Clinical Development

Genta has developed extensive data on Genasense^® from a number of Phase 1, Phase 2 and Phase 3 clinical trials. These studies have been conducted in patients with a wide variety of tumor types, including melanoma, acute and chronic leukemia’s, non-Hodgkin’s lymphoma (NHL), and cancers of the prostate, colon, lung, breast and other tumor types. More than 2,500 patients have been studied in non-randomized and randomized trials.

Genasense is an investigational anticancer agent undergoing testing in various forms of cancer. The safety and efficacy of Genasense have not been established for any use.  Studies are currently underway to examine the potential role of Genasense in a variety of clinical indications.

• Clinical Plan
• Advanced Melanoma
• Chronic Lymphocytic Leukemia (CLL)
• Non Hodgkin's Lymphoma (NHL)

• GM301

  Genta performed a large randomized controlled trial – GM301 -- in patients with advanced melanoma. GM301 was conducted in patients who had not previously received systemic chemotherapy. A total of 771 patients were randomized to receive Genasense plus dacarbazine (DTIC) or dacarbazine alone. The primary end-point of the study was overall survival; secondary end-points included overall response, durable response (i.e. a major response lasting > 6 months), and progression-free survival (PFS).

  The Effect of LDH: Patients in study GM301 were prospectively stratified prior to randomization on the basis of serum LDH (< or > 1.1 times the upper limit of normal [ULN]). LDH is a blood test that has been independently validated as the strongest predictor of survival in advanced melanoma.  Results from the GM301 trial were published in the Journal of Clinical Oncology.

  • Bedikian AY, et al.: Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group. J Clin Oncol., 24(29):4738-45 

   

  The AGENDA Trial

  AGENDA was designed to complement the previous clinical study (GM301) in those patients who had derived maximal survival benefit, as defined by a low-normal level of LDH.  In 2009, Genta completed accrual to AGENDA – a randomized, double-blind, placebo-controlled study in which patients who had not previously received chemotherapy were randomly assigned to receive Genasense plus dacarbazine (DTIC) or dacarbazine alone. Enrollment was limited to patients whose baseline LDH was 0.8 times the upper limit of normal. (The only differences between AGENDA and the preceding GM301 study were the double-blind design and the LDH enrollment limitation.)

  The study’s co-primary endpoints were progression-free survival (PFS) and overall survival (OS).  Secondary endpoints include durable response, overall response rate (ORR), disease-control rate (DCR), and safety.  A total of 315 patients were accrued from sites in the U.S., Canada, Western Europe, and Australia.

  The initial results from AGENDA (released in October 2009) did not show statistically significant increases in the group that received Genasense for PFS, ORR, or DCR, although the observed differences in each endpoint were numerically superior in the group that received Genasense. According to the prespecified analysis plan, the statistical significance of durable response – a secondary endpoint that measures the proportion of patients who achieved a complete or partial response that lasts > 6 months – was too early to evaluate.

  Overall survival – the other co-primary endpoint in AGENDA – was also too early to evaluate, as prospectively specified.  At the time of initial data release, a futility analysis, defined as > 50% conditional power to observe a statistically significant benefit of Genasense under the prospectively assumed hazard ratio of 0.69, was met for overall survival. Thus, the prospectively specified analyses for both overall survival and durable response will be conducted when the data are mature. The safety profile of Genasense in AGENDA was consistent with prior studies.

  
  Genasense Plus Temodar^® and Abraxane^® in Advanced Melanoma
  Genasense is currently being studied in this triple combination regimen in patients with advanced metastatic melanoma.

  The safety and efficacy of Genasense have not been established for any use.

• After completing an initial single-agent trial of Genasense in heavily pre-treated patients with chronic lymphocytic leukemia (CLL), Genta initiated a randomized controlled Phase 3 study in relapsed/refractory patients.  Eligible patients had failed standard treatment, including at least two cycles of fludarabine. After stratification, 241 patients were randomized to receive chemotherapy with fludarabine and cyclophosphamide (Flu/Cy) with or without Genasense. The primary endpoint was an increase in complete remission (CR) (defined as CR plus nodular partial remission [nPR]). Secondary end-points included duration of CR, overall response rate (ORR, defined as CR plus PR), time-to-progression, and overall survival.  Results from the Phase 3 CLL trial, including survival results with 5-years of followup, were published in the Journal of Clinical Oncology.

  • O'Brien S, et al.:  Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 25(9):1114-20, 2007.
  • O'Brien S, et al.: 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen.  J Clin Oncol. 27(31):5208-12, 2009.

   

  Studies are currently underway to examine the safety and efficacy of Genasense in a variety of clinical indications.  The safety and efficacy of Genasense have not been established for any use.

• Like CLL, non-Hodgkin’s lymphoma (NHL) is a prototypic disease for over-expression of Bcl-2.  (In fact, the protein was originally discovered in a B-cell lymphoma, which accounts for its name.) Preclinically, both single-agent activity of Genasense as well as synergy with multiple agents (including alkylators and rituximab) have been extensively documented in NHL. A number of exploratory trials have been conducted using Genasense in NHL.  Results from a multicenter trial of Genasense plus rituximab have recently been published in the British Journal of Haematology.

  • Pro B, et al.:   Phase II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in combination with rituximab in patients with recurrent B-cell non-Hodgkin lymphoma.  Br J Haematol. 143(3):355-60. 2008  

   

  Studies are currently underway to examine the safety and efficacy of Genasense in a variety of clinical indications.  The safety and efficacy of Genasense have not been established for any use.