Phase I trial of the somatostatin analog octreotide acetate in the treatment of fluoropyrimidine-induced diarrhea.

1995 ◽  
Vol 13 (1) ◽  
pp. 222-226 ◽  
Author(s):  
S Wadler ◽  
H Haynes ◽  
P H Wiernik
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Response To Therapy ◽  
Somatostatin Analog ◽  
Watery Diarrhea ◽  
Gastrointestinal Malignancies ◽  
Octreotide Acetate

PURPOSE Diarrhea is one of the dose-limiting toxicities for administration of fluorouracil (5FU) in patients with gastrointestinal malignancies and can result in severe morbidities or mortality. The somatostatin analog octreotide acetate has been used in the treatment of 5FU-induced diarrhea with promising results. A phase I trial was initiated to determine the maximum-tolerated dose of octreotide acetate that could be administered in this setting. PATIENTS AND METHODS Patients were required to have National Cancer Institute Common Toxicity Criteria > or = grade 2 diarrhea or watery diarrhea secondary to treatment with 5FU or a modulated 5FU regimen. At least three patients were treated at each dose level; after satisfactory completion of this dose level (zero of three or one of six patients with < or = grade 2 toxicity), additional patients were added at the next dose level. Doses of octreotide acetate studied were 50 to 2,500 micrograms subcutaneously three times daily for 5 days. RESULTS A total of 35 patients received 49 courses of therapy. The only significant toxicities occurred at 2,500 micrograms. At this dose level, one patient developed an allergic reaction with flushing, nausea, and dizziness after each of the first two injections. A second patient developed asymptomatic hypoglycemia with a serum glucose level of 26 mg/dL. The maximum-tolerated dose was 2,000 micrograms. The efficacy of the treatment correlated significantly (P = .01) with the dose of octreotide administered, and more patients completed the course of therapy at the higher doses. CONCLUSION Octreotide acetate can be safely administered for the treatment of fluoropyrimidine-induced diarrhea in patients with gastrointestinal malignancies. The dose-limiting toxicities were allergic (nausea, rash, and light-headedness) and endocrine (hypoglycemia). There was a significant correlation between complete response to therapy and octreotide dose.

Phase I Trial of Intravenous Thymidine and Carboplatin in Patients With Advanced Cancer

1999 ◽  
Vol 17 (9) ◽  
pp. 2922-2922 ◽  
Author(s):  
H. Ian Robins ◽  
Kendra Tutsch ◽  
Doerthe M. Katschinski ◽  
Elaine Jacobson ◽  
Minesh Mehta ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Combined Therapy ◽  
High Grade Glioma ◽  
Maximum Tolerated Dose ◽  
Metastatic Colon Cancer ◽  
Minor Response ◽  
The North ◽  
A Minor

PURPOSE: To evaluate the biologic interactions and toxicities of carboplatin combined with a 24-hour infusion of thymidine 75 mg/m2 in a phase I trial. PATIENTS AND METHODS: Thirty-two patients with cancer refractory to conventional therapy were treated. The first set of patients (n = 7) received thymidine alone 4 weeks before subsequent planned courses of thymidine combined with carboplatin followed (4 weeks) by carboplatin alone. Carboplatin was administered over 20 minutes at hour 20 of the 24-hour thymidine infusion. The carboplatin dose was escalated in patient groups: 200 mg/m2 (n = 3); 300 mg/m2 (n = 7); 350 mg/m2 (n = 4); 400 mg/m2 (n = 3); 480 mg/m2 (n = 10); and 576 mg/m2 (n = 5). At the maximum-tolerated dose (480 mg/m2), five patients received combined therapy first and carboplatin alone second, and five patients received carboplatin first and combined therapy second. Maintenance therapy for stable or responding patients was combined therapy. RESULTS: Evaluation demonstrated a trend toward thymidine protection of carboplatin-induced treatment-limiting thrombocytopenia. Neutropenia with carboplatin alone or in combination was negligible. Thymidine alone had no myelosuppressive effects and produced reversible grade 1 or 2 nausea and vomiting (57%), headache (25%), and grade 1 neurotoxicity (22%). Thymidine did not enhance expected carboplatin toxicities. There was no therapy-related infection or bleeding. Analysis of platinum in plasma ultrafiltrate and urine showed no effect by thymidine. Similarly, thymidine pharmacokinetics was not affected by carboplatin. As predicted, nicotinamide adenine dinucleotide levels in peripheral lymphocytes were increased during exposure to carboplatin and/or thymidine but were decreased by carboplatin alone. In three patients with high-grade glioma, responses included one complete remission (21 months) and one partial remission (14 months) at the 480-mg/m2-dose level, and disease stabilization (7 months) at the 400-mg/m2-dose level. A minor response was observed in a patient with metastatic colon cancer (5 months) at the 480-mg/m2-dose level. CONCLUSION: The combination of carboplatin and thymidine as described is well tolerated. The data presented have resulted in a phase II study by the North American Brain Tumor Consortium.

Multi-Agent Phase I Trials in Childhood Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4528-4528
Author(s):  
Richard Sposto ◽  
Elizabeth A. Raetz ◽  
Charles P. Reynolds ◽  
Paul S. Gaynon
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Cell Transplant ◽  
Phase I Trials ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Background: Single agent phase I trials with conventional methodology may not be suitable for children with relapsed leukemia. Accrual of children with ALL in relapse to single-agent phase I trials is poor due to clinical urgency and a &gt; 30% likelihood of complete response (CR) with a variety conventional agents combinations (Br J Haematol.2005; 131(5): 579) with the option of hematopoietic stem cell transplant in remission. As most drugs are ultimately used in combination, a Phase I trial testing a new agent in combination with conventional agents would seem most useful and might increase accrual. However, with conventional phase I methodologies determination of a maximum tolerated dose is complicated by the toxicities of the accompanying conventional agents and by the background morbidity of relapsed leukemia. Methods: The Children’s Oncology Group (COG) study, AALL01P2, employed vincristine, prednisone, doxorubicin, and pegylated asparaginase for children with ALL in first marrow relapse. We determined the incidence of conventional non-hematologic dose limiting toxicities (DLT’s) and modeled the impact on a hypothetical phase I trial of a candidate agent with no additional toxicity. Results: Among 111 patients on AALL01P2, 19% had conventional non-hematologic DLT’s. Induction therapy was judged clinically acceptable. With a traditional Phase I escalation scheme that accepts 0/3 and 1/6 DLT’s at a dose-level and rejects 2/3 and 2/6 DLT’s, an agent that adds no morbidity would be rejected as too toxic at any dose 30% of the time. Conclusion: Background morbidity confounds identification of an acceptable dose of a non-toxic new agent tested in combination with conventional drugs for recurrent ALL. We propose a modification to the traditional Phase I design that increases the DLT thresholds to 1/3 and 2/6, which effectively compensates for background toxicity and reduces the chance of falsely rejecting an acceptable agent.

A Phase I Trial of Two Sequence-Specific Schedules of Decitabine and Vorinostat in Patients with Acute Myeloid Leukemia (AML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 908-908 ◽  
Author(s):  
Karen W.L. Yee ◽  
Mark D. Minden ◽  
Joseph Brandwein ◽  
Aaron Schimmer ◽  
Andre Schuh ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Concurrent Schedule ◽  
Maximum Tolerated Dose ◽  
Leukemic Cells ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Sequential Schedule ◽  
Grade 3

Abstract Background: Epigenetic silencing of genes has been documented in AML. This phase I trial evaluates the safety, tolerability, and maximum tolerated dose (MTD) of two schedules of administration of the hypomethylating agent decitabine in combination with the pan-selective histone deacetylase inhibitor vorinostat. Methods: Patients receive escalating doses of oral vorinostat administered either sequentially [100 mg bid (n=4), 200 mg bid (n=4), or 200 mg tid (n=8) Days 6–21] or concurrently [100 mg (n=3) or 200 mg (n=6) bid Days 1–21 or 200 mg tid (n=2) Days 1–14] with decitabine (20 mg/m2/d IV Days 1–5) every 28 days. Results: Twenty-seven patients with AML have been treated. Median age was 67 years (range, 32–82 years). Median ECOG status 1 (range, 0 to 2). Eighteen patients (67%) had received prior therapy (median, 1 regimen; range, 0 to 4 regimens); 3 had received a prior allogeneic stem cell transplant. A total of 85 cycles have been administered, with a median of 2 cycles (range, 1 to 13 cycles); 10 patients (37%) have received 3 or more cycles of therapy. One of 7 patients treated at dose level 3 of the sequential schedule developed dose-limiting toxicities (DLT), consisting of grade 3 fatigue, weakness, and mucositis. Therefore, the MTD was not reached in the 3 planned dose levels of the sequential schedule. One DLT (grade 3 fatigue) occurred in 6 patients treated at dose level 2 of the concurrent schedule. Most common drug-related non-hematological toxicities of any grade (all CTCAE grades 1 or 2) were nausea (71%), fatigue (54%), diarrhea (54%), vomiting (42%), anorexia (25%), constipation (13%), abdominal pain (13%), dehydration (13%), and headache (13%). No other non-hematological grade 3 or 4 toxicities were observed. Of the 25 evaluable patients, one patient achieved an incomplete CR (without neutrophil recovery), one a morphologic leukemia-free state (without blood count recovery), and three partial remissions (1 achieved red cell transfusion independency and a second normalization of platelet counts). Seven of these patients remain on study for 2.7 to 13.5+ months. Correlative studies examining histone acetylation and gene promoter methylation in leukemic cells at baseline and after treatment, as well as plasma pharmacokinetic levels for both decitabine and vorinostat are being evaluated. Conclusions: The combination of decitabine and vorinostat is safe, well-tolerated, and has clinical activity in patients with AML. Enrollment is ongoing.

Phase I/II trial of sorafenib combined with FOLFOX4 in untreated patients with advanced gastric adenocarcinoma: Phase I results.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14606-e14606
Author(s):  
Yihebali Chi ◽  
Jianliang Yang ◽  
Feng Du ◽  
Sheng Yang ◽  
Yongkun Sun ◽  
...  
Keyword(s):  
Phase I ◽  
Gastric Adenocarcinoma ◽  
Dose Level ◽  
Standard Dose ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Combination Regimen ◽  
Phase Ii Studies ◽  
Best Response ◽  
Advanced Gastric Adenocarcinoma

e14606 Background: Sorafenib (Sor) is a potent inhibitor of multiple intracellular and cell surface kinases. FOLFOX4 was demonstrated to be an active and well-tolerated chemotherapy for advanced gastric adenocarcinoma (AGA). The phase I portion of the phase I/II study is designed to assess the maximum tolerated dose (MTD) of Sor combined with standard dose FOLFOX4, as well as safety, tolerance, and activity of the combination in patients (pts) with AGA. Methods: Pts with AGA with ECOG 0-1 and without prior chemotherapy or radiotherapy were eligible. Three patients per cohort were treated with FOLFOX4 [Oxaliplatin (85 mg/m2), LV (200mg/m2) and 5-FU (400 mg/m2), followed by 5-FU continuously infusion (1200mg/ m2) for 44h every 2 weeks, up to 8 cycles, along with escalating doses of Sor (200, 400, 600mg) PO BID, continuously. If one patient experienced DLT, three additional patients were entered at the same dose level. Dose escalation continued until DLTs were experienced in two or more out of six patients, which was then defined as the MTD. Radiographic responses were assessed every 6 weeks per RECIST v1.0. Results: Nine pts were enrolled. Median age was 59.3 yr (range 42.6-71.6). M/F: 6/3; ECOG PS 0/1: 2/7. One out of 6 pts experienced DLT (G3 HFSR) in dose level 1 (200 mg BID), and 2 out of 3pts experienced DLT in dose level 2 (400 mg BID). The Sor 200mg BID was therefore identified as the MTD when combined with FOLFOX4. Major toxicity of this combination include neutropenia (G3/4: 7/3), leucopenia (G3/4: 2/0), HFSR (G3/4: 2/0) and incomplete bowel obstruction (G3/4: 1/0). One patient experienced G4 ALT/AST elevation accompanied with G3 GGT/bilirubin elevation, which led to treatment discontinuation. Preliminary efficacy data in 9 evaluable pts included 1 complete response (CR), 6 partial responses (PR) and 1 stable disease (SD) as best response. Median time to progression was 6.6 months. Median overall survival was 12.2 months. Conclusions: The MTD of Sor when used in combination of FOLFOX4 in AGA is 200mg PO BID, and this combination regimen has a manageable toxicity profile and promising activity in AGA. This efficacy and safety profiles need to be confirmed in further phase II studies.

scholarly journals Phase I Trial of First-in-Class ATR Inhibitor M6620 (VX-970) as Monotherapy or in Combination With Carboplatin in Patients With Advanced Solid Tumors

2020 ◽  
Vol 38 (27) ◽  
pp. 3195-3204 ◽  
Author(s):  
Timothy A. Yap ◽  
Brent O’Carrigan ◽  
Marina S. Penney ◽  
Joline S. Lim ◽  
Jessica S. Brown ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Gynecologic Cancer ◽  
Progression Free Survival ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Best Response ◽  
Recommended Phase Ii Dose

PURPOSE Preclinical studies demonstrated that ATR inhibition can exploit synthetic lethality (eg, in cancer cells with impaired compensatory DNA damage responses through ATM loss) as monotherapy and combined with DNA-damaging drugs such as carboplatin. PATIENTS AND METHODS This phase I trial assessed the ATR inhibitor M6620 (VX-970) as monotherapy (once or twice weekly) and combined with carboplatin (carboplatin on day 1 and M6620 on days 2 and 9 in 21-day cycles). Primary objectives were safety, tolerability, and maximum tolerated dose; secondary objectives included pharmacokinetics and antitumor activity; exploratory objectives included pharmacodynamics in timed paired tumor biopsies. RESULTS Forty patients were enrolled; 17 received M6620 monotherapy, which was safe and well tolerated. The recommended phase II dose (RP2D) for once- or twice-weekly administration was 240 mg/m2. A patient with metastatic colorectal cancer harboring molecular aberrations, including ATM loss and an ARID1A mutation, achieved RECISTv1.1 complete response and maintained this response, with a progression-free survival of 29 months at last assessment. Twenty-three patients received M6620 with carboplatin, with mechanism-based hematologic toxicities at higher doses, requiring dose delays and reductions. The RP2D for combination therapy was M6620 90 mg/m2 with carboplatin AUC5. A patient with advanced germline BRCA1 ovarian cancer achieved RECISTv1.1 partial response and Gynecologic Cancer Intergroup CA125 response despite being platinum refractory and PARP inhibitor resistant. An additional 15 patients had RECISTv1.1 stable disease as best response. Pharmacokinetics were dose proportional and exceeded preclinical efficacious levels. Pharmacodynamic studies demonstrated substantial inhibition of phosphorylation of CHK1, the downstream ATR substrate. CONCLUSION To our knowledge, this report is the first of an ATR inhibitor as monotherapy and combined with carboplatin. M6620 was well tolerated, with target engagement and preliminary antitumor responses observed.

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]

scholarly journals Phase I Trial of Bevacizumab Plus Escalated Doses of Sunitinib in Patients With Metastatic Renal Cell Carcinoma

2009 ◽  
Vol 27 (9) ◽  
pp. 1432-1439 ◽  
Author(s):  
Darren R. Feldman ◽  
Michael S. Baum ◽  
Michelle S. Ginsberg ◽  
Hani Hassoun ◽  
Carlos D. Flombaum ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Dose Level ◽  
Renal Cell ◽  
Phase I Trial ◽  
Objective Response ◽  
Safety Information ◽  
Maximum Tolerated Dose ◽  
Chronic Therapy

PurposeBoth bevacizumab and sunitinib target the vascular endothelial growth factor pathway and demonstrate activity against advanced renal cell carcinoma (RCC). In this phase I study, the maximum-tolerated dose (MTD) and safety of sunitinib in combination with bevacizumab were examined in patients with advanced RCC.Patients and MethodsThree cohorts of three to six patients were treated with escalated doses of daily oral sunitinib (ie, 25 mg, 37.5 mg, 50 mg) for 4 weeks followed by a 2-week break and with fixed doses of bevacizumab (10 mg/kg) intravenously once every 2 weeks. Dose-limiting toxicities (DLTs) were assessed during the first cycle to determine the MTD, and an expanded cohort was treated to obtain additional safety information.ResultsOf 26 study participants, 25 received treatment at one of three dose levels. Grade 4 hemorrhage, identified as a DLT, occurred in one patient in each of cohorts 2 and 3. The MTD was determined to be sunitinib 50 mg/bevacizumab 10 mg/kg, but chronic therapy at this dose level frequently resulted in grades 3 to 4 hypertension and hematologic and vascular toxicities. Overall, 48% of patients discontinued treatment because of adverse events. One complete and 12 partial responses were observed, which provided an objective response rate of 52%.ConclusionIn this phase I trial of patients with metastatic RCC, the combination of sunitinib and bevacizumab caused a high degree of hypertension and vascular and hematologic toxicities at the highest dose level. We do not plan to pursue additional study of this regimen at these doses in patients with RCC.

Phase I Trial of Intrathecal Liposomal Cytarabine in Children With Neoplastic Meningitis

2004 ◽  
Vol 22 (19) ◽  
pp. 3916-3921 ◽  
Author(s):  
L. Bomgaars ◽  
J.R. Geyer ◽  
J. Franklin ◽  
G. Dahl ◽  
J. Park ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Trial ◽  
Maintenance Phase ◽  
Maximum Tolerated Dose ◽  
Neoplastic Meningitis ◽  
Liposomal Cytarabine ◽  
Disease Stabilization ◽  
Recommended Phase Ii Dose

Purpose We performed a phase I trial of intrathecal (IT) liposomal cytarabine (DepoCyt; Enzon Pharmaceuticals, Piscataway, NJ and SkyePharma Inc, San Diego, CA) to determine the maximum-tolerated dose, the dose-limiting toxicities, and the plasma and CSF pharmacokinetics of IT lipsomal cytarabine in children ≥ 3 years of age with advanced meningeal malignancies. Patients and Methods Eighteen assessable patients received IT liposomal cytarabine through either an indwelling ventricular access device or via lumbar puncture. Liposomal cytarabine was given once every 2 weeks during induction, once every 4 weeks during consolidation, and once every 8 weeks during the maintenance phase of treatment. The initial dose was 25 mg, with subsequent escalations to 35 and 50 mg. CSF pharmacokinetic samples were obtained in a subset of patients. Results Arachnoiditis, characterized by fever, headache, nausea, vomiting, and back pain was noted in the first two patients at the 25 mg dose level. Therefore, subsequent patients were treated with dexamethasone, beginning the day of liposomal cytarabine administration and continuing for 5 days. Headache (grade 3) was dose limiting in two of eight patients enrolled at the 50 mg dose level. Eight of the 14 patients assessable for response demonstrated evidence of benefit manifest as prolonged disease stabilization or response. Conclusion The maximum-tolerated dose and recommended phase II dose of liposomal cytarabine in patients between the ages of 3 and 21 years is 35 mg, administered with dexamethasone (0.15 mg/kg/dose, twice a day for 5 days). A phase II trial of IT liposomal cytarabine in children with CNS leukemia in second or higher relapse is in development.

Phase I trial of bevacizumab plus sunitinib in patients (pts) with metastatic renal cell carcinoma (mRCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5099-5099 ◽  
Author(s):  
D. R. Feldman ◽  
G. V. Kondagunta ◽  
E. A. Ronnen ◽  
P. Fischer ◽  
R. Chang ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Rapid Progression ◽  
Hematologic Toxicity ◽  
Phase Ii Trials ◽  
Dose Levels

5099 Background: Bevacizumab, an intravenous monoclonal antibody against VEGF, and sunitinib, an oral multi-targeted tyrosine kinase inhibitor of VEGF and PDGF receptors, both have activity in mRCC [NEJM 349:427–434; JAMA 295:2516–2524]. Combining bevacizumab and sunitinib may increase antitumor efficacy by maximizing inhibition of the VEGF pathway. The safety and maximum tolerated dose (MTD) of sunitinib in combination with bevacizumab was assessed in this Phase I trial. Methods: Cohorts of 3–6 pts with mRCC received escalating doses of sunitinib (dose levels: 25, 37.5, and 50 mg po) daily for 4 weeks (wks) followed by 2 wks off with fixed- dose bevacizumab (10 mg/kg iv) every 2 wks continuously. Pre-determined dose-limiting toxicities (DLTs) in the first 6-wk cycle included Grade (Gr) 4 neutropenia, ≥Gr 3 thrombocytopenia of ≥7 days, Gr 4 hypertension or proteinuria, and other Gr 3 non-hematologic toxicity of ≥7 days. Pts who came off study prior to completion of cycle 1 for any reason other than a DLT were replaced. Serum VEGF levels were measured before and during cycles 1 and 2. Results: 16 pts (11 male, 5 female, median age 57) were enrolled. Of 8 patients entered at the first dose level (sunitinib 25 mg, bevacizumab 10 mg/kg), 2 were replaced; 1 never received treatment and 1 did not complete cycle 1 due to rapid progression of disease (PD). No DLTs occurred in the remaining 6 evaluable pts in this cohort. At the 2nd dose level (n =6, sunitinib 37.5 mg, bevacizumab 10 mg/kg), 1 pt receiving low molecular weight heparin had a DLT of Gr 4 hemorrhage. 2 pts have enrolled in the 3rd dose level (sunitinib 50 mg, bevacizumab 10 mg/kg) but are not yet evaluable for toxicity or response. Gr 3/4 toxicities over all cycles included Gr 3 hypertension (n=4), Gr 3 proteinuria (n=2), Gr 3 abdominal pain (n=2), Gr 4 hemorrhage (n=1), and Gr 3 hand/foot syndrome (n=1). 13 pts were evaluated for best response–4 had partial responses, 7 had stable disease, and 2 had PD. Serum VEGF levels decreased during cycle 1 in all pts. Conclusions: The combination of sunitinib and bevacizumab in mRCC pts was tolerable at the first 2 dose levels. Once the MTD is identified, further testing of this combination in phase II trials may be indicated for mRCC as well as other malignancies. [Table: see text]

Phase I trial of docetaxel administered as a 1-hour infusion in children with refractory solid tumors: a collaborative pediatric branch, National Cancer Institute and Children's Cancer Group trial.

1997 ◽  
Vol 15 (4) ◽  
pp. 1538-1543 ◽  
Author(s):  
S M Blaney ◽  
N L Seibel ◽  
M O'Brien ◽  
G H Reaman ◽  
S L Berg ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Intravenous Infusion ◽  
Phase I Trial ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Cancer Group ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Dose Limiting Toxicity

PURPOSE A phase I trial of docetaxel was performed to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities, and the incidence and severity of other toxicities in children with refractory solid tumors. PATIENTS AND METHODS Forty-four children received 103 courses of docetaxel administered as a 1-hour intravenous infusion every 21 days. Doses ranged from 55 to 150 mg/m2, MTD was defined in heavily pretreated and less heavily pretreated (< or = 2 prior chemotherapy regimens, no prior bone marrow transplantation [BMT], and no radiation to the spine, skull, ribs, or pelvic bones) patients. RESULTS Dose-related neutropenia was the primary dose-limiting toxicity. The MTD in the heavily pretreated patient group was 65 mg/m2, but the less heavily pretreated patients tolerated a significantly higher dose of docetaxel (maximum-tolerated dose, 125 mg/m2). Neutropenia and constitutional symptoms consisting of malaise, myalgias, and anorexia were the dose-limiting toxicities at 150 mg/m2 in the less heavily pretreated patients. Thrombocytopenia was not prominent, even in patients who experienced dose-limiting neutropenia. Common nonhematologic toxicities of docetaxel included skin rashes, mucositis, and mild elevations of serum transaminases. Neuropathy was uncommon. Peripheral edema and weight gain were observed in two of five patients who received more than three cycles of docetaxel. A complete response (CR) was observed in one patient with rhabdomyosarcoma, a partial response (PR) in one patient with peripheral primitive neuroectodermal tumor (PPNET), and a minimal response (MR) in two patients with PPNET. Three of the four responding patients were treated at doses > or = 100 mg/m2. CONCLUSION The recommended phase II dose of docetaxel administered as a 1-hour intravenous infusion in children with solid tumors in 125 mg/m2. Because neutropenia was the dose-limiting toxicity and thrombocytopenia was mild, further escalation of the dose should be attempted with granulocyte colony-stimulating factor (G-CSF) support.

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