Effects of Chemotherapy

June 15, 2015

Janssen R&D reported results of a phase III study of trabectedin (Yondelis) compared to dacarbazine for advanced liposarcoma (LPS) or leiomyosarcoma (LMS) previously treated with an anthracycline and at least one additional chemotherapy regimen. Both treatments were administered via an IV infusion every three weeks with the trabectedin dose of 1.5mg/m2 given over 24 hours v. dacarbazine dose of 1g/m2 given over 20-120 minutes. In this randomized, active-controlled study in patients with advanced LPS or LMS, trabectedin significantly reduced the risk of disease progression or death by 45% compared with those who received dacarbazine (hazard ratio [HR] = 0.550; P<0.0001; median [M] 4.2 v. 1.5 months, respectively), with results validated through an audit by independent radiologists. Safety findings were consistent with the well-characterized safety profiles of both agents, with the most common grade 3-4 toxicities in the trabectedin v. the dacarbazine groups being decreased absolute neutrophil count (40% v. 25%), decreased platelets (19% v. 20%) and transient increases in liver transaminases, including alanine transaminase (29% v. 1%). Drug-related deaths occurred in 2.1% of patients in the trabectedin group v. 0% of patients in the dacarbazine group. Trabectedin is approved in 77 countries in North America, Europe, South America and Asia for the treatment of advanced STS as a single agent. Janssen submitted an NDA to the FDA on November 24, 2014, which was granted Priority Review on February 3, 2015.

July 14, 2014

Merck reported results for a phase III study of EMEND (aprepitant) in the prevention of chemotherapy-induced nausea and vomiting (CINV) in pediatric cancer patients, aged 6 months to 17 years. In the randomized, double-blind, active-comparator study of 302 participants, patients receiving emetogenic chemotherapy were randomly assigned to receive an EMEND plus ondansetron regimen (n=152) or a control regimen (placebo plus ondansetron) (n=150). The first dose of EMEND (plus ondansetron) was administered on day one of chemotherapy, then subsequently (without ondansetron) later on days two and three. In the study, 51% of patients receiving the EMEND regimen achieved the primary endpoint of complete response in the delayed phase of CINV, versus 26% of those in the control group (p<0.0001). For the secondary endpoints, 66% of patients receiving the EMEND regimen achieved a complete response in the acute phase of CINV, versus 52% of those receiving the control regimen (p=0.0135). In addition, complete response in the overall phase was higher in patients receiving the EMEND regimen versus the control regimen (40% v. 20%, p=0.0002). No vomiting in the overall phase was observed in 47% v. 21% of patients receiving the EMEND regimen compared to the control regimen, respectively (p<0.0001). Merck plans worldwide regulatory submissions for EMEND, beginning in the U.S. in the second half of 2014.

July 9, 2012

A.P. Pharma issued results from a phase III comparative study of APF530 and palonosetron (Aloxi) for the treatment of chemotherapy-induced nausea and vomiting. In this multi-center, randomized, observerblind, actively-controlled, double-dummy, parallel group study, subjects received APF530 high dose (10mg granisetron), APF530 low dose (5mg granisetron) or the currently approved dose of palonosetron. Patients used a daily diary to record severity of nausea, vomiting episodes, use of rescue medication and satisfaction with nausea/vomiting control over a five-day period following chemotherapy. Analysis indicated that both doses of APF530 offered comparable nausea control and patient satisfaction to palonosetron over a five-day period. The drug was safe and well tolerated. A.P. Pharma will continue to analyze the phase III data.

February 20, 2012

Soligenix issued preliminary results from a phase I/II trial of SGX201, a time-release formulation of oral beclomethasone dipropionate, for the prevention of acute radiation enteritis. This multicenter, open-label, sequential, dose-escalation study, dubbed BDP-ENT-01, enrolled 16 subjects with rectal cancer who were scheduled to undergo concurrent radiation and chemotherapy prior to surgery. The subjects received 1, 2, 3 or 4mg of SGX201 three times daily, with dosing administered throughout the duration of radiation therapy plus one week. Oral administration of SGX201 was safe and well tolerated across all four dose groups. There was also evidence of a potential dose response with respect to diarrhea, nausea and vomiting and the assessment of enteritis. The incidence of diarrhea was lower than that seen in historical control data.

July 27, 2009

MaxyGen issued positive results from a phase IIa trial of MAXY-G34 for the treatment of chemotherapy-induced neutropenia. This multiple ascending dose study enrolled 35 female subjects with breast cancer undergoing TAC chemotherapy. The subjects received MAXY-G34 at doses of 10, 30, 45, 60 or 100 g/kg or Neulasta at a fixed dose of 6 mg. Both study medications were administered as a single, subcutaneous injection 24 hours post chemotherapy. The primary endpoint was the duration of severe neutropenia in chemotherapy cycle 1. The primary endpoint was reached; the mean duration of severe neutropenia for MAXY-G34 dose groups ranged from 0.8 to 2.2 days, versus 2.0 days in the Neulasta control group. In addition, none of the subjects treated with MAXY-G34 required rescue therapy due to insufficient efficacy. MAXY-G34 was safe and well-tolerated.

March 16, 2009

AGI Therapeutics issued positive results from a phase II trial of AGI-004, a transdermal patch for the treatment of chemotherapy-induced diarrhea (CID). This trial enrolled 64 subjects across Europe and evaluated two doses of the AGI-004 transdermal patch, applied once-daily, or placebo. The co-primary endpoints were a reduction in the incidence of patient-recorded diarrhea (response defined as less than four bowel movements per day) and reduction in the number of bowel movements per day. A reduction in the incidence of diarrhea was reached with statistical significance at the higher of two doses of AGI-004 when compared with placebo. This response for the higher dose of AGI-004 was further supported by a statistically significant difference in the secondary endpoint of patient recorded severity of diarrhea. A reduction in the number of bowel movements per day showed a positive trend but did not reach statistical significance. Positive trends were observed in the other secondary measurement of reduction in the use of rescue anti-diarrheal medications. Benefits in the primary endpoints were observed with the lower dose however, statistical significance was not reached.

October 20, 2008

GTx issued positive results from a phase IIb trial of ostarine for the treatment of cancer cachexia. This randomized, double blind, placebo controlled study enrolled 150 subjects with various cancers in the US and Argentina. The subjects received Ostarine 1 mg, Ostarine 3 mg or placebo once daily for four months. The primary endpoint was change in total lean body mass at 16 weeks. Topline results show that Ostarine treatment resulted in a statistically significant increase in lean body mass compared to placebo. Both doses of Ostarine also resulted in clinically meaningful increases (greater than 1 kg) in lean body mass compared to baseline. In addition, Ostarine treatment improved muscle function in a 12 step stair climb test measuring speed and calculating power, a secondary endpoint of the study. Treatment was well tolerated; adverse events were similar across the study arms. Based on the results, GTx plans to move forward with the development of Ostarine.

October 6, 2008

A. P. Pharma issued mixed results from a phase III trial of APF530, a vaccine for the treatment of rabies. This randomized, single-blinfor the prevention of chemotherapy induced nausea and vomiting (CINV). This randomized, observer-blind, actively-controlled, double-dummy, parallel group study enrolled 1,395 subjects in the U.S, India and Poland. In each group, the subjects received in the first chemotherapy treatment cycle either APF530 high dose (10mg), APF530 low dose (5mg) or the currently approved dose of Aloxi, along with standardized doses of a corticosteroid. In subsequent treatment cycles (up to three additional cycles), the subjects were re-randomized to either of the two APF530 doses. The primary endpoint was non-inferiority of APF530 compared to Aloxi in terms of acute and delayed onset CINV following both moderately and highly emetogenic chemotherapy. The 10mg dose of APF530 achieved complete response (CR) rates that were numerically higher than Aloxi across all four assessments. The primary endpoint was achieved for three assessments, including moderately emetogenic (acute and delayed onset) and highly emetogenic (acute onset), but it was not achieved for the highly emetogenic delayed onset assessment. Treatment was generally well tolerated. Based on the results, A.P Pharma is planning to su

October 15, 2007

CuraGen released negative results from a phase II trial of velafermin for the treatment of oral mucositis. This randomized, double-blind, placebo-controlled study enrolled 390 subjects on high dose chemotherapy, in the United States. The subjects received a single infusion of either placebo or one of three dose levels of velafermin (10 mcg/kg, 30 mcg/kg or 60 mcg/kg) administered 24 hours after an autologous bone marrow transplantation. The primary endpoint was the reduction in incidence of severe oral mucositis in the subjects receiving 30 mcg/kg compared to placebo. While treatment was deemed to be safe and well tolerated, the primary endpoint was not met. Based on the results, CuraGen has decided to discontinue the development of velafermin.

July 9, 2007

Progenics and Wyeth reported positive results from an open label phase III extension trial of subcutaneous methylnaltrexone (MNTX) for the treatment of opioid-induced constipation (OIC). This three month extension trial enrolled 82 subjects who had completed a previous phase III trial (MNTX 302). Of these subjects, 42 had received subcutaneous methylnaltrexone in the prior trial and 40 had received placebo. Of the subjects who had prior MNTX the mean laxation response rates (laxation within four hours) were 45.5% during the first month, 57.7% in the second month, and 57.3% in the third month. Of the subjects with no prior MNTX experience, laxation response rates were 48.3% during the first month, 47.6% in the second month, and 52.1% in the third month. This long term data were included in the NDA filing currently under review by the FDA.

December 1, 2006

Prostrakan reported positive results from a phase III trial of Sancuso for the treatment of emesis caused by chemotherapy, radiotherapy or anesthetics. This randomized, parallel group, double-blind, double-dummy study enrolled 641 subjects receiving moderately (ME) or highly emetogenic (HE) multi-day chemotherapy, across international sites. The patch was applied 24 to 48 hours before the first dose of chemotherapy, and kept in place for 7 days. Oral granisetron (2 mg) was administered daily for the duration of the chemotherapy regimen, one hour before each dose of chemotherapy. The primary endpoint was the proportion of subjetcs achieving no vomiting/retching, only mild nausea and no rescue medication from the first administration until 24 hours after the start of the last days administration of multi-day chemotherapy. Efficacy was established in 60.2% of subjects in the Sancuso arm and 64.8% of subjects receiving oral granisetron (difference -4.89%; 95% confidence interval -12.91% to +3.13%).

October 3, 2005

AP Pharma has reported positive results of a phase II trial of their investigational anti-emetic APF530, for the treatment and prevention of nausea and vomiting associated with chemotherapy. Safety data yielded no evidence of serious adverse events and a positive overall tolerability profile. Pharmacokinetic data established dose- proportional plasma levels, time to maximum concentration and overall expose, and supported use of a single subcutaneous dose of the drug 30 minutes prior to initiation of chemotherapy. Single subcutaneous doses provided sustained plasma exposure over time, of a duration suitable for treating both acute (day 1) and delayed (days 2-7) emetic symptoms. Efficacy data, measuring the number of emetic episodes, use of rescue medication, and the degree of daily patient-reported nausea, yielded positive results in both the acute: better than 90% of subjects in the lower 2 dosing groups and slightly less than 80% of subjects in the high dose group were acute-phase complete responders (no emetic episodes, no rescue medication), and in the delayed phase, complete response rates were better than 90%, better than 80%, and just under 70% for the low, middle and high dose groups, respectively. This open-label, dose-ascending study enrolled 45 chemotherapy patients, who received one of 3 single subcutaneous doses of the drug (5, 10 or 15 mg) prior to chemotherapy followed by a 7 day observational follow-up.

March 22, 2004

AVI BioPharma reported positive results from a clinical trial investigating AVI-4557, an oral Neugene antisense drug. Results showed that administration of AVI-4557 lowered midazolam levels by 700 ml/min from a baseline of 877 ml/min. Maximal blood concentration (Cmax) increased from 51 ng/ml pre-dose to 81 ng/ml post-dose. The study was designed to investigate AVI-4557 ability to inhibit expression of CYP and alter the pharmacokinetics of midazolam, an anesthetic drug metabolized by CYP. The study evaluated a 10mg midazolam dose, followed by five daily oral doses of AVI-4557. The primary endpoint was a reduced rate of midazolam metabolism as demonstrated by a decrease in midazolam clearance and an increase in midazolam (Cmax).

February 3, 2003

Amgen reported positive results from a phase III trial investigating rHu-KGF, a natural keratinocyte growth factor for the treatment of oral mucositis as a complication of cancer treatments. Preliminary results from the randomized, double blind trial were positive on all endpoints showing a highly significant decrease in both the duration and incidence of severe mucositis. In addition, results showed that the drug was well tolerated. The study enrolled subjects who underwent bone marrow transplantation treatment for hematologic malignancies such as lymphoma, multiple myeloma, and leukemia.

October 7, 2002

Preliminary results of a phase III trial of Intrabiotic Pharmaceuticals' iseganan HCL in subjects undergoing high dose chemotherapy showed that the trial did not meet its primary endpoint of reducing oral mucositis. Though well tolerated, the results indicated that there was no significant difference between the 43% of iseganan subjects and 37% of placebo subjects who did not develop severe oral mucositis. There was also no significant difference between iseganan and placebo subjects in the reduction of pain, swallowing difficulty, proportion of subjects who developed oral muscositis and narcotic use. As a result of these findings, Intrabiotics is discontinuing development of iseganan for the treatment of severe oral mucositis.

August 12, 2002

The results of a phase I trial of OC-1012 for the treatment of mucositis, a serious side effect of chemotherapy and head and neck radiation therapy, showed no safety issues with the compound. In addition, OC-1012 positively changed the mucositis profile over time. Subjects in the trial were bone marrow transplant patients undergoing chemotherapy treatment. OC-1012 is being developed by OraPharma.

April 22, 2002

Preliminary analysis of phase III trial results indicate that palonosetron, a 5-HT3-receptor antagonist for chemotherapy-induced nausea and vomiting, met the targeted efficacy endpoints. Additionally, an analysis assessing the complete response rate for the 24-120 hour time period favored palonosetron over comparator agents. The phase III program compared palonosetron to currently marketed 5-HT3-antagonists and included over 130 medical centers in North America and Europe. Subjects received single intravenous doses of palonosetron or a comparator prior to treatment with moderately or highly emetogenic chemotherapy. The primary efficacy endpoint was the acute complete response rate, which was defined as the percentage of subjects who did not experience vomiting or receive rescue medication in the 24-hour period after receiving chemotherapy. Palonosetron is being developed by Helsinn Healthcare and MGI Pharma.

December 10, 2001

Positive results were reported from a phase I trial of Inhale Therapeutic Systems' inhaleable leuprolide, a peptide analog used to treat prostate cancer and endometriosis. Data showed that a powdered formulation of leuprolide developed with Inhale's Inhance pulmonary delivery technology administered the drug with a bioavailability of 18% (inhaleable versus injectable systemic delivery). In the 12-subject trial, the powdered leuprolide dose was packaged in a single capsule, and subjects inhaled the drug using a small dry powder inhaler.

The final results from a phase IIb trial of Valentis' interleukin-2 (IL-2) GeneMedicine product did not confirm positive interim findings. The randomized trial was designed to compare the IL-2 GeneMedicine product plus standard chemotherapy to standard chemotherapy alone in subjects with advanced head and neck cancer. The trial data demonstrated that the positive trend in the IL-2 treatment group versus the chemotherapy alone group was not sustained throughout the trial. The trial was conducted in collaboration with Roche Holdings.

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