A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors.

BACKGROUND: Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors. PATIENTS AND METHODS: Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response. CONCLUSIONS: The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.

PIK3CA mutations in plasma circulating tumor DNA predict survival and treatment outcomes in patients with advanced cancers.

BACKGROUND: Oncogenic mutations in PIK3CA are prevalent in diverse cancers and can be targeted with inhibitors of the phosphoinositide-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway. Analysis of circulating tumor DNA (ctDNA) provides a minimally invasive approach to detect clinically actionable PIK3CA mutations. PATIENTS AND METHODS: We analyzed PIK3CA hotspot mutation frequency by droplet digital PCR (QX 200; BioRad) using 16 ng of unamplified plasma-derived cell-free DNA from 68 patients with advanced solid tumors (breast cancer, n = 41; colorectal cancer, n = 13; other tumor types, n = 14). Results quantified as variant allele frequencies (VAFs) were compared with previous testing of archival tumor tissue and with patient outcomes. RESULTS: Of 68 patients, 58 (85%) had PIK3CA mutations in tumor tissue and 43 (74%) PIK3CA mutations in ctDNA with an overall concordance of 72% (49/68, κ = 0.38). In a subset analysis, which excluded samples from 26 patients known not to have disease progression at the time of sample collection, we found an overall concordance of 91% (38/42; κ = 0.74). PIK3CA-mutated ctDNA VAF of ≤8.5% (5% trimmed mean) showed a longer median survival compared with patients with a higher VAF (15.9 versus 9.4 months; 95% confidence interval 6.7-17.1 months; P = 0.014). Longitudinal analysis of ctDNA in 18 patients with serial plasma collections (range 2-22 time points, median 5) showed that those with a decrease in PIK3CA VAF had a longer time to treatment failure (TTF) compared with patients with an increase or no change (10.7 versus 2.6 months; P = 0.048). CONCLUSIONS: Detection of PIK3CA mutations in ctDNA is concordant with testing of archival tumor tissue. Low quantity of PIK3CA-mutant ctDNA is associated with longer survival and a decrease in PIK3CA-mutant ctDNA on therapy is associated with longer TTF.

Targeted methylation sequencing of plasma cell-free DNA for cancer detection and classification.

Background: Targeted methylation sequencing of plasma cell-free DNA (cfDNA) has a potential to expand liquid biopsies to patients with tumors without detectable oncogenic alterations, which can be potentially useful in early diagnosis. Patients and methods: We developed a comprehensive methylation sequencing assay targeting 9223 CpG sites consistently hypermethylated according to The Cancer Genome Atlas. Next, we carried out a clinical validation of our method using plasma cfDNA samples from 78 patients with advanced colorectal cancer, non-small-cell lung cancer (NSCLC), breast cancer or melanoma and compared results with patients' outcomes. Results: Median methylation scores in plasma cfDNA samples from patients on therapy were lower than from patients off therapy (4.74 versus 85.29; P = 0.001). Of 68 plasma samples from patients off therapy, methylation scores detected the presence of cancer in 57 (83.8%), and methylation-based signatures accurately classified the underlying cancer type in 45 (78.9%) of these. Methylation scores were most accurate in detecting colorectal cancer (96.3%), followed by breast cancer (91.7%), melanoma (81.8%) and NSCLC (61.1%), and most accurate in classifying the underlying cancer type in colorectal cancer (88.5%), followed by NSCLC (81.8%), breast cancer (72.7%) and melanoma (55.6%). Low methylation scores versus high were associated with longer survival (10.4 versus 4.4 months, P < 0.001) and longer time-to-treatment failure (2.8 versus 1.6 months, P = 0.016). Conclusions: Comprehensive targeted methylation sequencing of 9223 CpG sites in plasma cfDNA from patients with common advanced cancers detects the presence of cancer and underlying cancer type with high accuracy. Methylation scores in plasma cfDNA correspond with treatment outcomes.

Multiplex KRASG12/G13 mutation testing of unamplified cell-free DNA from the plasma of patients with advanced cancers using droplet digital polymerase chain reaction.

Background: Cell-free DNA (cfDNA) from plasma offers easily obtainable material for KRAS mutation analysis. Novel, multiplex, and accurate diagnostic systems using small amounts of DNA are needed to further the use of plasma cfDNA testing in personalized therapy. Patients and methods: Samples of 16 ng of unamplified plasma cfDNA from 121 patients with diverse progressing advanced cancers were tested with a KRASG12/G13 multiplex assay to detect the seven most common mutations in the hotspot of exon 2 using droplet digital polymerase chain reaction (ddPCR). The results were retrospectively compared to mutation analysis of archival primary or metastatic tumor tissue obtained at different points of clinical care. Results: Eighty-eight patients (73%) had KRASG12/G13 mutations in archival tumor specimens collected on average 18.5 months before plasma analysis, and 78 patients (64%) had KRASG12/G13 mutations in plasma cfDNA samples. The two methods had initial overall agreement in 103 (85%) patients (kappa, 0.66; ddPCR sensitivity, 84%; ddPCR specificity, 88%). Of the 18 discordant cases, 12 (67%) were resolved by increasing the amount of cfDNA, using mutation-specific probes, or re-testing the tumor tissue, yielding overall agreement in 115 patients (95%; kappa 0.87; ddPCR sensitivity, 96%; ddPCR specificity, 94%). The presence of ≥ 6.2% of KRASG12/G13 cfDNA in the wild-type background was associated with shorter survival (P = 0.001). Conclusion(s): Multiplex detection of KRASG12/G13 mutations in a small amount of unamplified plasma cfDNA using ddPCR has good sensitivity and specificity and good concordance with conventional clinical mutation testing of archival specimens. A higher percentage of mutant KRASG12/G13 in cfDNA corresponded with shorter survival.

Retreatment with anti-EGFR based therapies in metastatic colorectal cancer: impact of intervening time interval and prior anti-EGFR response.

BACKGROUND: This retrospective study aims to investigate the activity of retreatment with anti-EGFR-based therapies in order to explore the concept of clonal evolution by evaluating the impact of prior activity and intervening time interval. METHODS: Eighty-nine KRAS exon 2-wild-type metastatic colorectal patients were retreated on phase I/II clinical trials containing anti-EGFR therapies after progressing on prior cetuximab or panitumumab. Response on prior anti-EGFR therapy was defined retrospectively per physician-records as response or stable disease ≥6 months. Multivariable statistical methods included a multiple logistic regression model for response, and Cox proportional hazards model for progression-free survival. RESULTS: Retreatment anti-EGFR agents were cetuximab (n = 76) or cetuximab plus erlotinib (n = 13). The median interval time between prior and retreatment regimens was 4.57 months (range: 0.46-58.7). Patients who responded to the prior cetuximab or panitumumab were more likely to obtain clinical benefit to the retreatment compared to the non-responders in both univariate (p = 0.007) and multivariate analyses (OR: 3.38, 95 % CI: 1.27, 9.31, p = 0.019). The clinical benefit rate on retreatment also showed a marginally significant association with interval time between the two anti-EGFR based therapies (p = 0.053). Median progression-free survival on retreatment was increased in prior responders (4.9 months, 95 % CI: 3.6, 6.2) compared to prior non-responders (2.5 months, 95 % CI, 1.58, 3.42) in univariate (p = 0.064) and multivariate analysis (HR: 0.70, 95 % CI: 0.43-1.15, p = 0.156). CONCLUSION: Our data lends support to the concept of clonal evolution, though the clinical impact appears less robust than previously reported. Further work to determine which patients benefit from retreatment post progression is needed.

The prognostic significance of left ventricular ejection fraction in patients with advanced cancer treated in phase I clinical trials.

BACKGROUND: New targeted agents may cause acute cardiac events. The purpose of our study was to investigate the incidence and the prognostic significance of left ventricular ejection fraction (LVEF) in phase I trials. PATIENTS AND METHODS: Between October 2008 and September 2011, the records of 1166 consecutive patients with advanced cancer treated in the Phase I Clinic who underwent echocardiography were retrospectively reviewed. RESULTS: Most of the patients were White (78%), and the most common tumor types were colorectal cancer and melanoma. Of 1166 patients, 177 (15.2%) patients had an LVEF of <50%. No difference in overall survival (OS) between patients with LVEF ≥ 50% and patients with LVEF < 50% was seen (median OS 7.4 versus 7.0 months, P = 0.84). Patients with LVEF ≤ 35% had shorter survival compared with those with LVEF between 35% and 50% (median 4.2 versus 8.0 months; P = 0.005). In multivariate analysis of patients with LVEF < 50%, independent factors predicting longer survival were LVEF > 35%, ≤2 prior systemic therapies, ≤2 metastatic sites, and normal lactate dehydrogenase and albumin levels. CONCLUSION: Echocardiography would improve patient selection for enrollment in phase I clinical trials. These data suggest that it is safe to treat patients with LVEF between 35% and 50%.

Body composition and survival in the early clinical trials setting.

PURPOSE: Delineate the relationships between body composition parameters, 90-day mortality and overall survival, and correlate them with known prognostic factors in an early clinical trials clinic. PATIENTS AND METHODS: We studied 306 consecutive patients with various tumours; body composition was analysed by computerised tomography images. Survival was measured from the first clinic visit, at 90-day period and until death/last follow-up visit. RESULTS: Median patient age was 56 years; 159 patients were men. Ninety-day mortality rate was 12%. Median overall survival was 9 months. In multivariate analyses, high MD Anderson Cancer Center (MDACC) score (p < 0.0001) [lactate dehydrogenase (LDH) > normal, albumin < normal, Eastern Cooperative Oncology Group (ECOG) performance status > 1, metastatic sites > 2, gastrointestinal (GI) tumours], low skeletal muscle index (SMI) (p = 0.0406) and male gender (p = 0.0077) were independent predictors of poor survival. If Royal Marsden Hospital (RMH) score (LDH > normal, albumin 2) was used in lieu of MDACC score, it was also significant (p = 0.0003). Including SMI and gender in the MDACC or RMH score improved the accuracy of the original model (p = 0.006 and p = 0.0037, respectively). CONCLUSION: Patients with low SMI have shorter survival. Gender and SMI strengthens the accuracy of MDACC or RMH scores as prognostic tools. Prospective validation of these findings is warranted.

Aberrations in the epidermal growth factor receptor gene in 958 patients with diverse advanced tumors: implications for therapy.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are associated with the response to EGFR inhibitors in patients with non-small-cell lung cancer (NSCLC). We sought to investigate EGFR aberrations in patients with diverse advanced cancers. PATIENTS AND METHODS: Patients referred to the phase I clinic were evaluated for the presence of EGFR mutations and response to therapy. RESULTS: EGFR aberrations were detected in 34 of 958 patients (3.5%). Though EGFR mutations were most frequent in NSCLC (21 of 131, 16%), they were also present in a variety of other solid tumors (13 of 827 patients, 1.6%) including adrenocortical (1/10 patients), skin (1/24), breast (1/55), carcinoid (1/8), cholangiocarcinoma (1/20), head and neck (1/61), ovarian (1/84), parathyroid (1/1), salivary gland (1/20), renal (1/17), sarcoma (2/38), and thymic carcinomas (1/7). Of the 13 EGFR aberration-positive non-NSCLC patients (median number of prior systemic therapies = 3), 6 had treatment with an EGFR inhibitor. Two patients (diagnosis = parathyroid tumor and basal cell carcinoma) achieved stable disease (SD), lasting 6 and 7 months, respectively. CONCLUSION: We found EGFR aberrations in 1.6% of a large group of patients with diverse tumors other than NSCLC, and treatment with an EGFR inhibitor could be associated with prolonged SD.

Electrocardiograms (ECGs) in phase I anticancer drug development: the MD Anderson Cancer Center experience with 8518 ECGs.

BACKGROUND: Cardiac sequelae from oncologic drugs are important in early cancer drug development. Prolongation of the corrected QT interval (QTc) by noncardiac drugs is the most common cause of drug development delays, nonapprovals and postmarketing withdrawals by the US Food and Drug Administration. PATIENTS AND METHODS: We analyzed 8518 electrocardiograms (ECGs) in 525 consecutive cancer patients enrolled in 22 industry-sponsored phase I clinical trials, starting 1 January 2006. RESULTS: Seventy-four patients [14%, 95% confidence interval (CI) 11% to 17%] with normal QTc at baseline had QTc intervals above upper limit of normal after treatment initiation; 33 (6%, 95% CI 4% to 9%) had prolonged QTc intervals at baseline, and only one (3%, 95% CI 0% to 16%) worsened after dosing. Seven of 33 patients (21%, 95% CI 9% to 39%) with prolonged baseline QTc had normalization of QTc intervals after dosing. All QTc prolongations were clinically insignificant; study drugs were continued uneventfully. Two of 525 patients (0.4%, 95% CI 0% to 1%) experienced cardiac serious adverse events (myocardial infarction possibly related to drug and unstable atrial flutter related to metastatic disease). Both cardiac events were detected by clinical assessment, not surveillance ECGs. CONCLUSION: Frequent ECG monitoring provided no clinically significant information in 525 patients in early phase trials.

Risk of serious toxicity in 1181 patients treated in phase I clinical trials of predominantly targeted anticancer drugs: the M. D. Anderson Cancer Center experience.

BACKGROUND: This study assessed toxicity in advanced cancer patients treated in a phase I clinic that focuses on targeted agents. PATIENTS AND METHODS: An analysis of database records of 1181 consecutive patients with advanced cancer who were treated in the phase I program starting 1 January 2006 was carried out. RESULTS: All patients were treated on at least 1 of the 82 phase I clinical trials. Overall, 56 trials (68.3%) had only targeted agents, 13 (15.9%) only cytotoxics, and 13 (15.9%) targeted and cytotoxic agents. Rates of grade 3 and 4 toxicity that were at least possibly drug related were 7.1% and 3.2%, respectively, and 5 of the 1181 patients (0.4%) died from toxicity that was at least possibly drug related. The most common grade 3 or more toxic effects were neutropenia, thrombocytopenia, anemia, dehydration, infection, altered mental status, bleeding, vomiting, nausea, and diarrhea. Eastern Cooperative Oncology Group (ECOG) performance status greater than zero and use of a cytotoxic agent were selected as independent factors associated with serious toxicity. CONCLUSION: Phase I trials of primarily targeted agents showed low rates of toxicity, with 10.3% of patients experiencing grade 3 or 4 toxicity and a 0.4% rate of death, at least possibly drug related.

Ofatumumab in the treatment of chronic lymphocytic leukemia.

Ofatumumab is a type I fully human monoclonal antibody (IgG1) that binds to a unique epitope on the human CD20 molecule expressed on the surface of B cells. It binds specifically to both the small and large extracellular loops of the CD20 molecule. A phase I-II study demonstrated that ofatumumab was well tolerated and resulted in objective responses. In a phase II study of ofatumumab in fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) or fludarabine-refractory CLL with bulky (> 5 cm) lymphadenopathy, the response rates were 58% and 47%, respectively. This study led to accelerated approval of ofatumumab by the U.S. Food and Drug Administration for the treatment of CLL refractory to fludarabine and alemtuzumab. In a phase II study of ofatumumab with fludarabine and cyclophosphamide in untreated CLL, patients were randomized to ofatumumab 500 mg (group A) or 1000 mg (group B) (initial dose, 300 mg, both groups), combined with fludarabine and cyclophosphamide. The higher ofatumumab dose resulted in a higher complete response (CR) rate (50%), compared to the lower-dose ofatumumab group (CR, 32%) (overall response rates, 77% and 73%, respectively). A phase III study of ofatumumab combined with fludarabine and cyclophosphamide versus fludarabine and cyclophosphamide in relapsed CLL are ongoing, as well as several clinical trials of ofatumumab. Ofatumumab has significant antileukemic activity and ongoing clinical trials will determine the role of ofatumumab in CLL.

Low-dose interleukin-11 in patients with bone marrow failure: update of the M. D. Anderson Cancer Center experience.

BACKGROUND: Recombinant interleukin (IL)-11 is a thrombopoietic growth factor. The purpose of this study was to assess the toxicity, safety and efficacy of low-dose recombinant IL-11 in patients with bone marrow failure (BMF). PATIENTS AND METHODS: Patients with BMF due to myelodysplastic syndromes (MDS), graft failure, chemotherapy or aplastic anemia (AA) were treated. Patients were required to have a platelet count of <20 x 10(9)/l, or a platelet count of <50 x 10(9)/l with an absolute neutrophil count <1 x 10(9)/l, or a hemoglobin value <10 g/dl. Treatment consisted of daily IL-11 at a dose of 10 mug/kg subcutaneously followed by a 2-week rest period. Two induction courses were given. Responders could receive maintenance therapy. RESULTS: Thirty-three patients (MDS, n=14; AA, n=16; prolonged thrombocytopenia following stem cell transplantation or chemotherapy, n=3) were evaluable. Their median age was 58 years (range 5-85). Three patients (9%) had poor risk cytogenetics. Nine patients (27%) responded to IL-11 (six MDS, three AA). Of these, three patients treated with IL-11 alone (n=1) or IL-11 together with other growth factors (n=2) showed multilineage recovery. The median time to response was 0.9 months (range 0.3-11). Factors associated with higher response rates in univariate analysis were age >50 years (P=0.008), diagnosis of MDS versus AA (P=0.025) and creatinine level >1 mg/dl (P=0.0004). The median response duration was 3 months (range 1.4-34.5+). Amongst responders, the median increment in platelet count was 111 x 10(9)/l (range 43-165). The most common side-effects were grade 1-2 lower extremity edema, conjunctival injections and fatigue. Grade 3 toxicities included arrhythmia (n=1) and transient ischemic attack (n=1). Ten patients (30%) had no side-effects. CONCLUSIONS: Low-dose IL-11 has activity in patients with BMF and is generally well tolerated.

Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes.

The purpose of this study was to determine the efficacy of and tolerance to antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndrome (MDS). Therapy consisted of ATG 40 mg/kg/day daily intravenously (i.v.) for 4 days; cyclosporine daily orally for 6 months with levels titrated between 200 and 400 mg/dl; and methylprednisone 1 mg/kg i.v. daily before each dose of ATG. Of 32 patients treated, 31 patients were evaluable. The median age was 59 years (range, 28-79 years). A total of 18 patients had refractory anemia (RA) or RA with ringed sideroblasts (RARS), 10 patients had RA with excess blasts (RAEB), two patients had RAEB in transformation, and one patient had chronic myelomonocytic leukemia. ATG, cyclosporine, and methylprednisone induced complete (N=4) or partial (N=1) remission in five patients (16% of total; RA, two patients; RARS, two patients; and RAEB, one patient). Durable complete remissions were observed in three of 18 patients (17%) with RA (N=1) or RARS (N=2) (12, 41+, and 60+ months). The most common adverse events were fever and allergic reactions. Hepatic and renal dysfunction, albeit consistently reversible, occurred in 19 and 13% of the patients, respectively. In conclusion, an ATG-based regimen can produce durable complete remissions in a subset of patients with MDS.

Outcome in patients with nonleukemic granulocytic sarcoma treated with chemotherapy with or without radiotherapy.

Granulocytic sarcoma (GS) is an extramedullary tumor composed of immature myeloid cells. The objectives of this study were to describe the frequency, presenting characteristics, and survival in patients with nonleukemic GS by conducting a review of all untreated patients presenting to the MD Anderson Cancer Center between January 1990 and June 2002. In all, 21 patients with nonleukemic GS, 1520 patients with acute myeloid leukemia (AML), and 402 patients with high-risk myelodysplastic syndrome (MDS) were identified. GS occurred in 1.4% of patients with AML, and 1.1% of patients with AML or high-risk MDSs. The median patient age was 57 years (range, 7-81). Among 20 patients with available cytogenetics in tissue and/or bone marrow, six had chromosome 8 abnormalities. The median follow-up of surviving patients is 12 months (range, 7-75). In all, 20 patients were treated. Patients were treated with AML-type chemotherapy (n=16), chemotherapy and radiotherapy (n=3), or radiotherapy alone (n=1). A total of 13 patients (65%) achieved complete remission and one patient (5%) achieved partial remission. The median overall survival was 20 months (range, 1-75), median overall failure-free survival was 12 months (range, 1-75). The median survival of patients with chromosome 8 abnormalities was 12 months compared with 40 months of those without (P=0.17). Novel therapies for patients with GS are required.

Hodgkin's disease in patients infected with human immunodeficiency virus: frequency, presentation and clinical outcome.

We report the frequency, presenting characteristics, progression-free survival, event-free survival, overall survival and AIDS-free survival of patients with previously untreated Hodgkin's disease (HD) in the setting of infection by human immunodeficiency virus (HIV). To accomplish this we retrospectively reviewed all untreated patients presenting to the University of Texas M.D. Anderson Cancer Center between July 1985 and August 1999 with HD and HIV infection. All available records were reviewed to determine presentation, clinical characteristics, treatment outcome, progression-free survival and overall survival. We identified 887 patients with HD and 3,500 with Non-Hodgkin's Lymphoma (NHL). The ratio of NHL to HD in HIV-negative versus HIV-positive patients was 3.9 versus 6.9, respectively. There were 14 HIV-positive patients with HD and 97 with NHL. The median age of the HIV-positive HD patients was 33 years, and 13 were male. Three patients had Acquired Immune Deficiency syndrome (AIDS) at the time of HD diagnosis, and seven had B-symptoms. Ann Arbor stage was I in one, II in three, III in four and IV in six patients. Mixed cellularity histology was seen in eight, bone marrow involvement in five and extranodal disease in seven patients. Four patients had elevated serum lactate dehydrogenase, three low serum albumin, and nine elevated serum beta2-microglobulin, The median CD4 count was 160/microl. Eleven patients received ABVD or equivalent regimens, followed by radiotherapy in five. One patient was treated with COPP and radiotherapy, one with NOVP and radiotherapy and one only with radiotherapy. All patients received some antiretroviral therapy, but it was variable over the years. With a median follow-up of 64 months for survivors, the projected 5-year progression-free survival was 64%, event-free survival 45%, overall survival 54% and AIDS-free survival 45%. Six patients died of complications arising from HIV infection, including one patient who had preexisting AIDS at HD presentation. Two patients died of HD, without developing other conditions diagnostic of AIDS. We conclude that in our referral patient population HIV infection is associated with preferential development of NHL rather than HD, which appears curable with standard treatment regimens. Since HIV-related deaths exceed those caused by HD, future investigation should focus on integration of chemotherapy and highly active antiretroviral therapy.

Liposomal vincristine in relapsed non-Hodgkin's lymphomas: early results of an ongoing phase II trial.

OBJECTIVE: Vincristine is an active agent in lymphomas, but is often neurotoxic, and the resulting dose reductions have been associated with lower remission and survival rates in Hodgkin's disease. Liposomal vincristine (Onco-TCS) has prolonged half-life, reaches higher concentration in tumors and lymph nodes than in nerves, and administered at full doses appears to be less neurotoxic, and more active then free vincristine in mice bearing L-1210 and P-388 leukemias. We therefore explored its activity in relapsed non-Hodgkin's lymphomas (NHL) and acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Eligible patients had histologically proven relapse, age > or = 16 years, normal renal function, neutrophils > 500/microliter, platelets > 50,000/microliter, and no HIV infection, central nervous system disease, or serious neuropathy. Patients were treated with 2.0 mg/m2 of liposomal vincristine i.v. over 60 minutes q 14 days. Responders received up to 12 injections. RESULTS: Of the 51 registered patients, 35 are currently evaluable for response. Median age was 62 years (range 19-86), and 21 were male. The median number of prior regimens was 3 (range 1-10) and had included vincristine in all patients, of whom 51% were refractory to their last regimen. Serum LDH was high in 46%, and beta 2-microglobulin > 3.0 mg/l in 63% of patients. Of the 155 administered injections, 138 (89%) were at the 2.0 mg/m2 level. The median injected dose was 3.8 mg (range 2.6-4.8 mg), and median number of injections was 4 (range 1-12). Responses were seen in 14 of 34 (41%) patients with NHL (95% confidence intervals (95% CI) 25%-59%). Response rates were 10% for indolent, 71% for transformed, and 47% for aggressive NHL, but the 95% confidence intervals overlapped. Median progression-free survival was 5.5 months for responders. Grade 3-4 motor or sensory neuropathy was seen in 11, and caused termination of therapy in five patients. All five had prior neuropathy, two had previously received paclitaxel, one platinum, and two paclitaxel and platinum. Fever was detected in three patients, but there were no toxic deaths. CONCLUSIONS: Liposomal vincristine is active and well tolerated in this heavily pretreated population with relapsed NHL, but can be neurotoxic in a fraction of patients heavily exposed to prior neurotoxic agents. These data, if confirmed, would suggest a potential role for liposomal vincristine in the combination therapy of previously untreated patients with NHL.