2-Chlorodeoxyadenosine treatment of low-grade lymphomas.

1992 ◽  
Vol 10 (3) ◽  
pp. 371-377 ◽  
Author(s):  
A C Kay ◽  
A Saven ◽  
C J Carrera ◽  
D A Carson ◽  
D Thurston ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Antineoplastic Agent ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Significant Activity ◽  
Prior Therapy ◽  
Significant Toxicity ◽  
Duration Of Response

PURPOSE Because of the need to identify effective new agents in the treatment of non-Hodgkin's lymphoma and because of the high activity of the purine analog 2-chlorodeoxyadenosine (2-CdA) against chronic lymphocytic leukemia and hairy cell leukemia, a phase II trial of 2-CdA was initiated in patients with low-grade lymphocytic lymphomas. PATIENTS AND METHODS Forty patients with low-grade lymphocytic lymphomas including diffuse small lymphocytic, follicular small-cleaved, and follicular mixed histologies were enrolled onto the study. Conventional therapies had failed in all patients, and six patients had lymph node biopsies showing evidence of histologic evolution to a higher-grade lymphoma. A total of 107 courses of 2-CdA were administered. There were 27 males and 13 females. The median age was 59 years (range, 37 to 80 years). Patients had received a median of three prior therapies (range, one to six therapies). RESULTS An overall response rate of 43% was achieved, with eight patients experiencing complete responses (CRs) and nine patients experiencing partial responses (PRs). The duration of responses ranged from 1 to greater than 33 months without maintenance therapy (median duration of response, 5 months). Histology and prior therapy history did not seem to correlate with responses. Significant toxicity was limited to bone marrow suppression; 18% of patients developed neutropenia, and 30% developed thrombocytopenia. CONCLUSIONS This phase II trial demonstrates that 2-CdA is an effective antilymphocyte, antineoplastic agent with significant activity as a single agent in patients with recurrent or refractory low-grade lymphocytic lymphoma. Responses were achieved with an acceptable toxicity profile. Further trials of this agent in previously untreated patients and in combination regimens are indicated and will be developed.

Phase II trial of paclitaxel by 24-hour continuous infusion for relapsed non-Hodgkin's lymphomas: Southwest Oncology Group trial 9246.

1998 ◽  
Vol 16 (2) ◽  
pp. 574-578 ◽  
Author(s):  
O W Press ◽  
M LeBlanc ◽  
T J O'Rourke ◽  
S Gagnet ◽  
R A Chapman ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Complete Response ◽  
Low Grade ◽  
High Grade ◽  
Oncology Group ◽  
Southwest Oncology Group ◽  
Hodgkin's Lymphomas

PURPOSE The Southwest Oncology Group (SWOG) recently conducted a multiinstitutional phase II trial to determine the complete response (CR) and partial response (PR) rates, toxicities, and progression-free and overall survivals of patients with relapsed non-Hodgkin's lymphomas (NHLs) treated with a 24-hour continuous infusion of paclitaxel at a dose of 175 mg/m2. PATIENTS AND METHODS Sixty-six patients with relapsed NHL who had received minimal prior therapy (one prior chemotherapy regimen for intermediate- to high-grade NHL [44 patients] or one or two prior regimens for low-grade NHL [22 patients]) were premedicated with dexamethasone, diphenhydramine, and cimetidine and then treated with continuous intravenous infusion paclitaxel over 24 hours every 21 days. RESULTS Eleven of 66 patients (17%) achieved rigorously documented objective remissions, including two CRs (3%) and nine PRs (14%). In addition, another five patients (8%) achieved apparent PRs on a single computed tomographic (CT) scan. Responses were brief, lasting a median of 3 months (5 months for indolent lymphomas and 3 months for intermediate- to high-grade lymphomas). Grade 4 or 5 granulocytopenia was the only common serious toxicity, and occurred in 42 of 66 patients (64%). CONCLUSION Paclitaxel is generally well tolerated when given as a continuous infusion of 175 mg/m2 over 24 hours, despite predictable granulocytopenia. However, single-agent paclitaxel has modest clinical efficacy compared with other available treatments for relapsed NHL.

First-line treatment with single agent rituximab, followed by maintenance rituximab plus anti-idiotype Id-KLH active immunotherapy vaccine (FavId) in patients (pts) with low-grade non-Hodgkin lymphoma (NHL): Preliminary results of a phase II trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8080-8080 ◽  
Author(s):  
E. Raefsky ◽  
F. A. Greco ◽  
D. R. Spigel ◽  
S. Litchy ◽  
V. Gian ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Active Immunotherapy ◽  
Low Grade ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

8080 Background: Single agent rituximab produces a high response rate when used as first-line treatment, and maintenance rituximab prolongs remission duration. Active immunotherapy is a promising treatment approach, when administered following remission induction by initial therapy. In this phase II trial, we evaluate the feasibility, toxicity, and efficacy of administering concurrent maintenance rituximab plus Id-KLH vaccine in pts with low-grade NHL. Methods: Pts with previously untreated low-grade NHL (grade 1/2 follicular or SLL) who were judged to be candidates for single agent rituximab therapy were eligible. All pts had initial biopsy for production of the Id-KLH vaccine. All pts received rituximab 375mg/m2 IV, weekly × 4. Pts with CR/CRu, PR, or stable disease at 8 weeks proceeded with maintenance rituximab (standard 4 week courses at 6 month intervals for 3 courses) and Id-KLH vaccination (Id-KLH 1cc day 1; GMCSF 250μg SQ days 1–4) monthly × 8, beginning month 3, then every 2 months during the second year. Pts were monitored for response rate, progression- free survival, and toxicity. Results: To date, 36 of a planned 56 pts have been enrolled. Idiotype vaccine was successfully manufactured in 27 of 32 pts (84%), with 4 in production. Of the 27 pts for whom Id-KLH was successfully manufactured, 2 progressed during rituximab. 19 of 25 pts (14FL;5SLL) have had response determined after rituximab: 8 PR (42%), 11 stable (58%; 4 of 5 SLL). Pts have now received rituximab maintenance therapy plus Id-KLH for durations of 6 - 34 months. 6 of 19 pts (3 SLL) progressed at months 5, 6, 9, 9, 10, and 12, respectively. Treatment has been well tolerated, with no unusual toxicities observed. Rituximab-related hypotension and atrial fibrillation occurred in 1 pt. The most common Id-KLH related adverse event has been injection site reaction. Conclusions: Concurrent maintenance therapy with rituximab plus Id-KLH is safe and well tolerated. At present, 6 of 25 pts (24%) have progressed (including 3 of the 5 SLL pts) with a median followup of 19 months. This trial is continuing. No significant financial relationships to disclose.

PX-171–004, a multicenter phase II study of carfilzomib (CFZ) in patients with relapsed myeloma: An efficacy update

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8537-8537 ◽  
Author(s):  
R. Vij ◽  
M. Wang ◽  
R. Orlowski ◽  
A. K. Stewart ◽  
S. Jagannath ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
Durable Response ◽  
Prior Therapy ◽  
Duration Of Response ◽  
Secondary Endpoints ◽  
Relapsed Disease

8537 Background: Carfilzomib (CFZ) is a proteasome inhibitor, active against hematologic malignancies. Preclinically, CFZ overcomes bortezomib (BTZ) resistance in multiple tumors, including myeloma (MM). PX-171–004 is an ongoing Phase II study evaluating safety and efficacy of CFZ in MM patients with relapsed disease after 1–3 prior therapies. Overall Response Rate (ORR) of 35.5% for all subjects was previously reported (ASH 2008); updated data are now available. Methods: Patients were divided into two cohorts: BTZ-naïve and BTZ-exposed. CFZ 20 mg/m2 was administered Days 1, 2, 8, 9, 15 and 16 in a 28-day cycle, for up to 12 cycles. Dexamethasone 4 mg po was administered prior to each dose in Cycle 1. The primary endpoint was ORR, defined as Partial Response (PR) or better. Secondary endpoints included Duration Of Response (DOR) and Time To Progression (TTP). Results: 31 patients were enrolled; 14 (45%) BTZ-naïve and 17 (55%) BTZ-exposed. Of the BTZ-exposed cohort, 2 subjects received BTZ exclusively as a single agent, 6 had BTZ in a chemotherapy combination, and 9 received BTZ in a transplant regime. Overall, 23 (74%) subjects had > 1 prior therapy and 27 (87%) received transplant. In BTZ-naïve patients, CFZ achieved an ORR of 57%; median DOR of 8.6 mos (range >1.9 to >9.7 mos). To date, 7 patients (50%) remain progression free and 3 patients have completed 12 cycles. The median follow-up was 10 mos and the median TTP has not been reached. For the BTZ- exposed group, CFZ achieved an ORR of 18%; median DOR not yet reached (>8.5 mos) (range >1 d to >8.5 mos). 7 patients (41%) are progression free and 3 patients have completed 12 cycles. Median follow-up and TTP were 9.2 and 8.9 mos, respectively. Conclusions: These preliminary results demonstrate that single-agent CFZ is tolerable for at least 1 yr and achieves sustained responses in relapsed MM. Prior BTZ mono/combination therapy does not preclude durable response with CFZ. These data support continuing evaluation of CFZ in the treatment of relapsed MM. [Table: see text] [Table: see text]

Phase II Trial of Pulse Dosed Lenalidomide In Previously Treated Chronic Lymphocytic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1383-1383 ◽  
Author(s):  
Georg Aue ◽  
Susan Soto ◽  
Janet Valdez ◽  
Diane C Arthur ◽  
Xin Tian ◽  
...  
Keyword(s):  
Side Effects ◽  
Chronic Lymphocytic Leukemia ◽  
Partial Response ◽  
Phase Ii ◽  
Stable Disease ◽  
Phase Ii Trial ◽  
Lymphocytic Leukemia ◽  
Bulky Disease ◽  
Starting Dose ◽  
Duration Of Response

Abstract Abstract 1383 Introduction: Lenalidomide (L) has activity in relapsed chronic lymphocytic leukemia (CLL). The mechanism of action is not well understood but may involve stimulation of anti-leukemic immune responses. Myelosuppression especially neutropenia is a concerning side effect. We reasoned that pulsed dosing of lenalidomide could reduce myelosuppression while maintaining the immune stimulatory effect. To test this concept we initiated a single center, phase II trial (ClinicalTrials.gov Identifier: NCT00465127) of lenalidomide given in cycles of 3 weeks on, 3 weeks off drug (42 day cycles). Methods: Patients (pts) with relapsed CLL or small lymphocytic lymphoma with ANC>500/ul and platelets >20,000/ul were eligible. The primary endpoint defined as response after 4 cycles has been recorded for all participants. Pts with partial response were allowed to receive up to 4 additional cycles. The starting dose for the first 10 pts was 20 mg daily; the starting dose for pt 11 onwards was lowered to 10 mg daily because of toxicities observed in other L trials for CLL. TLS prophylaxis with Allopurinol was mandated during cycle 1–3. Deep venous thrombosis (DVT) prophylaxis was not mandated unless risk factors were present. Ibuprofen and corticosteroids were allowed to treat symptoms of a cytokine release syndrome (CRS, defined by LN swelling, fever, fatigue, pain, chills, dehydration). Responses were assessed by IWCLL criteria and included CT scanning. Patient characteristics (n=33) were: median age 64 years (36-78); median number of prior therapies 3 (range 1–7); 52% Rai stage III-IV; 70% bulky disease; 30% fludarabine refractory; 56% (of 27 pts) ZAP70 pos; 64% (of 25 pts) unmutated immune globulin VH mutation status; 43% del 17p; 15% del 11q. Results: A total of 131 cycles of L were given. 31 pts received at least 2 cycles of therapy (range 2–8) and were evaluable for response: 5 (16%) partial response (PR), 18 (58%) stable disease, and 8 (26%) progressive disease. 4 of 5 responding pts had del 17p and bulky disease. In responders (n=5, PR) vs non responders (n=26, SD+PD) the PFS was 16 vs 6 months (p>0.01), and the time to next therapy was 17 vs 6 months (p>0.01), respectively. Once treatment was stopped, duration of response was short lived (median 6 months, range 2–18). 4 out of 5 responders were observed in the 20 mg dose starting group versus only 1 responder in the 10 mg group (p=0.03). There was no difference in the CRS score between the 2 groups (2.5 vs 1.5, p=0.17). Hematologic responses were observed in 11 out of 24 CLL pts (45%). At the completion of 4 cycles CD4 and CD8 counts increased by 20%, while NK cell counts remained unchanged. Dose modifications/withdrawl: 41% of cycles required dose adjustments prior to or during cycles 1–4. 9 pts (27%) did not complete 4 cycles of L because of: autoimmune cytopenias (2 pts), side effects (4 pts; CRS 1 pt, neutropenia 3 pts), withdrawal from study (2 pts), and disease progression (1 pt). Toxicity: Gr 3/4 neutropenia was observed in 56% of 131 cycles, often worsening with cumulative cycles. Gr 3/4 thombocytopenia and anemia were seen in 30% and 15% of cycles, respectively. Gr 1/2 and 3/4 infections occurred in 23% and 11% of cycles, respectively, 8 of those in the setting of neutropenia. Gr 3 CMV colitis, PCP pneumonia and Candedemia each were observed once. 1 patient died from streptococcal sepsis in cycle 4. Gr 1/2 and 3/4 CRS were observed in 43% and 10% of cycles, respectively. A CRS was encountered in 78% of first cycles typically within the first week, and in 48%, 38% and 30% of cycles 2–4, respectively. 6 DVTs (Gr 3) were diagnosed in 5 pts. Other common side effects were fatigue (62%), rash (39%) and muscle cramps (27%), all Gr 1/2. No case of tumor lysis syndrome was seen. Conclusion: L cycled 3 weeks on, 3 weeks off led to stable disease in the majority of pts and induced PRs in 16% of relapsed CLL patients with high risk disease. Pulse dosing of L did not lead to reduced toxicities. Myelosuppression and infections remain a major concern. 4 out of 5 responders were observed in the 20 mg cohort arguing for higher L starting doses. Notably, side effects, particularly the CRS, were similar in the two cohorts. Once L was discontinued, the duration of response was short, suggesting a need for continued therapy in pts who are able to tolerate the drug. Disclosures: Off Label Use: Lenalidomide is not FDA approved in Chronic Lymphocytic leukemia.

Multi-Center Phase II Study of Perifosine (KRX-0401) Alone and in Combination with Dexamethasone (dex) for Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Promising Activity as Combination Therapy with Manageable Toxicity.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1164-1164 ◽  
Author(s):  
Paul Richardson ◽  
S. Lonial ◽  
A. Jakubowiak ◽  
A. Krishnan ◽  
J. Wolf ◽  
...  
Keyword(s):  
Phase Ii ◽  
Stable Disease ◽  
Single Agent ◽  
Gene Array ◽  
In Vivo Studies ◽  
Significant Activity ◽  
Prior Therapy ◽  
Best Response

Abstract INTRODUCTION: Perifosine (peri) is an oral, novel synthetic alkylphospholipid, with multiple effects on signal transduction pathways, including inhibition of Akt and activation of JNK. In vitro studies showed that peri induces cytotoxicity in both MM cell lines and patient (pt) MM cells resistant to conventional therapies, and augments dexamethasone (dex) and bortezomib-induced MM cell cytotoxicity (Hideshima T. et. al. BLOOD 2006). In vivo studies showed antitumor activity in a human plasmacytoma mouse model. Here we report the results of a phase II trial of peri, alone and + dex, in pts with relapsed or relapsed / refractory MM. METHODS: Pts received 150 mg of peri daily for a 21 day (d) cycle, and were assessed every cycle by serum- and/or urine-electrophoresis. Eligible pts had symptomatic relapsed or relapsed / refractory MM. Pts were permitted to receive bisphosphonate treatment. Concomitant steroids (prednisone > 10 mg/d), creatinine of > 3.0 mg/dL, and hemoglobin < 8.0 g/dL within 14 d of enrollment were exclusion criteria. Progressing pts, documented on 2 occasions at least one week apart, had dex 20 mg twice per week added to peri. Toxicities were assessed by NCI-CTCAE, v3.0. RESULTS: 64 pts (35 M/ 29 F, median age 62, range 38–79) have been treated to date. Median lines of prior treatment was 4 (range 1–11); 32 (50%) pts had relapsed and refractory MM. Prior therapy included dex (95%), thalidomide (89%), bortezomib (73%), lenalidomide (30%) and ASCT (61%). Among 48 pts currently evaluable for response, best response (EBMT criteria) to single agent peri after ≥ 2 cycles was MR in 1 pt, stable disease (< 25% reduction in M-protein) in 22 pts (46%). Dex was added in 37 pts with PD, with 31 pts evaluable for response on the combination as follows: Peri + Dex N (%) Duration (wks) PR 4 (13%) 17, 24, 44+, 46+ MR 8 (25%) 3+, 12+, 19, 21, 25, 30, 32, 55+ Stable Disease 15 (47%) 6+ − 46 (median 12)* *4 pts ongoing at 6, 9, 11 and 24 wks Most common adverse events included nausea (74%, 8% G3); vomiting (61%, 5% G3); diarrhea (65%, 2% G3); fatigue (31%, 2% G3), increased creatinine (51%, 7% G3/4 in the context of PD and light chain nephropathy but reversible) and anemia (63%, 5% G3). 10 pts had G3/4 neutropenia which resolved. Dose reduction was required to 100 mg/d (n=16) or to 50 mg/d (n=4). 9 pts discontinued treatment due to side effects. Attributable toxicities otherwise proved manageable with supportive care and no peripheral neuropathy or DVT seen. CONCLUSION: Perifosine as monotherapy has modest activity, but in combination with dex showed significant activity in pts with relapsed/refractory MM, achieving PR + MR in 38%, and/or stabilization of disease in 47% of evaluable pts to date. It was generally well tolerated, although caution in pts with renal dysfunction is warranted. PK, IHC and gene array studies are ongoing. Other novel studies with peri in combination with bortezomib and with lenalidomide +/−dex are underway.

Clinical Activity and Safety of the Combined Therapy with the AKT Inhibitor Perifosine and the Multikinase Inhibitor Sorafenib In Heavily Pretreated Patients with Relapsed/Refractory Lymphomas: Preliminary Results of a Phase II Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2861-2861
Author(s):  
Carmelo Carlo-Stella ◽  
Anna Guidetti ◽  
Simonetta Viviani ◽  
Liliana Devizzi ◽  
Paola Matteucci ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Akt Inhibitor ◽  
Multikinase Inhibitor ◽  
Significant Toxicity ◽  
Heavily Pretreated

Abstract Abstract 2861 Introduction: The AKT inhibitor Perifosine (Æterna Zentaris GmBH, Germany) has been shown in phase II studies to induce partial responses in a variety of solid tumors. Sorafenib (Nexavar, Bayer) is an oral multikinase inhibitor exerting in vitro and in vivo antiproliferative, antiangiogenic, and proapoptotic effects in a variety of hematological and nonhematological tumors. Our preclinical data demonstrating that the combination of Perifosine and Sorafenib induces gene expression profiling and signaling changes associated with a synergistic cytotoxic activity against lymphoma cell lines in vitro and in vivo, established the rationale for this ongoing phase II study aimed to determine safety and activity of Perifosine/Sorafenib combination therapy in relapsed/refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Methods: Between July 2008 and July 2010, 26 out of 36 planned patients (18 males and 8 females; median age, 42 years; range, 19–73 years) with relapsed/refractory diffuse large B cell lymphoma (DLBCL, n = 3), follicular lymphoma (FL, n = 3), Waldenstrom macroglobulinemia (WM, n = 1), chronic lymphocytic leukemia (CLL, n = 4), and HL (n = 15) who have failed second- or subsequent-line salvage chemo-radiotherapy were enrolled in this trial. Prior to study entry, patients received a median of 5 (range 2 – 11) lines of treatment with autologous SCT performed in 19 (73%) and an additional allogeneic SCT in 10 (38%) patients. At study entry, 7 patients had relapsed and 19 refractory lymphoma. Perifosine (50 mg BID, per os) was initially administered as single agent for 4 weeks to assess tolerability and tumor response. Patients achieving less than partial remission (PR) were given the combination therapy, i.e., Perifosine (50 mg BID, per os) plus Sorafenib (400 mg BID, per os) until disease progression or clinical significant toxicity. Patients achieving ≥PR went off-study and continued with Perifosine (50 mg BID, per os) alone until disease progression or clinical significant toxicity. Tumor responses were assessed according to the revised response criteria for malignant lymphoma of the International Working Group. NCI CTCAE v3.0 was used for toxicity assessment. The study was approved by the Institutional Ethical Committee. Results: After a 4-week treatment with Perifosine alone, 22 out of 26 patients achieved <PR and were started on Perifosine/Sorafenib combination therapy. As of July 2010, a median of 5 months (range, 2 – 18) combination therapy have been administered, and 22 patients are evaluable for toxicity and response. In contrast, 4 patients who achieved ≥PR went off-study and continued therapy with Perifosine single agent. Combination therapy was well tolerated without significant adverse events. No patients interrupted the treatment due to toxicity. The most common drug-related hematological toxicities included grade 1–2 anemia (5%), neutropenia (5%), and thrombocytopenia (18%). Non-hematological toxicities included grade 1–2 diarrhea (27%) and hand-foot syndrome (27%). Three patients (14%) experienced grade 3 infections [pneumonia (n = 2), skin infection (n = 1)]. Best response to Perifosine/Sorafenib therapy included 5 (23%) PR with median response duration of 9 months (range, 1– 12) with 2 of 5 patients having received an allogeneic SCT. Eleven patients (50%) achieved stable disease (SD) with 7 patients (32%) achieving SD for ≥4 months, while 6 patients (27%) progressed. Interestingly, all responding patients had a diagnosis of HL, thus raising to 33% the PR rate in this histological subgroup. At a median follow-up of 11 months (range, 5 – 25), study patients (n = 22) have a median overall survival (OS) of 15 months and a projected 2-year OS of 42% (95% CI: 20% - 66%), with a median time to progression (TTP) for patients achieving PR or SD (n = 16) of 7 months. The subgroup of HL patients (n =15) has a median OS of 16 months and a projected 2-year OS of 42% (95% CI: 12% - 72%), with a median TTP for patients achieving PR or SD (n = 11) of 10 months. Conclusions: Perifosine/Sorafenib combination therapy has a good toxicity profile and is well tolerated by heavily pretreated, refractory/relapsed lymphoma patients. Preliminary results from this phase II trial suggest that Perifosine/Sorafenib combination therapy exerts significant anti-lymphoma activity in at least one third of relapsed/refractory HL patients, whereas no response other than SD was observed in NHL patients. Disclosures: Off Label Use: Sorafenib for lymphoma.

A phase II trial of oxaliplatin and docetaxel in patients with androgen independent prostate cancer (AIPC) who have progressed to two prior regimens of chemotherapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15545-15545 ◽  
Author(s):  
T. Feinstein ◽  
L. J. Appleman ◽  
D. M. Friedland ◽  
S. A. Jacobs ◽  
W. A. Ferri ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Free Survival ◽  
Duration Of Response ◽  
Psa Response ◽  
Previously Treated ◽  
Grade 3

15545 Background: Single agent docetaxel has demonstrated survival benefit in AIPC. In a phase I study of single agent oxaliplatin at our institution, two patients with AIPC experienced a substantial and durable reduction in PSA. Thus, we hypothesised that a combination of oxaliplatin and docetaxel maybe beneficial in AIPC. Methods: This single arm phase II trial in patients with previously treated (0–2 regimens) and progressive AIPC commenced in June 2005, with the objectives of evaluating PSA response rates, progression free survival, and the toxicity (tolerance/safety) of the regimen. In patients with soft tissue disease, measurable responses were assessed by RECIST criteria. Using Simon stage II design, a total of 37 patients with AIPC will be accrued. No prior treatment with platinum was allowed. Treatment consisted of oxaliplatin (110 mg/m2) and docetaxel (60 mg/m2), administered intravenously every 21 days for a maximum of 6 cycles. Results: 27 men have been enrolled to date: median age 66 yrs (56–84). 21 of 27 men have completed at least two cycles of the above regimen, and are evaluable. Prior therapies included antiandrogens (100%); ketaconazole (14%); docetaxel alone or in combination (27%); anthracyclines (27%); and vaccine (5%). Median PSA at baseline was 88 ng/ml (range 2.2–3559.4). 62% of patients received all six cycles. PSA declines of ≥50% were noted in 11 of 21 patients: 3 of 8 responders being chemo-naïve; and 8 of 13 with prior chemotherapy exposure. In addition, 4 of 11 patients with measurable disease at baseline, had a partial response. Treatment was well tolerated with no treatment-related deaths. The most significant grade 3/4 adverse event (AE) was neutropenia (43%). Grade 2 or less fatigue (66%), neuropathy (53%) diarrhea (47%), nausea (41%), anorexia (29%), thrombocytopenia (12%) and anemia (6%). Conclusions: The combination of oxaliplatin and docetaxel has promising activity in both chemo-naïve and previously treated AIPC. This 2-stage study will accrue a total of 37 patients. Final analysis will include time to progression, duration of response, and median survival. [Table: see text]

Combination immunotherapy with ipilimumab and nivolumab in patients with rare gynaecological malignancies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6091-6091
Author(s):  
Oliver Klein ◽  
Damien Kee ◽  
Bo Gao ◽  
Ben Markman ◽  
Linda R. Mileshkin ◽  
...  
Keyword(s):  
Clear Cell ◽  
Single Agent ◽  
Low Grade ◽  
Gynecological Cancers ◽  
Prior Therapy ◽  
Gynecological Malignancies ◽  
Duration Of Response ◽  
Radiological Response ◽  
Grade 3 ◽  
Tumor Types

6091 Background: Up to 50% of gynecological cancers are considered rare. The outcome of these patients (pts) is poor given a lack of scientific and clinical knowledge. Immunotherapy using single agent anti- PD-1/PD-L1 treatment (tx) has shown only modest activity in patients with common gynecological malignancies, such as high grade serous ovarian cancer (ca) and microsatellite stable endometrial ca. Combined CTLA-4/PD-1 blockade using ipilimumab (ipi) and nivolumab (nivo) has demonstrated superior efficacy compared to single agent anti-PD-1 therapy in pts with advanced melanoma and renal cell ca. To date, no trials have been undertaken with ipi/nivo in patients with rare gynecological malignancies. Methods: 41 pts with advanced rare gynecological malignancies were enrolled into the CA209-538 trial. Pts received nivo 3mg/kg and ipi 1mg/kg q 3 weekly for four doses, followed by nivo 3mg/kg q 2 weekly. Tx continued for up to 96 weeks, or until disease progression or the development of unacceptable toxicity. Response (RECIST 1.1) was assessed every 12 weeks. The primary endpoint was clinical benefit rate (CBR = CR +PR + SD). Exploratory endpoints include correlation of efficacy with biomarkers (incl PD-L1/TMB). Results: Pts with 10 rare tumor types were enrolled (Table). 39/41 pts have received prior therapy (1-7 lines). Objective responses were observed in 11 pts (27%) including pts with vaginal SCC, ovarian clear cell and low grade serous ca, ovarian and uterine carcinosarcoma, uterine clear cell, uterine serous ca and leiomyosarcoma. A further 9 pts had SD as their best radiological response resulting in a CBR of 49%. The median duration of response had not been reached (range 3.5 – 25+ months) with seven responses being ongoing. 63% of pts experienced an immune related adverse event (irAEs) with 4 pts developing Grade 3/4 irAEs. Conclusions: Ipi/Nivo tx demonstrates efficacy in a range of different rare gynecological cancers with a significant number of durable responses being observed. Tumor agnostic biomarkers are required to assist with better patient selection. Clinical trial information: NCT02923934. [Table: see text]

Single-Agent Monoclonal Antibody Efficacy in Bulky Non-Hodgkin's Lymphoma: Results of a Phase II Trial of Rituximab

1999 ◽  
Vol 17 (6) ◽  
pp. 1851-1851 ◽  
Author(s):  
T. A. Davis ◽  
C. A. White ◽  
A. J. Grillo-López ◽  
W. S. Velásquez ◽  
B. Link ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase Ii ◽  
Hodgkin’S Lymphoma ◽  
Phase Ii Trial ◽  
Single Agent ◽  
Lesion Size ◽  
Hodgkin's Lymphoma ◽  
Antibody Concentration ◽  
Low Grade ◽  
Non Hodgkin's Lymphoma

PURPOSE: A phase II trial was performed to evaluate the safety and efficacy of rituximab, a chimeric anti-CD20 monoclonal antibody, in patients with bulky (> 10-cm lesion) relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-one patients received intravenous infusions of rituximab 375 mg/m2 weekly for four doses. All patients had at least one prior therapy (median, three; range, one to 13) and had progressive disease at study entry. Patients were a median of 4 years from diagnosis. RESULTS: No patient had treatment discontinued because of an adverse event. No patient developed human antichimeric antibody. The overall response rate in 28 assessable patients was 43% with a median time to progression of 8.1 months (range, 4.5 to 18.6+ months) and median duration of response of 5.9 months (range, 2.8 to 12.1+ months). The average decrease in lesion size in patients who achieved a partial response was 76%, and patients with stable disease had a decrease in average lesion size of 26%. Median serum antibody concentration was higher in responders compared with nonresponders, and a negative correlation was shown between antibody concentration and tumor bulk at baseline. CONCLUSION: Rituximab single-agent outpatient therapy is safe and shows significant clinical activity in patients with bulky relapsed or refractory low-grade or follicular B-cell NHL.

Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies.

1991 ◽  
Vol 9 (1) ◽  
pp. 175-188 ◽  
Author(s):  
H G Chun ◽  
B Leyland-Jones ◽  
B D Cheson
Keyword(s):  
Clinical Trials ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Cytotoxic Action ◽  
Low Grade ◽  
Significant Activity ◽  
Prolymphocytic Leukemia ◽  
Lymphoid Malignancies ◽  
Fludarabine Phosphate ◽  
Combination Regimens

Fludarabine phosphate is the 2-fluoro, 5'-monophosphate derivative of vidarabine (ara-A) with the advantages of resistance to deamination by adenosine deaminase (ADA) and improved solubility. The mechanism of cytotoxic action of the compound appears to involve metabolic conversion to the active triphosphate. Fludarabine phosphate has substantial activity against lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and low-grade non-Hodgkin's lymphoma (NHL). Its single-agent activity in CLL appears at least comparable to those of other conventional combination regimens. Its activity in Hodgkin's disease, mycosis fungoides, and macroglobulinemia, although suggestive, needs to be further defined and clinical trials are warranted in hairy cell leukemia, prolymphocytic leukemia, and previously untreated myeloma. The compound does not appear active against most common solid tumors. Early clinical trials indicated significant myelosuppression and the potential for severe neurotoxicity. Toxicity on the currently used low-dose schedules includes transient and reversible myelosuppression, nausea and vomiting, diarrhea, somnolence/fatigue, and elevations of liver enzymes and/or serum creatinine. Possible pulmonary toxicity has been suggested in several patients. The currently used low-doses of fludarabine phosphate, even with repeated administration, are well tolerated and appear safe with a negligible risk for severe neurotoxicity. Based on its single-agent activity and tolerability, the Food and Drug Administration recently granted group C designation of the drug for the treatment of patients with refractory CLL outside the clinical trials setting. The use of fludarabine phosphate in combination regimens and its impact on the natural history of the lymphoid malignancies is yet to be determined. Fludarabine phosphate may well occupy a pivotal role in the management of CLL and low-grade NHL.

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