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Zevalin (Ibritumomab Tiuxetan) Demonstrated Activity in Several Investigational Phase 2 Trials Presented at the 51st Annual Meeting of the American Society of Hematology

  • Radio Immunotherapy (RIT) Demonstrated Activity as Consolidation After Immuno Chemotherapy in Elderly DLBCL Patients and Follicular Lymphoma Patients
  • ZEVALIN also Demonstrated Activity in Stem Cell Transplantation
  • ZEVALIN is Currently Indicated for the Treatment of Patients with:
    • Previously Untreated Follicular Non-Hodgkin's Lymphoma (NHL), Who Achieve a Partial or Complete Response to First-Line Chemotherapy
    • Relapsed or Refractory, Low-Grade or Follicular B-Cell Non-Hodgkin's Lymphoma

IRVINE, Calif.--(BUSINESS WIRE)--Dec 11, 2009 - Spectrum Pharmaceuticals, Inc. (NasdaqGM:SPPI), a commercial stage biotechnology company with a primary focus in oncology, today announced that clinical data on ZEVALIN (ibritumomab tiuxetan) was presented at the 51st Annual Meeting of the American Society of Hematology (ASH), which was held December 5-8, 2009 at the Ernest N. Morial Convention Center in New Orleans, Louisiana.

The following are three key ZEVALIN-related abstracts of the 14 that were presented at the conference.

Shown below are the summary descriptions of study Patients and Methods, Results, and Conclusions, as shown on the ASH website.

Abstract #2720 – A Phase II Trial of Rituximab-CHOP Chemotherapy Followed by Yttrium 90 (90Y) Ibritumomab Tiuxetan (90Y-IT) for Previously Untreated Elderly Diffuse Large B-Cell Lymphoma (DLBCL) Patients

Authors:

 

      Pier Luigi Zinzani1, Mariapaola Fina1*, Monica Tani1*, Vittorio Stefoni2*, Letizia Gandolfi1*, Alessandro Broccoli1*, Cinzia Pellegrini1*, Enrico Derenzini1*, Giuseppe Rossi, MD3, Emanuele Angelucci4, Gianluca Gaidano5, Maria Concetta Petti6*, Maurizio Martelli7*, Umberto Vitolo8, Stefano Fanti9* and Michele Baccarani1*

 

1Institute of Hematology and Medical Oncology “L. & A. Seràgnoli”, Bologna, Italy

 

2On the behalf of Intergruppo Italiano Linfomi (IIL), Hematology 2, AOU San Giovanni Battista, Torino, Italy

 

3Department of Hematology, Spedali Civili, Brescia, Italy

 

4On behalf of GIMURELL and IIL, Hematology 2, AOU San Giovanni Battista, Torino, Italy

 

5Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy

 

6Dept. of Clinical Oncology, Hematology-Istituto Regina Elena, Rome, Italy

 

7Hematology, University La Sapienza, Roma, Italy

 

8Hematology 2, AOU San Giovanni Battista, Turin, Italy

 

9Department of Nuclear Medicine, University of Bologna, Bologna, Italy

 

*signifies non-member of ASH

 

Introduction: In 2008 we published a phase II trial about the combination of 6 cycles of CHOP plus 90Y-IT for previously untreated elderly patients with DLBCL. The CCR was 95% with OS at 2 years of 95% and PFS at 2 years of 75%. The results of this study support a further evaluation of 90Y-IT in combination of chemotherapy. We conducted a prospective, single-arm, non-randomized, phase II trial with CHOP plus Rituximab followed by 90Y-IT reducing the number of CHOP cycles from 6 to 4 but introducing Rituximab. The rationale is to utilize all the therapeutic approaches (chemotherapy, immunotherapy and radioimmunotherapy) reducing conventional chemotherapy and probably related toxicity.

Patients and Methods: Patient eligibility was represented by: patients older than 60 years with biopsy proven, untreated, bidimensionally measurable stage II, III or IV DLBCL. Expression the CD-20 antigen; WHO performance status of 0 to 2. Patients were treated with standard CHOP chemotherapy plus Rituximab every 21 days for 4 cycles. Patients were restaged 4 to 6 weeks after completion of 4 cycles of R-CHOP chemotherapy. Patients achieving CR, PR or SD after chemotherapy were eligible for consolidation with 90Y-IT provided the granulocyte count was greater than 1500/microl, the platelet count exceeded 100.000/microl and the bone marrow examination at the completion of chemotherapy demonstrated no more than 25% involvement with lymphoma. All patients were to receive a single dose of 90Y-IT 14.8 MBq/kg (0.4 mCi/kg). Fifty-five patients have been enrolled: 26 were male and 29 female; the median age was 70 years (range 60-83); 17 were stage II, 38 were stage III-IV.

Results: Fifty-one patients had completed the R-CHOP treatment and the overall response rate was 94.1% including 30 (58.8%) of patients in CR and 17 (35.3%) in PR. Treatment was well tolerated; grade 3-4 AEs are comparable with previous experience and the most common grade 3-4 AEs was neutropenia. At this time 47 patients had just received 90Y-IT and 45 are evaluable. In particular, 9/17 (52.9%) patients converted from PR to CR after treatment with 90Y-IT.

Conclusions: These preliminary data indicate that radioimmunotherapy appears highly effective and feasible as “consolidation” after 4 cycles of immunochemotherapy in elderly DLBCL patients, improving quality of response without any cumulative toxicity.

Disclosures: Off Label Use: The drug Yttrium 90 (90Y) Ibritumomab Tiuxetan (90Y-IT) (Zevalin) is off-label for Diffuse Large B-Cell Lymphoma (DLBCL).

ZEVALIN is not approved for the use described in the above abstract.

Abstract #3743 – A Phase II Trial of R-FM (Rituximab, Fludarabine and Mitoxantrone) Chemotherapy Followed by Yttrium 90 (90Y) Ibritumomab Tiuxetan (90Y-IT) for Untreated Follicular Lymphoma (FL) Patients

Authors:       Pier Luigi Zinzani1, Monica Tani1*, Alessandro Broccoli1*, Enrico Derenzini1*, Alessandro Pulsoni2*, Amalia De Renzo3*, Stefano Fanti4*, Mariapaola Fina1*, Letizia Gandolfi1*, Cinzia Pellegrini1*, Vittorio Stefoni1* and Michele Baccarani1*
1Institute of Hematology and Medical Oncology “L. & A. Seràgnoli”, Bologna, Italy

 

2Dipartimento Biotecnologie Cellulari ed Ematologia, Universita' La Sapienza, Roma, Italy

 

3Department of Haematology, Federico II University, Naples, Italy, Napoli, Italy

 

4Department of Nuclear Medicine, University of Bologna, Bologna, Italy

 

*signifies non-member of ASH

 

Introduction: In 2008 we published a multicenter non-randomized phase II trial of fludarabine and mitoxantrone plus 90Y-IT in untreated patients with FL. By the end of the entire treatment regimen 95% of the patients achieved complete remission (CR). With a median follow-up of 30 months, 3-year PFS was estimated to be 76% and 3-year OS 100%. On the basis of these results we are currently conducting a prospective, multicenter, non-randomized, phase II study of R-FM followed by 90Y-IT in untreated patients with FL in which the number of fludarabine and mitoxantrone cycles has been decreased to four and in which rituximab is administered before each cycle. The rationale of the trial is to use different forms of treatment and to reduce the use of conventional chemotherapy and its related toxic effects.

Patients and Methods: Patients eligibility is represented by: age more than 18, stage II-IV, FL grade I-II, WHO performance status 0-2. Patients are treated with standard FM chemotherapy plus rituximab every 28 days for 4 cycles. Patients are restaged 4 to 8 weeks after completion of immunochemotherapy and those achieving at least a partial response are eligible for 90Y-IT. All patients receive a single dose of 90Y-IT 14.8 MBq/kg. At the time of the analysis we enrolled 55 patients. 25 patients were male and 30 female; the median age was 56 years (range 26-84); 12 patients were stage II, 13 stage III and 30 stage IV; 11 patients had a bulky disease. 52 patients completed the induction chemotherapy, all except 5 were eligible for the consolidation treatment with 90Y-IT and 44 patients were restaged after the entire treatment regimen.

Results: After the R-FM chemotherapy, the overall response rate was 92.3% (48/52) including 39 (75%) CR and 9 (17.3%) partial remissions (PR). Time to event analyses, including TTP and duration of response are pending further follow-up. Treatment was well tolerated grade 3-4 haematologic AEs (mostly neutropenia) were seen in 50% of the patients. Among the 44 patients (9 PR and 35 CR) subsequently treated with 90Y-IT and reassessed for the response, 8/9 (88.9%) PR patients improved their remission status from PR to CR. 90Y-IT toxicity included mostly grade 3-4 neutropenia and thrombocytopenia and was comparable to the literature data.

Conclusions: These preliminary data indicate that radioimmunotherapy appears highly effective and feasible as “consolidation” after short (4 cycles) immunochemotherapy in FL patients, improving quality of response without any cumulative toxicity.

Abstract 868 – Stem Cell Transplantation with 90yttrium Ibritumomab Tiuxetan (90YIT) in Non-Hodgkin's Lymphoma (NHL): Observations from PET Pre-Treatment Imaging and Responses in Allografted Refractory Follicular Histologies

Authors:       Issa F Khouri1, Robyn Harrell2*, Rosamar Valverde1*, Martin Korbling1*, Taghi Manshouri3*, Barry Samuels4*, Farzaneh Maadani1*, Grace-Julia Okoroji1*, Roland L Bassett Jr.5*, Alousi Amin1*, Paolo Anderlini1*, Marcos De Lima1*, Sergio Giralt1*, Chitra Hosing1*, Partow Kebriaei1*, Uday Popat1*, Muzaffar Qazilbash1*, Naoto Ueno1*, Anne Marie Stachowiak6*, Bill Erwin7*, Luis Fayad8*, Barbara Pro8*, Nathan Fowler8*, Peter McLaughlin8*, Sattva Neelapu8*, Anas Younes8*, Richard Champlin1* and Donald Podoloff9*
1Stem Cell Transplantation and Cellular Therapy, UT MD Anderson Cancer Center, Houston, TX

 

2Biostatistics, UT MD Anderson Cancer Center, Houston

 

3Leukemia, UT MD Anderson Cancer Center, Houston, TX

 

4Diagnostic Radiology, UT MD Anderson Cancer Center, Houston, TX

 

5Biostatistics, UT MD Anderson Cancer Center, Houston, TX

 

6Diagnostic Imaging, UT MD Anderson Cancer Center, Houston, TX

 

7Imaging Physics, UT MD Anderson Cancer Center, Houston, TX

 

8Lymphoma/Myeloma, UT MD Anderson Cancer Center, Houston, TX

 

9Nuclear Medicine, UT MD Anderson Cancer Center, Houston, TX

 

*signifies non-member of ASH

 

Background: Relapse continues to be the primary cause of treatment failure in patients (pts) with NHL undergoing transplantation. We have previously reported the adverse prognostic value of PET+ in autologous transplants (AUTO) and disease refractoriness in pts undertaking a non-myeloablative allogeneic transplantation (NST). In order to improve outcome, we and others have previously established the feasibility of addition of 90YIT to the transplant conditioning. Herein, we report the long-term efficacy of this strategy in 74 pts.

Methods: Each pt received a single dose of 90YIT (0.4 mCi/kg on day -14) with BEAM as a conditioning regimen in AUTO candidates [relapsed chemosensitive diffuse large cell b-cell (DLBCL); relapsed chemosensitive follicular (FL) if no matched sibling donor was available; mantle cell (MCL) in first remission; age ‰¤ 65], or with fludarabine, cyclophosphamide and rituximab (Blood 2008:111:5530) in candidates for NST (relapsed chemosensitive or refractory FL and MCL, transformed NHL if not candidates for AUTO, CLL, up to 50% marrow involvement with disease, age ‰¤ 70).

Results: This cohort included 40 pts (DLBCL=25, FL=11, MCL=3, SLL =1). Median age was 53 (range, 31-65) years. Median prior treatments was 2 (range, 1-4). At transplant, 21(52.5%) were in CR, 16 (40%) in PR, and 3 pts (7.5%) with DLBCL had stable disease. Nine pts (22.5%) had elevated LDH and 7 of 38 (18%) were PET+. At study entry, median serum rituximab level was 5mcg/ML (range, 0-56.4), and soluble CD20 serum level was 457 nM/L (range, 20.7-1501). Adverse events were similar to those with BEAM alone, and 4 pts (10%) developed secondary malignancies. Median time to >ANC 500 was 9 (range, 7-12) days and to platelet >20,000/mm3 was 11 (range, 2-90) days. At a median follow-up time of 3.6 (range, 1.4 - 4.9) years, the 3-year overall (OS) and progression-free survival rates (PFS) were 78% and 64%, respectively. We were not able to identify important determinants of outcome; this included PET+, serum rituximab and soluble CD20. Although histology had no statistically significant impact, a persistent pattern of relapse over time was observed in FL (PFS at 1-, 2- and 4-year were 91%, 64% and 45%, respectively), whereas a plateau was observed in DLBCL at 24 months (PFS of 76%). This cohort included 34 pts (FL=11, CLL=20, DLBCL=2, MCL=1). Median age was 59 (range, 29-70). Eight of the 11 pts with FL had high [n=6 (55%)] or intermediate [n=2 (18%)] FLIPI at study entry; 8 (73%) were PET+, and 6 (55%) had refractory disease (non-responding or progressing to at least two lines of therapies such as R-CHOP or RICE). Seven pts with CLL (35%) had refractory disease; 10 of 16 (62.5%) had unmutated IgVH, and 5 of 14(36%) had p53 mutation. Peripheral blood from HLA-compatible sibling donors was the source of graft in all pts. Tacrolimus and methotrexate were used for GVHD prophylaxis. Median time to ANC >500 was 11(range, 8-17) days, and to platelets > 20,000/mm3 was 10 (range, 0-55 days). Median donor T cells at days 30 and 90 were 90% and 100%, respectively. Cumulative incidence (CI) of acute II-IV GVHD was 32% (none had grade 3, one had grade IV), and the CI of extensive chronic GVHD was 44%. With a median follow-up time of 22 (range, 3-73) months, the PFS rates at 3-year for FL and CLL were 100% and 37%, respectively. The causes of failure in CLL were progression (n=6) and complications related to chronic GVHD (n=2).

Conclusions: These data provide evidence that combining 90YIT at 0.4mCI/kg with the conditioning improves outcomes in NHL pts undergoing AUTO or NST, but not in CLL. Our results also represent the first report showing that the combination may overcome the negative prognostic value of PET+ in NHL, and that the addition of 90YIT to NST conditioning can induce long-term remission in relapsed refractory FL without added toxicity. Verification of our results in a larger cohort of pts is highly warranted.

ZEVALIN is not approved for the use described in the above abstract.

For more information about the ASH annual meeting and for a complete list of abstracts, including additional abstracts presented about ZEVALIN, please refer to the conference Web site at www.hematology.org.

About ZEVALIN® and the ZEVALIN Therapeutic Regimen

ZEVALIN (ibritumomab tiuxetan) for intravenous injection is indicated for the treatment of patients with previously untreated follicular non-Hodgkin's Lymphoma (NHL), who achieve a partial or complete response to first-line chemotherapy. ZEVALIN is also indicated for the treatment of patients with relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma.

ZEVALIN is a CD20-directed radiotherapeutic antibody administered as part of the ZEVALIN therapeutic regimen. The ZEVALIN therapeutic regimen consists of three components: rituximab, Indium-111 (In-111) radiolabeled ZEVALIN for imaging, and Yttrium-90 (Y-90) radiolabeled ZEVALIN for therapy. The ZEVALIN therapeutic regimen is a form of cancer therapy called radio immunotherapy. Radio immunotherapy (RIT) is an innovative form of cancer treatment with a mechanism of action that is different from traditional chemotherapy. RIT builds on the combined effect of a targeted biologic monoclonal antibody augmented with the therapeutic effects of a beta-emitting radioisotope.

Important ZEVALIN® Safety Information

Deaths have occurred within 24 hours of rituximab infusion, an essential component of the ZEVALIN therapeutic regimen. These fatalities were associated with hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, or cardiogenic shock. Most (80%) fatalities occurred with the first rituximab infusion. ZEVALIN administration results in severe and prolonged cytopenias in most patients. Severe cutaneous and mucocutaneous reactions, some fatal, can occur with the ZEVALIN therapeutic regimen.

Please see full Prescribing Information, including Boxed WARNINGS, for ZEVALIN and rituximab.

About Spectrum Pharmaceuticals

Spectrum Pharmaceuticals is a commercial-stage biotechnology company with a primary focus in oncology. The Company's strategy is comprised of acquiring and developing a broad and diverse pipeline of late-stage clinical and commercial products; establishing a commercial organization for its approved drugs; continuing to build a team with people who have demonstrated skills, passion, commitment and have a track record of success in its areas of focus; and, leveraging the expertise of partners around the world to assist it in the execution of its strategy. For more information, please visit the Company's website at www.sppirx.com.

Forward Looking Statements – This press release may also contain forward-looking statements regarding future events and the future performance of Spectrum Pharmaceuticals that involve risks and uncertainties that could cause actual results to differ materially. These statements include but are not limited to statements that relate to Spectrum's business and its future, Spectrum's ability to identify, acquire, develop and commercialize a broad and diverse pipeline of late-stage clinical and commercial products, establishing a commercial organization for Spectrum's approved drugs, continuing to build Spectrum's team, leveraging the expertise of partners around the world to assist Spectrum in the execution of its strategy, the safety and efficacy of ZEVALIN and any statements that relate to the intent, belief, plans or expectations of Spectrum or its management, or that are not a statement of historical fact. Risks that could cause actual results to differ include the possibility that Spectrum's existing and new drug candidates may not prove safe or effective, the possibility that Spectrum's existing and new drug candidates may not receive approval from the FDA, and other regulatory agencies in a timely manner or at all, the possibility that Spectrum's existing and new drug candidates, if approved, may not be more effective, safer or more cost efficient than competing drugs, the possibility that Spectrum's efforts to acquire or in-license and develop additional drug candidates may fail, Spectrum's lack of revenues, limited marketing experience, dependence on third parties for clinical trials, manufacturing, distribution and quality control and other risks that are described in further detail in Spectrum's reports filed with the Securities and Exchange Commission. Spectrum does not plan to update any such forward-looking statements and expressly disclaim any duty to update the information contained in this press release except as required by law.

SPECTRUM PHARMACEUTICALS, INC. ®, ZEVALIN®, TURNING INSIGHTS INTO HOPE™ and the Spectrum Pharmaceutical logos are registered trademarks of or trademarks owned by Spectrum Pharmaceuticals, Inc. or its subsidiaries.

© 2009 Spectrum Pharmaceuticals, Inc. All Rights Reserved.

 

Contact: Spectrum Pharmaceuticals
Paul Arndt
Senior Manager, Investor Relations
949-788-6700 x216

 

Posted: December 2009

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