Spectrum Pharmaceuticals - Chancen und Risiken? (Seite 91)

[Ville7]

Zitat von Ville7: Neue Short Interest Zahlen:

4/30/2012 21,368 Millionen

Das bedeutet innerhalb von 14 Tagen erneut eine gewaltige Steigerung von diesmal + 3,045 Millionen Aktien.

40-45% des Floats sind nun short. Das ist die höchste Anzahl die ich je gesehen habe.

Das ist noch zu toppen: nur 14 Tage später sind weitere 2,8 Mio Aktien zusätzlich geshortet worden. Ca. 50% des Floats sind nun short. Das ist wirklich unverständlich und das habe ich so noch nirgends gesehen.

Die neuen Zahlen am

5/15/2012 24,159 Millionen

[Ville7]

A phase (Ph) I/II study of belinostat (Bel) in combination with cisplatin, doxorubicin, and cyclophosphamide (PAC) in the first-line treatment of advanced or recurrent thymic malignancies.

Sub-category:
Thymic Malignancies

Category:
Lung Cancer - Non-small Cell Local-regional/Small Cell/Other Thoracic Cancers

Meeting:
2012 ASCO Annual Meeting

Abstract No:
7103

Citation:
J Clin Oncol 30, 2012 (suppl; abstr 7103)
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Session: Lung Cancer - Non-small Cell Local-regional/Small Cell/Other Thoracic Cancers

Type: General Poster Session

Time: Saturday June 2, 1:15 PM to 5:15 PM

Location: S Hall A2
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Author(s): Anish Thomas, Arun Rajan, Sean Khozin, Eva Szabo, Corey Allan Carter, Udayan Guha, Michell Manu, Arlene W Berman, Tricia Kunst, Richard Piekarz, David S. Schrump, Giuseppe Giaccone; National Cancer Institute, Bethesda, MD

Abstract Disclosures

Abstract:

Background: Belinostat is a hydroxamic acid histone deacetylase (HDAC) pan-inhibitor with single agent activity in thymic malignancies. PAC has activity against thymic cancers. Synergy between Bel and several chemotherapeutic agents, including P, A, and C, has been demonstrated in preclinical models. Methods: Patients with histologically confirmed, treatment naive advanced thymic malignancies, PS<2, measurable disease, and adequate renal, hepatic and hematopoietic functions were eligible. Ph1 evaluated safety and tolerability of the combination using increasing dose levels (DL) of Bel (1000-2000 mg/m² over 48 h CIVI) and PAC (50/50/500 mg/m² IV/cycle) (3+3 dose escalation schema), administered every 21 days for no more than 6 cycles followed by optional maintenance Bel every 4 weeks. Primary end point of Ph2 is overall response rate (ORR). Results: From March 2010 to January 2012, 13 patients were enrolled [7 thymoma (T), 6 thymic carcinoma (TC); 8 in Ph1 and 5 in Ph2; median age: 49 years (range, 23-76)]. In Ph1, 6 patients were treated at DL1 (Bel 1000 mg/m2+ PAC) and 2 patients at DL2 (Bel 2000 mg/m2+ PAC). Dose Limiting Toxicities were Grade 3 nausea and diarrhea, and Grade 4 neutropenia and thrombocytopenia. Recommended phase II dose (RP2D) was set at DL1. Most common grade 3/4 treatment-related adverse events (AE) were lymphocytopenia (100%), leucopenia (85%), neutropenia (77%) thrombocytopenia (54%), anemia (38%), hypophosphatemia (38%), hypomagnesemia, hypokalemia, elevated AST, prolonged QTc and infusion-catheter related thromboembolic complications (23% each). Outcomes included one complete response (CR; T at DL1), 6 partial responses (PR; 4 T, 2 TC; 4 in Ph1, 2 in Ph2) and 6 stable disease (SD; 2 T, 4 TC; 3 each in Ph1 and Ph2). Four patients previously deemed unresectable underwent surgical resection. Conclusions: Belinostat in combination with PAC has activity in thymic malignancies with a predicable AE profile. ORR was 54% including 33% PR in the TC subgroup. RP2D of the combination has been defined. Accrual to Ph2 part and molecular profiling of patient tumors is ongoing.

[Ville7]

Results of a phase II study of pralatrexate in patients with advanced/metastatic relapsed transitional cell carcinoma of the urinary bladder.

Sub-category:
Bladder Cancer

Category:
Genitourinary Cancer

Meeting:
2012 ASCO Annual Meeting

Abstract No:
4574

Citation:
J Clin Oncol 30, 2012 (suppl; abstr 4574)
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Session: Genitourinary Cancer

Type: General Poster Session

Time: Sunday June 3, 8:00 AM to 12:00 PM

Location: S Hall A2
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Author(s): Yohann Loriot, Karim Fizazi, Joan Carles, Garry Alan Weems, Lacey Chance, Neeraj R. Agrawal; Institut Gustave Roussy, Villejuif, France; Institut Gustave Roussy, University of Paris Sud, Villejuif, France; Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain; Allos Therapeutics, Westminster, CO; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT

Abstract Disclosures

Abstract:

Background: Antifolate agents have demonstrated activity in transitional cell carcinoma (TCC), a disease with very poor outcomes in advanced stages. Pralatrexate (FOLOTYN, Allos Therapeutics, Inc., Westminster, CO), a folate analogue targeting dihydrofolate reductase, is designed for enhanced uptake and accumulation in tumor cells. The objective of this study was to examine the activity and safety of pralatrexate in patients (pts) with advanced/metastatic TCC of the urinary bladder after failure of prior chemotherapy. Methods: Pts with histologically confirmed TCC (>50% TCC in tumor) received pralatrexate 190 mg/m² intravenously on days 1 and 15 of a 28‑day cycle supplemented with vitamin B12 and folic acid. Included pts had Eastern Cooperative Oncology Group performance status of 0–1, measurable disease, and prior treatment with ≤1 platinum- and/or methotrexate-based regimen in the recurrent/metastatic setting. Results: Thirty pts were enrolled and treated. All pts received prior platinum-based therapy, and 7 pts (23%) received methotrexate in a multidrug regimen. One pt had a confirmed partial response (PR); 4 additional pts had unconfirmed PRs. Twelve pts had stable disease. The median number of cycles received was 2 (range, 1–24), and median time on treatment was 56 days (range, 1–714). The median progression-free survival (PFS) and overall survival for all pts was 4.0 months (95% confidence interval [CI], 2.1–4.5) and 9.3 months (95% CI, 5.6–13.2), respectively. Eight pts (27%) had PFS >6 months and 3 pts (10%) had PFS >12 months. Eight pts (27%) underwent dose reductions, all due to mucositis. Six pts (20%) discontinued the study due to treatment-related adverse events (AEs)—mainly mucositis. The most frequent treatment-related AEs were stomatitis (77%), asthenia (30%), vomiting (27%), and anemia, nausea, and neutropenia (23% each). Conclusions: Pralatrexate showed evidence of activity and durable disease control when used as a single agent in pts with advanced bladder cancer, although the overall response rate was modest. Further study of pralatrexate in this setting should focus on improving drug delivery and evaluation of novel combination approaches.

[Ville7]

A phase II study of PXD101 (belinostat) in relapsed and refractory aggressive B-cell lymphomas (rel/ref ABCL): SWOG S0520.

Sub-category:
Lymphoma

Category:
Lymphoma and Plasma Cell Disorders

Meeting:
2012 ASCO Annual Meeting

Abstract No:
e18536

Citation:
J Clin Oncol 30, 2012 (suppl; abstr e18536)

Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with the 2012 Annual Meeting but not presented at the Meeting, can be found online only.

The publication-only abstracts are not included in the print or USB versions of the ASCO Annual Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a supplement (see citation on left).

Author(s): Daniel Oscar Persky, Steven H. Bernstein, Bryan H. Goldman, Lisa M. Rimsza, Richard I. Fisher, Thomas P. Miller; University of Arizona Cancer Center, Tucson, AZ; University of Rochester Medical Center, Rochester, NY; Southwest Oncology Group Statistical Center, Seattle, WA; University of Arizona Department of Pathology, Tucson, AZ; University of Rochester, Rochester, NY

Abstract Disclosures

Abstract:

Background: The mechanism of action of histone deacetylase inhibitors (HDACI) in lymphomas is unknown. Loss of major histocompatibility Class II antigens (MHC II) in diffuse large B-cell lymphomas (DLBCL) is associated with decreased tumor infiltrating T lymphocytes (TIL) and poor survival. Transcription of MHC II is controlled by CIITA, which is itself regulated by histone acetylation, We hypothesized that PXD101 (belinostat), an HDACI, would increase MHC II expression in tumor cells, enhance immunosurveillance and improve outcome. Methods: Theprimary objective was to evaluate response rate and toxicity of PXD101 in patients (pts) with rel/ref ABCL with up to 5 prior chemotherapy regimens. Secondary objectives were to estimate the 6-month progression-free survival (PFS) and to assess MHC II and TIL. In a two-stage design, if at least 1 response was observed in the first 20 pts, another 20 pts would be accrued. PXD101 was administered at 1000 mg/m2 IV days 1-5 of 21-day cycle for up to 2 years. Results: The study was closed due to lack of response in the first stage. Of 22 pts enrolled, 19 were evaluable. Median age was 69, and median number of prior treatments was 3 (range 1-4). 18 pts had DLBCL and 1 had B-cell lymphoma, unclassifiable. Grade 4 toxicities were fatigue and muscle weakness (1) and lymphopenia (1). Despite initially finding no responses, 2 partial responses (PR) were observed at 5 and 13 months after registration, for an overall response rate (95% CI) of 10.5% (1.3-33.1%); 3 pts had stable disease (SD), lasting 4.7, 30.4+, and 40.7+ months. With a minimum follow-up of 2.0 yrs, median and 6-month PFS are 2.1 months (1.3-3.8) and 21.1% (6.6-41.0%); median and 6-month overall survival are 13.4 months (95% CI not yet estimable) and 57.9% (33.2-76.3%), respectively. Conclusions: Despite early closure, delayed PR was seen in 2 of 19 pts, and 2 pts had SD lasting 30.4+ and 40.7+ months. Therefore 4 pts (21%) who did not achieve complete response, very unusually, have not progressed for ≥2.0 yrs. Standard chemotherapy response assessment may not be appropriate for HDACI, which may require development of new biomarkers of response. Further work focuses on combining HDACI with standard chemotherapy.

[Ville7]

A phase II trial 90y-ibritumomab tiuxetan in combination with reduced intensity regimen of fludarabine (flu) and melphalan (mel) followed by allo-HCT in patients with refractory B-cell lymphoma.

Sub-category:
Allogeneic Bone Marrow

Category:
Leukemia, Myelodysplasia, and Transplantation

Meeting:
2012 ASCO Annual Meeting

Abstract No:
6545

Citation:
J Clin Oncol 30, 2012 (suppl; abstr 6545)
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ASCO Annual Meeting!

Session: Leukemia, Myelodysplasia, and Transplantation

Type: General Poster Session

Time: Monday June 4, 1:15 PM to 5:15 PM

Location: S Hall A2
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Author(s): Auayporn Nademanee, Andrew Antony Raubitschek, Ni-Chun Tsai, Jennifer Simpson, Neil Martin Kogut, Leslie Popplewell, Firoozeh Sahebi, Maria L. Delioukina, Stephen J. Forman; City of Hope, Duarte, CA; City of Hope Cancer Center/Beckman Research Institute, Duarte, CA; Cedars-Sinai Medical Center, Los Angeles, CA

Abstract Disclosures

Abstract:

Background: RIC allo-HCT has reduced transplant-related mortality (TRM) in patients with relapsed NHL. However, relapses do occur despite potential graft vs. lymphoma (GVL) effect. We hypothesized that adding Zevalin to Flu/Mel may improve disease control and reduce relapse post allo-HCT. Methods: Patients received In- Zevalin on day -21 followed by 90Y- Zevalin 0.4mCi/kg on day -14, flu 25 mg/m2 daily on days -9 to -5 and mel 140 mg/m2 on day -4. Rituximab (R) level was measured on Day -22 and -15 and if the level was ≥ 10 μg/ml, R was not given prior to In-Zevalin or 90Y- Zevalin to enhance biodistribution. Tacrolimus and sirolimus was used for GVHD prophylaxis. Between 10/2007 and 11/2011, 31 were treated. Median age 55 (range 27-67), median regimen =3 (range 2-8). Median time from diagnosis to HCT was 20 mo (range 5-105). Histology: DLBCL (including transformed lymphoma)=14 (45%), MCL=7 (23%), FL=5 (16%) and SLL/CLL=5 (16%). Disease status at HCT: 1CR=7, Relapse=9, ≥2CR=5, primary refractory =10. Fifteen had chemoresistant and 19 had FDG PET+ at HCT. Donors: sib=13, URD=18. Results: All patients engrafted with the median time to ANC ≥500 and platelet ≥ 20,000 was 14 (range 10-28) and 13.5 days (range 11-28), respectively. There were 10 deaths from disease progression (2) infection (5) GVHD (1) and multi-organ failure (2). TRM at day +100 and at 1 yr was 6.5% and 17%, Five with DLBCL relapsed between 3-7 mos. Grade II-IV acute GVHD was 65%, Grade III-IV was 16%, chronic GVHD was 65%. Fifteen became PET- at day +100 while 4 remained PET+ and relapsed. Twenty-one are alive at a median followup of 24 mos (range 2-46). The 2 yrs OS and PFS was 65% (95% CI, 51-75%) and 57% (95% CI, 46-67%), respectively. Univariate analysis identified disease status predict for OS and PFS while histology predict for PFS. Conclusions: This study demonstrates the feasibility of adding Zevalin to flu/mel in the allo-HCT setting for B-cell NHL and suggest that this approach could be used to provide early disease control before GVL effect takes place. Innovative approaches should be explored in DLBCL.

[VaJo]

Nein nur depressiv lol. Wenn man immer frohen Mutes auf die Daten wartet und dann zwickts plötzlich.

[Ville7]

Inwischen so negativ?

[VaJo]

Würde ja nach der alten Logik bedeuten das die Belinostat Daten auch nicht sonderlich gut sind. Hats schon wieder ein Leck gegeben?

[Ville7]

Neue Short Interest Zahlen:

4/30/2012 21,368 Millionen

Das bedeutet innerhalb von 14 Tagen erneut eine gewaltige Steigerung von diesmal + 3,045 Millionen Aktien.

40-45% des Floats sind nun short. Das ist die höchste Anzahl die ich je gesehen habe.

[Ville7]

Rüberkopiert aus dem Topotarget Thread:


Belinostat CUP:

Noch einmal vor Augen geführt, denn
1. sollte die Studie bereits Juli / August 2011 ausgewertet werden können
2. sagt Topotarget, dass sie es sehr unwahrscheinlich finden, mit dieser Studie die Zulassung erhalten zu können und 20-40% Verbesserung als so positiv ansehen würden, dass eine weitere Entwicklung (in Phase III) durchgeführt werden sollte.

Nun, für den Fall, dass der CaP Arm keine irregulär hervorragenden Ergebnisse liefert, sollte man sich die zu erwartenden Daten noch einmal ansehen. Die besten historischen Daten für CaP Studien waren 6,4 Monate PFS (Progression Free Survival progressionsfreies Überleben), einige gingen auch nur mit gut 3 Monaten daher. Gehen wir von 6, 7, 8 oder 9 Monaten für CaP aus müssten wir gemäß Exponentialfunktion auf folgende Werte kommen, wenn der Code Ende April gebrochen wurde:

CaP ------- BelCaP --------- Prozentual
6 --------- 19,5 ----------- + 225%
7 --------- 18 ------------- + 157%
8 --------- 17 ------------- + 112%
9 --------- 15,5 ----------- + 72%

D.h. in all diesen Szenarien könnte der von der FDA vorgegebene exorbitant hohe Endpunkt (+60%) erreicht werden, was zu einer Registrierung in USA (und vielleicht auch EU) führen könnte.

Bei aller Vorsicht, die bei Phase II Daten von open labeled, randomized trials mit einer Sample Size von nur 89 Patienten geboten ist, darf man diese positive Spekulation aber nicht vernachlässigen. Es ist und bleibt eine extrem riskante Spekulation mit großem Up- und Downside.