Sequential Topoisomerase I (Topo I) and Topoisomerase II (Topo II) Inhibitors in Relapsed/Refractory Aggressive NHL: Results of CALGN 59906, a Phase II Study of Doxorubicin and Topotecan.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2500-2500 ◽  
Author(s):  
Sonali M. Smith ◽  
Jeffrey L. Johnson ◽  
Donna Niedzwiecki ◽  
J. Paul Eder ◽  
George P. Canellos ◽  
...  
Keyword(s):  
Phase Ii ◽  
Topoisomerase I ◽  
Phase Ii Study ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Large Cell ◽  
Cell Transplant ◽  
Histologic Subtype ◽  
Sequential Administration ◽  
Topo Ii

Abstract Topoisomerase enzymes are critical components of genomic replication and function to minimize torsional stress on DNA. Inhibition of topoisomerase function leads to DNA strand breaks followed by apoptosis. In malignant lymphomas, topo II inhibitors (anthracyclines, epidophyllotoxins) are part of many active regimens, and topo I inhibitors (camptothecins) show modest single agent activity. Supported by preclinical data, we hypothesized that the sequential administration of a topo II inhibitor followed by a topo I inhibitor would be potentially synergistic, with enhanced cytotoxicity of the topo I inhibitor due to increased target enzyme levels following topo II inhibition. The treatment regimen consisted of doxorubicin 25 mg/m2 IV on day 1 and topotecan 1.75 mg/m2/d IV on days 3–5, repeated at 21 day intervals. The primary objective of this phase II study was to determine the overall response rate, time to progression, and toxicity in patients with relapsed/refractory aggressive NHL. Eligible patients had recurrent or refractory aggressive NHL, no prior camptothecins, and limited prior anthracycline exposure (<400 mg/m2 prior doxorubicin; <96 mg/m2 prior mitoxantrone), and an ejection fraction ≥ 45% at baseline. Results: From July 2000 to August 2003, 26 patients were registered. One registered patient did not start protocol treatment and is excluded from analysis. Of 22 patients with a known histologic subtype, 18 had diffuse large B cell lymphoma and there was one case each of Burkitt’s, follicular grade III, anaplastic large cell, and anaplastic large cell, Hodgkin’s like lymphoma. The median age was 58 (range 23–74) years. All patients were heavily pretreated with a median of 2 (range 1–5) prior regimens, including 5 patients who had a prior stem cell transplant (SCT). A median of 2 cycles (range 1–6) were administered. Five patients (20%, 95% CI 0.07, 0.42) responded with 1 (4%) complete remission (CR) and 4 (16%) partial remissions (PR); an additional 3 (12%) patients had stable disease. 12 (48%) patients progressed during or after the first cycle and 5 (20%) progressed after the second cycle. The one patient achieving a CR had Burkitt’s lymphoma, and received a total of 6 cycles; this patient remains in remission 21 months following the end of treatment. Of the PR patients, 2 remain in PR at 1.5 and 12 months following therapy, and 2 patients have progressed at 1.5 and 6 months. Interestingly, 4 of the 5 responders had prior SCT. The main toxicity was hematologic, with 14 (63%) and 9 (41%) patients having grade 3 or 4 neutropenia and thrombocytopenia, respectively. Three patients had febrile neutropenia. There were no treatment-related deaths. Seven patients remain alive and 18 patients have died. The median follow-up time for surviving patients is 14 (range 7–27) months. The median event-free survival is 1.3 months and the median overall survival is 3.6 months. The combination of doxorubicin and topotecan is well-tolerated and has modest activity in relapsed/refractory NHL, with an occasional patient having a prolonged remission.

L-mind: MOR208 combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large b-cell lymphoma (R-R DLBCL)—A single-arm phase II study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7514-7514 ◽  
Author(s):  
Kami J. Maddocks ◽  
Eva González Barca ◽  
Wojciech Jurczak ◽  
Anna Marina Liberati ◽  
Johannes Duell ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
International Prognostic Index ◽  
Single Agent ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Cell Of Origin

7514 Background: The Fc-enhanced CD19 antibody MOR208 and the immunomodulatory drug LEN have demonstrated single agent activity in patients (pts) with R-R DLBCL. MOR208 and LEN have shown synergy in vitro and in vivo in preclinical lymphoma models. This ongoing phase II study assesses the safety and efficacy of MOR208 + LEN in pts with R-R DLBCL. Methods: Pts >18 years old with R-R DLBCL, ECOG 0–2, adequate organ function, having previously received ≥1 but not more than 3 prior therapies, including ≥1 CD20-targeting regimen and who are not candidates for autologous stem cell transplant (ASCT), are eligible. Treatment comprises up to 12, 28-day (d) cycles (C) of MOR208 12 mg/kg IV, weekly during C1–3 (loading dose d4 of C1); every second week C4–12 + LEN 25 mg po d1–21, C1–12. Pts progression-free after 12 cycles receive up to 12 additional cycles of MOR208 (every second week). The primary endpoint is the overall response rate (ORR) by central radiology assessment. Secondary endpoints include disease control, duration of response, progression-free and overall survival, safety, and response by cell of origin and other biomarkers. A preplanned safety evaluation was undertaken. Results: 31 of 80 planned pts were enrolled prior to data cutoff (3 January 2017). Median age was 74 years (range 47–82); 45% of pts received ≥2 prior lines of therapy; 23% had rituximab refractory disease; 74% had Ann Arbor stage ≥III disease; 65% had elevated lactate dehydrogenase level, and 52% had a poor revised International Prognostic Index (3-5). The most common treatment-emergent adverse events (any grade/grade ≥3 [% pts]) were neutropenia (39/26), anemia (23/0) thrombocytopenia (16/6), infections (26/10) diarrhea (13/0), pyrexia (13/0), and rashes (13/6). Of 26 response evaluable pts (median follow-up 3.3 months), ORR (investigator assessed) was 58% (15 pts), with 7 (27%) complete responses. Median time to response was 1.8 months. Conclusions: The combination of MOR208 + LEN is well tolerated and shows promising activity in pts with R-R DLBCL. Accrual and follow-up of pts is ongoing, as are cell of origin and other biomarker analyses. Clinical trial information: NCT02399085.

Dose-Dense Induction Followed by Autologous Stem Cell Transplant (ASCT) as 1st Line Treatment in Peripheral T-Cell Lymphomas (PTCL) - A Phase II Study of the Nordic Lymphoma Group (NLG).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 401-401 ◽  
Author(s):  
Francesco d’Amore ◽  
Thomas Relander ◽  
Grete Lauritzsen ◽  
Esa Jantunen ◽  
Hans Hagberg ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Large Cell ◽  
High Dose ◽  
Cell Transplant ◽  
Post Transplant ◽  
Patient Cohort ◽  
Alk Positive ◽  
The Impact

Abstract Systemic PTCL, with the exception of alk-positive anaplastic large cell lymphoma (ALCL), have a poor prognosis. ASCT has been shown to have a favourable impact on relapsed PTCL. Therefore, the NLG designed a prospective multicenter phase II study to evaluate the impact of a dose-intensified induction schedule (6 courses of two-weekly CHOEP) consolidated in 1st PR/CR with high-dose therapy (BEAM) followed by ASCT in previously untreated systemic PTCL. This is the largest prospective PTCL-specific trial published so far. Newly diagnosed non-primary cutaneous PTCL cases aged 18–67 yrs were eligible for enrollment. Cases of alk-positive ALCL were excluded. From Oct 2001 to Feb 2006, 99 histologically confirmed PTCL cases were included in the study: PTCL unspecified (n=41), alk-neg ALCL (n=24), AILT (n=15), enteropathy-type (n=12), panniculitis-like (n=3), T/NK nasal-type (n=2), hepatosplenic (n=2). The M/F ratio was 1.8 and the median age 55 yrs (range 20–67 yrs). Although almost 2/3 of the cases presented with advanced-stage disease (62%), B-symptoms (61%) and/or elevated s-LDH (63%), the majority of them (65%) had a good performance score (WHO 0–1) at diagnosis. Of the 77 patients, where information was available for all 6 induction courses, 68 (88%) were in CR (31) or PR (37) after the 3rd and 66 (86%) after the 6th course. A total of 58 patients (75%) went through ASCT indicating that at least a fourth of this younger patient cohort has a primary refractory disease and fails therapy before reaching the transplant. Treatment-related toxicity after both induction and high-dose treatment was manageable. Of the 58 transplanted patients, 50 (86%) were still in remission at re-evaluation short after transplant. In 39 patients follow-up data one year post-transplant were available: 30 are still in CR and 9 have relapsed, suggesting that post-transplant relapses probably account for another 25% of the original patient cohort. In conclusion, the present data indicate that a time- and dose-intensified schedule is feasible and effective in previously untreated systemic PTCL. Continuous remissions are not uncommon, but a longer follow-up is needed to further characterize long-term remission rates and evaluate their impact on time-to-treatment failure and overall survival.

The Efficacy and Safety of Lenalidomide Oral Monotherapy in Patients with Mantle Cell Lymphoma Previously Treated with Bortezomib: Pooled Data from Two Phase II Studies (NHL-002 and NHL-003).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1560-1560 ◽  
Author(s):  
Craig B. Reeder ◽  
T.E. Witzig ◽  
Julie M. Vose ◽  
Pier Luigi Zinzani ◽  
Rena Buckstein ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Prior Treatment ◽  
Cell Transplant ◽  
Phase Ii Trials ◽  
Phase Ii Studies ◽  
Mantle Cell

Abstract Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-cell lymphoma that if not cured with aggressive chemoimmunotherapy and stem cell transplant is usually fatal. The intravenous proteasome inhibitor bortezomib produces an overall response rate (ORR) of 33% in patients with relapsed MCL (J Clin Oncol2006;24(30):4867–74). Unfortunately, most patients eventually relapse and new agents are needed for this disease. Two recently conducted phase II trials (NHL-002 and NHL-003) tested single-agent lenalidomide for patients with relapsed MCL. Fifty-four patients with MCL were enrolled into the two studies; 26% (14/54) had received prior bortezomib and they are the subject of this report. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least one prior treatment regimen including prior bortezomib were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Therapy was continued as tolerated or until disease progression. The 1999 IWLRC methodology was used to assess response and progression. Results: The 14 patients in this study were heavily pretreated with a median of 4 (2–6) prior treatments (including bortezomib) and 50% were bortezomib-refractory. Median age was 66 (45–84) years and 6 (43%) patients were female. Median time from diagnosis to lenalidomide treatment was 3.3 (0.7–7.6) years. The ORR with lenalidomide was 57% (8/14), including 21% (3/14) complete response (CR)/unconfirmed CR and 36% (5/14) partial responses. One (7%) patient had stable disease. The most common grade 3 or 4 adverse events were neutropenia (50%), thrombocytopenia (43%), anemia (21%), fatigue (21%), and leukopenia (21%). Neutropenic fever occurred in 7% of patients. Conclusion: These results demonstrate that lenalidomide oral monotherapy is very effective with manageable side effects in patients with relapsed or refractory MCL who had received prior treatment with bortezomib.

SGN-30 (Anti-CD30 mAb) Has a Single-Agent Response Rate of 21% in Patients with Refractory or Recurrent Systemic Anaplastic Large Cell Lymphoma (ALCL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2718-2718 ◽  
Author(s):  
Andres Forero-Torres ◽  
STeven H. Bernstein ◽  
Ajay Gopal ◽  
Francine Foss ◽  
John P. Leonard ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Objective Response ◽  
Cell Transplant ◽  
Cutaneous Lesions ◽  
Ecog Performance Status ◽  
Good Tolerability ◽  
Poor Prognostic Factor

Abstract SGN-30 is a monoclonal antibody directed against the CD30 antigen expressed on some hematologic malignancies. Based on encouraging phase I data, a multicenter phase II study was conducted treating patients with refractory or recurrent CD30-positive ALCL with an ECOG performance status of ≤ 2. Thirty-nine patients (24M, 15F) with ALCL were enrolled, with a median age of 57 (range 23–82) and a median of 3 prior therapies (range 2–5). Nine patients had previously received a stem cell transplant. Eighty-five percent of tumors were negative for ALK, a poor prognostic factor. SGN-30 was administred at 6 mg/kg/wk (90 minute infusion, premedications were not required) for 6 consecutive weeks. After 24 patients were enrolled, the dose was escalated to 12 mg/kg/wk in subsequent patients. (Patients with stable disease or objective response were eligible to receive additional cycles of SGN-30. Five patients received ≥ 2 cycles of SGN-30.) Response assessments, as determined by CT scans, were performed 2 weeks after the last infusion. Best response is shown below: CR PR SD PD Pending Eval ORR *Both CRs have ongoing durations of >365 days; both patients received additional cycles of SGN-30. **PRs had durations of 27, 53, 139 and 167 days; two additional patients have ongoing durations of 86+ and 25+ days. ***Three SDs have ongoing durations of 96+, 365+, and 365+ days. Two additional patients had SD for 71 and 174 days. 2* 6** 5*** 24 2 21% Three drug-related toxicities ≥ Grade 3 were reported (each was considered possibly related to SGN-30): 1) lymphopenia, 2) catheter related infection and 3) urticaria. No other significant hematologic or biochemical toxicities have been observed. There was one definitely related serious adverse event (Grade 2) in a patient who experienced a transient exacerbation of his cutaneous lesions after 2 doses of SGN-30 but achieved a partial response after continuing on study. This phase II study represents one of the largest prospectively designed trials in relapsed/refractory ALCL and demonstrates good tolerability and clinically meaningful antitumor activity of SGN-30, especially in ALK negative patients who have a particularly poor prognosis.

Safety and efficacy of YM155 in diffuse large B-cell lymphoma (DLBCL)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8502-8502 ◽  
Author(s):  
B. D. Cheson ◽  
J. M. Vose ◽  
N. L. Bartlett ◽  
A. Lopez ◽  
R. H. Van der Jagt ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Solid Tumors ◽  
Phase Ii ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Vein Thrombosis ◽  
Grade 3 ◽  
Anti Tumor Activity

8502 Background: Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. YM155, a survivin suppressant, has exhibited anti-tumor activity in solid tumors and non-Hodgkins lymphoma (NHL), including DLBCL patients enrolled in Phase I and Phase II monotherapy studies. Methods: Two studies enrolled 43 DLBCL patients; a Phase I study enrolled patients with solid tumors and NHL (n=1 relapsing DLBCL and n=1 refractory DLBCL), and a Phase II study enrolled refractory DLBCL patients (n=41). YM155 was administered at 4.8 mg/m2/day (Phase I) and at 5 mg/m2/day (Phase II) as a 168-hour continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until disease progression or unacceptable toxicity. Results: Data are presented for the first 27 patients (Phase I and Phase II) who have completed therapy. Median age was 61 (23–80) years and 63% were male. Three patients (11%) had partial responses (PR) confirmed by independent review using Cheson criteria (N=2; 1999 criteria and N=1; 2007 updated criteria). All responders received 2 prior regimens. Two responders were refractory to their last regimen and one had relapsed approximately 2 years after stem cell transplant (SCT). One patient responded after 2 cycles, completed 5 total cycles and proceeded to SCT (disease-free > 3.7 years post SCT). A second patient responded after 3 cycles, completed 7 total cycles and proceeded to SCT in OCT08. The third patient responded after 12 cycles and received 26 total cycles (1.5 years) before disease progression. The most common (>4%), treatment-related grade 3/4 adverse events included anemia (16.0%) and neutropenia, fatigue, hemoglobin decrease and deep vein thrombosis (8.0% each). Conclusions: YM155 is well tolerated and has modest single-agent, anti-tumor activity in relapsed/refractory DLBCL patients. Because of single-agent activity and preliminary data showing synergism when YM155 is combined with other agents additional clinical studies are being planned. [Table: see text]

A phase II study of oral gimatecan (ST1481) in women with progressing or recurring advanced epithelial ovarian, fallopian tube and peritoneal cancers

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5088-5088 ◽  
Author(s):  
S. Pecorelli ◽  
I. Ray-Coquard ◽  
N. Colombo ◽  
D. Katsaros ◽  
C. Lhomme ◽  
...  
Keyword(s):  
Fallopian Tube ◽  
Phase Ii ◽  
Topoisomerase I ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Ca 125 ◽  
Response Analysis ◽  
Free Interval

5088 Background: Gimatecan, a new camptothecin derivative, is a potent topoisomerase I inhibitor, active by oral route. Methods: A multicenter two stage Simon design phase II study was performed to evaluate the single agent antitumor activity of gimatecan. Secondary objectives were safety, time to event/time related parameters, and translational medicine evaluations. Women with advanced epithelial ovarian, fallopian tube or peritoneal cancer who had progressed or recurred after prior treatment with platinum and taxanes, had a progression-free interval from last platinum-based therapy < 12 months, had measurable disease by RECIST or assessable by CA 125 (GCIG criteria) and a ECOG performance status ≤ 1 were eligible. Gimatecan 0.8 mg/m2 was administrated orally for five consecutive days every four weeks. Radiological response was assessed every two cycles. Results: From June to December 2005, 70 women [median age 61 years (range 37–79)] were treated in 10 European sites. Number of prior chemotherapy regimens was: 1 in 20, 2 in 35, 3 in 15 patients, respectively. Progression-free interval from last platinum-based therapy was 0–6 months in 51 patients and 6–12 months in 19 patients. The study is still ongoing, and to date 40 consecutive patients are assessable. Preliminary response analysis indicated a 23.5% response rate based on CA 125 (8/34) and a 10% response rate based on RECIST (3/29). Main toxicity was hematological, namely thrombocytopenia and neutropenia. Conclusions: Preliminary results suggest that oral gimatecan administered as single agent is active, with bone marrow suppression resulting at present as the main toxicity in these patients previously treated with platinum and taxanes. However, many patients are still on treatment and data need to mature to have a broader picture of activity and safety. [Table: see text]

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