Phase I study of RAD001 (everolimus), cetuximab, and irinotecan as second-line therapy in metastatic colorectal cancer (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15115-e15115
Author(s):  
S. Sharma ◽  
T. Reid ◽  
S. Hoosen ◽  
C. Garrett ◽  
J. Beck ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Clin Oncol ◽  
Dose Level ◽  
Phase I Study ◽  
Open Label ◽  
Kras Mutations ◽  
Kras Status ◽  
Dose Limiting Toxicity ◽  
Unacceptable Toxicity

e15115 Background: The PI3K/AKT/mTOR pathway is frequently dysregulated in colorectal cancer (Cancer Res 2005;65:11227). In a phase I study in patients with advanced solid tumors, everolimus an oral mTOR inhibitor demonstrated clinical benefit including a partial response in pts with colorectal cancer (J Clin Oncol 2008;26:1603–10; J Clin Oncol 2008; 26:1588–95). Methods: This open-label, multicenter phase I study uses a Bayesian logistic model to identify feasible doses of everolimus + irinotecan + cetuximab. Adult pts with mCRC progressing despite prior 5-FU/oxaliplatin (FOLFOX) or capecitabine/oxaliplatin (XELOX) plus bevacizumab (if standard practice) were treated using a sequential dose escalation scheme (Table). Dose decisions were driven by the probability of dose-limiting toxicity (DLT) in the first 2 cycles. Dose level decisions were based on maximizing the probability that end-of-cycle-2 DLT rate would be within the targeted toxicity interval (20% to <35%) and minimizing the risk of over-dosing (< 5% risk of unacceptable toxicity and < 25% risk of excessive/unacceptable toxicity). Results: 18 pts were treated from April ‘07 to August ‘08, 5 pts at dose level A1 and 13 pts at dose level B1. Two DLTs (G3 rash on cycle 2 day 1 lasting > 7 days and G3 mucositis on cycle 1 day 14 lasting > 7 days, 1 pt each) were reported in 4 evaluable pts at dose level A1. No DLTs were reported in 7 evaluable patients at dose level B1. Conclusions: At dose level B1 everolimus in combination with irinotecan and cetuximab was generally well tolerated. The study was stopped due to changes in clinical practice based on emerging data indicating that cetuximab has limited efficacy in mCRC patients with KRAS mutations and that efficacy data favors daily RAD001 over weekly dosing. Patients in this study were treated with cetuximab irrespective of KRAS status. [Table: see text] [Table: see text]

Phase I Study of a Weekly Schedule of Irinotecan, High-Dose Leucovorin, and Infusional Fluorouracil as First-Line Chemotherapy in Patients With Advanced Colorectal Cancer

1999 ◽  
Vol 17 (3) ◽  
pp. 907-907 ◽  
Author(s):  
Udo Vanhoefer ◽  
Andreas Harstrick ◽  
Claus-Henning Köhne ◽  
Wolf Achterrath ◽  
Youcef M. Rustum ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Advanced Colorectal Cancer ◽  
High Dose ◽  
Weekly Schedule ◽  
First Line ◽  
Dose Levels ◽  
Line Chemotherapy

PURPOSE: To determine the maximum-tolerated dose (MTD) of a weekly schedule of irinotecan (CPT-11), leucovorin (LV), and a 24-hour infusion of fluorouracil (5-FU24h) as first-line chemotherapy in advanced colorectal cancer and to assess preliminary data on the antitumor activity. PATIENTS AND METHODS: Twenty-six patients with measurable metastatic colorectal cancer were entered onto this phase I study. In the first six dose levels, fixed doses of CPT-11 (80 mg/m2) and LV (500 mg/m2) in combination with escalated doses of 5-FU24h ranging from 1.8 to 2.6 g/m2 were administered on a weekly-times-four (dose levels 1 to 4) or weekly-times-six (dose levels 5 to 6) schedule. The dose of CPT-11 was then increased to 100 mg/m2 (dose level 7). RESULTS: Seventy-nine cycles of 5-FU24h/LV with CPT-11 were administered in an outpatient setting. No dose-limiting toxicities were observed during the first cycle at dose levels 1 to 6, but diarrhea of grade 4 (National Cancer Institute common toxicity criteria) was observed in three patients after multiple treatment cycles. Other nonhematologic and hematologic side effects, specifically alopecia and neutropenia, did not exceed grade 2. With the escalation of CPT-11 to 100 mg/m2 (dose level 7), diarrhea of grade 3 or higher was observed in four of six patients during the first cycle; thus, the MTD was achieved. Sixteen of 25 response-assessable patients (64%; 95% confidence interval, 45% to 83%) achieved an objective response. CONCLUSION: The recommended doses for further studies are CPT-11 80 mg/m2, LV 500 mg/m2, and 5-FU24h 2.6 g/m2 given on a weekly-times-six schedule followed by a 1-week rest period. The addition of CPT-11 to 5-FU24h/LV seems to improve the therapeutic efficacy in terms of tumor response with manageable toxicity.

Phase I study of ridaforolimus with cetuximab for patients with advanced non-small cell lung cancer (NSCLC), colorectal cancer, and head and neck cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8075-8075
Author(s):  
Angela Marie Taber ◽  
Humera Khurshid ◽  
Kimberly Perez ◽  
Ariel E. Birnbaum ◽  
Adam J. Olszewski ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Head And Neck Cancer ◽  
Phase I ◽  
Head And Neck ◽  
Dose Level ◽  
Neck Cancer ◽  
Phase I Study ◽  
Mtor Inhibitor ◽  
Egfr Antibody

8075 Background: mTOR inhibition may overcome PI3K/AKT pathway mediated resistance to anti-EGFR therapy. We performed a phase I study to determine the dose-limiting toxicity (DLT) of ridaforolimus, an investigational oral mTOR inhibitor, in combination with the anti-EGFR antibody cetuximab. Methods: Patients with advanced NSCLC, colorectal cancer, and head and neck cancer that progressed after at least 1 prior regimen for metastatic disease were eligible. ECOG performance status 0-1. Patients with previously treated brain metastases that were stable for >3 months were eligible. Wild-type K-RAS was required in colon cancer. All patients received cetuximab 400 mg/m2 week 1 followed by 250 mg/m2 weekly. Three dose levels of ridaforolimus were planned: 20mg, 30mg, and 40mg daily, 5 days each week, on a 28-day cycle. Results: 12 patients were entered with NSCLC (n=7), colon cancer (n=4), and head and neck cancer (n=1). The median age was 58 (42-69). The median number of prior regimens for metastatic disease, by disease type, was NSCLC (n=3), colorectal (n=4), head & neck (n=4). Three patients completed the first dose level without DLT. Two of 3 patients at dose level 2 had dose-limiting mucositis. The first dose level was then expanded with six additional patients with NSCLC without any further dose-limiting toxicities. The recommended phase II dose of ridaforolimus is 20 mg daily, 5 days a week, in combination with cetuximab. Response and prolonged stable disease was demonstrated in NSCLC. Conclusions: The DLT of the combination of ridaforolimus and cetuximab is mucositis. The activity observed in heavily pretreated patients with NSCLC suggests that the combination of an mTOR inhibitor with an EGFR antibody merits further investigation in NSCLC. Clinical trial information: NCT01212627.

A phase I study of pazopanib in combination with FOLFOX 6 or capeOx in subjects with colorectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4133-4133
Author(s):  
J. Brady ◽  
M. Middleton ◽  
R. S. Midgley ◽  
M. K. Mallath ◽  
P. Corrie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitor ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Safety Data ◽  
Organ Function ◽  
Adequate Organ Function ◽  
Dose Limiting Toxicity

4133 Background: Pazopanib (paz) is a tyrosine kinase inhibitor of VEGFR-1, -2, -3, PDGF-α, -β, and c-kit. Inhibition of angiogenic pathways in combination with chemotherapy has been shown to benefit patients (pts) with colorectal cancer (CRC). Methods: Pts with previously untreated advanced or metastatic CRC and adequate organ function were assigned to paz with FOLFOX6 (FO) or capeOx (CO) by their physician. Doses of paz were escalated with full strength chemotherapy, starting at 400mg daily. The optimally tolerated regimen (OTR) was the combination dose at which <1/6 pts experienced dose-limiting toxicity (DLT). Results: Fifty pts were enrolled in FO (paz 400 mg, n=6; 800, 15), CO (400, 12; 800, 9) and reduced capecitabine (rc) CO (800, 8) cohorts: median age = 55.5, M/F = 37/13. Pts have remained on therapy for a median of 3 (range 0–17) months. Three pts remain on study. Safety data is available on 41. The most common AEs are summarized in the table below. The OTR was exceeded with CO in combination with 800 mg and 400 mg of pazopanib, but was not exceeded with 800 mg pazopanib when capecitabine was reduced to 850 mg/m2 twice daily or with FO with 800 mg pazopanib. Efficacy and pharmacokinetic analyses are ongoing. Conclusions: The OTRs were achieved at 800 mg paz with full-dose FO, and at 800mg paz with rcCO. [Table: see text] [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.

High-dose ifosfamide with mesna uroprotection: a phase I study.

1990 ◽  
Vol 8 (1) ◽  
pp. 170-178 ◽  
Author(s):  
A D Elias ◽  
J P Eder ◽  
T Shea ◽  
C B Begg ◽  
E Frei ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Continuous Infusion ◽  
Dose Level ◽  
Phase I Study ◽  
Autologous Bone Marrow ◽  
High Dose ◽  
Autologous Bone ◽  
Dose Limiting Toxicity ◽  
Cns Toxicity

Phase II trials of ifosfamide have been performed with standard doses of 5 to 8 g/m2/course. In this phase I study, 29 patients were treated with a 4-day continuous infusion ifosfamide to determine the maximum-tolerated dose and the nonhematologic dose-limiting toxicity. Autologous bone marrow support was to have been used for the subsequent dose level if granulocytes were more than 500/microL for more than 14 days in two of two to five patients at a given dose level. Doses were escalated from 8 to 18 g/m2 ifosfamide. Mesna was given at an equivalent dose by continuous infusion for 5 days. At the 18 g/m2 dose level, dose-limiting renal insufficiency and a median of 11 days (range, 8 to 18 days) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion ws not used. The duration of myelosuppression, the frequency and severity of mucositis, and renal tubular acidosis were all dose-dependent. Mild to moderate CNS toxicity also appeared to be related to dose; however, severe CNS toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. Transient hematuria (greater than 50 red blood cells [RBCs]/high power field) occurred once but did not affect treatment. There were nine responses (two complete) in 27 heavily pretreated assessable patients including seven responses in 20 patients with advanced refractory sarcoma. Ifosfamide with mesna uroprotection can undergo considerable dose escalation over the usual prescribed doses before nonhematologic dose-limiting toxicity is encountered. Ifosfamide has broad cytotoxicity against solid tumors and may prove to be an important addition to high-dose combination chemotherapy regimens.

A phase I study of the humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) TheraCIM-h-R3 (nimotuzumab) in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13054-13054
Author(s):  
A. M. Brade ◽  
L. Siu ◽  
A. M. Oza ◽  
B. Southwood ◽  
M. De Borja ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Performance Status ◽  
Advanced Solid Tumors ◽  
Eligibility Criteria ◽  
Skin Biopsies ◽  
Grade 3

13054 Background: Nimotuzumab is a humanized mAb against the extracellular ligand binding domain of EGFR. Although well tolerated when combined with radiotherapy in previous studies, the pharmacodynamics (PD) of nimotuzumab has not been elucidated. This phase I study was designed to evaluate the safety, tolerability and PD of nimotuzumab. Methods: Eligibility criteria included advanced solid tumors refractory to standard therapy and performance status of ECOG 0–2. Nimotuzumab was administered intravenously weekly × 6 and then every other week (6 weeks = 1 treatment cycle). Tumor and skin biopsies were obtained at baseline and after 2 weeks of treatment. Results: To date, 9 patients (7 m/2 f, median age 60, 7 colorectal cancer, ECOG 0:1:2 = 5:3:1, prior therapy 1:2:3+ = 1:3:5) have been treated on the first 2 dose levels (100 mg and 200 mg) for a total of 13 treatment cycles. The most common toxicities, mainly grade 1- 2, were lymphopenia (n = 8 patients), fatigue (n = 8), abnormal liver function tests (n = 7) and anemia (n = 6). Observed grade 3 toxicities include: pain (n = 3), hyponatremia (n = 2), elevated ALP (n = 2), fatigue (n = 1), hyperglycemia (n = 1) and hyperkalemia (n = 1). One patient at the first dose level experienced grade 3 fatigue, at least possibly attributable to nimotuzumab, and thus considered as a dose-limiting toxicity (DLT). No DLT were observed in the expanded cohort and dose level 2. No skin toxicities were observed. Stable disease was seen in 3 patients with colorectal cancer. PD from tumor and skin biopsies will be presented, and may clarify the reason for the lack of skin toxicity. Conclusions: Overall nimotuzumab was well tolerated, with disease stabilization observed in heavily pretreated patients. Accrual continues at dose level 3 (400 mg) with one further planned dose level (800 mg). [Table: see text]

A phase I study of 1-methyl-D-tryptophan in combination with docetaxel in metastatic solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS2620-TPS2620 ◽  
Author(s):  
Erica Jackson ◽  
Susan E. Minton ◽  
Roohi Ismail-Khan ◽  
Heather Han ◽  
Anthony Neuger ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Overall Response Rate ◽  
Tumor Antigens ◽  
Indoleamine 2 ◽  
Solid Malignancy ◽  
Level 3 ◽  
Dose Levels ◽  
Unacceptable Toxicity

TPS2620 Background: The indoleamine 2, 3 dioxygenase pathway (IDO) can create immune suppression and unresponsiveness to tumor antigens in tumor-bearing hosts. 1-methyl-D-tryptophan (1-MT), an oral inhibitor of the IDO pathway, showed favorable toxicity profile and biologic activity in prior studies. Remarkably, in prior animal models (MMTV-neu mice), 1-MT in combination with chemotherapy produced 30% greater tumor regressions. Based on this data, a phase I trial was initiated to study the synergism of 1-MT with docetaxel. The primary goal of this trial is to determine the MTD and toxicity for the combination of docetaxel and oral 1-MT. A secondary endpoint will be to determine the PK data and the overall response rate. Methods: This phase I study utilizes a 3+3 design comprised of five dose levels. Dose levels 1-4 will evaluate docetaxel 60mg/m2 IV d1 q3wks plus 1-MT at 300mg, 600mg, 1000mg, and 2000mg PO BID d1-21 respectively. Dose level 5 is docetaxel 75mg/m2 IV d1 q3wks + 1-MT 2000mg PO BID d1-21. Eligibility for this study includes patients with measurable metastatic solid malignancy, no prior docetaxel for metastatic disease, age ≥18, life expectancy >4 months, and adequate organ/marrow function. Patients will be excluded if they meet any of the following criteria: chemotherapy within the past 3 weeks, untreated brain metastases, active autoimmune disease, or GI disease causing malabsorption. In addition, any patients who have received prior immunotherapy such as ipilimumab are excluded. Treatment will continue until disease progression, unacceptable toxicity, or patient/physician discretion. Accrual to dose level 3 is complete and dose level 4 accrual is underway. The PK of 1-MT and docetaxel will also be characterized, using an HPLC assay. PK measurements for 1-MT are drawn on C1D1 after a single dose of 1-MT is given and then on C1D8 after the morning dose of 1-MT is given. (Drawn at 0,1,2,4,8,12,24, and 48 hours) Because IDO is hypothesized to cause regulatory T cell expansion, circulating Tregs will be quantified utilizing flow cytometry for CD4+CD25+ FoxP3+ cells. (NCT01191216)

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.

Phase I study of temsirolimus (CCI-779), carboplatin, and paclitaxel in patients (pts) with advanced solid tumors: NCIC CTG IND 179

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3558-3558
Author(s):  
A. M. Oza ◽  
C. Kollmannsberger ◽  
H. Hirte ◽  
S. Welch ◽  
L. Siu ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Solid Malignancies ◽  
Recommended Phase Ii Dose ◽  
Dose Levels ◽  
Further Development ◽  
Dose Limiting Toxicity

3558 Background: Temsirolimus (T) has encouraging activity in many malignancies, including endometrial cancer and a combination with carboplatin and paclitaxel would logical regimen for further development. This trial was designed to assess the safety and tolerability of this combination and expand experience at the recommended dose in pts with endometrial and ovarian cancers. Methods: A 3+3 dose escalation Phase I study has been conducted in pts with advanced solid malignancies suitable for carboplatin and paclitaxel chemotherapy who had not received more than 2 prior lines of chemotherapy. To date, 31 eligible pts with a median age of 59 have been treated and 27 are evaluable for toxicity. Pts were entered in 6 dose levels, with the first two levels administering T on Days 8 and 15 and the next 4 levels switching to a D1, 8 administration. Eighteen had received prior chemotherapy and 15 prior radiation. Results: Day 8, 15 administration of T was not feasible due to myelosuppression on day 15. The combination of carboplatin and paclitaxel on day 1 with T on D1 and 8 has been well tolerated, and patients have received a median of 5 cycles of therapy. At dose level 6 (T 25 mg D1 and 8, paclitaxel 175 mg/m2 D1, carboplatin AUC 6 D1) dose limiting toxicity (DLT) was seen in one of 6 pts treated to date (Gr 4 thrombocytopenia) and a second pt had a possible DLT ( Gr 3 fatigue in presence of baseline fatigue). This dose level is being expanded in 4 endometrial and ovarian cancer pts. The regimen is active: of the 26 patients with follow-up data, there have been 10 with partial response (38.5%; med. duration 7.1 mo [1.0–12.7]) and 12 with stable disease (46%; med. duration 6.9 mo [1.3- 7.8]). One patient had progressive disease and three were inevaluable. Conclusions: The results indicate this combination is well tolerated and requires additional assessment in a Phase II setting. The recommended Phase II dose will be dose level 6 provided no further DLTs are observed in the additional 4 patients entered. [Table: see text] No significant financial relationships to disclose.

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