A phase I study of GTI-2040 (G), an antisense to ribonucleotide reductase (RNR), in combination with high-dose AraC (HiDAC) in acute myeloid leukemia (AML)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6561-6561
Author(s):  
G. Marcucci ◽  
R. B. Klisovic ◽  
W. Wei ◽  
S. Liu ◽  
P. Paschka ◽  
...  
Keyword(s):  
Phase I ◽  
Ribonucleotide Reductase ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Phase Ii Trials ◽  
Refractory Aml ◽  
Dna Incorporation ◽  
Count Recovery

6561 Background: RNR converts ribonucleotides to deoxyribonucleotides for DNA synthesis. AraC is converted into AraC triphosphate (AraCTP) and competes with deoxycytidine for DNA incorporation. We hypothesized that RNR downregulation by G leads to lower deoxycytidine levels, preferential AraCTP incorporation into DNA and increased cytotoxicity. A CTEP-sponsored Phase I dose escalation study of G +HiDAC in relapsed/refractory AML tested this hypothesis. Methods: Cohort I (18–59 yrs) received G (dose level (DL) 1: 3.5 mg/m2/d) by continuous IV infusion (CIVI) on d 1–6 + AraC IV q12 hrs on d 2, 4, 6 (DL1: 2500 mg/m2/dose). Cohort II (≥60 yrs) received G CIVI on d 1–6 +AraC IV on d 2 −6 (DL1: 1500 mg/m2/d). An ELISA-based assay measured plasma and intracellular concentration (IC) of G. Results: To date, cohort I included 9 pts with relapsed and 9 with refractory AML; 9 had intermediate and 9 adverse risk cytogenetics (CyG); 8 received prior HiDAC. Cohort II included 10 pts with relapsed and 6 with refractory AML; 8 pts had intermediate and 8 high risk CyG; 5 pts received prior HiDAC. Toxicities were comparable to HiDAC alone. The younger pts had higher AUC and longer t1/2. Of 16 pts evaluable in cohort I (median time to 1st relapse 6 mos), 6 had complete remission (CR) and 1 incomplete CR (no disease and incomplete blood count recovery). In cohort II, no responses were observed. At 120 hrs of antisense infusion, median G IC in marrow cells was higher (i.e., 175 vs75 nM) in younger than in older pts. A median 50% decrease in RNR protein was noted in 5/9 and 5/10 pts in cohort I and II, respectively. In cohort I, a median 50% decrease and 200% increase in RNR was noted in CR (n=4) and non-responder (NR; n=9) pts, respectively. In cohort II R2 downregulation did not predict response. In cohort I 62% of the ICs was in nucleus and 21.2% in cytoplasm in CR pts (n=3) vs. 20.3% and 53.5% in NR pts(n=5). Conclusions: G/HiDAC is feasible. Robust plasma and IC levels of G and target downregulation are achievable in vivo. Responses (41%) were observed only in the younger cohort, where CR pts had higher G nuclear IC and target downregulation than NR pts. Dose escalation continues in the younger cohort to establish a dose for Phase II trials. No significant financial relationships to disclose.

Phase I Study of Non-Engrafting Allogeneic, Mismatched, Unmanipulated Peripheral Blood Mononuclear Cell Infusions to Treat Poor-Prognosis Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2562-2562
Author(s):  
Elizabeth F Krakow ◽  
Julie Bergeron ◽  
Silvy Lachance ◽  
Denis-Claude Roy ◽  
Jean-Sebastien Delisle
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Therapy ◽  
Dose Escalation ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
High Dose ◽  
Infusion Reactions ◽  
Acute Myeloid ◽  
Refractory Aml

BACKGROUND: Non-engrafting or microchimeric allogeneic immunotherapies might dramatically benefit patients with acute myeloid leukemia (AML). Mismatched G-CSF-mobilized peripheral blood (PB) and NK cells administered after chemotherapy increase complete remission (CR) and overall survival rates in poor-prognosis AML, without significant risk of graft-versus-host disease (GVHD). For example, as first-line therapy in elderly patients, the G-CSF-mobilized approach increased disease-free survival from 10% to 39% in a randomized trial (Guo et al, Blood 2011). By contrast, this trial addresses the safety of unprimed, unselected HLA-mismatched cell therapy in chemorefractory or relapsed AML, to avoid exposing donors to G-CSF and further minimize the risk of GVHD. Secondary objectives include describing the incidence of CR, GVHD, prolonged aplasia, and infusion reactions. METHODS/PATIENTS: Seven patients (median 63, range 57-68 years) with primary refractory AML (n = 1) or 1st (n = 4) or 2nd (n = 2) marrow relapse at a median of 2.9 (range, 1.6-8.0) months after completing consolidation were enrolled on this ongoing dose-escalation trial (NCT 1793025). Four had intermediate-risk caryotypes or FLT3 -ITD, 3 high-risk - including 2 with extremely complex and monosomal caryotypes and deleted or mutated TP53. One had therapy-related AML, 1 likely evolved from MDS, while 1 relapsed with bilineage leukemia (myeloid + T cell). Participants were ineligible for allotransplant due to comorbidities or adverse AML genetics. They had 14%-92% marrow blasts before re-induction, with either NoVE (n = 5), high-dose ara-C/VP16 (n = 1), or high-dose ara-C/mitoxantrone (n = 1). Donors were mismatched to recipients in varying degrees (n = 3 haploidentical and 4 with 0-3/10 allele-level matches). Target CD3+ cell dose was 1 x 107/kg for the 1st 4 patients and 5 x 107/kg for the next 3. Unmanipulated PB mononuclear cells were infused 24-48 hours after the last dose of re-induction chemotherapy (''day 0''). Marrow was evaluated on day 14 and upon hematopoietic recovery. RESULTS: SAFETY: Two patients experienced neutropenic fever from several hours to 5 days after cell infusion, but we observed no definite acute or delayed infusion reactions and no GVHD. One patient with cirrhosis developed septic shock with liver/renal failure prior to the infusion and declined dialysis; his long-term endpoints could not be assessed but he tolerated the infusion well. Sustained platelets > 100 × 109/L and neutrophils > 1 × 109/L occurred at +16-31 days and +14-39 days respectively in patients who achieved CR. RESPONSES: One patient achieved near morphologic CR (≤6% marrow blasts, normal PB) at day +29 and was consolidated with an HLA-identical sibling transplant at day +49; she remains in CR 28 months later. Two achieved CR lasting 77 and 164 days in the absence of further therapy. Three had persistent AML. BIOLOGY:Products contained mainly T cells (72%-80%) with varying proportions of NK (9%-17%), NK/T (0.6%-6%), B (7%-14%), and CD14+ (10%-17%) cells. Two broad patterns of total lymphocyte counts were observed: dramatic bursts from ≤ 0.2 to ≥ 1.0 (up to 1.4) × 109/L peaking days 5-8 post infusion, vs. stability/gradual recovery; numbers are too small to draw conclusions about any association with CR (p = 0.4 Fisher exact test). Lymphocyte bursts were not seen in 45 historical controls treated with chemotherapy alone (p = 0.02 for association with cell therapy). No patient-donor pairs were predicted to exhibit NK alloreactivity mediated by C1 or C2 KIR-ligand mismatching, and only 1 pair each had predicted Bw4-mediated donor-vs-recipient and recipient-vs-donor reactivity, respectively. When tested, marrow macrochimerism was undetected (n = 2). CONCLUSIONS: The incidence of life-threatening infections and duration of aplasia in the heavily-pretreated patients observed thus far do not exceed that expected with chemotherapy alone. Cell infusion is well-tolerated. The 42% (95% CI, 25%-84%) CR rate warrants continued dose escalation per protocol, especially because (1) we administer only 1 infusion and (2) our patients are treated with relapsed/refractory AML baring extremely poor prognostic features. Our results suggest that rejection of donor cells protects against engraftment and GVHD, and might sometimes be associated with a lymphocyte burst. Biologic correlations to identify ways to optimize anti-leukemic effects will be performed. Disclosures No relevant conflicts of interest to declare.

Epigenetic Targeting Via Transcriptional Inhibition of DNA Methyltransferase: a Phase I Study of Bortezomib in Combination with 5-Azacytidine in Adults with Relapsed or Refractory Acute Myeloid Leukemia (AML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2065-2065
Author(s):  
William Blum ◽  
Rebecca B. Klisovic ◽  
Alison Walker ◽  
Ramiro Garzon ◽  
Shujun Liu ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Phase I ◽  
Dose Escalation ◽  
Dna Methyltransferase ◽  
Single Agent ◽  
Objective Response ◽  
Epigenetic Mechanism ◽  
Dna Hypomethylation ◽  
Refractory Aml ◽  
Count Recovery

Abstract Abstract 2065 Poster Board II-42 Background: Hypomethylating agents have significant clinical activity in myelodysplastic syndromes (MDS) and AML. In AML, we recently demonstrated a novel epigenetic mechanism of action for the proteasome inhibitor bortezomib (Liu, Blood 2008). Bortezomib induced hypomethylation of leukemic cells in vitro and in vivo via depletion of the Sp1/NF-kB transcriptional activation complex on the DNA methyltransferase 1 (DNMT1) gene promoter, which results in down-regulation of DNMT1 mRNA and enzyme, DNA hypomethylation and re-expression of otherwise hypermethylated target genes. Based on this preclinical work, we designed a phase I dose escalation study of 5-azacytidine (AZA) in combination with bortezomib in AML. Methods: Adults with relapsed or refractory AML by WHO criteria and preserved organ function with ECOG ≤2 were eligible. Previous decitabine or AZA was permitted. Patients received AZA at 75mg/m2 IV daily for days (d) 1-7. Bortezomib was gradually dose escalated–dose level 1 (DL 1): 0.7mg/m2 by IV push given immediately after AZA on d 2 and 5; DL 2: 0.7mg/m2 on d 2, 5, 9, and 12; DL 3: 1.0mg/m2 on d 2, 5, 9, and 12; and DL 4: 1.3mg/m2 on d 2, 5, 9, and 12. Cycles were repeated every 28 d, regardless of count recovery or response at least until 3 cycles were administered. Responses were graded by International Working Group criteria for AML (Cheson, JCO 2003). Bortezomib was discontinued after 3 cycles if no objective response of complete remission (CR), CR with incomplete count recovery (CRi), or partial remission (PR) was achieved, but AZA could be continued beyond this timepoint in the absence of disease progression. For responding patients, 12 or more cycles of therapy were permitted. Dose limiting toxicities (DLT) were assigned for cycle 1 of therapy. Given the high likelihood of infection in this population regardless of therapy, infection was not considered a DLT. Six additional patients were treated at the recommended phase 2 dose (RP2D). Results: 23 patients were enrolled with a median age of 65 years (range, 42-81) and had received a median of 2 prior inductions (range, 1-5). Median presenting WBC was 3,700/uL (500-59,100/uL); median BM blast was 26% (2-93%). 14 patients were refractory to last therapy received, including 4 with primary refractory AML. 9 patients had relapsed disease; all but 2 of these had prior CR duration <1 year. Patients received a median of 2 cycles of study therapy (range, 1-12+ cycles). Dose escalation was halted once the target bortezomib dose was reached; the RP2D was AZA at 75mg/m2 d 1-7 plus bortezomib 1.3mg/m2 d, 2, 5, 9, 12. Though no toxicities were considered to be DLT in this study, infection and/or febrile neutropenia were universal. Death within 8 weeks occurred in 5 patients (22%) due to pneumonia (1), sepsis (1), or progressive disease (3). Two patients had discontinuation of bortezomib after 2 cycles due to Grade 3 neuropathy; only 1 patient received bortezomib beyond 3 cycles. In 3 patients without objective response (and with no progression), AZA alone was continued after 3 cycles of combination therapy; each reported a subjective improvement in fatigue without bortezomib. Overall, the objective response rate was 26% (6/23). Responses were as follows: 3- CR, 2- CRi, and 1-PR. One CRi patient (in cytogenetic remission also) who discontinued study treatment after 2 cycles due to unrelated trauma subsequently had complete count recovery, but a repeat marrow examination was not performed. Three patients went on to allogeneic transplantation due to response achieved. Response followed the typical pattern of azanucleoside activity, requiring more than one cycle of therapy; the median number of cycles to initial response was 2 (range, 1-5). 5/6 responders had response to combination therapy; one patient responded following 5 cycles of treatment, the last 2 cycles with AZA as a single agent. Conclusions: The combination of 5-azacytidine and bortezomib is well tolerated and active in this cohort of relapsed or refractory AML patients. Additional studies to further elucidate the role of proteasome inhibition as a mediator of hypomethylating activity in AML are warranted. Correlatives studies are ongoing. Disclosures: Blum: Celgene: Research Funding.

scholarly journals Venetoclax in Combination with High-Dose Chemotherapy Is Active and Well-Tolerated in Children with Relapsed or Refractory Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 178-178
Author(s):  
Seth E Karol ◽  
Thomas Alexander ◽  
Amit Budraja ◽  
Stanley Pounds ◽  
Kristin E Canavera ◽  
...  
Keyword(s):  
Stock Options ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Complete Response ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Children And Young Adults ◽  
Acute Myeloid ◽  
Refractory Aml ◽  
Count Recovery

Introduction: Venetoclax (VEN) is a potent and selective inhibitor of BCL-2. It has demonstrated activity in adults with acute myeloid leukemia (AML) in combination with low-dose cytarabine (&lt;100mg/m2/day) and hypomethylating agents. Here, we report safety and activity of VEN in combination with intermediate- and high-dose cytarabine with or without idarubicin in children and young adults with relapsed or refractory AML. Methods: VEN was given daily for 28 days and chemotherapy was started on day 8, or earlier in cases of disease progression. Dosages of VEN and chemotherapy were escalated separately using a rolling-six design. Response to the VEN window was determined using total peripheral blood blast count or, in a subset of patients, bone marrow blast percentage as determined by flow-cytometry based minimal residual disease (MRD). Pharmacokinetics of VEN both as a single agent and in combination with chemotherapy were measured in a subset of patients treated at the maximum tolerated combination dose of VEN. Response to therapy was determined using bone marrow evaluation between days 29-50 of therapy. All patients received antimicrobial prophylaxis, typically with levofloxacin and micafungin. Azoles were prohibited during VEN administration. Results: Thirty-six patients aged 2-22 years were enrolled. All dose levels were tolerated. The recommended phase 2 dose of VEN in combination with high-dose cytarabine with or without idarubicin was 360 mg/m2 daily (max 600mg). One patient (treated with 240mg/m2 of VEN and intermediate-dose cytarabine) experienced a dose-limiting toxicity due to delayed count recovery and one patient died of recurrent colitis (at dose level 3) which first occurred during prior therapy and was deemed unrelated to VEN. Patients experienced a mean of 2.4 non-hematologic grade 3+ toxicities, with infections including culture-negative febrile neutropenia, sepsis, and colitis the most common toxicities. Patient-reported quality of life was similar at study entry and at the completion of cycle 1 and was within normal limits in most patients. Among 22 patients receiving VEN with high-dose cytarabine ± idarubicin, 14 (64%) achieved a complete response (CR) or complete response with incomplete count recovery (CRi). Response to the VEN window was associated with end of cycle 1 response; 13/15 (87%) patients with a greater than 80% reduction in peripheral blasts achieved a partial response (PR; 3) or CR/CRi (10). In contrast, only 8/15 (53%) patients with less than an 80% reduction in blasts responded to combination therapy (7 CR, 1 PR). Window response to VEN was associated with BH3 dependence as determined by cytochrome c release from leukemia cells in a flow-cytometry based assay. 5 of the 6 (83%) patients with primary BCL-2 dependence had a &gt;80% reduction in blasts; the single patient with a poor response had a change to BCL-XL dependence at the end of cycle 1. In contrast, 4 of the 6 (66%) patients with primary BCL-XL dependence had a &lt;80% reduction in blasts; the 2 patients with a &gt;90% reduction had secondary BCL-2 dependence. None of the 4 patients with FLT3-ITD or point mutations responded as determined by end of cycle 1 marrow. VEN levels were consistent across weights and ages and similar to levels seen in adults. The levels were similar between patients who did and did not receive idarubicin (mean AUC24 38.3 ± 32.7 vs. 47.3 ± 22.9 μg•h/mL). Conclusion: VEN combined with high-dose cytarabine or high-dose cytarabine and idarubicin was well tolerated and effective in children and young adults with relapsed or refractory AML. Enrollment continues to refine estimates of response rate. VEN window response is associated with BH3 dependence and end of cycle 1 response rates. Targeting BCL-XL or FLT3 may improve response to combination therapy. Table Disclosures Karol: Abbvie: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study.. Alexander:AbbVie: Other: travel funding. Salem:AbbVie: Employment, Other: Stock/stock options. Palenski:Abbvie: Employment, Other: Stock/ stock options. Opferman:AbbVie: Research Funding. Rubnitz:AbbVie: Research Funding.

A Phase I Study of GTI-2040, an Antisense to Ribonucleotide Reductase (RNR) in Combination with High-Dose Cytarabine (HiDAC) in Relapsed or Refractory Acute Myeloid Leukemia (AML): Pharmacokinetics (PK), Pharmacodynamic (PD) and Clinical Results.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2790-2790 ◽  
Author(s):  
Rebecca B. Klisovic ◽  
W. Blum ◽  
X. Wei ◽  
S. Liu ◽  
C. Kefauver ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
Intermediate Risk ◽  
Refractory Disease ◽  
Phase Ii Trials ◽  
Disease Response ◽  
Level 1 ◽  
Grade 3 ◽  
Dna Incorporation

Abstract GTI-2040 is a 20-mer antisense to the R2 component of RNR mRNA. RNR is required for the conversion of ribonucleotides to deoxyribonucleotides, a crucial step during DNA synthesis and repair. Cytarabine (AraC) is a cytotoxic agent that is converted into AraC triphosphate (Ara-CTP) and is the backbone of several regimens in AML. Ara-CTP competes with deoxycytidine for DNA incorporation. We hypothesize that RNR downregulation by GTI-2040 results in decrease of levels of deoxycytidine thereby leading to a preferential DNA incorporation of ARA-CTP and increase in its cytotoxic activity. To test this hypothesis we undertook a CTEP-sponsored Phase I dose-escalation study of GTI-2040 plus HiDAC in patients (pts) with relapsed or refractory AML. Pts were stratified in 2 cohorts according to age. Cohort I (18–59 yrs) received escalating doses of GTI-2040 (dose level 1: 3.5 mg/m2/d) by continuous IV infusion (CIVI) on d 1–6 combined with escalating doses of cytarabine IV over 2 hrs q12 hrs on d 2, 4, and 6 (dose level 1: 2500 mg/m2/dose). Cohort II (≥60 yrs) received GTI CIVI on d 1–6 and cytarabine IV over 4 hrs on d 2 to 6 (dose level 1: 1500 mg/m2/d). To date, 30 pts were enrolled. Pts received median of 1 prior regimen (range 1–3). Cohort I included 8 pts with relapsed and 6 with refractory disease; 7 had intermediate risk cytogenetics (CyG) and 7 adverse CyG; 6 received prior HiDAC. Cohort II included 10 pts with relapsed and 6 with refractory disease; 8 pts had intermediate risk CyG and 8 high risk CyG; 5 pts received prior HiDAC. Toxicities were comparable to HiDAC therapy alone. Grade 3/4 non-hematologic toxicities included fatigue, fevers, anorexia, pneumonitis, and catheter related infections; a grade 3 reversible cerebellar toxicity (n=1) was observed at level 1/cohort I. An ELISA-based assay with a limit of quantification of 50 pMol was used to determine GTI2040 plasma and intracellular (IC) concentrations. Dose-dependent increase in plasma steady state concentration (Css) and area under the curve (AUC) of GTI2040 was observed in both cohorts, although higher AUC and longer t1/2 were demonstrated in the younger pts compared to the older ones. In cohort I, disease responses were seen at all dose levels Five of 14 pts achieved complete remission (CR) and one achieve incomplete CR (CRi; i.e., no marrow disease and incomplete blood count recovery). In cohort II, no disease response was observed. Median IC GTI2040 concentration in BM mononuclear cells at 120 hours following start of antisense infusion was higher in younger (i.e., 175 nM) than in older (i.e., 75 nM) pts. A median decrease in R2 protein levels of 50% (range 50–90%) detected by immunoblotting was noted in 5/9 and 5/10 pts in cohort I and II, respectively. In cohort I CR pts (n=4) had a median 50% decrease and non-responders (n=9) had a median 200% increase in R2 levels. In cohort II changes in R2 levels did not predict disease response. In summary, combination of GTI-2040/HiDAC is feasible. PK/PD studies demonstrate achievable plasma and IC levels of the antisense and target downregulation. Disease response was observed only with the dose/schedule administered to younger pts. Dose escalation in this group continues to establish a recommended dose for Phase II trials. [NCI U01 CA 76576-05].

scholarly journals Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

2006 ◽  
Vol 24 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Andrew J. Vickers ◽  
Joyce Kuo ◽  
Barrie R. Cassileth
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Free Text ◽  
Phase Ii Trials ◽  
Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma.

1998 ◽  
Vol 16 (6) ◽  
pp. 2169-2180 ◽  
Author(s):  
A L Yu ◽  
M M Uttenreuther-Fischer ◽  
C S Huang ◽  
C C Tsui ◽  
S D Gillies ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Target Cells ◽  
Complement Dependent Cytotoxicity ◽  
Clinical Responses

PURPOSE To evaluate the toxicity, immunogenicity, and pharmacokinetics of a human-mouse chimeric monoclonal antibody (mAb) ch 14.18 directed against disialoganglioside (GD2) and to obtain preliminary information on its clinical efficacy, we conducted a phase I trial in 10 patients with refractory neuroblastoma and one patient with osteosarcoma. PATIENTS AND METHODS Eleven patients were entered onto this phase I trial. They received 20 courses of mAb ch 14.18 at dose levels of 10, 20, 50, 100, and 200 mg/m2. Dose escalation was performed in cohorts of three patients; intrapatient dose escalation was also permitted. RESULTS The most prevalent toxicities were pain, tachycardia, hypertension, fever, and urticaria. Most of these toxicities were dose-dependent and rarely noted at dosages of 20 mg/m2 and less. Although the maximum-tolerated dose was not reached in this study, clinical responses were observed. These included one partial (PR) and four mixed responses (MRs) and one stable disease (SD) among 10 assessable patients. Biologic activity of ch 14.18 in vivo was shown by binding of ch 14.18 to tumor cells and complement-dependent cytotoxicity of posttreatment sera against tumor target cells. An anti-ch 14.18 immune response was detectable in seven of 10 patients studied. CONCLUSION In summary, with the dose schedule used, ch 14.18 appears to be clinically safe and effective, and repeated mAb administration was not associated with increased toxicities. Further clinical trials of mAb ch 14.18 in patients with neuroblastoma are warranted.

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