Date: 2015-12-01
Type of information: Interim results
phase: 2
Announcement: interim results
Company: PledPharma (Sweden)
Product: PledOx™
Action
mechanism: PledOx™ (calmangafodipir) is a compound that, among other things prevents the side effects of chemotherapy in cancer treatment. PledOx has been shown in studies to protect against "oxidative stress" - a condition in which the cell's most important protection is not sufficient against the levels of reactive oxygen species generated as a result of the chemotherapy treatment. By mimicking the enzyme superoxide dismutase (SOD), PledOx boosts the cells endogenous protection and thereby prevents side effects that would otherwise arise as a result of the "oxidative stress".
Disease: reduction of side effects caused by the chemotherapy FOLFOX in patients treated for metastatic colorectal cancer
Therapeutic area: Cancer - Oncology
Country: Sweden, USA, Bulgaria, Denmark, Portugal, Georgia, Serbia, Germany
Trial
details: The PLIANT study is divided in two parts. A dose-escalation phase, in order to determine the correct dose level, and a randomized phase, with the goal to establish PledOx’s effect. The dose-escalation phase comprises of 9-12 patients from three selected medical centers in Sweden and one in the U.S. – the Oncology clinic at Uppsala University Hospital, Karolinska University Hospital, Department of Oncology, Linköping University Hospital and the Cancer Therapy & Research Center at The University of Texas Health Science Center in San Antonio , USA. Next phase, the randomized phase, planned for 126 patients from approximately 30 centers in Europe and the United States, the patients will be divided into three equal groups to receive either placebo or PledOx in two different doses. (NCT01619423)
The clinical trial material for PLIANT has been manufactured by Recipharm Pharmaceutical Development.
Latest
news: * On December 1, 2015, Pledpharma announced that PledPharma's CEO Jacques Näsström will present new in-depth long-term data from a preliminary interim analysis of the ongoing follow-up phase of the company's pivotal Phase IIb study PLIANT of PledOx®. Importantly, this data show that 24 weeks after completion of treatment PledOx® reduces the incidence and intensity of chemotherapy induced neuropathy by 75 percent compared with placebo. The difference was statistically significant (p <0.01). Earlier this year, PledPharma presented results from PLIANT showing that PledOx® reduces the appearance of nerve damage symptoms by 43 percent compared to placebo during treatment. These results were based on the treating doctor's assessment of the severity of the symptoms. However, the long-term data now being presented are based on the patients' own assessments of symptoms and show that the effect of pretreatment with PledOx® is even more pronounced at 24 weeks post treatment. Treatment by PledOx® with a 5 µmol / kg dose was found to keep the symptoms stable at a low level during the first 24 weeks after completion of treatment, while the placebo group showed increased neuropathy. Patients in this dosage group estimated the magnitude of neuropathy to be 62 percent lower than patients in the placebo group at week 12, and 75 percent lower at 24 weeks after completion of chemotherapy. The difference is statistically significant (p<0.01 at 24 weeks and p<0.05 at 12 weeks). For the group receiving the placebo the incidence and severity of symptoms increased significantly until week 12 and then levelled out at a high level. * On November 19, 2015, PledPharma announced that the company has completed an end of phase II/pre phase III-meeting with the FDA, which provides guidance on how to perform the continued documentation of PledOx®. A final protocol from the meeting is expected in December 2015. During the meeting, new follow up-data from the final Phase IIb-trial (PLIANT) with PledOx® was presented. The results from two follow-ups, at 12 and 24 weeks after completed treatment, show that PledOx® reduces the risk for persistent symptoms from nerve damage that occur in connection with chemotherapy for advanced colorectal cancer in a statistically significant way.PledPharma has, as announced previously, presented results that demonstrate that PledOx® decreases the incidence of symptoms caused by nerve damage by 43 percent compared with placebo during ongoing treatment and that PledOx® does not negatively affect the anti-cancer effect of the chemotherapy (See below). * On June 26, 2015, Pledpharm announced that the company has presented additional results from the PLIANT study at the scientific conference MASCC (Multinational Association of Supportive Care in Cancer) in Copenhagen, Denmark. The study results presented at MASCC show that patients treated with PledOx® have a lower risk than the placebo group to suffer from nerve damage. As previously reported, the incidence of symptoms caused by sensory nerve damage (neuropathy) was 43 percent lower in the group of patients treated with PledOx® at a dose of 5 µmol/kg, compared to the placebo group. New data from three different test methods consistently show a positive effect of the treatment. The data also clearly confirms that the anti-cancer effect of chemotherapy was not negatively impacted by PledOx® treatment. It was concluded that PledOx® had a benign safety profile and was not associated with any serious adverse effects. The additional results revealed that symptoms occur later and disappear faster after pretreatment with PledOx®. The findings were presented by Associate Professor Devalingam Mahalingam, M.D., Ph.D., University of Texas Health Science Center, San Antonio, Tx, USA and principal investigator for the PLIANT study in the United States. * On October 21, 2014, PledPharma announced that all 126 patients have now been included in the colorectal cancer study PLIANT and results are expected by the end of Q1 next year. The DSMB reports that the third and last futility analysis that included 30 patients, in addition to those 60 patients already analyzed, has been completed and that no negative impact on the anticancer effect of the chemotherapy has been observed. The analysis covers the first 90 patients in the study who have completed four treatment cycles with the chemotherapy mixture FOLFOX after pretreatment with either PledOx® or placebo. The approval means that PledOx did not weaken the anticancer effect of FOLFOX and that the PLIANT trial be concluded as planned. * On September 9, 2014, the DSMB reports that the second futility analysis that includes an additional 30 patients has been completed and that no negative impact on the anticancer effect of PledOx® has been observed. The analysis covers the first 60 patients in the study who have completed four treatment cycles with the chemotherapy mixture FOLFOX after pretreatment with either PledOx® or placebo. The approval means that PledOx did not weaken the anticancer effect of FOLFOX and that the PLIANT trial can thus proceed with recruitment of patients as planned. In the PLIANT study the drug PledOx is tested to reduce serious side effects from FOLFOX treatment of colorectal cancer. Many chemotherapy treatments can't be completed as planned due to serious and life-threatening side effects. The primary objective with the PLIANT study is to evaluate the reduction of adverse events related to a decrease in white blood cells (neutrophils) and sensory nerve disorders (neuropathy). Another futility analysis will be conducted after 90 patients have undergone four treatment cycles with chemotherapy, after pretreatment with either PledOx or placebo. * On August 26, 2014, Pledpharma announced that in total 11 patients have been treated in the open part of the study and preliminary analysis of the raw data indicated that PledOx® reduced the severe chemotherapy-induced side effects.The new data showed that PledOx was well tolerated by the additional 5 patients treated with Avastin® (bevacizumab) in combination with FOLFOX chemotherapy. With this, the open part of the study with a total of 11 patients is reported. The open part of the study was performed in order to determine tolerability and the correct dose level. Nine of these 11 patients underwent at least 6 cycles of FOLFOX and none of these patients showed a grade 2 or worse neuropathy against an expected outcome of at least two patients. These data also indicated a reduction of serious blood-related side effects with the 5 μmol/kg dose of PledOx. * On August 18, 2014, Pledpharma announced that the futility analysis in PLIANT study has been completed and approved by the DSMB. DSMB reports that no negative impact on the anticancer effect of the chemotherapy drug has been observed. The analysis covers the first 30 patients in the study who have completed four treatment cycles with the chemotherapy mixture FOLFOX after pretreatment with either PledOx® or placebo. The analysis showed that PledOx did not weaken the anticancer effect of FOLFOX. The analysis was conducted and approved by the independent expert panel DSMB (Drug Safety and Monitoring Board). The PLIANT trial can thus proceed with recruitment of patients as planned. Safety analyzes will be conducted after every additional 30 patients have undergone four treatment cycles with chemotherapy, after pretreatment with either PledOx or placebo. * On April 25, 2014, Pledpharma has announced that patient recruitment in the PLIANT study proceeds according to expectations. The ongoing cancer study PLIANT is running smoothly and currently all participating countries are actively recruiting patients to Part 2 of the study. At present, 25 patients have been treated in addition to those already treated the first part of the study. The results from the first part of the study, in which 11 patients were included, show that PledOx was well tolerated by patients undergoing standard chemotherapy with FOLFOX. Furthermore, results indicate that the severe sensory disturbances, which may occur during FOLFOX chemotherapy, did not occur in the patients pretreated with PledOx in Part 1 of the study. That PledOx appears to reduce the risk on chemotherapy-induced sensory nerve disorders, known as neuropathies, is what impresses most on the oncologists we talked to since this is a major clinical problem and the main reason for oxaliplatin-based chemotherapy being discontinued. We also noted that patients who received the lower dose of PledOx displayed fewer serious blood cell-related adverse events than patients treated with FOLFOX normally are expected to get. Based on these data, Pledpharma has lowered the highest dose in this study to optimize the effect of PledOx on both blood cells and sensory disturbances, which results in an expansion of the study and hence increased costs. * On February 12, 2014, PledPharma has announced that the first part of the study, the dose-escalation part (with PledOx® 2 and 10 micromol/kg) in order to determine tolerability and the correct dose level, has been completed. Patients have tolerated both doses of PledOx well. The raw data from the dose-escalation part have now been compiled in a preliminary analysis. One can observe that, unlike during normal FOLFOX treatment of colorectal cancer, no moderate or serious neuropathies (grade 2 or higher) were observed despite up to 8 cycles of FOLFOX. This was seen for both doses of PledOx. The expected outcome without PledOx-treatment is that approximately 30% of the patients will develop neuropathies of grade 2 or worse after 8 cycles. In addition, it seems that the low dose in particular appears to have the potential to reduce serious (grade 3) white blood-related side effects such as decrease in neutrophils. Neutrophils are an essential type of white blood cells in defending the body against bacterial infections. According to these data, the lower dose of PledOx will give the best effect. PledPharma has therefore applied to the regulatory authorities for reduction of the higher dose of 10 micromol/kg to 5 micromol/ kg. The reduction is primarily based on the apparent better effect on white blood cell-related side effects with the lower dose of PledOx. This change in dose also means that the full number (i.e. 42) randomized patients must be included in order to be able to statistically evaluate the new dose, which will result in an expansion of the study and an extension of the trial period. Patients treated with the new dose will, however, replace the majority of patients that should have be treated with the higher dose of 10 ?mol/kg since the dose change occurs early on in the study. The current estimate is that all patients should be included in the study before the end of 2014 and that overall (top-line) data should be available towards the end of the first quarter of 2015. Currently, all six patients in the dose escalation part have completed their treatment. Furthermore, all patients being treated with FOLFOX in combination with bevacizumab have started their treatment and DSMB has now given its initial approval to continue the treatment with bevacizumab in combination with FOLFOX. In addition, three patients are included in the second part of the study (the randomized part) and at the high end of 20 centers are actively recruiting patients to the study and these centers have identified an additional handful of candidates to include in the study. * On December 10, 2013, PledPharma has announced that the first patient has now been treated at Uppsala University Hospital int he randomized part of the Phase IIb study PLIANT. The study will evaluate whether pretreatment with PledPharma’s drug candidate PledOx® reduces severe side effects caused by the chemotherapy FOLFOX in patients treated for metastatic colorectal cancer. After analyzing the data from the first six patients enrolled in part 1 of the study, part 2 has now started. First out are the centers in Sweden and the United States closely followed by Bulgaria, Denmark and Portugal. Thereafter Georgia, Serbia and Germany will follow. PledPharma expect that the majority of centers can be initiated to begin enrollment of patients in December. In addition, the DSMB approved the continued dosing of the first patient in the U.S. who has received PledOx as pretreatment to FOLFOX in combination with Avastin. * On November 13, 2013, PledPharma has received approval from the DSMB (Drug Safety Monitoring Board, an independent panel of experts) to start the randomized part of the Phase IIb study PLIANT. The study will evaluate whether pretreatment with PledPharma's drug candidate PledOx® reduces serious side effects caused by the chemotherapy FOLFOX in patients treated for metastatic colorectal cancer. The approval comes after the DSMB has analyzed the data from the first six patients enrolled in the study. With the green light to go-ahead, the second wider part of the PLIANT study can start. First out are the centers in Sweden and the United States closely followed by Bulgaria, Denmark and Portugal. Thereafter Germany, Serbia and Georgia will follow. Pledpharma expects that the majority of centers can begin enrolling patients in November / December. * On October 15, 2013, PledPharma has announced that the company has been authorized by DSMB to continue dosing with PledOx in the phase IIb study PLIANT. DSMB has analyzed the test results from the sixth patient, which was enrolled in the study two weeks ago. The study is now in the final phase of the first part, the so-called dose-escalation part. With the approval to proceed with the study, the sixth and last patient can continue to receive the second cycle of the higher dose of PledOx. When all six patients have completed treatment, the data from this open part will be analyzed and presented. The result from some 40 treatments with PledOx is expected to be reported towards the end of the first quarter 2014. * On February 26, 2013, PledPharma has announced that the company has received green light from the DSMB (Drug Safety Monitoring Board), an independent panel of experts, to continue patient recruitment for the phase IIb study PLIANT. The DSMB has analyzed the test results from the first patient that was enrolled in the study two weeks ago. The study is in the dose-escalation phase. With the approval to proceed with the study, the first patient is to receive the second dose of PledOx, while the next two patients to be included in the study in parallel can receive the first low dose of PledOx. When all three patients received at least one cycle of therapy, and the first patient received three cycles DSMB will re-evaluate the data to give approval for this procedure to be repeated for the higher dose of PledOx. * On February 13, 2013, PledPharma has announced that the first patient has been enrolled in the phase IIb study, PLIANT. This study will evaluate PledPharma's drug candidate PledOx™ ability to reduce side effects caused by the chemotherapy FOLFOX in patients treated for metastatic colorectal cancer. This patient has been included at the Oncology clinic at Uppsala University Hospital. As a second step after the first dose-escalation phase is completed, which is expected to take approximately 4-5 months, the study will expand to include 126 patients from at least 28 centers in Europe and the U.S. This study will demonstrate PledOx’s ability to reduce serious and some-times life-threatening side effects from chemotherapy. In this way, the patients will receive both a better quality of life, and hopefully an increased survival, says Jacques Näsström CEO PledPharma. * On January 30, 2013, PledPharma has announced that the company expands recruitment to the dose-escalation phase of PLIANT study with center in the U.S. The study will also include the Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio., U.S. for the first part of the study, the dose-escalation phase, together with the three centers in Sweden. * On January 21, 2013, PledPharma has received an Investigational New Drug (IND) approval from the FDA to conduct its Phase IIb study PLIANT in the U.S. Patients will be randomized to receive two different doses PledOx, the compound developed by PledPharma, or placebo. The estimated number of patients included in the randomized phase of the study is 126 (42 in each of the 3 groups). The study is planned to be carried out in several centers in Europe and the U.S. * On August 1, 2012, PledPharma has announced that its PledOx® phase IIb clinical trial application, PLIANT, was approved by the Swedish Medical Products Agency (MPA). Patients will be randomized to receive PledOx in a dose of 2 or 10 µmol/kg, or placebo. The randomization phase of the study will be preceded by a dose-escalation phase with the aim of determining PledOx clinical safety, tolerability and pharmacokinetic and pharmacodynamic properties (effects of the body on the drug, and of the drug on the body). The primary outcome measure will be the change in absolute neutrophil count (number of white blood cell subtype). Secondary outcomes will include effects on the occurrence of febrile neutropenia (sign of infection associated with loss of white blood cell subtype) and sensory neuropathy (pain and discomfort originating from peripheral nerve affection).
