Overall Median Duration Of Response Research Articles

Results of a Phase 2 NCI Multicenter Study of Romidepsin in Patients with Relapsed Peripheral T-Cell Lymphoma (PTCL).

Background: The histone deacetylase (HDAC) inhibitors are a class of epigenetic agents undergoing clinical testing. HDAC inhibitors modulate expression of genes involved in cell cycle regulation, leading to induction of differentiation or apoptosis. Romidepsin, a novel, HDAC inhibitor, has previously demonstrated activity as a single agent in patients (pts) with T-cell lymphoma in a phase 1 NCI study.Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced PTCL and as an exploratory endpoint, to examine the molecular effects of romidepsin in both PTCL and cutaneous T-cell lymphoma (CTCL).Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 43 PTCL pts from the NCI and 9 extramural sites. CTCL pts were also enrolled in this study. The clinical results for pts with PTCL are presented here; the clinical results for the pts with CTCL and the biomarker analyses for both PTCL and CTCL are presented elsewhere. This study is now closed to accrual. Pts with relapsed or refractory PTCL or primary cutaneous anaplastic large cell lymphoma were eligible. Pts received romidepsin 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 every 28 days. Responses were assessed using elements of the IWG criteria and RECIST, as appropriate, for pts with lymph node involvement and extranodal disease.Results: 43 pts (23[53%] men and 20 [47%] women) with a mean age of 58.1 (range: 27 to 84) years were treated with romidepsin. 31 pts received ≥ 2 cycles of therapy. Mean number of prior therapies was 3.9 (range 1 to 12). Objective disease response rates (ORR) are summarized in the table. The mean number of cycles of treatment was 6.8 (range 1–37) and the overall median duration of response was 8.3 months (range 1.6 months to 4.8+ yrs) for all pts. The median duration of response for the 7 pts who achieved CR was 8.5 months (range 4.6 months to 4.8+yrs). The most frequent drug-related AEs (all grades, all cycles) were generally mild and included: nausea (86%; 0% ≥grade 3), fatigue (79%; 0% ≥grade 3), decreased platelets (70%; 7% ≥grade 3), and decreased AGC (63%; 5% ≥grade 3). One death, in a pt with significant cardiovascular disease who had achieved a CR, was considered possibly related to treatment.Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 39% and median duration of response of 8.3 months) of romidepsin in pts with recurrent or refractory PTCL. Based on these promising results, a Phase 2B protocol investigating romidepsin in pts with progressive or relapsed PTCL is ongoing at multiple international centers.All Pts N=43Pts ≥ 2 cycles N=31ORR (CR+PR), n (%)17 (39%)17 (55%)PR, n (%)10 (23%)10 (32%)CR, n (%)7 (16%)7 (23%)

Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial

To evaluate in a prospective multicenter trial the feasibility and clinical efficacy of the combination of alemtuzumab (Campath-1H) with the cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) regimen (CHOP-C) as the primary treatment for patients with peripheral T-cell lymphoma (PTCL), between January 2003 and December 2005, 24 consecutive patients with PTCL entered the study and received 8 CHOP courses. Alemtuzumab was added at 30 mg subcutaneously at day -1 initially to the first 4 courses (4 patients), and then to all 8 courses (20 patients). Complete remission (CR) was achieved in 17 (71%) patients, 1 had partial remission, and 6 had stable/progressive disease. At a median follow-up of 16 months (range, 5-42 months), 14 patients were alive, 9 had died from progressive disease, and 1 had died from pneumonia at day +198 while in CR. So far, 13 are disease-free, with an overall median duration of response of 11 months. The most frequent side effects were grade 4 neutropenia and cytomegalovirus (CMV) reactivation. Major infections were Jacob-Creutzfeldt (J-C) virus reactivation, pulmonary invasive aspergillosis, Staphylococcus sepsis, and pneumonia. This study shows that CHOP-C: (1) is a feasible chemoimmunotherapy regimen; (2) is effective in PTCL with a high rate of CR achievement; and (3) is associated with mostly manageable infectious complications. This clinical trial was registered with the Osservatorio Nazionale sulla Sperimentazione cinica as ID no. 141202.

Response of Canine Cutaneous Epitheliotropic Lymphoma to Lomustine (CCNU): A Retrospective Study of 46 Cases (1999–2004)

Background:Epitheliotropic lymphoma (ELSA) is an uncommon cutaneous canine malignancy of T lymphocytes. A consensus regarding the therapeutic standard of care is lacking, warranting evaluation of chemotherapeutic agents traditionally employed against canine nodal lymphoma in the treatment of ELSA.Hypothesis:The purpose of this retrospective, multi‐institutional study was to evaluate the efficacy of 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU) in the treatment of ELSA.Animals:Forty‐six dogs with adequate follow‐up and treatment response information.Methods:All cases were diagnosed histopathologically. Immunohistochemisty (CD3, CD79a) was performed on 42/46 samples.Results:Presenting skin lesions included generalized scales (25/46), plaques or nodules (22/46), mucocutaneous lesions (14/46), and corneal involvement (1/46). Lymph node involvement and Sézary syndrome were documented in 7 and 2 dogs, respectively. The median number of CCNU treatments was 4 (range, 1–11), with a median starting dose of 60 mg/m2(range, 30–95). Of the 46 dogs, 15 achieved complete remission, 23 achieved partial remission, 5 had stable disease, and 3 had progressive disease, for an overall response rate of 83%. The median number of treatments to achieve a response was 1 (range, 1–6). The overall median duration of response was 94 days (range, 22–282). Sixteen dose reductions were required because of neutropenia (10/46), thrombocytopenia (1/46), anemia (1/46), increased liver enzyme activity (3/46), or unspecified reasons (1/46).Conclusions and Clinical Implications: Given the high response rate and well tolerated protocol, prospective studies are warranted to investigate the utility of CCNU alone or in multi‐agent protocols for the treatment of ELSA.

Long term follow up after treatment of hairy cell leukemia with 2-CdA

16518 Background: Hairy cell leukemia (HCL) is a chronic B cell disorder that follows an indolent but progressive course. The ability of new purine analogue deoxyadenosine to induce long lasting complete remission in patients with hairy cell leukemia has revolutionized the treatment of this disease. We report the long term outcomes of patients with HCL treated in Shiraz, in south of Iran,with this drug. Methods: Between October 1993 till April 2004, 79 patients with classic symptomatic hairy cell leukemia were treated with 2-cholorodeoxy adenosine (2-CdA) with dose of 0.1 mg/kg of body weight per day by continuous intravenous infusion for 7 days. Results: sixty nine (87%) of patients achieved an initial complete response and 10 (12.6) a partial response with an overall median duration of response follow up of 78 months. Five patients had relapsed at a median of 43 months. All of 5 patients after relapse treated with second courses of 2-CdA, 4 (80%) achieved second complete responses and one (20%) partial response. In our study we had not any case of second malignancy after treatment with 2-CdA with median follow up of 82.5 months. Conclusion: This study confirms single course of 2-CdA induced long lasting complete response in the vast majority of patients. Relapse rate for complete responders were low. Patients who relapse can be successfully retreated with this drug, so we conclude 2-CdA had high efficacy and a favorable acute and long term toxicity profile in our patients in south of Iran, without any increase in risk of second malignancy. No significant financial relationships to disclose.

Response of Canine Cutaneous Epitheliotropic Lymphoma to Lomustine (CCNU): A Retrospective Study of 46 Cases (1999–2004)

Epitheliotropic lymphoma (ELSA) is an uncommon cutaneous canine malignancy of T lymphocytes. A consensus regarding the therapeutic standard of care is lacking, warranting evaluation of chemotherapeutic agents traditionally employed against canine nodal lymphoma in the treatment of ELSA. The purpose of this retrospective, multi-institutional study was to evaluate the efficacy of 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU) in the treatment of ELSA. Forty-six dogs with adequate follow-up and treatment response information. All cases were diagnosed histopathologically. Immunohistochemisty (CD3, CD79a) was performed on 42/46 samples. Presenting skin lesions included generalized scales (25/46), plaques or nodules (22/46), mucocutaneous lesions (14/ 46), and corneal involvement (1/46). Lymph node involvement and Sézary syndrome were documented in 7 and 2 dogs, respectively. The median number of CCNU treatments was 4 (range, 1-11), with a median starting dose of 60 mg/m(2) (range, 30-95). Of the 46 dogs, 15 achieved complete remission, 23 achieved partial remission, 5 had stable disease, and 3 had progressive disease, for an overall response rate of 83%. The median number of treatments to achieve a response was 1 (range, 1-6). The overall median duration of response was 94 days (range, 22-282). Sixteen dose reductions were required because of neutropenia (10/46), thrombocytopenia (1/46), anemia (1/46), increased liver enzyme activity (3/46), or unspecified reasons (1/46). Given the high response rate and well tolerated protocol, prospective studies are warranted to investigate the utility of CCNU alone or in multi-agent protocols for the treatment of ELSA.

The Radioisotope Contributes Significantly to the Activity of Radioimmunotherapy

A multicenter, randomized study was undertaken to estimate the single agent activity of Tositumomab and to determine the contribution of radioisotope-labeling with (131)I to activity and toxicity by comparing treatment outcomes for Tositumomab and Iodine I 131 Tositumomab (BEXXAR) to an equivalent total dose of unlabeled Tositumomab. Seventy-eight patients with refractory/relapsed non-Hodgkin's lymphoma were randomized to either unlabeled Tositumomab or Iodine I 131 Tositumomab. Patients progressing after unlabeled Tositumomab could cross over to receive Iodine I 131 Tositumomab. The median follow-up at analysis was 42.6 months (range 1.9 to 71.5 months). Responses in the Iodine I 131 Tositumomab versus unlabeled Tositumomab groups: overall response 55% versus 19% (P = 0.002); complete response 33% versus 8% (P = 0.012); median duration of overall response not reached versus 28.1 months (95% confidence interval: 7.6, not reached); median duration of complete response not reached in either arm; and median TTP 6.3 versus 5.5 months (P = 0.031), respectively. Of the patients who had a complete response after initial Iodine I 131 Tositumomab therapy, 71% (10 of 14) continued in complete response at 29.8 to 71.1 months. Two patients who achieved a complete response after unlabeled Tositumomab had ongoing responses at 48.1 to 56.9 months. Nineteen patients received Iodine I 131 Tositumomab crossover therapy. Responses after crossover versus prior response to unlabeled Tositumomab were as follows: complete response rates of 42% versus 0% (P = 0.008); overall response 68% versus 16% (P = 0.002); median durations of overall response 12.6 versus 7.6 months (P = 0.001); and median TTP 12.4 versus 5.5 months (P = 0.01), respectively. Hematologic toxicity was more severe and nonhematologic adverse events were more frequent after Iodine I 131 Tositumomab than after Tositumomab alone. Elevated thyrotropin occurred in 5% of patients. Seroconversion to human antimurine antibody after Iodine I 131 Tositumomab, unlabeled Tositumomab, and Iodine I 131 Tositumomab-crossover was 27%, 19%, and 0%, respectively. Unlabeled Tositumomab showed single agent activity, but in this direct comparison, all of the therapeutic outcome measures were significantly enhanced by the conjugation of (131)I to Tositumomab.

A phase II study of oral eniluracil/fluorouracil in patients with anthracycline-refractory or anthracycline- and taxane-refractory advanced breast cancer

Eniluracil is an effective inactivator of dihydropyrimidine dehydrogenase, the initial and rate limiting enzyme in the catabolism of fluorouracil. The current study was done to determine the objective tumour response of a 28-day oral regimen of eniluracil-fluorouracil in patients with advanced breast cancer. This was a multicentre, phase II study in patients with anthracycline-refractory (AR) or anthracycline- and taxane-refractory (ATR) advanced breast cancer. Oral eniluracil (10 mg/m2) and fluorouracil (1 mg/m2) were taken twice daily for 28 days of each 35-day treatment course. In this study, 106 patients received treatment: 62 patients in the AR stratum and 44 patients in the ATR stratum. The objective tumour response rate in the intent-to-treat population was 18% (95% confidence intervals (CI): 11%-27%), including three complete responses. The response rate was similar in both strata: 19% in the AR and 16% in the ATR stratum. The overall median duration of response was 23.6 weeks. The treatment was well tolerated with a low incidence of grade 3 or 4 toxicities that were considered attributable to study medication. Treatment with oral eniluracil-fluorouracil was well tolerated by patients with advanced breast cancer. The efficacy data were comparable with those of other published studies in this group of refractory patients.

Cladribine with or without prednisone in the treatment of previously treated and untreated B‐cell chronic lymphocytic leukaemia — updated results of the multicentre study of 378 patients

Between January 1992 and January 1999, we treated 378 B-chronic lymphocytic leukaemia (CLL) patients with cladribine (2-CdA), and 255 of the patients were also treated with prednisone. A total of 194 patients were previously untreated, and 184 had relapsed or refractory disease after previous other therapy. Complete response (CR) was obtained in 111 (29.4%) and partial response (PR) in 138 (36.5%) patients, giving an overall response (OR) rate of 65.9%. CR and OR were achieved more frequently in patients in whom 2-CdA was a first-line treatment (45.4% and 82.5% respectively) than in the pretreated group (12.5% and 48.4% respectively) (P < 0.0001). The median duration of OR for previously untreated patients was 14.7 months and for pretreated patients 13.5 months (P = 0.09). The median survival evaluated from the beginning of 2-CdA treatment was shorter in the pretreated group (16.3 months) than in the untreated group (19.4 months) (P < 0.0001). A total of 117 (63.9%) patients died in the pretreated group and 63 (32.6%) in the untreated group. In pretreated patients, 2-CdA + prednisone (P) and 2-CdA alone resulted in similar OR (51.0% and 45.0% respectively; P = 0.4). In contrast, in untreated patients, 2-CdA + P produced a higher OR (85.4%) than 2-CdA alone (72.1%) (P = 0.04). Infections and fever of unknown origin, observed in 91 (49.4%) pretreated and 74 (38.1%) untreated patients (P = 0.03), were the most frequent toxic effects. Our results indicate that 2-CdA is an effective, relatively well-tolerated drug, especially in previously untreated CLL.

A phase II study of single agent paclitaxel in patients at first relapse following initial chemotherapy for breast cancer

This study was initiated to evaluate the safety and efficacy of 3-weekly paclitaxel given at 225 mg/m 2 over 3 hours without colony stimulating factor support in patients at their first relapse following adjuvant therapy for breast cancer. Thirty patients were entered into the study; all were assessable for response and toxicity. All patients had received adjuvant/neo-adjuvant chemotherapy, 22 patients had had prior hormonal therapy and 26 previous adjuvant radiotherapy. The group was characterized by a short time to first relapse (median 7.5 months (range 2–43)) and widespread disease, with 22 patients having multiple disease sites including: nodes (43%), skin and soft tissue (43%), liver (40%), lung (37%) and bone (50%). A total of 219 cycles of paclitaxel were given, with a median of eight per patient. The major non-haematological toxicities were: grade 3 alopecia (82% cycles), grade 2/3 arthralgia/myalgia (26%), grade 2/3 fatigue (16%) and grade 2/3 peripheral nervous system toxicity (12%). Haematological toxicity was mainly neutropenia of short duration, with grade 4 counts documented in 16% of cycles. Thrombocytopenia was minimal and there were no significant hyper-sensitivity reactions. The objective response rate was 60% (95% CI 42.5–77.5) with one complete response and 17 partial responses. The median duration of overall response was 30 weeks (range 15–75+ (95% CI 25–33)) with a median survival time for all patients of 42 weeks (range 1–124+). This study demonstrates that paclitaxel 225 mg/m 2 is well tolerated as a 3-hour infusion and can be given safely in an outpatient setting without routine use of granulocyte colony stimulating factor. The response rate is encouraging and shows that this regimen is effective in this poor prognosis patient population.

Docetaxel: an interesting new drug for the treatment of head and neck cancers and soft tissue sarcomas

Results are summarized for two phase II studies of docetaxel as first-line therapy for advanced squamous cell carcinoma of the head and neck (SCCHN) and one study of docetaxel as second-line therapy for advanced soft tissue sarcomas. In all three studies, docetaxel was administered at a dose of 100 mg/m2 by intravenous infusion over 1 h every 3 weeks. A total of 62 patients were enrolled in the SCCHN trials, of whom 57 were evaluable for response. The combined overall response rate in the SCCHN patients was 35%. Median duration of overall response was 6.5 months in the EORTC-ECTG study. In the DFCI study, median durations of complete and partial remission were 6.75 months and 4.45 months, respectively. These results are at least comparable to those achieved with other single-agent therapies in this setting. In the soft tissue sarcoma study, 29 of the 31 patients enrolled were evaluable for response. Five patients (17%) achieved a partial response to docetaxel as second-line therapy and a further nine (31%) had stable disease. Median duration of response in these patients with soft tissue sarcomas was 5 months. Again, these results are similar to those seen with the three most active single agents in soft tissue sarcomas when used as second-line therapy. Docetaxel may therefore represent a useful drug in both advanced SCCHN and soft tissue sarcomas.

Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group.

A phase II study was conducted to evaluate the antitumor effect and toxicity of CPT-11 in patients with metastatic colorectal cancer. From December 1989 to March 1991, 67 patients with metastatic colorectal cancer were enrolled in this study. Sixty-three patients were assessable for toxicity and response. Their median age was 57 years (range, 24 to 72). Forty-six patients (73%) had a good performance status of 0 or 1. Fifty-one patients (81%) had received prior chemotherapy. The major sites of metastasis were liver (63%) and lung (44%). CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion, or as 150 mg/m2 every 2 weeks. The dose was reduced based on the grade of leukopenia and diarrhea, if necessary. A partial response was obtained in 17 of 63 assessable patients (27%; 95% confidence interval, 16% to 38%). The response rate in patients with prior radiotherapy or chemotherapy was 25% (13 of 52). Liver metastases showed a 15% (six of 40) response and lung metastases showed a 39% (11 of 28) response. The median duration of partial response was 127 days (range, 49 to 353) and the median overall duration of response was 208 days (range, 99 to 381). The major toxicities (> or = grade 3) were leukopenia (16%), diarrhea (13%), nausea and vomiting (13%), and alopecia (11%). Adverse effects were generally well tolerated and reversible. Treatment could be continued on an outpatient basis for patients without severe toxicity. Hemorrhagic cystitis was not encountered in this study. CPT-11 showed promising antitumor activity against metastatic colorectal cancer that was resistant to prior therapy. Further clinical trials of combination chemotherapy using CPT-11 are justified.

Successful treatment of hairy cell leukemia with β‐ser interferon

Twelve patients with hairy cell leukemia underwent treatment with beta-ser interferon, a type I interferon with potent antiproliferative activity. Ten of the 12 patients had had prior therapy and the median time from diagnosis to initiation of treatment was 8.5 months (range 1 month to 18 years). Bone marrow involvement ranged from 90-100% hairy cells. Beta-ser interferon was administered as an intravenous injection of 90 million units per dose, three times weekly. Dose reductions were by dose and by frequency in individual patients. Ten of 12 patients (83%) responded, including 7 complete (CR) and 3 partial (PR) responses. The median time to at least PR was 6 months and the median time to CR was 12 months. The median duration of overall response (PR + CR or PR) is 31+ months (range 26(+)-40+ months). Of the 6 patients who underwent dose reductions due to toxicity or poor tolerance, 4 CR patients reverted to PR, and 2 PR patients have increased the number of hairy cells in the marrow, while maintaining normal peripheral blood counts. One each of these has regained CR and PR status after an increase in dose.

Combined chemotherapy for recurrent and metastatic nasopharyngeal carcinoma.

Thirty-two patients (24 males, 8 females; median age 54 yrs) with recurrent and/or metastatic undifferentiated carcinoma of the nasopharyngeal type were treated with chemotherapy. Remissions were observed in 17 of 32 (53.2%) with 5 complete (CR) (15.6%) and 12 partial responses (PR) (37.6%). A combination of cisplatin and 5-fluorouracil was the most effective regimen (CR + PR = 83.3%). Objective responses. (CR + PR) were 47% (CR = 11.7%) in schemes without cisplatin and 60% (CR = 20%) in cisplatin-based combinations. The median overall duration of response was 7.2 months. The median overall survival time was 10.3 months: 15.1 months for responders and 5.2 for non-responders. No important toxicity was observed.

Combination chemotherapy with cisplatin and etoposide in bronchogenic squamous cell carcinoma and adenocarcinoma. A study by the EORTC lung cancer working party (Belgium).

Cisplatin and etoposide combination was used in 94 patients with measurable or evaluable bronchogenic squamous cell carcinoma or adenocarcinoma. The overall response rate was 38% with four complete remission (CR). In patients with locoregional disease who did not receive any prior anticancer therapy the response rate was 56% (19/34) with three CR, significantly (P = 0.02) higher than that observed in the other patients (28%). The overall median duration of response was 36.7 weeks. Patients with locoregional disease who did not receive any prior anticancer therapy had a median duration of response of 43.6 weeks; longer than that (27.5 weeks) in the other patients. Overall, responding patients survived significantly longer (P less than 0.0001) than non responders (median survival 60.0 weeks versus 23.0). Toxicity was tolerable; gastrointestinal side effects were occasionally responsible for discontinuation of therapy and sepsis was the cause of death in two neutropenic patients. No serious nephrotoxicity was observed. The combination of cisplatin and etoposide should probably be tested in combination with surgery of radiotherapy.

Cyclical combination chemotherapy for advanced breast carcinoma.

Twenty-five patients with advanced metastatic breast cancer were treated with the combination of methotrexate 60 mg/M(2) and 5-fluorouracil 700 mg/M(2) intravenously on the first and eighth days, and cyclophosphamide 100 mg/M(2) and prednisone 40 mg/M(2) by mouth daily for the first 14 days of a 28-day cycle. The patients had had no previous chemotherapy or extensive radiotherapy and all but two had not responded to hormonal therapy or endocrine ablation. The major metastatic lesions were: lung (12 patients), liver (four patients), bone (four patients), soft tissue (three patients), nodes (two patients). Seventeen of the 25 patients (68%) responded to treatment with seven complete remissions; these included patients suffering metastatic lesions in the lung, nodes, and soft tissue. The overall median duration of response was nine months (range 6-26 months). Toxicity was primarily haematological, but the group received an average of at least 75% of their calculated dose for each monthly cycle. Haematological toxicity was most pronounced in patients with liver dysfunction and bone marrow involvement. Out of eight nonresponders seven died, with a median survival of six months. Only six of 17 responders died, and the median survival in this group will exceed thirteen months. There was no correlation between the length of the metastasis-free interval after previous treatment and subsequent response to chemotherapy.