March 28, 2016
Janssen-Cilag International issued phase III results of ZYTIGA (abiraterone acetate) plus prednisone for early and less aggressive chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). COU-AA-302 was an international, randomized, double-blind, placebo-controlled study that included 1,088 men with mCRPC who had not received prior chemotherapy and were randomized to receive ZYTIGA (abiraterone acetate) 1,000 milligrams (mg) administered orally once-daily plus prednisone 5mg administered twice-daily or placebo plus prednisone 5mg administered twice-daily. The co-primary endpoints of the study were rPFS and OS. The post-hoc analysis used the final dataset for the intent-to-treat population (n=1,088), to stratify patients into Group 1 (BPI 0-1, PSA <80 ng/ml and GS <8) and Group 2 (BPI=2 and/or PSA=80ng/ml and/or GS=8). The study provided an 11.8 months overall survival (OS) benefit (53.6 months vs. 41.8 months; HR=0.61 [95% CI, 0.43-0.87]; p=0.0055), compared to an active control of placebo plus prednisone. The post-hoc analysis divided patients into two groups to identify which group experienced a greater treatment benefit. The patients in Group 1 were in an earlier, less advanced and less symptomatic stage of the disease (which was defined as having a Brief Pain Inventory [BPI] Short Form score of 0-1, prostate-specific antigen [PSA] below 80ng/ml and a Gleason score [GS] of below 8). Those in Group 2 were in a later, more advanced and more symptomatic stage of the disease (defined as a having a BPI of 2 or over and/or PSA of 80ng/ml or above, and/or a GS of 8 or more). The analysis revealed that patients in both groups experienced an OS benefit when treated with ZYTIGA plus prednisone, compared to placebo plus prednisone (Group 1: 11.8 months; HR=0.61 [95% CI, 0.43-0.87]; p=0.0055) (Group 2: 2.8 months; HR=0.84 [95% CI, 0.72-0.99]; p=0.0321).
January 25, 2016
Merrimack Pharmaceuticals issued results of a phase III study of ONIVYDE (irinotecan liposome injection) in combination with fluorouracil (5-FU) and leucovorin achieved a substantial improvement in 12-month overall survival in patients with post-gemcitabine metastatic pancreatic adenocarcinoma when compared to 5-FU and leucovorin alone. The randomized, open label study in patients with metastatic adenocarcinoma of the pancreas who received prior gemcitabine-based therapy was the largest phase III study in this setting to date. A total of 417 patients were randomized across the three arms. Primary survival analysis was based on 313 events and showed that ONIVYDE in combination with 5-FU and leucovorin significantly improved overall survival v. 5-FU and leucovorin alone: 6.1 months v. 4.2 months (p=0.012, unstratified hazard ratio (HR) =0.67, 95% CI: [0.49-0.92]). The monotherapy regimen in this study did not show improvement over the 5-FU and leucovorin arm: 4.9 v. 4.2 months (p=0.94, HR=0.99, 95% CI: [0.77-1.28]). No new safety or tolerability concerns were note in the updated analysis. The primary NAPOLI-1 study results were the basis of the recent FDA and Taiwan FDA approval of ONIVYDE in combination with 5-FU and leucovorin for the treatment of patients with metastatic adenocarcinoma of the pancreas after disease progression following gemcitabine-based therapy. Merrimack and Baxalta have entered into an exclusive licensing agreement for the development and commercialization of ONIVYDE outside of the U.S. and Taiwan. Baxalta’s marketing authorization application for the treatment of patients with metastatic adenocarcinoma of the pancreas who have been previously treated with gemcitabine-based therapy is currently under review with the EMA.
Novocure issued results of a phase II trial showing Tumor Treating Fields (TTFields) therapy plus first-line chemotherapy gemcitabine is tolerable and safe in patients with advanced pancreatic cancer. The first cohort of the prospective, single-arm study included 20 patients with advanced pancreatic cancer whose tumors could not be removed surgically and who had not received chemotherapy or radiation therapy prior to the clinical trial. The primary endpoint measured the incidence and severity of treatment-related adverse events. As a result of TTFields therapy, 10 patients experienced treatable contact dermatitis. No serious adverse events related to TTFields were reported. Fourteen patients reported serious adverse events unrelated to TTFields therapy. In relation to these reported results for gemcitabine alone, PANOVA patients who received TTFields therapy plus first-line gemcitabine experienced a median progression free survival of 8.3 months compared to 3.7 months, a median overall survival of 14.9 months compared to 6.7 months and a median one-year survival of 55% compared to 22%. Thirty percent of the evaluable tumors had partial responses compared to 7% with gemcitabine alone and another 30% had stable disease. The PANOVA trial includes a second cohort testing TTFields plus gemcitabine and nab-paclitaxel in an additional 20 patients. Based on these data, the company will accelerate planning of a phase III clinical trial in pancreatic cancer.
December 14, 2015
Takeda Pharmaceutical has reported results of a phase III trial of NINLARO (ixazomib) for relapsed and/or refractory multiple myeloma. The TOURMALINE-MM1 trial is an international, randomized, double-blind, placebo-controlled trial designed to evaluate once-weekly oral ixazomib plus lenalidomide and dexamethasone compared to placebo plus lenalidomide and dexamethasone. Trial results demonstrate a statistically significant (35%) improvement in progression free survival (PFS), with patients treated in the ixazomib arm living for a significantly longer time without their disease worsening compared to patients in the control arm (20.6 months vs. 14.7 months in control group; Hazard Ratio [HR] 0.742; p = 0.012). Overall response rate (ORR) was 78.3% in the ixazomib arm and median duration of response was 20.5 months, v. 71.5% and 15 months in the control group. Median PFS in high-risk patients (HR 0.543; HR 0.596 in patients with del(17p)) was similar to that in the overall patient population and in standard-risk patients. The most common grade three adverse events included neutropenia, anemia, thrombocytopenia and pneumonia. Gastrointestinal events included diarrhea, nausea, and vomiting. Peripheral neuropathy rates were 28% in the IRd arm v. 21% in the control arm, 35% v. 21% had rash events, 8% v. 10% had acute renal failure, and 4% v. 3% had heart failure. NINLARO was recently approved by the FDA in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy.
December 7, 2015
Exelixis has issued results of a phase III
trial of Cotellic (cobimetinib) in patients
with previously untreated resectable, locally
advanced or metastatic melanoma carrying a
BRAF V600E or V600K mutation, in combination
with vemurafenib. In October, Exelixis
announced the coBRIM trial met its OS secondary
endpoint, demonstrating a statistically
significant increase in OS for the combination
of Cotellic and vemurafenib compared to vemurafenib
monotherapy. The median OS was
22.3 months for the combination of Cotellic
and vemurafenib v. 17.4 months for vemurafenib
alone, corresponding to a 30% reduction
in the rate of death for the combination
as compared to vemurafenib alone (hazard
ratio [HR]=0.70, 95% confidence interval [CI]
0.55-0.90, p=0.005). Ongoing study monitoring
did not identify any new safety signals. On
Nov. 10, the FDA approved Cotellic as a treatment
for patients with BRAF V600E or V600K
mutation-positive unresectable or metastatic
melanoma, in combination with vemurafenib.
Cotellic was first approved in Switzerland in
late August. The Cotellic approvals are based
on data from coBRIM, the phase III pivotal trial
conducted by Genentech in 495 patients with
previously untreated unresectable, locally
advanced or metastatic melanoma carrying a
BRAF V600 mutation. Genentech sponsored
the U.S. NDA and Roche sponsored the Swiss
regulatory application. Roche also filed a
Marketing Authorization Application (MAA)
with the EMA in late 2014, and the Committee
for Medicinal Products for Human Use issued
a positive recommendation on the MAA in
September of this year. Roche anticipates a
decision from the European Commission by
Merrimack and Baxalta have reported
results of a global, randomized, open-label
phase III trial of Onivyde, in combination
with 5-FU and leucovorin, for treatment of
metastatic adenocarcinoma of the pancreas.
Patients were enrolled at 76 sites in North
America, South America, Europe, Asia and
Oceania. A total of 417 patients were randomized
across the three arms. The Onivyde combination
regimen demonstrated a significant
increase in median overall survival v. 5-FU and
leucovorin alone: 6.1 months v. 4.2 months
(p=0.012, unstratified hazard ratio for death
(HR) =0.67, 95% CI: [0.490.92]). The monotherapy
regimen in the study did not show
improvement over the 5-FU and leucovorin
arm: 4.9 v. 4.2 months (p=0.94, HR=0.99, 95%
CI: [0.771.28]). Onivyde in combination with
5-FU and leucovorin achieved a longer progression-
free survival compared with the 5-FU
and leucovorin arm (3.1 months v. 1.5 months;
unstratified HR=0.56 [95% CI, 0.410.75]). Unconfirmed
objective response rate was higher
in the Onivyde in combination with 5-FU and
leucovorin arm than in the 5-FU and leucovorin
arm: 16% (19/117) v. 1% (1/119) (difference
15.4 percentage points, 95% CI, 8.5-22.3;
p<0.0001). The most common grade three
or four adverse events that occurred more
frequently in the Onivyde combination arm
(>2% incidence v. 5-FU and leucovorin) were
neutropenia, diarrhea, vomiting and fatigue.
Study results were the basis of the recent FDA
and Taiwan FDA approval. In May 2015, the
EMA accepted for review Baxalta’s marketing
authorization application for Onivyde based
on the same clinical results.
August 12, 2013
GlaxoSmithKline issued results of a randomized, double-blind, phase III, placebo controlled trial of pazopanib monotherapy in women with epithelial ovarian, fallopian tube or primary peritoneal cancer whose disease had not progressed after completing standard debulking surgery and first-line chemotherapy. After completion of five or more cycles of platinum-taxane chemotherapy, 940 patients were randomized 1:1 to receive 800mg pazopanib once daily or placebo for up to 24 months (median time from diagnosis to randomization was approximately seven months). Pazopanib treatment reduced the risk of disease progression or death by 23% (HR = 0.77; 95% CI: 0.64-0.91; p = 0.0021). The incidence of serious adverse events was higher in the pazopanib group compared to the placebo group (26% v. 11%). Regulatory applications will be submitted before 2014.
June 10, 2013
Boehringer Ingelheim issued results from a phase III trial of LUME-Lung 1 for the treatment of advanced non-small cell lung cancer (NSCLC). This randomized, openlabel, double-blind study enrolled 1,314 patients with locally advanced or metastatic (stage IIIb/IV or recurring) NSCLC after first-line therapy. The subjects received nintedanib 200mg BID plus docetaxel 75mg/m(2) once a day for three weeks (n=655), or docetaxel plus placebo (n=659). LUME-Lung 1 improved progression-free survival (PFS)—the primary endpoint—as a second-line treatment in patients with NSCLC compared to docetaxel alone. Secondary endpoints included overall survival. Results showed patients treated with nintedanib plus docetaxel lived for a median of 3.4 months before their tumor started to grow again, versus 2.7 months with docetaxel alone (HR 0.79; p=0.0019). The most common adverse events (AEs) of any grade in the nintedanib combination and docetaxel alone groups were diarrhea (42.3% v. 21.8%, respectively) and ALT elevations (28.5% v. 8.4%, respectively). Incidence of > grade 3 AEs was 71.3% in patients treated with nintedanib plus docetaxel compared to 64.3% with docetaxel alone. A higher incidence of > grade 3 diarrhea and elevated ALT were observed in patients treated with nintedanib plus docetaxel compared to docetaxel alone (> grade 3 diarrhea: 6.6% v. 2.6%; elevated ALT: 7.8% v. 0.9%). Incidence of > grade 3 hypertension, bleeding and thrombosis were similar in both treatment arms. There was a 1% difference in discontinuation between the treatment arms, with 22.7% of patients stopping treatment with nintedanib plus docetaxel versus 21.7% with docetaxel alone.
April 5, 2010
GW Pharmaceuticals and Otsuka reported positive preliminary results from a phase IIb trial of Sativex for the treatment of pain related to cancer. This international, randomized double-blind placebo-controlled parallel-group study enrolled 360 subjects with advanced cancer who experienced inadequate analgesia during optimized chronic opioid therapy. The subjects received three dose ranges of Sativex a low dose (1-4 sprays per day), mid dose (6-10 sprays per day), and high dose (11-16 sprays per day) over a 5 week treatment period. Sativex or placebo was administered as add-on treatment to strong opioid therapy and the subjects remained on stable doses of their background optimized opioid therapy during the study. The primary efficacy measure of the study was a patient assessment of pain using a 0-10 Numeric Rating Scale (NRS), which was analyzed using three , the 30% responder analysis, continuous response analysis and change from baseline analysis in NRS average pain. The 30% responder analysis was numerically in favor of Sativex but did not show a statistical difference compared to placebo. The continuous response analysis did show statistically significant results in favor of Sativex for both the low and mid dose groups versus placebo (p≡0.008 and p≡0.038, respectively). The change from baseline in NRS average pain score also showed a statistically significant difference between the Sativex low dose group and placebo (p≡0.006). The Sativex low dose group also showed a statistically significant difference versus placebo in reducing sleep disruption, a key secondary endpoint (p≡.003).
September 1, 2008
Xenome reported positive results from a phase II trial of Xen2174 for the treatment of chronic cancer pain. This study enrolled 37 subjects who received a single increasing dose of Xen2174 (from 0.025 to 40 mg) injected into the fluid surrounding the spine for four days. Xen2174 was found to be well tolerated. Evidence of pain relief was seen at most dose levels over the four day observation period and was characterized by rapid onset of action and long-lasting effect. The majority of adverse events attributable to Xen2174 were either mild or moderate. Analysis of Xen2174 levels demonstrated that standard pharmacokinetic parameters varied in a predictable manner with increasing doses. Peak drug levels and rates of clearance were within acceptable clinical parameters. Based on the results, Xenome plans to commence a phase II trial of Xen2174 for acute, post-surgical pain by the end of 2008.
September 17, 2007
Akela released positive results from a phase IIb trial of Fentanyl TAIFUN for the treatment of pain. This double-blind, randomized extension study enrolled 50 subjects with break-through cancer pain who received titrated doses of Fentanyl-TAIFUN or placebo. Statistical significance was reached in the trials primary endpoints when compared to placebo. The median time to significant pain relief in the Fentanyl TAIFUN group, as measured by a decrease of at least 2 points on the numerical pain scale (NPS), was 5.2 minutes (P=0.007). The mean difference in sum of pain intensity difference (SPID) was also in favor of Fentanyl TAIFUN for the whole 60 min pain episode (P=0.050). This was already seen in numerical pain scale scores up to 15 minutes (P=0.008) when compared to placebo. Based on the results Akela is preparing for phase III trials.
May 28, 2007
Sosei reported positive results from a phase I trial of AD 923 for the treatment of breakthrough pain in cancer. This open-label, single dose, cross-over, randomized study enrolled 24 subjects in the US. It was designed to evaluate the pharmacokinetics of AD 923 (sublingual fentanyl spray) compared to Actiq (oral fentanyl) and fentanyl citrate injection. Statistical significance was reached in median time to maximum plasma concentration (Tmax) for AD 923 compared to Actiq (40 minutes versus 120 minutes, respectively). The higher absolute bioavailability of AD 923 compared with Actiq also reached statistical significance. Treatment was well tolerated, with no significant adverse events. Sosei has reached agreement with EU regulatory authorities to move AD 923 directly into phase III trials. They are in discussions with the FDA to determine the requirements for a phase III program in the United States.
January 24, 2005
GW Pharmaceuticals has announced preliminary results of a phase III trial of Sativex (tetrahydrocannabinol/cannabidiol), their fixed-dose direct cannabinoid-receptor agonist, for the treatment of severe cancer pain. GW is also pursing development of the drug for multiple sclerosis and neuropathy/neuropathic pain in Canada and the UK; the drug is not currently in development in US markets. Study results indicated that the drug met its primary endpoint, with a significant improvement in patient-reported experience of pain (p=0.014), vs. placebo. This included a significantly greater portion of subjects receiving Sativex reporting a 30% or greater reduction in pain, vs. placebo (40% of subjects receiving Sativex; p=0.024). Furthermore, the study indicated that subjects who received only tetrahydrocannabinol did not show a significant improvement in ratings of pain vs. placebo (p=0.24), confirming Sativex’s fixed-dose combination. This multi centre double-blind, placebo-controlled parallel group study randomized 117 patients experiencing severe cancer pain unresponsive to opioid therapy to receive Sativex, tetrahydrocannabinol alone, or placebo at a 1:1:1 ratio. The company announced that it would review any additional steps needed for regulatory submission, including the design of an additional confirmatory phase III trial.
Phytopharm issued positive interim data from a ongoing phase II proof-of-principle study of their drug Cogane (PYM50028), for the treatment of Alzheimer’s disease. The interim safety review yielded no serious safety concerns, based on data from the first 60 subjects. Furthermore, independent review estimated a total necessary enrollment of between 200 and 238 subjects (the secondary purpose of the interim review). This randomized, double-blind, placebo-controlled study was designed to evaluate the safety, efficacy and pharmacokinetic profile of PYM50028 after once daily oral administration for 12 weeks to patients with Alzheimer's disease. Phytopharm announced plans to submit the necessary applications to expand the trial size, based on these results.
August 26, 2002
In a long-term clinical study of Ligand's morphine product, Avinza, 137 subjects with chronic, moderate-to-severe pain of malignant and non-malignant origin were evaluated for safety and efficacy over a one-year treatment period. These subjects had each completed one of four previous clinical trials with Avinza. The median daily dose of Avinza was 120 mg at baseline, 180 mg at six months and remained stable from six to 12 months. Subjects did not experience any statistically significant changes in pain or intensity, indicating that Avinza may provide effective long-term analgesia. In a second study with Avinza, 300 subjects with osteoarthritis took Avinza for up to 30 weeks. In one portion of the study, the safety and efficacy was compared to placebo and to MS Contin. Compared to placebo, Avinza taken once-daily in the morning showed statistically significant improvement in physical functioning compared to placebo at all four weekly visits. Similar significant improvement was found at the first three visits in subjects who took Avinza once-daily in the evening. In subjects receiving MS Contin, significant improvements in physical functioning were observed only at the first weekly visit.