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Sorry should be on same thread.....I will delete last one Part 2...

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    Sorry should be on same thread.....I will delete last one

    Part 2

    OK
    So let’s examine in detail the three announcements put out by Starpharma in regards to DEP® Irinotecan alone and in combinations

    Starpharma have conducted 3 disclosed preclinical studies with DEP® Irinotecan

    • In multiple cancer models
    • In pancreatic cancer model
    • In a combination cancer model
    In the first clinical trial a disclosed dosage of 25 mg was administered
    In the second and third trial an undisclosed dosage of Dep Irinotecan was administered due to pending intellectual property filings


    Below are all three announcements with my comments



    DEP® irinotecan outperforms irinotecan in multiple cancer models
    DEP® irinotecan is Starpharma’s dendrimer version of the already marketed major cancer drug, irinotecan, and one of several Starpharma internal DEP® candidates under development (others include DEP® docetaxel and DEP®cabazitaxel).

    Irinotecan is primarily used to treat colorectal cancer, which, although one of the most common cancer types, remains an area of significant unmet need with few treatment options. Irinotecan was originally commercialised under the brand name Camptosar® and achieved peak sales of US$1.1 billion prior to losing patent exclusivity. Irinotecan has a US FDA “Black Box” warning for severe diarrhoea and myelosuppression (including neutropenia).

    In Starpharma’s studies, a single treatment cycle of DEP® irinotecan administered on days 1, 8 and 15 significantly improved anti-tumour activity and enhanced survival compared to irinotecan (Camptosar®) in all cancer models tested. In the SW-620 colon cancer model, DEP® irinotecan resulted in complete tumour regression and 100% survival.

    DEP® irinotecan is one of several anti-cancer DEP® products being developed internally by Starpharma, along with DEP®docetaxel, which is currently in the advanced stages of phase 1 clinical trial and will soon enter phase 2, and DEP® cabazitaxel, which will enter clinical trials later this year. Starpharma also has a number of partnered DEP®programs, including multiple compounds in drug development with AstraZeneca and world-leading antibody-drug conjugate companies.

    About Irinotecan
    Conventional irinotecan is a pro-drug, which, following intravenous administration, needs to be converted in the liver to the active anti-cancer agent, known as SN-38. In contrast, Starpharma’s DEP® irinotecan incorporates the active irinotecan derivative (i.e., SN-38), avoiding the need for hepatic conversion. DEP® irinotecan is expected to accumulate preferentially in tumour tissue to exert its superior anti-tumour effect, as is seen with DEP® docetaxel and other DEP® conjugates (Diagram 1).



    Diagram 1: Graphical representation of conversion of irinotecan to SN-38 by the liver, and the direct delivery of DEP®irinotecan to the tumour

    Irinotecan is used as a component of first line therapy for the treatment of colorectal cancer (CRC), which is one of the most common cancers in the world, affecting more than 1 million individuals annually. CRC is the third most common cancer to affect both men and women, and the third-leading cause of cancer-related death, accounting for 8% of all annual cancer mortalities.

    Study Methods and Results
    Two xenograft studies (using HT-29 and SW-620 – human colon cancer cells) were conducted for Starpharma by an internationally recognized translational cancer group as part of a wider program of studies to assess DEP®conjugates. A xenograft study uses human cancer cells, which are then implanted in a mouse, and is a well‑established means of assessing efficacy of anti-cancer therapies.
    A unique feature of the SW620 colon carcinoma cell line is it is derived from primary and secondary tumours resected from a single patient. As such, it may represent a valuable resource for examining genetic changes late in colon cancer progression. In order to verify this, the cell line have been characterized to determine whether phenotypic differences have been retained despite long-term cell culture in vitro. The metastasis-derived SW620 cells have a fibroblast-like appearance. Xenografts of SW620 xenografts form solid sheets of tumour cells. They are highly tumourigenic and metastatic. Furthermore, SW620 cells show less susceptibility to apoptosis induction by TNFalpha and anti-Fas monoclonal. Findings from these investigations therefore indicate that SW480 and SW620 cell lines do show appropriate phenotypic differences and represent an interesting model for studying the genetic events in the late stages of colon cancer progression.


    Balb/c mice were inoculated subcutaneously with either the HT-29 or SW-620 cancer cell line (10 and 6 mice/group, respectively). Mice were dosed with saline (vehicle), DEP® irinotecan (25mg/kg) and irinotecan (90mg/kg) on days 1, 8 and 15 (all drug groups were dosed at the pre-determined maximum tolerated dose for each therapy). Tumour growth data were analysed in GraphPad Prism for ANOVA followed by Dunnett’s post-hoc test. The tumour volume data represent the mean ± standard error of the mean (SEM). Kaplan-Meier survival curves were analysed using the Log-rank (Mantel-Cox) test.

    Note the Irinotecan dosage was 360 % times greater than the Dep Irinotecan dosage


    SW-620 Xenograft:

    Complete tumour regression and 100% survival was observed in DEP® irinotecan treated animals bearing the colon cancer tumour cell line, SW-620. The tumour inhibition and survival effects of DEP® irinotecan were markedly improved compared with the irinotecan treated group and the differences were highly statistically significant (P<0.0001 and P<0.0045, respectively) (see Figures 1 and 2).


    Figures 1 and 2




    Figures 1 and 2: Efficacy (anti-tumour effect – mean tumour volume) and survival curves comparing DEP® irinotecan to irinotecan and saline (vehicle) control. DEP® irinotecan showed markedly enhanced efficacy and survival rates compared to irinotecan and the differences were highly statistically


    significant (P<0.0001 and P<0.0045, respectively).

    In DEP® irinotecan-treated animals, complete tumour regression was seen as early as day 29 after the first dose and maintained to the end of the study at day 119 (Figure 3). In this model, there was no tumour regression seen with irinotecan (the anti-cancer effect was limited to a delay in tumour growth). DEP® irinotecan was well tolerated in the model.

    Figure 3




    Figure 3: Tumour regression – SW-620 xenograft: DEP® irinotecan induced complete tumour regression in all mice tested, an effect that was sustained until the end of the study (day 119). This enhanced effect was highly statistically significant compared with the effect of irinotecan (P<0.0001). In contrast to treatment with DEP® irinotecan, tumour regression was not observed following treatment with irinotecan, and irinotecan only induced a delay in tumour growth compared with vehicle.

    HT-29 Xenograft:
    DEP® irinotecan was also shown to be very effective in this colon cancer (HT-29) tumour model, which typically responds poorly to irinotecan (Figures 4 and 5). DEP® irinotecan treatment resulted in an 11.8-fold improvement in survival compared with irinotecan (Table 1).

    In this study, irinotecan did not achieve appreciable anti-cancer activity compared to saline, whereas DEP® irinotecan exhibited a significant anti-cancer effect (Figure 4). DEP® irinotecan was significantly more effective than irinotecan (P<0.0001) for both enhanced efficacy and survival (see Figures 4 and 5). DEP® irinotecan was also well tolerated in this model.

    Figure 4


    Figure 5





    Figures 4 and 5: Efficacy (anti-tumour effect – mean tumour volume) and survival curves comparing DEP® irinotecan to irinotecan and vehicle control. DEP® irinotecan showed enhanced efficacy and survival rates compared with irinotecan and the differences were highly statistically significant (P<0.0001 and P<0.0001, respectively).





    Table 1



    Table 1: The enhanced survival benefit seen in mice treated with DEP® irinotecan was an 11.8-fold improvement compared to that seen with irinotecan, with a 50% survival increase of 83 days over saline (vehicle). Irinotecan survival improvement was only 7 days more than that seen with vehicle.

    The HT-29 cell-line is a cell-line in which irinotecan effectiveness is poor. Despite this, DEP® irinotecan was able to induce substantial tumour regression, which was not seen with irinotecan (Figure 6). A significantly enhanced tumour inhibition effect was seen with DEP® irinotecan compared with irinotecan (P<0.0001 – Dunnett’s post-hoc test). At day 36, tumour growth inhibition versus saline (vehicle) was only 21% for irinotecan and 95% for DEP® irinotecan.

    This significant differential anti-tumour effect of the two agents demonstrates the potential for DEP® irinotecan to overcome the lack of responsiveness to irinotecan in this model.



    Figure 6


    Figure 6: Tumour regression – HT-29 xenograft: DEP® irinotecan induced tumour regression in all mice tested, an effect that was observed until the end of the study (day 130). This enhanced effect was statistically significant compared with the effect of irinotecan (P<0.0001). In contrast to treatment with DEP® irinotecan, tumour regression was not observed following treatment with irinotecan, and irinotecan only induced a very short transient delay in tumour growth compared with vehicle.
    DEP® irinotecan outperforms in pancreatic cancer model

    • DEP®irinotecan alone showed complete tumour regression and 100% survival in a human pancreatic cancer model. This is compared with only very limited inhibition (and no regression) with standard irinotecan (Camptosar®) alone, and in combination with 5- fluorouracil (5-FU)
    • The complete tumour regression induced by DEP®irinotecan was despite the fact that the human pancreatic cancer model used virtually did not respond to conventional irinotecan (Camptosar®) alone and in combination with 5-FU
    • This efficacy study builds on previously announced excellent efficacy data for DEP®irinotecan in human colon cancer models
    • Starpharma is currently completing final development activities and undertaking finished product manufacture and other trial preparations for the DEP®irinotecan phase 1 / 2 trial
    Melbourne, Australia; 5 September 2018: Starpharma (ASX: SPL, OTCQX: SPHRY) today announced that its proprietary DEP®irinotecan development candidate showed significant efficacy and safety benefits over standard irinotecan in combination with 5-FU in a mouse xenograft model of human pancreatic cancer (Figure 1 and 2). The human pancreatic tumour model used in this study virtually did not respond to the traditional irinotecan regimen (irinotecan + 5-FU), whereas complete tumour regression and 100% survival was achieved using Starpharma’s DEP®irinotecan.
    Pancreatic cancer is a leading cause of death among oncologic diseases, with a one-year relative survival rate of 20%, and a five-year survival rate of only 7%. Metastatic pancreatic cancer remains resistant to current chemotherapy and radiotherapy, where irinotecan containing combination therapies such as FOLFIRINOX (combination of 5-FU, leucovorin, irinotecan, and oxaliplatin) are used as a first line treatment.
    Irinotecan was originally commercialised under the brand name Camptosar® and achieved peak annual sales of US$1.1 billion. Irinotecan has a US FDA “Black Box” warning for both severe diarrhoea and myelosuppression (including neutropenia), making it an ideal candidate for Starpharma’s DEP® technology.
    These efficacy results build on previously announced significant efficacy and safety benefit data for DEP® irinotecan(announced on 6 June 2017) in a number of colon cancer models.
    Dr Jackie Fairley, Starpharma CEO, commented: “These results for DEP® irinotecan of complete tumour regression and 100% survival are really impressive given the model used was virtually un-responsive to conventional irinotecan. Pancreatic cancer is known to have one of the lowest survival rates and remains an area of significant unmet medical need with substantial opportunity for better patient outcomes. These results provide additional validation of the DEP® platform’s ability to significantly improve efficacy alone and in combination compared to relevant originator products.”
    In this human pancreatic cancer model, conventional irinotecan (Camptosar®) alone or in combination with 5-FU displayed only limited tumour inhibition but no tumour regression whatsoever (Figure 1). In addition, conventional irinotecan alone or in combination with 5-FU showed no appreciable overall survival benefit compared to saline (Figure 2).
    In contrast, Starpharma’s DEP® irinotecan was significantly more efficacious than standard irinotecan alone and in combination with 5-FU, demonstrating significant anti-cancer efficacy with complete tumour regression (P<0.0001) (Figure 1). These impressive findings are despite the fact that this human pancreatic cancer model virtually did not respond to irinotecan alone or in combination with 5-FU.








    Study Methods
    This study was conducted for Starpharma by a leading international cancer research institution. The NOD-scid Interleukin 2 receptor gamma chain null mice were inoculated subcutaneously with CAPAN-1 (8 mice/group, respectively). Mice were dosed with saline vehicle, DEP® irinotecan (Maximum Tolerated Dosemce-anchor[1]), irinotecan (40mg/kg) or irinotecan + 5FU (40 and 50 mg/kg) on days 1, 8 a


    nd 15 (all drug groups). Tumour growth data were analysed in GraphPad Prism for ANOVA followed by Dunnett’s post-hoc test. The tumour volume data represent the mean ± standard error of the mean (SEM). Kaplan-Meier survival curves were analysed using the Log-rank (Mantel-Cox) test. 5kb)
    mce-anchor[1] Dose not disclosed pending intellectual property filings

    DEP® irinotecan combination outperforms in refractory human colon cancer model
    • DEP®irinotecan, a proprietary nanoparticle formulation, in combination with cetuximab (Erbitux®) showed complete suppression of tumour growth and 100% survival in an irinotecan-refractory human colon cancer model
    • The significant antitumor effect induced by DEP®irinotecan was despite the fact that leading colon cancer treatments, irinotecan (Camptosar®) and Erbitux®, showed limited activity in this human colon cancer model
    • This study builds on previously announced promising efficacy data for DEP®irinotecan in human colon and pancreatic cancer models
    • Starpharma is currently completing final trial preparations for the DEP®irinotecan phase 1/2 trial expected to start mid-year

    ERBITUX® (cetuximab) is approved:
    • In combination with radiation therapy for the initial treatment of a certain type of locally or regionally advanced head and neck cancer
    • In combination with platinum-based chemotherapy and fluorouracil for the initial treatment of patients with a certain type of head and neck cancer whose tumor has returned in the same location or spread to other parts of the body
    • For use alone to treat patients with a certain type of head and neck cancer whose tumor has returned in the same location or spread to other parts of the body and whose disease has progressed following platinum-based chemotherapy
    Metastatic Colorectal Cancer
    ERBITUX is approved for the treatment of certain patients who have colorectal cancer that has spread to other parts of the body. Only patients whose tumors are KRAS wild-type (which means they have a KRAS mutation-negative gene), and whose tumors have a protein called epidermal growth factor receptor (EGFR), should receive ERBITUX. An FDA-approved test is used to determine if tumors have these particular traits. Treatment with ERBITUX is given in the following three ways:
    • In combination with FOLFIRI (irinotecan, fluorouracil, leucovorin) for patients who are being treated for this type of cancer for the first time
    • In combination with another chemotherapy drug, irinotecan, for patients whose disease has progressed after receiving chemotherapy with irinotecan
    • As a single agent:
      • For patients whose disease has progressed after receiving both irinotecan and oxaliplatin
      • For patients who are unable to tolerate chemotherapy with irinotecan
    ERBITUX is not approved to treat colorectal cancer in patients whose tumors have mutations in genes called RAS (often called "RAS mutant"), or in patients for whom the mutational status of the genes is not known.
    WARNING: ALLERGIC REACTIONS AND HEART ATTACK
    ERBITUX can cause serious and sometimes fatal allergic reactions. Serious allergic reactions due to ERBITUX therapy occurred in 2.2% of patients receiving ERBITUX during clinical studies; 1 patient died. The risk of anaphylactic reactions may be increased in patients with a history of tick bites, red meat allergy, or in the presence of certain antibodies which can react to ERBITUX.

    • Symptoms can include trouble with breathing (including tightening of the airways, wheezing, or hoarseness), low blood pressure, shock, loss of consciousness, and/or heart attack. Report these signs and symptoms of infusion reactions, as well as fever, and/or chills to your doctor or nurse.
    • Approximately 90% of the severe allergic reactions occurred with the first treatment with ERBITUX (even if the patient had been premedicated with antihistamines), although some patients experienced their first severe allergic reaction during a later treatment.
    • Your doctor or nurse should watch you closely for these symptoms during treatment and for at least 1 hour following treatment and may need to stop therapy in the event of an allergic reaction. After the allergic reaction resolves, your doctor may be able to restart therapy.
    • If you have a severe allergic reaction, treatment with ERBITUX must be stopped immediately and not started again.
    ERBITUX can cause heart attack or sudden death.
    • Heart attack or sudden death occurred in 2% of 208 patients with head and neck cancer treated with radiation therapy and ERBITUX in a clinical study. Three patients with a prior history of coronary artery disease died within six weeks after receiving the last dose of ERBITUX. One patient with no prior history of coronary artery disease died one day after the last dose of ERBITUX.
    • Heart problems resulting in death or sudden death occurred in 3% of 219 patients with head and neck cancer treated with ERBITUX and platinum-based chemotherapy with fluorouracil in a clinical study.
    TOTAL YEARLY SALES OF ERBITUX AND CAMPTOSAR IS CURRENTLY AU$3.97 BILLION
    Starpaharma today announced that its patented nanoparticle formulation, DEP® irinotecan, showed significant efficacy and safety benefits over leading colorectal cancer drugs irinotecan (Camptosar®) and cetuximab (Erbitux®), in the irinotecan-refractory HT-29 human colon cancer model.
    These impressive results were despite the fact that these standard colorectal cancer (CRC) treatments, Camptosar®and/or Erbitux®, showed limited activity in this preclinical model.
    Irinotecan (Camptosar®) is used as a component of first line therapy for the treatment of CRC, which is one of the most common cancers in the world, affecting more than 1 million individuals annually and is the third-leading cause of cancer-related death. DEP® irinotecan is a novel nanoparticle formulation of SN-38, the active constituent of irinotecan (Camptosar®), delivered using Starpharma’s patented DEP® platform.
    Cetuximab (Erbitux®) is marketed by Eli Lilly and Merck KGaA and is indicated for use in approximately 50% of CRC cases, with US$1.6 billion in sales in 2018. Camptosar® achieved peak annual sales of US$1.1 billion.
    The results for DEP® irinotecan in this irinotecan-refractory human colon cancer model (see figures below) build on previously announced data for DEP® irinotecan in multiple human cancer models. These results also add further support to the growing body of data demonstrating that DEP® drugs perform better when used in combination (e.g. when used with Erbitux®) than the originator product (e.g. Camptosar®) used in that same combination. These results are timely given the upcoming commencement of Starpharma’s DEP® irinotecan phase 1/2 trial.
    Dr Jackie Fairley, Starpharma CEO, commented: “These impressive results for DEP® irinotecan once again demonstrate the significant advantage conveyed by the DEP® platform. Combinations using DEP® drugs are consistently showing better performance than the same combinations using the originator products (e.g. Camptosar®). These results are particularly interesting given we have also previously shown the beneficial effect of using DEP® docetaxel, DEP® cabazitaxel and AZD0466 as part of a combination therapy approach.”
    Study Results
    In this irinotecan-refractory human colon cancer model (HT-29 xenograft), the combination of cetuximab (Erbitux®) and irinotecan (Camptosar®) displayed limited tumour inhibition (Figure 1a). In contrast, DEP® irinotecan in combination with cetuximab (Erbitux®) resulted in significantly enhanced anti-cancer efficacy (Figure 1a) and survival (Figure 1b) despite the DEP® irinotecan doses being approximately one third (low dose) and approximately two thirds (high dose) of the maximum tolerated dose for this combination[1].



    Figure 1a: Tumour volume vs time: DEP® irinotecan + Erbitux® compared with irinotecan (Camptosar®) and Erbitux®in combination in a mouse xenograft (human colon cancer model) (p<0.001)[2]



    Figure 1b: Kaplan-Meier survival curve: DEP® irinotecan + Erbitux® compared with irinotecan (Camptosar®) + Erbitux® in combination in a mouse xenograft (human colon cancer model). Survival curves for both high and low doses of DEP® irinotecan in combination with Erbitux® were significantly different to irinotecan (Camptosar®) + Erbitux® (p<0.001)
    Study Methods

    The xenograft study used an HT-29 cell line (irinotecan-refractory human colon cancer) and was conducted for Starpharma by an internationally recognized translational cancer group as part of a wider program of studies to assess DEP® conjugates in combination with other leading cancer drugs. A xenograft study uses human cancer cells, which are then implanted in a mouse, and is a well‑established means of assessing efficacy of anti-cancer therapies.
    Balb/c mice were inoculated subcutaneously with the colon (HT-29) cell line (8 mice/group). Mice were dosed with saline (vehicle), DEP® irinotecan (low and high dose), and irinotecan (Camptosar®) (35 mg/kg) IV once per week and cetuximab (Erbitux® 25 mg/kg) IP twice per week. Irinotecan (Camptosar®) and cetuximab (Erbitux®) were dosed at the pre-determined maximum tolerated dose for the combination; however, DEP® irinotecan doses were approximately one third (low dose) and approximately two thirds (high dose) of the maximum tolerated dose for this combination.
    Tumour growth data were analysed in GraphPad Prism for ANOVA followed by Dunnett’s post-hoc test. The tumour volume data represent the mean ± standard error of the mean (SEM). Kaplan-Meier survival curves were analysed using the Log-rank (Mantel-Cox) test. (Note: If error bars do not display on the graphs, they are not visible because they are shorter than the height of the symbol.)
    [1] Doses of DEP® irinotecan are not disclosed for intellectual property reasons.
    [2] Irinotecan (Camptosar®) and DEP® irinotecan dosed IV weekly, Erbitux® dosed twice weekly IP.



    @Domesticgod
    Having looked at the announcement again there are a couple of things that struck me.


    Firstly, the tumour size does not appear to decrease in the chart.

    That's right. However there is complete suppression of growth using the high dose of Dep Irinotecan in combination with Erbitux. The tumor does not grow any larger

    And in the low dose there was an increase it took over 50 days to get to the same level as the Irinotecan/Erbitux combination. We can only guess at how low the dosage is.....but we can assume Starpharma is comparing it to the 35 mg of Irinotecan. There is a very noticable difference in the graph comparing the two. And in fact the control (saline solution) versus the Irinotecan combination are very similar until high 20's (possibly day 27-28)

    Remember Starpharma is using the HT-29 human colon cancer model.

    You will notice the survival rate in Dep Irinotecan combination was 100% after 60 days with high dose (2/3 of maximum dosage), around 40% after 55 days (1/3 of maximum dosage)

    Whereas the maximum tolerated dosage of Irinotecan combination.......survival rate was 0% after 48 days versus saline solution of 0% after 45 days

    Refractory CRC means that the cancer may continue to grow despite treatment. The cancer may be resistant at the beginning of treatment or it may become resistant during treatment.




    In the previous trial of pancreatic cancer last year it could be seen that the tumour actually decreased in size, before increasing again. Does anyone have an explanation?

    Yes......Dep Irinotecan works fantastically in Pancreatic Cancer. Compared to the combination of Irinotecan - 5-FU.....it really is insignificant in my opinion






    Secondly, I personally didn't think the low dose of Dep irinotecan was that much different to standard irinotecan, regardless of what the text wants us to believe. That is to say, it was not a significant improvement.

    You may be right DG......however you remember in the first preclinical with Dep Irinotecan versus Irinotecan the doses were 25mg versus 90 mg.....So I am thinking that these doses could be in the same proportion in the combination trials. We just need to wait and see until the IP is registered






    Thirdly, and back to frivolity again folks, why call the two thirds MTD dose of Dep irinotecan the “high” dose? What if they want to dose at the full strength of standard irinotecan in the future? Do they call that the “extreme” dose? Hardly inspirational, is it? I think they should have called it the “medium dose”. IMO.

    Semantics or maybe the low dosage is 9.7 mg and the high dosage is 23 mg and the full dosage is 35 mg.......I could be completely wrong.....time will tell


    These are still great results in comparison to what is currently available.

    I agree DG.... the results are fantastic
 
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