Friday, January 4, 2013

Celator commences third phase of leukemia study CPX-351 (Cytarabine:Daunorubicin) liposome)


Celator Pharmaceuticals has commenced patient enrollment in the phase-III study of CPX-351 in untreated high-risk acute myeloid leukemia (AML).

The open-label trial is designed to assess CPX-351 (cytarabine:daunorubicin) liposome injection compared to cytarabine and daunorubicin therapy (7+3) as first-line therapy in high risk (secondary) AML patients 60-75 year old.

Celator chief medical officer Arthur Louie said, "Clinical studies completed to date suggest that CPX-351 may provide an opportunity to improve outcomes in AML, particularly for high-risk patients whose prognosis on standard therapy is poor."

Patients who have pathological diagnosis of AML based on WHO criteria, with confirmation of therapy-related AML, AML with a history of myelodysplasia (MDS), AML with a history of chronic myelomonocytic leukemia, De novo AML with karyotypic abnormalities characteristic of MDS will participate in the study.

Subjects will be randomized with either CPX-351 (100u/m2; days one, three, and five by 90 minute infusion) or 7+3 (cytarabine 100mg/m2/day by continuous infusion for seven days and daunorubicin 60mg/m2 on days one, two, and three) in 1:1 ratio and will be assessed for clinical adverse events in addition to laboratory evaluations.
Overall survival is the primary efficacy endpoint of the multicenter study scheduled to be conducted in the US and Canada.

Celator chief executive officer Scott Jackson said, "The initiation of this study is an important milestone for CPX-351 and for Celator. We hope the data it provides will allow us to seek regulatory approval for CPX-351 and, ultimately, make an important and much-needed treatment option available to patients with AML."

The company is conducting the study in collaboration with The Leukemia & Lymphoma Society (LLS), which supported the CPX-351 development through its Therapy Acceleration Program.

Original articles:

http://clinicaltrials.pharmaceutical-business-review.com/news/celator-commences-third-phase-of-leukemia-study-cpx-351-271212

Friday, August 31, 2012

Intrarectal Administration of Clodronate Liposomes


Currently, a single paper cited intrarectal administration of clodronate liposomes [1]. Few details of the the instillation method were provided and it is unclear as to whether a polycarbonate tip on an automatic pipettor or a glass-capillary type micropipette was used for the instillation of the liposome suspension. The key questions relate to how long the suspension was retained in the colon and how far into the colon the suspension penetrated although the authors observe that macrophage depletion was limited to the descending colon. The authors do not report fasting the animals or eliminating fiber from the animal diet prior to dosing the clodronate liposomes as has been incorporated into other protocols for colitis [2]. Likewise, the effectiveness of the instilled liposome suspension would seem to be affected by the colon content at the time of dosing.
The appropriate volumes for enemas is reported to be 0.2 ml for mice and 1 ml for rats [2] although several papers use 0.1 ml doses in mice and as much as 3 ml in rats. We have not identified standard protocols for intrarectal injections in rodents, but many report holding the rodents in a vertical, head-down position for a minute or so post-intrarectal instillation. This would appear to be a reasonable addition to the method that should increase the efficacy of intrarectal delivery.
Many also utilize rubber or plastic tubing for delivering the liquids 2 cm or more beyond the rectum into the descending colon, or more specifically, an intracolonic instillation. Since the rectal tissue plays little or no role in the disease process, ensuring that the clodronate liposome suspension has maximal access to the colon may enhance and/or extend the depletion period. A study utilizing fluorescently- and/or visibly- (DiI incorporation accomplishes both) labelled liposomes could assist in the evaluation of the retention of the intrarectally-delivered liposomes as well as their distribution within the colon.
Colonic macrophages have been shown to demonstrate decreased phagocytic activity due to the ingestion of dextran sodium sulfate (DSS) [3, 4, 5]. The majority of the data in this paper was collected in animals which were dosed with clodronate liposomes on days -1, +1, +3 and +5; the animals were given water containing DSS beginning on day 0. This could mean that treatment with clodronate liposomes post-oral administration of DSS to mice may result in ineffective depletion due to limited uptake of clodronate liposomes by colonic macrophages which are non-phagocytic due to blockade by DSS, thus the surprisingly rapid repopulation (50% replenished by day 7) of macrophages even after 4 intrarectal treatments with clodronate liposomes. If DSS is dosed to the animals prior to any clodronate liposome treatment, would any  depletion be observed? We believe that this is an important factor to consider.
Another contrary interpretation of the data in the Qualls, et. al. paper is that macrophage uptake of DSS may limit DSS-induced inflammation, therefore macrophage depletion may result in the colon tissues being exposed to higher levels of DSS.
Qualls, et. al. chose not to include empty liposome control groups in their studies due to the fact that the control liposomes induced “a partial reduction in the percentage of  in the colon and could affect the physiology of the remaining colonic  (data not shown…” We would argue that this is precisely the rationale for including empty liposome controls and that any results should be compared to those obtained with empty liposome controls. These control results may very well have elucidated some of the potential effects of macrophages in the disease. For example, does a reduction in the phagocytic capacity of macrophages (due to liposome uptake without associated toxicity ) and in the absence of macrophage destruction have any effect on the disease?  blockade by control liposomes could reduce the uptake of DSS by the resident MΦ; this may reduce the initial inflammatory response since  would not be able to phagocytose DSS or worsen the disease because uptake of DSS by resident  lessens the DSS effect on colonic tissue. Any reduction in the number of  in the colon or changes in  morphology induced by control (empty) liposomes should have been a transient reaction since liposomes are not toxic to , but they can inhibit  phagocytosis for several hours.
It is common to observe an increase in neutrophil infiltration into the pulmonary space post-clodronate, but not control, liposome treatment. Perhaps neutrophil infiltration as a result of clodronate liposome treatment is a factor in this model as well, but no clodronate-liposome treated animals in the absence of DSS-induced colitis were evaluated for neutrophil infiltration.
And, finally, a primary function of the colon is in providing a highly effective barrier around the colon. Therefore, it is possible that this barrier is impermeable to free clodronate and that clodronate released from liposomes or dead/dying macrophages could temporarily accumulate locally attaining concentrations which could effect surrounding cells (see Intrapulmonary Administration for detailed discussion). While clodronate sequestration seems most unlikely inside the colon, it remains a pertinent control since intracolonic clodronate administration has not been previously evaluated to our knowledge.
This paper illustrates the necessity of considering the effects of control and clodronate liposomes on the chosen model. Given that the model employed a particulate agent (DSS) which is phagocytosed by , detailed analysis of the effects of  blockade by both DSS, clodronate liposomes and control liposomes must be performed. Since each of these particles will likely evoke  blockade, any observed results may simply be due to which particle reached the  first.
Wanatabe, et. al. utilized poly-lactic acid µspheres containing clodronate, dosed intrarectally, to deplete macrophages in an IL-10 deficient mouse model of colitis, therefore the only particle type affecting the  was the clodronate µspheres [7]. Unfortunately, they did not assess the effects of control µspheres (without clodronate), but they did observe increased disease activity when the colonic  were depleted. Their study was much less rigorous than the Qualls, et. al. study as they did not pursue the effects of neutrophil infiltration nor evaluate cytokine and chemokine production. However, their study results do suggest that the use of a particulate material in inducing the collitis, as Qualls, et. al. did, does not change the conclusion that colonic macrophages play a pivotal role in ameliorating acute colitis in these animal models.
More recently, Qualls et. al. reported that depletion of dendritic cells (DC) alone in CD11c-DTR mice suppressed DSS-induced colitis, but without the concomitant increase in CXCL1, neutrophil influx and MPO activity [8]. We believe that this result further presses the question of the role of clodronate liposomes (or clodronate liposome  depletion) in neutrophil influx and activation. An initial, single dose of intrarectal clodronate liposomes for depleting resident MΦ/DC along with multiple intravenous doses of clodronate liposomes could perhaps accomplish colonic MΦ/DC depletion and prevent subsequent repopulation (by depleting circulating monocytes) allowing for colonic recovery from any potential effects of clodronate liposome  depletion, such as neutrophil influx, should it occur. Induction of DSS-mediated colitis post-recovery would allow distinction of possible neutrophil influx and activation as a result of clodronate liposome depletion from the neutrophil effects due to the absence of colonic .
Again, we emphasize that although the goal of clodronate liposome-mediated macrophage depletion is usually to generate animals which are normal in every other way except that they are devoid of macrophages, there can be effects due to
  1. Liposome administration…control groups treated with empty liposomes are necessary.
  2. Clodronate administration…control groups treated with unencapsulated (free) clodronate are necessary.
  3. Clodronate liposome administration…macrophages are not killed for several hours post-treatment and may not behave as untreated macrophages in the interim.
  4. Macrophage death…even relatively “silent” apoptotic cell death will solicit other macrophages, immature monocytes or other cells (i.e. neutrophils) to clear cellular debris and these cells may “report” extensive cell death in order to recruit replacement mononuclear cells.
Therefore, experiments elucidating the effects of the process of macrophage depletion may need to be considered and incorporated into the study.
The authors further reported an increase in IL-6 as a result of DC depletion and suggested that IL-6 may be the key to the increased severity in colitis after DC depletion. While these authors stated that IL-6 is reported to inhibit neutrophil infiltration, at least one of their cited references exclusively discusses the proinflammatory effects of IL-6 on neutrophils and other cells [9]. (Two of the other references appear to focus on the anti-inflammatory effects of IL-6 in exercise-induced inflammation.) IL-6 or its mRNA levels were not evaluated in the earlier study in which clodronate liposomes were used to deplete MΦ/DC, but the authors reported in this 2009 paper that they observed an increase in IL-6 production when both  and DC were depleted (unpublished data) although the mode of depletion was not specified. While we are not well read in the substantial literature on experimental colitis, we believe that clodronate liposome studies including the controls that we proposed earlier may be helpful in dissecting the contributions of the various inflammatory cells, cytokines and chemokines in this model.

References

  1. Qualls JE, Kaplan AM, van Rooijen N, Cohen DA. Suppression of experimental colitis by intestinal mononuclear phagocytes. J Leukoc Biol. 2006 Oct 1;80(4):802–15.
  2. Fretland DJ, Widomski DL, Anglin CP, Walsh RE, Levin S, Gasiecki AF, et al. Mucosal protective activity of prostaglandin analogs in rodent colonic inflammation. Inflammation. 1992;16(6):623–9.
  3. Dieleman, Palmen, Akol, Bloemena, Peña, Meuwissen, et al. Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines. Clinical & Experimental Immunology. 1998;114(3):385–91.
  4. Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya R. A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. Gastroenterology. 1990 Mar;98(3):694–702.
  5. Ohkusa T, Okayasu I, Tokoi S, Araki A, Ozaki Y. Changes in Bacterial Phagocytosis of Macrophages in Experimental Ulcerative Colitis.Digestion. 1995;56(2):159–64.
  6. Venkatraman A, Ramakrishna BS, Pulimood AB, Patra S, Murthy S. Increased Permeability in Dextran Sulphate Colitis in Rats: Time Course of Development and Effect of Butyrate. Scandinavian Journal of Gastroenterology. 2000 Oct;35(10):1053–9.
  7. Watanabe N, Ikuta K, Okazaki K, Nakase H, Tabata Y, Matsuura M, et al. Elimination of Local Macrophages in Intestine Prevents Chronic Colitis in Interleukin-10-Deficient Mice. Digestive Diseases and Sciences. 2003;48(2):408–14.
  8. Qualls JE, Tuna H, Kaplan AM, Cohen DA. Suppression of experimental colitis in mice by CD11c+ dendritic cells. Inflammatory Bowel Diseases. 2009;15(2):236–47.
  9. Mudter J, Neurath MF. IL-6 signaling in inflammatory bowel disease: Pathophysiological role and clinical relevance. Inflammatory Bowel Diseases. 2007;13(8):1016–23.

Click reference to view publication summary.

Publication 1.
Qualls JE, Kaplan AM, van Rooijen N, Cohen DA. Suppression of experimental colitis by intestinal mononuclear phagocytes. Journal of leukocyte biology. 2006;80(4):802–15. The contribution of innate immunity to inflammatory bowel disease (IBD) remains an area of intense interest. Macrophages (MØ) and dendritic cells (DC) are considered important ...

For more information visit:

www.clodrosome.com

Friday, August 10, 2012

The U.S. Food and Drug Administration today approved Marqibo (vincristine sulfate liposome injection)


A great day for liposomologists!

ENP Newswire - 10 August 2012
Release date- 09082012 - The U.S. Food and Drug Administration today approved Marqibo (vincristine sulfate liposome injection) to treat adults with a rare type of leukemia called Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL).
ALL is a rapidly progressing form of blood and bone marrow cancer that is more commonly diagnosed in children than adults. According to the National Cancer Institute, an estimated 6,050 men and women will be diagnosed with ALL and 1,440 will die from the disease this year.
Marqibo is approved for patients whose leukemia has returned (relapsed) two or more times, or whose leukemia has progressed following two or more regimens of anti-leukemia therapy. Marqibo contains vincristine, a commonly used anti-cancer drug, encased within a liposome, a drug delivery vehicle composed of material similar to that of cell membranes. It is an injection administered once a week by a health care professional.
'Marqibo's approval demonstrates the FDA's commitment to the development and approval of drugs that address serious, unmet medical needs,' said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. 'Marqibo provides an additional option for Philadelphia chromosome negative acute lymphoblastic leukemia patients whose disease is unresponsive to available therapies.'
Marqibo is approved under the FDA's accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides earlier patient access to promising new drugs while the company conducts additional clinical studies to confirm the drug's clinical benefit and safe use. Marqibo also received orphan-product designation by the FDA because it is intended to treat a rare disease or condition.
The drug's effectiveness was evaluated in a single clinical trial in adult patients whose leukemia had relapsed at least two times despite standard treatments, and who had at least one previous treatment response lasting at least 90 days. The study objective was to determine the response rate to Marqibo, as either a complete remission (CR) or a complete remission with incomplete blood count recovery (CRi). Of 65 patients enrolled, 10 patients, or 15.4 percent, responded with either a CR or CRi. In the 10 patients achieving CR or CRi, the median duration of documented remission was 28 days. The median time to the first event of relapse, death, or next therapy was 56 days.
The safety of Marqibo was evaluated in two single-arm trials of 83 patients who received the clinical treatment regimen. Serious adverse events such as low white blood cell counts with fever, low blood pressure, respiratory distress and cardiac arrest occurred in 76 percent of the patients studied. The most common side effects observed during clinical studies include constipation, nausea, low blood cell counts, fever, nerve damage, fatigue, diarrhea, decreased appetite, and insomnia.
Prescribing information for Marqibo will carry a Boxed Warning alerting patients and health care professionals that the drug must be administered only through a vein (intravenously) because it is deadly if administered in other ways, such as into the spinal fluid. The Boxed Warning also states that Marqibo has different dosage recommendations than vincristine sulfate injection alone. To avoid overdose, it is important for health care professionals to verify the drug name and the dose before administration. Special requirements for preparation of the drug are detailed in the label.
Marqibo is marketed by Talon Therapeutics Inc., based in South San Francisco, Calif.