Interim results of a phase I/IIa trial of a therapeutic CMV vaccine against recurrent glioblastoma (GBM).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2048-2048 ◽  
Author(s):  
Andrew B. Lassman ◽  
David A. Reardon ◽  
Eudocia Quant Lee ◽  
Fabio Massaiti Iwamoto ◽  
Francisco Diaz-Mitoma ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Phase I ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Vaccine Dose ◽  
High Dose ◽  
Vaccine Response ◽  
Dose Cohort ◽  
Recurrent Gbm

2048 Background: Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4+and CD8+T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. Methods: We have initiated a phase I/IIa clinical trial for patients with recurrent GBM using gB/pp65 enveloped virus-like particles (eVLPs) formulated with GM-CSF and administered intradermally. Subjects are vaccinated monthly until tumor progression, with immunomonitoring performed 2 weeks after each vaccination and MRI exams every 6 weeks. In phase I, eligible patients were age 18-70 with Karnofsky Performance Status at least 70, normal end-organ function, on stable or decreasing corticosteroids of at most 4mg dexamethasone (or equivalent), with recurrent GBM following any standard initial therapy and any number of recurrences. The primary endpoint was safety/tolerability and secondarily to assess immunogenicity. Three vaccine doses (0.4µg, 2µg, and 10µg pp65) were evaluated with 6 subjects in each cohort and DSMB safety review of the first 3 subjects in each cohort prior to enrolling additional subjects. Results: The DSMB identified no DLTs or safety concerns with any of the doses. Grade 2, 3 or 4 AEs occurred in 66%, 22% and 11% of participants, respectively, but were not related to vaccine administration. Twelve men and 6 women were enrolled with a median age 54 (range 39-66). Prior therapies included radiotherapy, temozolomide, and nivolumab. Immunological analyses demonstrate robust boosting of CMV-specific antibody titers and T cell responses against both gB and pp65 antigens in some but not all subjects, across all dose cohorts. Boosting of IFN-gsecreting T cells (measured by ELISPOT) exceeded the assay threshold for several subjects. Stable disease by MRI of 3 months or greater has been observed in 2 subjects in the high dose cohort and 1 subject in the low dose cohort and may correlate with vaccine response. Conclusions: The phase IIa extension phase of the trial planned to begin in Q2 2019 is designed to explore efficacy in an additional 10 subjects that will receive the optimal vaccine dose and includes the additional requirements of unifocal, measurable enhancing tumor 1-3 cm across at first recurrence and no prior immunotherapy. Clinical trial information: NCT03382977.

Results of a phase I/II clinical trial of BPX-101, a novel drug-activated dendritic cell (DC) vaccine for metastatic castration-resistant prostate cancer (mCRPC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 132-132 ◽  
Author(s):  
G. Sonpavde ◽  
J. D. McMannis ◽  
Y. Bai ◽  
M. Seethammagari ◽  
J. M. Bull ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Lung Metastases ◽  
Maintenance Phase ◽  
High Dose ◽  
Induction Phase ◽  
Castration Resistant Prostate Cancer ◽  
Dose Cohort ◽  
Radiologic Evaluation ◽  
Dc Vaccine

132 Background: We report results of a phase I/II clinical trial of BPX-101, a drug- activated autologous DC vaccine targeting PSMA. Methods: Men with progressive mCRPC following up to one prior chemotherapy regimen were enrolled in a 3+3 dose escalation trial evaluating BPX-101 and CD40 activating agent AP1903. BPX-101 was administered intradermally every 2 weeks for 6 doses, during the induction phase, and for nonprogressing patients, every 8 weeks for up to 5 doses during the maintenance phase. AP1903 (0.4 mg/kg) was infused 24 hours after each BPX-101 dose. Radiologic evaluation was performed every 12 weeks. Results: Planned enrollment of 12 subjects has been completed, including 3 each at 4 × 106 and 12.5 × 106 cells/dose, and 6 at 25 × 106 cells/dose. All vaccine products were releasable. Median Halabi- predicted survival was 13.8 months. Two subjects went off protocol prior to the end of induction due to progression, 8 reached end of induction, and 2 are nearing completion of induction. Toxicities (e.g. injection site reactions) were generally mild. One high dose subject experienced a single acute cytokine reaction during infusion of AP1903 at the second vaccination, but continued induction without further drug-related adverse events. Notably, one post- docetaxel subject in the low dose cohort achieved a RECIST PR, and one chemo-naive subject in the mid-dose cohort with extensive visceral, nodal, and bone metastases experienced a RECIST CR with docetaxel-based chemotherapy after induction and maintains an undetectable ultrasensitive PSA (0.009 ng/mL) 10 months after enrollment. A third subject, in the high-dose cohort, experienced near complete elimination of multiple lung metastases with otherwise stable disease by the end of induction. Robust immune responses were seen in all three. Conclusions: BPX-101 can be reliably manufactured and safely administered, followed by AP1903, at doses of at least 25 × 106 cells. Contrary to the observation that cancer vaccine therapy improves survival without short-term response, BPX-101-treated patients have experienced measurable disease responses, including near elimination of poor-risk visceral disease. [Table: see text]

scholarly journals Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma

2013 ◽  
Vol 118 (6) ◽  
pp. 1202-1219 ◽  
Author(s):  
Andrew E. Sloan ◽  
Manmeet S. Ahluwalia ◽  
Jose Valerio-Pascua ◽  
Sunil Manjila ◽  
Mark G. Torchia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Dose Escalation ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Recurrent Glioblastoma ◽  
Thermal Therapy ◽  
Laser Interstitial Thermal Therapy ◽  
Karnofsky Performance Status Score ◽  
Performance Status Score

Object Laser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose–escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM). Methods Adults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, side-firing laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation. Results Ten patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals–Case Medical Center). Their average age was 55 years (range 34–69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70–90). The mean tumor volume was 6.8 ± 5 cm3 (range 2.6–19 cm3), the percentage of tumor treated was 78% ± 12% (range 57%–90%), and the conformality index was 1.21 ± 0.33 (range 1.00–2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62–767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose. Conclusions NeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. Clinical trial registration no.: NCT00747253 (ClinicalTrials.gov).

scholarly journals Regulatory T cells for minimising immune suppression in kidney transplantation: phase I/IIa clinical trial

BMJ ◽  
2020 ◽  
pp. m3734
Author(s):  
Andy Roemhild ◽  
Natalie Maureen Otto ◽  
Guido Moll ◽  
Mohamed Abou-El-Enein ◽  
Daniel Kaiser ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Kidney Transplantation ◽  
Regulatory T Cells ◽  
Adverse Effects ◽  
Phase I ◽  
Kidney Transplant ◽  
Dose Escalation ◽  
Reference Group ◽  
High Dose

AbstractObjectiveTo assess whether reshaping of the immune balance by infusion of autologous natural regulatory T cells (nTregs) in patients after kidney transplantation is safe, feasible, and enables the tapering of lifelong high dose immunosuppression, with its limited efficacy, adverse effects, and high direct and indirect costs, along with addressing several key challenges of nTreg treatment, such as easy and robust manufacturing, danger of over immunosuppression, interaction with standard care drugs, and functional stability in an inflammatory environment in a useful proof-of-concept disease model.DesignInvestigator initiated, monocentre, nTreg dose escalation, phase I/IIa clinical trial (ONEnTreg13).SettingCharité-University Hospital, Berlin, Germany, within the ONE study consortium (funded by the European Union).ParticipantsRecipients of living donor kidney transplant (ONEnTreg13, n=11) and corresponding reference group trial (ONErgt11-CHA, n=9).InterventionsCD4+ CD25+ FoxP3+ nTreg products were given seven days after kidney transplantation as one intravenous dose of 0.5, 1.0, or 2.5-3.0×106 cells/kg body weight, with subsequent stepwise tapering of triple immunosuppression to low dose tacrolimus monotherapy until week 48.Main outcome measuresThe primary clinical and safety endpoints were assessed by a composite endpoint at week 60 with further three year follow-up. The assessment included incidence of biopsy confirmed acute rejection, assessment of nTreg infusion related adverse effects, and signs of over immunosuppression. Secondary endpoints addressed allograft functions. Accompanying research included a comprehensive exploratory biomarker portfolio.ResultsFor all patients, nTreg products with sufficient yield, purity, and functionality could be generated from 40-50 mL of peripheral blood taken two weeks before kidney transplantation. None of the three nTreg dose escalation groups had dose limiting toxicity. The nTreg and reference groups had 100% three year allograft survival and similar clinical and safety profiles. Stable monotherapy immunosuppression was achieved in eight of 11 (73%) patients receiving nTregs, while the reference group remained on standard dual or triple drug immunosuppression (P=0.002). Mechanistically, the activation of conventional T cells was reduced and nTregs shifted in vivo from a polyclonal to an oligoclonal T cell receptor repertoire.ConclusionsThe application of autologous nTregs was safe and feasible even in patients who had a kidney transplant and were immunosuppressed. These results warrant further evaluation of Treg efficacy and serve as the basis for the development of next generation nTreg approaches in transplantation and any immunopathologies.Trial registrationNCT02371434 (ONEnTreg13) and EudraCT:2011-004301-24 (ONErgt11).

scholarly journals ATIM-26. INTERIM RESULTS OF THE EXTENSION PHASE OF A PHASE I/IIA TRIAL OF A THERAPEUTIC CMV VACCINE AGAINST RECURRENT GLIOBLASTOMA (GBM)

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi7-vi7
Author(s):  
Patrick Wen ◽  
David Reardon ◽  
Eudocia Lee ◽  
Fabio Iwamoto ◽  
David Anderson ◽  
...  
Keyword(s):  
Phase I ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Initial Therapy ◽  
Immune Monitoring ◽  
Recurrent Glioblastoma ◽  
Extension Phase ◽  
Gm Csf ◽  
Enveloped Virus ◽  
Recurrent Gbm

Abstract Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4+and CD8+T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. We have initiated a phase I/IIa clinical trial for patients with recurrent GBM using gB/pp65 enveloped virus-like particles (eVLPs) formulated with GM-CSF and administered intradermally. In phase I, eligible patients were age 18–70 with Karnofsky Performance Status at least 70, normal end-organ function, on stable or decreasing corticosteroids of at most 4mg dexamethasone (or equivalent), with recurrent GBM following any standard initial therapy and any number of recurrences of any size. Patients were vaccinated monthly until tumor progression, with immune-monitoring performed 2 weeks after each vaccination and MRI exams every 6 weeks. The primary endpoint was safety/tolerability and secondarily to assess immunogenicity. Three vaccine doses (0.4µg, 2µg, and 10µg pp65) were evaluated with 6 patients in each cohort, and the DSMB identified no DLTs or safety concerns with any of the doses. The highest 10µg dose was chosen for the Phase IIa extension phase of the trial based on stable disease (3 months or longer) observed in 3/6 patients, which correlated with vaccine-induced IFN-γ-secreting T cell responses against CMV. Enrollment in phase IIa of the trial, which is designed to explore initial potential efficacy signals in an additional 10 patients that receive the optimal 10µg dose of vaccine, is expected in June 2019 and includes the additional requirements of unifocal, measurable enhancing tumor 1–3 cm across at first recurrence and no prior immunotherapy. Patients will be vaccinated monthly until clinical progression. Tumor responses and associated immunological biomarkers will be presented, and are expected to include initial data for all 10 patients.

scholarly journals Trans sodium crocetinate with temozolomide and radiation therapy for glioblastoma multiforme

2017 ◽  
Vol 126 (2) ◽  
pp. 460-466 ◽  
Author(s):  
John L. Gainer ◽  
Jason P. Sheehan ◽  
James M. Larner ◽  
David R. Jones
Keyword(s):  
Quality Of Life ◽  
Clinical Trial ◽  
Radiation Therapy ◽  
Glioblastoma Multiforme ◽  
Phase I ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Serious Adverse Events

OBJECTIVE A new drug, trans sodium crocetinate (TSC), has been developed to enhance the delivery of oxygen to hypoxic tissues. Cancerous tumors, such as glioblastoma multiforme (GBM), are very hypoxic, and it has been suggested that radiation therapy (RT) is more beneficial if tumors are better oxygenated. A Phase I/II clinical trial was conducted to determine the effect of adding TSC to RT sessions. METHODS An open, single-arm clinical trial incorporating the standard of care (SOC) for GBM was conducted at 18 clinical sites. There were 6 weeks of RT consisting of 2 Gy/day for 5 days/week, beginning after an initial resection or stereotactic biopsy to confirm GBM. Temozolomide (TMZ), 75 mg/m2, was given before each RT session. The TSC, 0.25 mg/kg, was intravenously administered around 45 minutes before an RT session 3 days/week, usually on Monday, Wednesday, and Friday. A Phase I run-in period included 2 cohorts. The first cohort contained 3 patients who were given a half dose of the intravenous TSC (that is, 0.25 mg/kg, 3 times per week for only the first 3 weeks of RT). After a Safety Monitoring Committee (SMC) had verified that no dose-limiting toxicity (DLT) had occurred, a second cohort of 6 patients was given the same dosage of TSC but for the full 6 weeks of RT. After the SMC verified that no DLTs had occurred, Phase II began, with the administration of the full 18 doses of TSC. Fifty additional patients were enrolled during Phase II. Following the completion of RT, the patients rested for a month. After that, SOC TMZ chemotherapy (150–200 mg/m2) was administered for 5 days of the 1st week of 6 monthly cycles. No TSC was administered during this chemotherapy phase or later in the trial. Any other follow-up therapies were administered at the discretion of the individual investigators. RESULTS Kaplan-Meier analysis showed that 36% of the full-dose TSC patients were alive at 2 years, compared with historical survival values ranging from 27% to 30% for the SOC. Survival for the biopsy-only subset of patients was 40%, as compared with 42.9% for those patients having a complete resection before treatment. In addition, 2 of the 3 Phase I, Cohort 1 patients survived at 2 years. Contrast MRI data suggested that considerable pseudoprogression had occurred. Both Karnofsky Performance Status (KPS) scores and quality of life (QOL) questionnaires indicated that a good quality of life existed for most patients throughout the trial. No serious adverse events occurring in the trial were attributed to TSC. CONCLUSIONS This trial contained a single arm consisting of 59 patients. The results strongly suggested that adding TSC during RT is beneficial for the treatment of GBM. Trans sodium crocetinate offers a novel, easily implemented way to combat hypoxia in tumor tissue. Clinical trial registration no.: NCT01465347 (clinicaltrials.gov)

Clinical scale facs-sorting and expansion of regulatory t cells (TREGS) for phase i clinical trial

Cytotherapy ◽  
2021 ◽  
Vol 23 (5) ◽  
pp. S196
Author(s):  
A. Ekwe ◽  
R. Au ◽  
B. McEnroe ◽  
M. Tan ◽  
A. Saldan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Regulatory T Cells ◽  
Phase I ◽  
Phase I Clinical Trial ◽  
Clinical Scale ◽  
Facs Sorting

Safety and efficacy outcomes with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma and low Karnofsky performance status: Results from the CheckMate 920 trial.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 315-315
Author(s):  
Thomas E. Hutson ◽  
Bradley Curtis Carthon ◽  
Jeffrey Yorio ◽  
Sunil Babu ◽  
Heidi Ann McKean ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Clear Cell ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Objective Response ◽  
Safety And Efficacy ◽  
Grade 3

315 Background: Combination therapy with nivolumab + ipilimumab (NIVO+IPI) has demonstrated long-term efficacy and tolerability for patients (pts) with previously untreated advanced renal cell carcinoma (aRCC). Most pivotal clinical trials in pts with aRCC have excluded pts with low Karnofsky performance status (KPS; < 70%). CheckMate 920 is a multi-arm, phase IIIb/IV, open-label clinical trial of NIVO+IPI treatment in pts enrolled in a community practice setting with aRCC and a high unmet medical need. We present safety and efficacy results for the cohort of pts with aRCC of any histology and KPS 50%–60% from CheckMate 920 (NCT02982954). Methods: Pts with previously untreated advanced/metastatic RCC and KPS 50%–60% received NIVO 3 mg/kg + IPI 1 mg/kg Q3W × 4 doses followed by 480 mg NIVO Q4W for ≤ 2 years or until disease progression/unacceptable toxicity. The primary endpoint was incidence of grade ≥ 3 immune-mediated adverse events (imAEs) within 100 days of last dose of study drug. Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 (both per investigator). Exploratory endpoints included overall survival (OS). Results: Of 25 treated pts with KPS 50%–60%, 76% were men; median age was 67 years (range, 34–81). IMDC risk was favorable in 0%, intermediate in 32%, and poor in 68% of pts; 84% had clear cell and 16% had non-clear cell RCC histology. With a minimum follow-up of 25 months, median duration of therapy (95% CI) was 2.3 months (2.1–7.7) for NIVO and 2.1 months (2.1–2.1) for IPI. The median number of doses (range) received was 4 (1–27) for NIVO and 4 (1–4) for IPI; 76% of pts received ≥ 4 NIVO doses and 68% received all 4 IPI doses. The only grade 3–4 imAEs by category were hepatitis (4.0%) and adrenal insufficiency (4.0%). No grade 5 imAEs occurred. Overall, 4 (16%) pts discontinued due to any-grade adverse events (n = 1 each for elevated AST, malignant neoplasm progression, back pain, and acetabulum fracture). Of 18 evaluable pts, ORR was 33.3% (95% CI, 13.3–59.0); no pts had a complete response and 6 had partial response. Median time to objective response was 4.5 months (range, 2.5–24.7). Median duration of objective response was 20.6 months (range, 0.03+–24.2+). Median PFS was 4.6 months (95% CI, 2.5–14.8). Median OS was 15.6 months (95% CI, 5.3–25.1). Conclusions: NIVO+IPI demonstrated an acceptable safety profile and promising antitumor activity in pts with previously untreated aRCC and KPS 50%–60%. The combination was tolerated at a dose intensity similar to that observed in clinical trials conducted in pts with higher KPS (≥ 70%). These data support the value of NIVO+IPI in pts who may not be considered ideal candidates for this therapy and consequently may have limited treatment options. Clinical trial information: NCT02982954 .

scholarly journals Provider Recommendations for Phase I Clinical Trials Within a Shared Decision-Making Model in Phase I Cancer Clinical Trial Discussions

2020 ◽  
Vol 16 (9) ◽  
pp. e859-e867
Author(s):  
Rachel S. Hianik ◽  
Gavin P. Campbell ◽  
Eli Abernethy ◽  
Colleen Lewis ◽  
Christina S. Wu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Decision Making ◽  
Clinical Trials ◽  
Phase I ◽  
Shared Decision Making ◽  
Phase I Trial ◽  
Performance Status ◽  
Shared Decision ◽  
Phase I Clinical Trials ◽  
Decision Making Model

PURPOSE: Debate continues over whether explicit recommendations for a clinical trial should be included as an element of shared decision making within oncology. We aimed to determine if and how providers make explicit recommendations in the setting of phase I cancer clinical trials. METHODS: Twenty-three patient/provider conversations about phase I trials were analyzed to determine how recommendations are made and how the conversations align with a shared decision-making framework. In addition, 19 providers (9 of whose patient encounters were observed) were interviewed about the factors they consider when deciding whether to recommend a phase I trial. RESULTS: We found that providers are comprehensive in the factors they consider when recommending clinical trials. The two most frequently stated factors were performance status (89%) and patient preferences (84%). Providers made explicit recommendations in 19 conversations (83%), with 12 of those being for a phase I trial (12 [63%] of 19). They made these recommendations in a manner consistent with a shared decision-making model; 18 (95%) of the 19 conversations during which a recommendation was made included all steps, or all but 1 step, of shared decision making, as did 11 of the 12 conversations during which a phase I trial was recommended. In 7 (58%) of these later conversations, providers also emphasized the importance of the patient’s opinion. CONCLUSION: We suggest that providers not hesitate to make explicit recommendations for phase I clinical trials, because they are able to do so in a manner consistent with shared decision making. With further research, these results can be applied to other clinical trial settings.

Phase I study of repeated cycles of high-dose cyclophosphamide, etoposide, and cisplatin administered without bone marrow transplantation.

1990 ◽  
Vol 8 (10) ◽  
pp. 1728-1738 ◽  
Author(s):  
J A Neidhart ◽  
W Kohler ◽  
C Stidley ◽  
A Mangalik ◽  
A Plauche ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Performance Status ◽  
Complete Response ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Tumor Type ◽  
Advanced Malignancy ◽  
Prior Therapy ◽  
And Performance

Forty-two patients with advanced malignancy judged unlikely to respond to standard treatment received high-dose combination chemotherapy with cyclophosphamide, etoposide, and cisplatin in a phase I trial. Twenty-two of these patients who had at least a partial response (PR) to the first cycle of therapy received a second cycle, and eight patients received three or more cycles of therapy. Bone marrow replacement was not used. The maximum-tolerated doses (MTDs) were cyclophosphamide 2.5 g/m2 on days 1 and 2; etoposide 500 mg/m2 on days 1, 2, and 3; and cisplatin 50 mg/m2 on days 1, 2, and 3. Hematologic toxicity was not dose-limiting by study design. Recovery to an absolute granulocyte count above 100/microL occurred at a median of 9 days from onset (range, 3 to 23 days) at the MTD. Recovery was delayed after the third cycle. Only one patient on his third cycle failed to recover peripheral blood counts and died of sepsis an day 43. Hematologic toxicity was not dose-dependent. Nonhematologic toxicities included emesis, fatigue, alopecia, diarrhea, and anorexia and were generally well tolerated. The dose-limiting toxicities were fatal pulmonary or cardiac toxicities in five of nine patients treated at the highest dose level. Patients likely to do well can be selected by tumor type, response to prior therapy, and performance status. Nine of 36 assessable patients had a complete response (CR) and 13 a PR for a response rate of 61%. Five patients (12%) remain alive and free of disease at 15 to 32 months. Repeated cycles of dose-intensive combination therapy can produce long-term disease-free remissions in patients with refractory tumor types. The toxicity of the regimen is acceptable if patients are carefully selected.

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