Date: 2016-04-27
Type of information: Results
phase: 3
Announcement: results
Company: Oasmia Pharmaceutical (Sweden)
Product: Paclical®/Apealea® (paclitaxel)
Action
mechanism: taxane derivative. Paclical® is a water-soluble and Cremophor- and albumin-free formulation of paclitaxel combined with Oasmia’s excipient technology XR-17. XR-17 is Oasmia's proprietary excipient and is based on Vitamin A. It forms micelles that are between 20 and 60 nanometres in size. XR-17 can also form micelles with water-soluble substances. This increases its potential uses significantly. Once XR-17 has delivered the encapsulated molecule or molecules to the target, the excipient is metabolized naturally. XR-17 facilitates the ease of administration and allows for higher doses than some of the other existing pharmaceutical products on the market, including cytostatics such as paclitaxel. Paclical has orphan drug designation in the EU and the US.
Disease: epithelial ovarian cancer
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The study was designed to achieve the following primary objective: PFS: to show non-inferiority of Paclical® (250 mg/m2) versus Taxol (175 mg/m2) using computed tomography (CT) scans according to Response Evaluation Criteria in Solid Tumors (RECIST), as assessed by central review. Inclusion criteria included patients who relapsed at least six months after end of first line or second line treatment including platinum based therapy. Paclical® was administered as a one-hour intravenous infusion at its recommended dose of 250 mg/m2. Taxol was administered as a three-hour intravenous infusion at its recommended dose of 175 mg/m2. Both drugs were dosed in six three-week cycles. Patients treated with Taxol received systemic pre-treatment with corticosteroids, antihistamines and H2 receptor antagonists. Patients treated with Paclical® did not receive such treatment. Carboplatin was given as an intravenous infusion starting 30 minutes after the end of the paclitaxel infusion. The carboplatin dose is based on kidney function measured as creatinine clearance (5-6 AUC) that means that the variation in dose between patients is large, with a mean of approximately 625 mg/cycle, but it can be twice that much for an individual patient. After completing the treatment cycles, patients were followed until progression.
Latest
news: * On April 27, 2016, Oasmia Pharmaceutical announced positive overall survival results for Paclical®/Apealea® in the Phase III study that included a total of 789 patients with epithelial ovarian cancer. These preliminary results showed non-inferiority between the two treatment groups of Paclical®/Apealea® in combination with carboplatin versus Taxol in combination with carboplatin. In fact, the overall survival in patients completing 6 treatment cycles was 25.7 months in patients that had received the Paclical®/Apealea® combination compared to 24.8 months in patients that had received the Taxol combination. The period from randomization to relapse or death (PFS) becomes shorter with the number of relapses, and hence treatment periods, that the patient goes through. A published study comparing the period of the first PFS with the second showed a difference of 7 months, 17.8 compared to 10.8 months. * On October 21, 2014, Oasmia Pharmaceutical announced that the full clinical trial report of Paclical®, for the treatment of epithelial ovarian cancer, shows a positive risk/benefit profile. The data will serve as the basis of a Marketing Authorisation Application to the European Medicines Agency (EMA), which the company intends to submit in Q2 2015. The Phase III open, randomized, multi-centre study, which included in total 789 patients, was designed to compare the efficacy and safety between Paclical and Taxol, which is also a paclitaxel-based product. Both Paclical and Taxol were administered in combination with carboplatin. The period from randomization to relapse or death (PFS) becomes shorter with the number of relapses, and hence treatment periods, that the patient goes through. A study comparing the period of the first PFS with the second showed a difference of 7 months, 17.8 compared to 10.8 months. The study showed a PFS period of 10.3 months for Paclical + carboplatin compared to 10.1 months for Taxol + carboplatin. The result corresponds well with literature data from studies in platinum sensitive patients in second line treatment, e.g. 10.8 months (ref 1) and 9.4 months. The study was designed to achieve the following primary objective: PFS: to show non-inferiority of Paclical (250 mg/m2) vs Taxol (175 mg/m2, using computed tomography (CT) scans according to Response Evaluation Criteria in Solid Tumors (RECIST), as assessed by central review. Inclusion criteria included patients who relapsed at least six months after end of first line or second line treatment including platinum based therapy. Paclical was administered as a one-hour intravenous infusion at its recommended dose of 250 mg/m2. Taxol was administered as a three-hour intravenous infusion at its recommended dose of 175 mg/m2. Both drugs were dosed in six three-week cycles. Patients treated with Taxol received systemic pre-treatment with corticosteroids, antihistamines and H2 receptor antagonists. Patients treated with Paclical did not receive such treatment to the same extent Carboplatin was given as an intravenous infusion starting 30 minutes after the end of the paclitaxel infusion. The carboplatin dose is based on kidney function measured as creatinine clearance (“5-6 AUC”) that means that the variation in dose between patients is large, with a mean of approximately 625 mg/cycle, but it can be twice that much for an individual patient. After completing the treatment cycles, patients were followed until progression. The risk/benefit analysis is based on data from the study, including: * On June 16, 2014, Oasmia Pharmaceutical announced that its lead human product Paclical® (paclitaxel) has successfully met its primary objective according to the study design, showing non-inferiority between Paclical and Taxol – both combined with the chemotherapeutic carboplatin – regarding progression free survival (PFS). The data show that Paclical, which has orphan designation for epithelial ovarian cancer in the EU and in the US, met the pre-defined requirement of non-inferiority compared with Taxol. The Phase III open, randomized, multi-centre study, which included in total 789 patients, was designed to compare the efficacy and safety between Paclical and Taxol, which is also a paclitaxel-based product. Both Paclical and Taxol were administered in combination with carboplatin.The period from randomization to relapse or death (PFS) becomes shorter with the number of relapses, and hence treatment periods, that the patient goes through. A study comparing the period of the first PFS with the second showed a difference of 7 months, 17.8 compared to 10.8 months. The study showed a PFS period of 10.3 months for Paclical + carboplatin compared to 10.1 months for Taxol + carboplatin. The result corresponds well with literature data from studies in platinum sensitive patients in second line treatment, e.g. 10.8 months and 9.4 months. Oasmia will complete a clinical trial report in the second half of 2014, including a risk/benefit analysis. Furthermore, the study will compare PFS assessed with CT (RECIST) and the biomarker CA 125. The data will serve as the basis of a Marketing Authorisation Application to the European Medicines Agency (EMA), which the company intends to submit in early 2015.
The results from the evaluation of the OS data confirm previous findings from June 2014 that the study had met the primary endpoint of Progression Free Survival (PFS) favoring Paclical®/Apealea®, and strengthens the positive risk/benefit profile for Paclical®/Apealea® published in October 2014.
The phase III study showed a PFS period of 10.3 months for Paclical + carboplatin compared to 10.1 months for Taxol + carboplatin. The result corresponds well with literature data from studies in platinum sensitive patients in second line treatment, e.g. 10.8 months (ref 1) and 9.4 months.
The study was designed to achieve the following primary objective:
PFS: to show non-inferiority of Paclical (250 mg/m2) vs Taxol (175 mg/m2, using computed tomography (CT) scans according to Response Evaluation Criteria in Solid Tumors (RECIST), as assessed by central review.
Inclusion criteria included patients who relapsed at least six months after end of first line or second line treatment including platinum based therapy. Paclical was administered as a one-hour intravenous infusion at its recommended dose of 250 mg/m2. Taxol was administered as a three-hour intravenous infusion at its recommended dose of 175 mg/m2. Both drugs were dosed in six three-week cycles.
Patients treated with Taxol received systemic pre-treatment with corticosteroids, antihistamines and H2 receptor antagonists. Patients treated with Paclical did not receive such treatment to the same extent. Carboplatin was given as an intravenous infusion starting 30 minutes after the end of the paclitaxel infusion. The carboplatin dose is based on kidney function measured as creatinine clearance (“5-6 AUC”) that means that the variation in dose between patients is large, with a mean of approximately 625 mg/cycle, but it can be twice that much for an individual patient. After completing the treatment cycles, patients were followed until progression.
Overall survival data was calculated as the time from randomization into the study to day of death independent of reason. Patients left the study at disease progression and received other treatment, either as participants in a clinical trial or following the treatment recommendation of the country/clinic. The nature of this treatment is not known, but it is anticipated that as it is a randomized study, any difference regarding treatment of the two groups would be minimal. Earlier this year, Oasmia applied for marketing approval of Apealea® (the alternatively branded name for Paclical®) in the European Union for treatment of ovarian cancer. This overall survival data will be added to the EMA application and will form the basis of the marketing application to the FDA in the United States.
The percentage of patients with a substantial decrease in tumour burden - including normalized levels of the biomarker used for this evaluation - is 86% for patients treated with Paclical and 85% for patients treated with paclitaxel (Taxol). The percentage of those with normalized biomarker levels (=complete response) is 62% for both treatments. This implies that Paclical is an effective treatment of ovarian cancer when used in combination with carboplatin.
Time of progression free survival is 10.2 months compared to Taxol (10.0 months) and is in line with what has previously been published for patients after the first or second relapses. More frequent CTs (every 3 months) were done in a substantial subgroup of 243 patients. The median PFS time in this subgroup was 12.2 months for Paclical and 10.2 for paclitaxel (Taxol).
The intended infusion time for Paclical is 1 hour, compared to Taxol’s 3-hour infusion time, and only on rare occasions were there any prolongation of the infusion time.
Corticosteroids and antihistamines are not indicated as pre-treatment before Paclical, which was confirmed in this study, as only a limited number of patients received such medication before treatment with Paclical.
The overall safety profile of Paclical is in line with what was expected for paclitaxel. However, a dose-dependent increase in frequency and severity of adverse events was not seen, apart from those related to the white blood cells. This means that despite the higher dose compared to Taxol, adverse events related to paclitaxel are not more common with Paclical.
Neuropathy (numbness of hands and feet) is an adverse event related to treatment with paclitaxel. Neuropathy is also seen with Paclical, but to a somewhat lesser degree than with Taxol, despite the higher Paclical dose.
Despite the adverse events reported, including frequent blood cell related adverse events, the dose was reduced in only 18% of the patients. Dose-reduction below 200 mg/m2 was rare. The investigators did thus not reduce the dose of Paclical to the level of Taxol (175 mg/m2).
All data examined shows a consistent although not significant advantage of Paclical in all efficacy variables compared with Taxol. The safety profile was similar with an expected increase in frequency and severity of white blood cell related events and a non-expected decrease in neuropathy. Dose reduction to the level of Taxol (175 mg/m2) was rare although allowed according to the protocol. Overall survival data are expected in Q3 2015.
