Phase Ib of anticancer stem cell antibody OMP-59R5 (anti-Notch2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 220-220 ◽  
Author(s):  
Eileen Mary O'Reilly ◽  
Lon S. Smith ◽  
Johanna C. Bendell ◽  
Fatima A. Rangwala ◽  
William Schmidt ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Regression ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Igg2 Antibody ◽  
Cell Antibody ◽  
Grade 3 ◽  
Anti Tumor Activity ◽  
Dose Limiting Toxicity ◽  
Clinical Trial Information

220 Background: OMP-59R5, a fully human IgG2 antibody, inhibits signaling of Notch2 and 3 receptors. Tumor regression was seen in Notch3 expressing patient-derived pancreatic cancer xenografts when OMP-59R5 was combined with Nab-P+Gem. The maximum tolerated dose (MTD) of single agent OMP-59R5 was 7.5 mg/kg every other week (Smith, EORTC 2012); the main dose limiting toxicity (DLT) was grade 3 diarrhea. This study is to determine the MTD, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of OMP-59R5 in combination with Nab-P+Gem in mPC. Methods: Cohorts of 3 to 6 pts were treated at each dose level of OMP-59R5. OMP-59R5 is given intravenously every other week (days 1 and 15) with GEM 1,000 mg/m2 alone (first two cohorts) or nab-P 125 mg/m2 and GEM 1,000 mg/m2 on days 1, 8, and 15 of every 28-day cycle. Results: By August 30, 2013, 24 pts were treated. No DLTs have occurred. Frequently reported (≥10%) OMP-59R5 treatment-related adverse events (AEs) were: diarrhea (44%), fatigue (44%), and nausea (16%); most were grade 1 or 2 and managed with supportive care. Frequent chemo-related AEs (≥10%) were cytopenia, fatigue, diarrhea, and nausea. GEM or Nab-P+Gem did not alter PK of OMP-59R5. See table for additional data. Conclusions: OMP-59R5 with Nab-P+ Gem is well tolerated. The MTD has not been reached. Encouraging anti-tumor activity is observed. Updated Safety, PK/PD, and efficacy data will be presented. Clinical trial information: NCT01647828. [Table: see text]

Phase I Trial Examining Addition of Gemcitabine to CHOP in Intermediate Grade NHL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4765-4765
Author(s):  
John L. Reagan ◽  
James N. Butera ◽  
Alan G. Rosmarin ◽  
Ahmed Nadeem ◽  
Fred J. Schiffman ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Phase I Trial ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Chop Chemotherapy ◽  
Intermediate Grade ◽  
Chemotherapeutic Regimen ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Abstract Abstract 4765 BACKGROUND Gemcitabine induces a 20% response as single agent therapy in patients with relapsed or refractory NHL. We report phase I findings of gemcitabine in combination with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. The protocol was modified during enrollment to include rituximab in CD 20+ lymphomas. METHODS Patients received CHOP plus gemcitabine at 500 mg/m2 (Cohort 1) or 750 mg/m2 (Cohort 2) on days 1,4 of each 21 day cycle. Accrual was suspended once each cohort was filled. Dose escalation occurred after all patients in the cohort were determined to not have a dose limiting toxicity. RESULTS Between 4/02 and 5/04 10 patients were enrolled and completed the study treatment (6 in cohort 1, 4 in cohort 2). In Cohort 1, grade 3 toxicities included neutropenia, anemia, neuropathy, and constipation. Grade 4 toxicities were febrile neutropenia, and thrombocytopenia. In Cohort 2, grade 3 toxicities included neutropenia, thrombocytopenia, mucositis, anemia and intestinal obstruction. Grade 4 toxicities included febrile neutropenia, neutropenia, and thrombocytopenia. One patient developed MDS 36 months after chemotherapy. Three of four patients in Cohort 2 developed dose limiting toxicities (mucositis and thrombocytopenia) requiring dose reduction of gemcitabine after cycle 1. Overall, the survival rate at 2.5 years was 71%. CONCLUSIONS This Phase I trial concludes that gemcitabine 500mg/m2 on days 1 and 4 of each 21 day cycle is the maximum tolerated dose when combined with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. Response rates are encouraging for this novel chemotherapeutic regimen. Disclosures: Off Label Use: Gemcitabine was added to standard CHOP chemotherapy in this trial.. Sikov:Eli Lilly: Honoraria.

Final results of phase Ib of anticancer stem cell antibody tarextumab (OMP-59R5, TRXT, anti-Notch 2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 278-278 ◽  
Author(s):  
Eileen Mary O'Reilly ◽  
Lon S. Smith ◽  
Johanna C. Bendell ◽  
John H. Strickler ◽  
Mark Zalupski ◽  
...  
Keyword(s):  
Stem Cell ◽  
Tumor Regression ◽  
Single Agent ◽  
Notch Pathway ◽  
Maximum Tolerated Dose ◽  
Hair Follicles ◽  
Stem Cell Markers ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Grade 3

278 Background: Tarextumab (TRXT), fully human IgG2 antibody, inhibits signaling Notch 2, 3 receptors. Tumor regression seen in Notch 3 patient-derived PC xenografts when TRXT added to Nab-P+Gem. The maximum tolerated dose (MTD) of single agent TRXT was 7.5mg/kg every other week (Smith, EORTC 2012); the main dose limiting toxicity (DLT) was Grade 3 diarrhea. This study evaluates MTD, pharmacokinetics (PK), pharmacodynamics (PD) and early efficacy of TRXT + Nab-P+Gem in mPC. Methods: Cohorts of 3-6 pts treated at 6 dose levels of TRXT. TRXT IV Days 1 + 15 with GEM 1000mg/m2 alone (first two cohorts) or nab-P 125 mg/m2 and GEM 1000mg/m2on Days 1, 8, 15 of every 28-day cycle. Biomarker analysis of surrogate tissue and tumor undertaken. Results: By 08/22/14, N= 40 treated. TRXT 15 mg/kg selected as Phase 2 dose. 1 DLT Grade 3 diarrhea in 15 mg/kg cohort. Frequently reported (≥15%) TRXT adverse events(AEs) were: diarrhea(60%), fatigue(43%), anemia(28%), decreased appetite (18%) and nausea(15%); most grade 1 or 2 and managed supportively. Other AEs (≥ 30%) were: cytopenia, alopecia, vomitng and peripheral edema. GEM or Nab-P+Gem did not alter PK of TRXT. Notch pathway-related genes, HEYL, HES2, NOTCH2 and cancer stem cell markers were altered in hair follicles at TRXT > 7.5 mg/kg combined with Nab-P+Gem. Plasma, blood RNA biomarkers were also modulated by TRXT + Nab-P+Gem. Conclusions: TRXT + Nab-P+ Gem is well tolerated. 15 mg/kg is the selected Phase 2 dose of TRXT. Encouraging anti-tumor activity was observed. Final safety, efficacy, PK and PD results in surrogate and serial tumor tissues will be presented. The Phase 2 randomized, placebo-controlled ALPINE study is underway. Clinical trial information: NCT01647828. [Table: see text]

CONKO-008: Oxaliplatin (O)/folinic acid (FA)/5-fluorouracil (5-FU) (24h) in combination with lapatinib as second-line therapy in pancreatic cancer after gemcitabine failure: A phase I trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14533-e14533
Author(s):  
Jens Stieler ◽  
Uwe Pelzer ◽  
Marianne Sinn ◽  
Jana Kaethe Striefler ◽  
Bernd Dörken ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tyrosine Kinase ◽  
Folinic Acid ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Phase Ii Trials ◽  
Starting Dose ◽  
Daily Dose ◽  
Grade 3 ◽  
Dose Limiting Toxicity

e14533 Background: ErbB-1 and ErbB-2 as its enhancer are expressed in pancreatic cancer. Based on the results of the 2nd-line chemotherapy (CT) with Oxaliplatin, 5-FU and Folinic acid (OFF) (CONKO-003; ASCO 2008) and the activity of EGFR- tyrosine kinase inhibition in pancreatic cancer (Moore JCO 2007), this trial aims to further improve therapeutic options for patients after Gemcitabine failure by combining OFF with lapatinib, a combined ErbB-1 and ErbB-2 tyrosine kinase inhibitor which showed preclinical synergy with 5-FU (Kim PloS One 2009). Methods: The daily dose of lapatinib combined with oxaliplatin 85 mg/m2 (2-4 h infusion d 8, 22), 5-FU 2000 mg/m2 (24 h continuous infusion d1,8,15,22 q d 42) and FA 200 mg/m2 (30 min infusion d1,8,15,22 q d 42). was expected to be between 750 to 1,500 mg, further dose intensification was not planned. Starting dose for lapatinib was set on 1,000 mg/day, with a minimum of 3 pts. on each level and extension to 6 pts. in case of a dose limiting toxicity (DLT). Maximum tolerated dose (MTD) was defined as a dose level (DL) below the level where 2/6 patients would show DLTs during cycle 1. Results: 18 Pts (12m/6w). have been enrolled in the trial.7 pts. were treated on 1,000 mg/d (DL 1), 5 pts. on level 1,250 mg/d (DL 2), and 6 pts. on 1,500 mg (DL 3). DLTs were met on DL 3 with diarrhea CTC grade 4 and concomitant neutropene enterocolitis in one patient and diarrhea CTC grade 3 in another patient. MTD is thus limited to 1,250 mg lapatinib in combination with OFF. Conclusions: With diarrhea as most prominent cumulative toxicity of the regimen, the maximum dose of lapatinib in combination with OFF is 1,250 mg. This dose may find further use in future phase II trials.

Phase I study of mFOLFOX-6, bevacizumab, and mTOR inhibitor RAD001 as first-line treatment of metastatic colorectal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 600-600 ◽  
Author(s):  
Glynn Weldon Gilcrease ◽  
John R. Weis ◽  
Kimberly Jones ◽  
Thaylon Davis ◽  
Marlene Mitchell ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mtor Inhibitor ◽  
Maximum Tolerated Dose ◽  
Mutation Status ◽  
Common Grade ◽  
Pten Deletion ◽  
Grade 3 ◽  
Anti Tumor Activity ◽  
Dose Limiting Toxicity

600 Background: This study was designed to determine the dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and efficacy of the mTOR inhibitor RAD001 in combination with mFOLFOX-6 and bevacizumab in metastatic colorectal cancer. Methods: Twenty patients with previously untreated metastatic colorectal cancer received mFOLFOX-6, bevacizumab and RAD001 using a standard three patient cohort dose escalation schema. Seventeen of the twenty patients were evaluable with a median age of 52 (ten females and seven males). RAD001 was administered orally at escalating doses of 2.5 mg, 5 mg and 10 mg daily. mFOLFOX-6 and bevacizumab were administered in standard fashion. Results: The most common grade 3/4 hematological adverse events (AEs) were neutropenia (59%), leucopenia (29%) and thrombocytopenia (12%). The most common grade 3 non-hematological AEs were diarrhea (24%) and hypokalemia (18%). One dose-limiting toxicity was noted at 10 mg/day due to grade 3 anorexia, grade 3 diarrhea, and grade 3 hypokalemia. Grade 1 mucositis was noted in 12% of patients and grade 2 mucositis was noted in 47% of patients. There was no grade 3/4 mucositis. Fourteen patients are evaluable for efficacy. The RR is 86% including 2 CRs, 7 PRs, and 3 SDs. Conclusions: RAD001 in combination with mFOLFOX6 and bevacizumab is well-tolerated at a dose of 10 mg/day. The regimen appears to be effective. Evidence of anti-tumor activity correlated with mutation status (k-ras, BRAF, PIK3CA) and PTEN deletion status will be presented.

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

scholarly journals Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick B. Johnston ◽  
Amanda F. Cashen ◽  
Petros G. Nikolinakos ◽  
Anne W. Beaven ◽  
Stefan Klaus Barta ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Peripheral T Cell Lymphoma ◽  
Grade 3

Abstract Background Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK). Methods Patients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m2 once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose. Results Twenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1–3 schedule, resulting in escalation to Day 1–5 schedule (n = 3). No DLTs were observed and Day 1–5 schedule with 1000 mg/m2 was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent. Conclusions Bel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT01839097.

Gemcitabine Plus Capecitabine Compared With Gemcitabine Alone in Advanced Pancreatic Cancer: A Randomized, Multicenter, Phase III Trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group

2007 ◽  
Vol 25 (16) ◽  
pp. 2212-2217 ◽  
Author(s):  
Richard Herrmann ◽  
György Bodoky ◽  
Thomas Ruhstaller ◽  
Bengt Glimelius ◽  
Emilio Bajetta ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Performance Status ◽  
Single Agent ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Metastatic Pancreatic Cancer ◽  
Karnofsky Performance Score ◽  
Phase Iii Trial ◽  
Good Performance Status ◽  
Grade 3

PurposeThis phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer.Patients and MethodsPatients were randomly assigned to receive GemCap (oral capecitabine 650 mg/m2twice daily on days 1 to 14 plus Gem 1,000 mg/m2by 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m2by 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks). Patients were stratified according to center, Karnofsky performance score (KPS), presence of pain, and disease extent.ResultsA total of 319 patients were enrolled between June 2001 and June 2004. Median overall survival (OS) time, the primary end point, was 8.4 and 7.2 months in the GemCap and Gem arms, respectively (P = .234). Post hoc analysis in patients with good KPS (score of 90 to 100) showed a significant prolongation of median OS time in the GemCap arm compared with the Gem arm (10.1 v 7.4 months, respectively; P = .014). The overall frequency of grade 3 or 4 adverse events was similar in each arm. Neutropenia was the most frequent grade 3 or 4 adverse event in both arms.ConclusionGemCap failed to improve OS at a statistically significant level compared with standard Gem treatment. The safety of GemCap and Gem was similar. In the subgroup of patients with good performance status, median OS was improved significantly. GemCap is a practical regimen that may be considered as an alternative to single-agent Gem for the treatment of advanced/metastatic pancreatic cancer patients with a good performance status.

Maximum-tolerated dose, toxicity, and efficacy of (131)I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin's lymphoma.

1998 ◽  
Vol 16 (10) ◽  
pp. 3246-3256 ◽  
Author(s):  
G L DeNardo ◽  
S J DeNardo ◽  
D S Goldstein ◽  
L A Kroger ◽  
K R Lamborn ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Radiation Dosimetry ◽  
Large Cell ◽  
Maximum Tolerated Dose ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Iodine 131 ◽  
Grade 3 ◽  
Dose Limiting Toxicity

PURPOSE Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced remissions in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine 131 ((131)I). Based on the strategy of fractionating the total dose, this study was designed to define the maximum-tolerated dose (MTD) and efficacy of the first two, of a maximum of four, doses of (131)I-Lym-1 given 4 weeks apart. Additionally, toxicity and radiation dosimetry were assessed. MATERIALS AND METHODS Twenty patients with advanced NHL entered the study a total of 21 times. Thirteen (62%) of the 21 entries had diffuse large-cell histologies. All patients had disease resistant to standard therapy and had received a mean of four chemotherapy regimens. (131)I-Lym-1 was given after Lym-1 and (131)I was escalated in cohorts of patients from 40 to 100 mCi (1.5 to 3.7 GBq)/m2 body surface area. RESULTS Mean radiation dose to the bone marrow from body and blood (131)I was 0.34 (range, 0. 1 6 to 0.63) rad/mCi (0.09 mGy/MBq; range, 0.04 to 0.17 mGy/ MBq). Dose-limiting toxicity was grade 3 to 4 thrombocytopenia with an MTD of 100 mCi/m2 (3.7 GBq/m2) for each of the first two doses of (131)I-Lym-1 given 4 weeks apart. Nonhematologic toxicities did not exceed grade 2 except for one instance of grade 3 hypotension. Ten (71 %) of 14 entries who received at least two doses of (131)I-Lym-1 therapy and 11 (52%) of 21 total entries responded. Seven of the responses were complete, with a mean duration of 14 months. All three entries in the 100 mCi/m2 (3.7 MBq/m2) cohort had complete remissions (CRs). All responders had at least a partial remission (PR) after the first therapy dose of (131)I-Lym-1. CONCLUSION (131)I-Lym-1 induced durable remissions in patients with NHL resistant to chemotherapy and was associated with acceptable toxicity. The nonmyeloablative MTD for each of the first two doses of (131)I-Lym-1 was 100 mCi/m2 (total, 200 mCi/m2) (3.7 GBq/m2; total, 7.4 GBq/m2).

Phase I study of spirogermanium given daily.

1983 ◽  
Vol 1 (5) ◽  
pp. 331-336 ◽  
Author(s):  
S S Legha ◽  
J A Ajani ◽  
G P Bodey
Keyword(s):  
Continuous Infusion ◽  
Tumor Regression ◽  
Dose Range ◽  
Maximum Tolerated Dose ◽  
Optimum Dose ◽  
Second Phase ◽  
Clinical Effects ◽  
Third Phase ◽  
Dose Levels ◽  
Dose Limiting Toxicity

Spirogermanium, an azaspirane compound, has recently had limited clinical trials using a schedule of intravenous injection one to three times every week. The observation of clinical antitumor activity and lack of myelosuppression prompted us to investigate further the clinical effects of spirogermanium administered on various schedules. A total of 52 patients with advanced metastatic tumors refractory to standard therapy were treated with spirogermanium. Three different schedules of drug administration were evaluated. Initially, a short daily IV infusion for 5 days every week was evaluated, starting with a dose of 30 mg/m2/day. A total of 22 patients received 69 courses with a dose range of 30-120 mg/m2/day for 5 days every week. The maximum tolerated dose was 100 mg/m2/day IV over 1 hr and 120 mg/m2 over 2-3 hr. In the second phase of the study, 12 patients received 41 courses of spirogermanium as a 24-hr continuous infusion for 5 days/wk at a dose of 150-375 mg/m2/day. The maximum tolerated dose was 200 mg/m2/day for 5 days. In the third phase of the study, 18 patients received spirogermanium as a continuous infusion daily for a median of 30 days (range 6-77 days) in a dose range of 100-200 mg/m2/day. The maximum tolerated dose was 150 mg/m2/day. Of the 44 assessable patients, 3 demonstrated a partial response and 3 had minor tumor regression; all responses occurred in lymphoma patients. The dose-limiting toxicity of spirogermanium was neurologic; other side effects consisted of mild anorexia, nausea and vomiting, and possible lung toxicity. There was no clear evidence of cumulative toxicity despite daily administration of spirogermanium. Our data suggest that spirogermanium can be administered daily by several different schedules, and the optimum dose depends on the infusion time and the duration of therapy. The delivery of drug by continuous infusion permitted administration of twofold higher dose levels compared to the standard IV schedules used in previous studies.

Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (9) ◽  
pp. 3037-3043 ◽  
Author(s):  
H S Nicholson ◽  
M Krailo ◽  
M M Ames ◽  
N L Seibel ◽  
J M Reid ◽  
...  
Keyword(s):  
Phase I ◽  
Children And Adolescents ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Cancer Group ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

PURPOSE The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). PATIENTS AND METHODS Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily. RESULTS Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. CONCLUSION The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.

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