m2, C= 1100 mg/m2; Level 4: D=20mg/m2, C=1250mg/m2. Results: 13 patients have thus far been treated. 11 are evaluable for toxicity and 10 for response (1 at dose level 4 was taken off study due to non-compliance before completion of cycle 1; another died of progressive cancer before completing cycle 1 at dose level 4; another is evaluable for toxicity but not yet for response). 9 with colon, 4 with rectal primary sites. Median follow-up= 5 mo (1–19 mo). Med age= 59 (30–75); #prior regimens for met disease 1–2, all of which were 5-FU based. Toxicities No dose limiting toxicities (DLT) until Dose Level 4. Dose Level 1: 1/3 developed grade 2 diarrhea and hand-foot syndrome and delayed grade 3 hand-foot; Dose Level 2: 2/3 developed grade 2 toxicities (hand-foot in one and diarrhea in the other); Dose Level 3: 1/3 developed delayed grade 2 hand-foot; Dose Level 4: 1 patient with delayed grade 2 hand-foot and grade 1 eye tearing; another developed DLT (grade 4 stomatitis/dehydration). Response 6/10 patients progressed after 2 cycles; 2 pts had stable disease, one lasting 4.6 mo; 2 patients had a partial response, one of which lasted 9 mo. The latter case had refractory disease to FOLFOX 4 but a 78% reduction in her liver metastases to D+C. Conclusions: The combination of low dose docetaxel, used as chemosensitizing agent, with capecitabine in this pretreated group of patients with metastatic CRC appears to be well tolerated, with no DLTs seen until Dose Level 4, and has modest activity. MTD determination awaits further accrual. No significant financial relationships to disclose.

Phase I trial of regorafenib, hydroxychloroquine, and entinostat in metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15580-e15580
Author(s):  
Timothy J Brown ◽  
Thomas Benjamin Karasic ◽  
Charles John Schneider ◽  
Ursina R. Teitelbaum ◽  
Kim Anna Reiss ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Weight Loss ◽  
Phase I ◽  
Metastatic Colorectal Cancer ◽  
Dose Level ◽  
Phase I Trial ◽  
Level 3 ◽  
Previously Treated ◽  
Level 1 ◽  
Dose Levels

e15580 Background: The antiangiogenic tyrosine kinase inhibitor regorafenib provides a survival benefit in patients with previously treated metastatic colorectal cancer. Antiangiogenic therapy causes hypoxic stress within tumor cells, which activate autophagy as a survival mechanism. Entinostat, a histone deacetylase (HDAC) inhibitor, increases dependence on autophagy through epigenetic mechanisms. Hydroxychloroquine (HCQ) blocks autophagy by blunting lysosomal acidification and is synergistic with antiangiogenic therapies. We hypothesized that HCQ and entinostat would be tolerable with regorafenib and potentiate the antitumor response. Methods: This was a 3+3 phase I trial to find the recommended phase II dose (RP2D) of HCQ and entinostat with regorafenib in patients with metastatic colorectal cancer previously treated with a fluoropyrimidine, oxaliplatin, and irinotecan. No prior regorafenib or HDAC inhibitor therapy was permitted. Regorafenib was dosed at 160mg daily on days 1-21 of 28-day cycles, with provision to lower the starting dose to 80mg if toxicity was excessive. Entinostat was dosed at 3mg weekly in dose level 1 and at 5mg weekly in dose levels 2 and 3 while HCQ was dosed at 200mg qAM and 400mg qPM in dose levels 1 and 2 and at 600mg BID at dose level 3. Expansion was planned at the RP2D with a primary endpoint of objective response rate. Results: Twenty-eight patients were screened, and 20 patients were enrolled from November 2017 to January 2020. Six patients were treated at dose level 1 with no dose-limiting toxicity. The starting regorafenib dose was reduced to 80mg after 3 patients discontinued therapy early due to fatigue or rash due to regorafenib. At dose level 2, 7 patients were enrolled to achieve 6 evaluable patients. One DLT (G3 fatigue) was noted and one patient withdrew consent after 14 days due to fever and tumor pain flare possibly related to treatment. Six patients enrolled at dose level 3; no DLTs were seen. One additional patient received HCQ 400mg BID instead of 600mg BID due to a clerical error. Weight loss (60%), fatigue (50%), and anorexia (50%) were the most common toxicities. Thirteen grade 3 toxicities were noted, with rash (15%), fatigue (10%), and alkaline phosphatase elevation (10%) the most common. No grade 4 toxicities were observed. Seven patients discontinued therapy early due to toxicity. Nearly all patients experienced rapid weight loss, with a range of 1.5 lbs to 27.1 lbs and a median weight loss of 9.5 lbs at two weeks. No objective responses were observed. The median PFS was 1.8 months, the median OS was 5.2 months, and no patient remained on study longer than 4 months. Expansion was not pursued due to toxicity and lack of efficacy. Conclusions: The combination of regorafenib, HCQ, and entinostat was poorly tolerated without evident activity in metastatic colorectal cancer. The substantial weight loss suggests a potential adverse metabolic interaction between these drugs. Clinical trial information: NCT03215264.

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.

Final Report of a Phase I Study of Clofarabine Plus High Dose Melphalan as a Conditioning Regimen for Allogeneic Transplantation

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 528-528
Author(s):  
Mark Kirschbaum ◽  
Anthony Selwyn Stein ◽  
Paul Frankel ◽  
Leslie Popplewell ◽  
Robert w Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Phase I ◽  
Dose Level ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Level 3 ◽  
Level 1 ◽  
Level 2 ◽  
Reduced Intensity

Abstract Abstract 528 Background: Allogeneic Stem Cell transplantation remains the only curative treatment modality for hematologic malignancies such as AML, ALL, and MDS. Reduced intensity regimens were designed which replaced the alkylating agent cyclophosphamide with the purine nucleoside antimetabolite, fludarabine, a potent immunosuppressive with a substantially milder toxicity profile. Clofarabine is a purine nucleoside analogue designed to exploit a double halogen strategy which confers resistance to adenosine deaminase, increases stability and bioavailability and makes the drug more efficient than fludarabine at inhibiting ribonucleotide reductase (RNR) and disrupting mitochondrial function, leading to apoptosis. Clofarabine is potentially a superior antileukemic agent as compared with fludarabine, thus enhancing the activity of the conditioning regimen. Aims: To evaluate a novel clofarabine containing regimen as conditioning for adult fully matched allogeneic stem cell transplant. Methods: phase I dose escalation: clofarabine (dose level 1 = 30 mg/m2, dose level 2 and 3 =40 mg/m2) IV daily days –7 to day –3 infused over 30 minutes IV, plus Melphalan (dose level 1 and 2, 100mg/m2, dose level 3, 140 mg/m2) administered over 30 minutes IV on day –2. Related or unrelated allogeneic stem cells were infused on day 0. GVHD prophylaxis: initially cyclosporine plus mycophenolate, then tacrolimus plus sirolimus was adopted as per City of Hope standard of care. Patients (pts) age ≥ 18 years with AML, ALL, MDS in either CR1, CR2 or in relapse (up to 50% marrow blasts), not deemed eligible for standard transplant regimens by the attending physician, or at high risk for relapse, are eligible. Results: 16 eligible pts, all with AML, have been treated thus far, 7,males, 9 females, with a median age of 63 years (30 – 66). Seven pts were in CR1, 2 pts were in CR2, 4 pts where induction failures, and 3 pts were in first relapse. Grade 3 non-hematologic toxicities included elevation of transaminases, diarrhea, and hyponatremia. No dose limiting toxicities (DLT) were seen in the 3 pts treated at dose level 1. One patient in dose level 2 died prior to engraftment due to hepatic, renal, and infectious toxicities; that dose level has been expanded to 12 patients and no further DLTs were seen. The first patient treated at dose level 3 developed multiorgan failure and died prior to engraftment. Given the excellent results seen in the two previous cohorts we opted not to dose escalate any further patients beyond clofarabine 40 mg/m2 and melphalan 100 mg/m2. Three patients with primary induction failure received an unrelated donor graft and had complete engraftment and obtained remission. The median time to ANC recovery is 14 days and to platelet recovery is 16 days (see table). Mild acute skin graft versus host disease (GvHD) was seen in five patients, mild chronic GvHD in four patients, one patient developed severe chronic GVHD of the liver and died at day 201 from CNS bleed due to tacrolimus-sirolimus related TTP-HUS. Of the 14 patients that successfully completed transplant (no DLT or engraftment difficulty), only one patient has relapsed, with median follow-up of 10.5 months (range 4–24). Conclusion: The combination of clofarabine and melphalan is a well tolerated reduced intensity conditioning regimen with enhanced anti-leukemia activity leading to complete engraftment of related and unrelated fully matched allogeneic stem cells. Complete engraftment with prolonged disease free survival was seen at both dose levels 1 and 2. Disclosures: Off Label Use: clofarabine as a component of the conditioning regimen for allogeneic transplant.

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]

A phase I study of investigational agent SGI-110 combined with irinotecan in previously treated metastatic colorectal cancer patients.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS797-TPS797 ◽  
Author(s):  
Judy Sing-Zan Wang ◽  
Elske C. Gootjes ◽  
Jennifer N. Uram ◽  
Marianna Zahurak ◽  
Anthony B. El-Khoueiry ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Response To Therapy ◽  
Metastatic Colon Cancer ◽  
Combination Methods ◽  
Previously Treated ◽  
Level 1 ◽  
Tumor Biopsies

TPS797 Background: Studies have suggested that epigenetic modifications may play a role in oncogenesis and acquired chemoresistance in certain cancers including colorectal cancer (CRC). Our preclinical data has shown that DNA hypermethylation may confer acquired chemoresistance, and that combining a hypomethylating agent can re-induce tumor sensitivity to irinotecan in CRC cell lines. We propose a phase I study to assess the safety and tolerability of SGI-110 with irinotecan therapy in metastatic colon cancer previously treated with irinotecan. This will be followed by a randomized phase II study to evaluate efficacy of the combination. Methods: We will enroll 12-22 patients at two institutions with metastatic colon adenocarcinoma previously treated with irinotecan to our phase I study. Dose escalation will be performed in a traditional 3+3 design, where patients receive SGI-110 30-45mg/m2 SQ days 1-5 in combination with irinotecan 125mg/m2 days 1, 8, and 15 (depending on the dose level) every 28 days, with or without G-CSF. Patients will be monitored for safety and tolerance with laboratory studies, clinical exam, and periodic CT scans to assess response to therapy. In addition, pharmacokinetic studies on peripheral blood and paired tumor biopsies will be obtained to assess for global demethylation and evaluation of biomarkers. Major eligibility criteria include measureable disease with accessibility for paired tumor biopsies, and prior treatment with irinotecan without limit on number of total therapies. Current Enrollment: Dose level 1 enrolled 6 patients and encountered 1 DLT following expansion for safety assessment. Dose level -1 enrolled 3 patients and encountered 2 DLTs, which has since prompted amendments for additional dose levels with modifications to scheduled growth factor support. Dose level -1G enrollment began in September 2014. Clinical trial information: NCT01896856.

A Phase I/II Study of Lenalidomide (R) with Low Dose Dexamethasone (d) and Cyclophosphamide (C) for Patients with Primary Systemic (AL) Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 428-428 ◽  
Author(s):  
Efstathios Kastritis ◽  
Maria Roussou ◽  
Magdalini Migkou ◽  
Konstantinos Pamboukas ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Low Dose ◽  
Alkylating Agents ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

Abstract Abstract 428 Lenalidomide (R) has significant activity in patients with multiple myeloma (MM). R has also shown activity in patients with AL amyloidosis, especially in combination with dexamethasone (D). However, AL patients are usually frail and R at the standard dose of 25 mg/day has been associated with significant toxicity. In MM patients, R with low dose D (Rd) has a better toxicity profile than the combination of R with high dose D. Alkylating agents, such as cyclophosphamide (C), are active in patients with AL and combinations of R with alkylating agents have given promising results in patients with MM. Thus, we designed a phase I/II trial of R, with low dose D and low dose C (RdC) in patients with AL. Primary objective of the study was to determine the maximum tolerated dose (MTD) for RdC and to assess hematologic response. Patients receive D 20 mg on days 1-4 (total 80 mg per cycle) , C on days 1-10, R on days 1-21 every 28 days, according to dose level (level 0: R 10 mg, C 50 mg, level 1: R 10 mg, C 100 mg, level 2: R 15 mg, C 100 mg). In the phase I part of the study, patients were observed for 2 cycles for determination of Dose Limiting Toxicity (DLT) according to a standard 3+3 design. Patients with a creatinine ≤2.5 mg/dL and adequate hepatic function were enrolled. All patients receive low-dose aspirin or LMWH if indicated. So far 23 patients have been enrolled in the study (16 in phase I, 7 in phase II). In the phase I study, 3 patients were enrolled in dose level 0, 7 in dose level 1 and 6 in dose level 2. Dose level 2, (R 15 mg, C 100 mg) is being further explored; 7 patients have been enrolled in phase II and accrual is ongoing. So far, 132 cycles of therapy have been administered; 8 patients have receive ≥6 cycles of RdC and 3 have completed 12 cycles of treatment. According to consensus criteria, heart was involved in 65%, kidneys in 61%, liver in 9% and 17% had AL-related peripheral neuropathy; 95% of the patients were Mayo stage II or III. Most patients (70%) were previously untreated. Among 7 pretreated patients, 2 had refractory disease, 2 had prior thalidomide and 5 had prior bortezomib. Hematologic response rates for patients who received at least 2 cycles of treatment, among all cohorts, was 64% and for the patients treated at dose level 2 was 75%. Median time to hematologic response was 2.5 months (range 0.9-4.8 months) for all patients and 1 month (range 0.9-2.9) for those treated at dose level 2. Organ responses have been recorded in 5 patients so far (3 cardiac and 3 renal responses, 1 patient had both cardiac and renal response). After a median follow-up of 7 months, 7 patients have died; 5 due to progressive heart amyloid, one patient had an acute MI followed by acute stent thrombosis and one died due to sepsis. The most common hematologic toxicities were anemia (grade 3/4 in 17%) and neutropenia (grade 3/4 in 17%). Most common non-hematologic toxicities were infection (grade ≥3 in 22%), fatigue (grade ≥3 in 9%), and rash (in 22%, grade 3 in 4%); also one patient suffered a stroke and one had DVT while on treatment with RdC. In parallel, and on a compassionate basis, AL patients with creatinine >2.5 mg/dL or on dialysis, were offered RdC with R dose adjusted according to CrCl. Initially R was given 15 mg every other day for CrCl <30 ml/min, or 15 mg thrice per week on the day after dialysis but due to toxicity R dose was reduced to 10 mg. So far, 13 patients have been treated with attenuated-dose RdC: 3 patients achieved a CR, one achieved a cardiac and one patient a liver response. However, the non-hematologic toxicity of the combination in patients with renal impairment was significant including fatigue (53%), infections (38%), rash (31%), diarrhea (15%), hyponatriemia (15%). Three patients discontinued treatment due to toxicity after the 1st cycle (including one early death due to non-neutropenic infection). In conclusion, RdC is an effective oral regimen for patients with AL amyloidosis, inducing significant rates of hematologic and organ responses. The recommended dose for RdC was R at dose of 15 mg, C at a dose of 100 mg and 20 mg of D and is further evaluated in the phase II of the study. Toxicity is manageable for patients with serum creatinine <2.5 mg/dL but can be significant for AL patients with more severe renal impairment. Lower doses of R, at 10 mg or less every other day or thrice per week should be used in these patients. Accrual in the phase II study is ongoing and updated results will be presented at the meeting. Disclosures: Dimopoulos: Celgene: Honoraria, Research Funding.

Dose-escalating study of continuative low dose of oral vinorelbine in patients with advanced breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1128-1128
Author(s):  
A. Felici ◽  
M. Russillo ◽  
S. Di Segni ◽  
A. Fabi ◽  
G. Ferretti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Low Dose ◽  
Metastatic Breast ◽  
Pharmacokinetic Analysis ◽  
Weekly Dose ◽  
Oral Vinorelbine ◽  
Level 3 ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

1128 Background: Low and continuative dose of antineoplastic drugs has been shown to have an antiangiogenic activity. The rapid absorption and relatively short half-life of the oral formulation of vinorelbine are favorable pharmacokinetic characteristics to test a continuative low-dose schedule. Methods: Patients with measurable metastatic breast cancer were treated with escalating dose of oral vinorelbine from 50 mg/m2 per week to 90 mg/m2 per week until progressive disease or unacceptable toxicity. These patients were administered one third of the total weekly dose 3 times per week, every other day. A pharmacokinetic analysis was planned at the first 3 weeks of drug assumption. Results: Of twenty-two patients included in the study, 3 were treated at 50 mg/m2/w (level 1), 5 at 60 mg/m2/w (level 2), 3 at 70 mg/m2/w (level 3), 8 at 80 mg/m2/w (level 4), and 3 at 90 mg/m2/w (level 5); we are still enrolling patients at this level. The median age was 59 years (range 23–75). The median number of prior lines of chemotherapy and hormonal therapy was 2 (range 0–4 for CT and 0–5 for OT). Fifteen of 22 patients had visceral metastasis. No dose-limiting toxicities have been observed until now. The main toxicities were: asymptomatic neutropenia grade 4 in two patients (1 in level 4 and 1 in level 5), asthenia grade 3 in 7 patients (1 at level 1, 2 at level 2, 1 at level 3, 3 at level 4), neurotoxicity grade 3 in two patients (one at level 2 and one at level 4). One patient experienced an intestinal sub-occlusion and hospitalization was required with no permanent side effects. One patient had a partial response, five a stable disease, fourteen progressed and two are not evaluated yet. At 1 year, five of the twenty evaluable patients are died by disease. Samples of twenty patients were collected for pharmacokinetic analysis that will be presented at the meeting. Conclusions: The continuative split 3 times per week oral vinorelbine is feasible, and at 90 mg/m2/w we have not reached yet the maximum tolerated dose. No significant financial relationships to disclose.

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.

Phase I/II study of oxaliplatin, fludarabine, cytarabine, and rituximab in patients (OFAR2) with Richter's syndrome (RS), and relapsed or refractory B-cell chronic lymphocytic leukemia (CLL)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7031-7031
Author(s):  
A. M. Tsimberidou ◽  
W. G. Wierda ◽  
W. K. Plunkett ◽  
S. O'Brien ◽  
S. Lerner ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Response Rate ◽  
Optimal Number ◽  
Lymphocytic Leukemia ◽  
Significant Activity ◽  
Neutropenic Sepsis ◽  
Level 3 ◽  
Level 1 ◽  
Level 2

7031 Background: The first Phase I-II clinical trial of oxaliplatin, fluradabine, 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 with a decrease in myelosuppression, the dose of oxaliplatin was increased to 30 mg 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: The OFAR2 regimen consisted of oxaliplatin 30mg/m2, D1–4; fludarabine 30mg/m2, Ara-C 0.5 g/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 wks. Prophylaxis for tumor lysis, DNA viruses, and PCP was given. Results: A total of 55 pts have been treated to date: 12 pts enrolled in phase I (dose level 1, n=3; dose level 2, n=6; and dose level 3, n=3). DLTs were noted in 2/3 pts in dose level 3 (G4 diarrhea, 1; G4 neutropenic sepsis, 1), therefore level 2 was the MTD. Forty-three pts were treated in the Phase II portion of the study (relapsed CLL, 35; RS, 8). The median age was 64 yrs (range, 40- 81); 50 (91%) had β2-microglobulin > 3 mg/L; platelets were < 100 x109/L in 22 pts; and 44 pts had > 1 prior therapies. FISH results were: 17p deletion, n=15; 11q del, n=7; trisomy 12, n=12; 13q del, n=8; normal, n=2; unknown, n=11. Overall, 33 pts had unmutated and 7 mutated IgVH gene; ZAP70 was positive in 30, and negative in 14. Six (46%) of 13 pts with 17p del by FISH responded to OFAR2 (nPR, 2; PR, 4). Eleven pts underwent stem cell transplantation as postremission or salvage therapy. The most common toxicity was myelosuppression. Conclusions: Preliminary results demonstrated that OFAR2 resulted in an overall response rate of 63%, had antileukemic activity in pts with 17p del and clinical outcomes appeared to be superior to those of OFAR1. Accrual is ongoing. [Table: see text] [Table: see text]

Phase I study of panobinostat (LBH589) and letrozole in post-menopausal women with metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13501-e13501 ◽  
Author(s):  
Winston Tan ◽  
Jacob B Allred ◽  
Alvaro Moreno-Aspitia ◽  
Donald W. Northfelt ◽  
James N. Ingle ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Metastatic Breast ◽  
Level 1 ◽  
Grade 3 ◽  
Level 2

e13501 Background: Loss of estrogen receptor alpha gene expression has been associated with insensitivity to endocrine therapy in human breast cancer patients. Histone deacetylase (HDAC) inhibitors have recently been found to restore sensitivity to the estrogen receptor by modulation of the estrogen and progesterone receptors. This had been shown with both aromatase and tamoxifen refractory and in triple negative cell lines . We performed a Phase I study of the combination of LBH589 (panobinostat) and letrozole to evaluate safety and tolerability in patients with metastatic breast cancer prior to the performance of a phase II trial. Methods: We enrolled postmenopausal women with metastatic breast cancer, ECOG PS 0 or 1, ANC>1500/mm3, platelets>100,000/mm3, normal total bilirubin, and ALT/AST adequate laboratory tests were eligible. Letrozole dose was 2.5 mg/day orally. Dose of LBH589: Level 1, 20 mg orally three times weekly; Level 2, 30 mg orally three times a week. Results: 12 patients (dose level 1:6 patients, dose level 2: 6 patients) have been enrolled. 43 cycles of treatment have been given to these12 patients. Initial cohort of 3 patients at the 20 mg dose level had no dose limiting toxicity (DLT). At the 30 mg dose level 3/6 patients had DLT (thrombocytopenia grade 1: 2 pts; grade 3:1 pt; grade 4: 1 pt; and diarrhea grade 3: 1 pt. One pt at the 30 mg dose level has a confirmed partial response and remains on study after 6 cycles of treatment. Subsequent cohort of 3 patients had 1 dose DLT with doubling of the creatinine. The main DLT was thrombocytopenia in 3/6 pts at the 30 mg dose level. Conclusions: The recommended dose for phase II testing of LBH589 is 20 mg orally 3 times per week in combination with standard dose letrozole.

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