FDA approves non-alcoholic Docetaxel Injection

In continuation of my update on Docetaxel

Teikoku Pharma USA, Inc. ("Teikoku" or "the Company") announced today that the U.S. Food and Drug Administration ("FDA") has approved Docetaxel Injection, Non-Alcohol Formula ("Docetaxel Injection") for the treatment of breast cancer, non-small cell lung cancer, prostate cancer, gastric adenocarcinoma, and head and neck cancer. Teikoku entered into an exclusive licensing agreement with Eagle Pharmaceuticals Inc. ("Eagle Pharmaceuticals") in October 2015 to market, sell and distribute Docetaxel Injection in the U.S.

The main difference, compared to other docetaxel formulations, is that Docetaxel Injection is the first non-alcohol formulation approved in the U.S. Further differentiating it from some of the currently marketed docetaxel formulations is that Teikoku's Docetaxel Injection:

• Requires no prior dilution with a diluent and is ready to add to the infusion solution; and
• Is available in three presentations: 20mg/ml in single-dose vials, and 80 mg/4 mL or 160 mg/8 mL in multiple-dose vials.............

FDA approves non-alcoholic Docetaxel Injection

Nintedanib in lung cancer: Added benefit depends on disease severity

In continuation of my update on Nintedanib

According to the findings, there is an indication of a minor added benefit of nintedanib in combination with docetaxel in patients without brain metastases. However, in patients with brain metastases, the new drug has more disadvantages than chemotherapy with docetaxel alone. This results in a hint of a lesser benefit of nintedanib with the extent "considerable."

Findings from the only study are biased: at most indications can be derived

In its dossier the drug manufacturer compares treatment comprising nintedanib plus docetaxel with treatment comprising placebo plus docetaxel. As the treatment period in the nintedanib arm was longer than in the placebo arm (median: 4.3 versus 3 months), the observation periods for the study arms differed. Except for overall survival, the results are therefore uncertain for all outcomes.

In principle, at most an indication of an added benefit can be derived from the results of the only study included in the manufacturer dossier. As the analysis of the data shows, the advantages or disadvantages of nintedanib in combination with docetaxel primarily depend on whether patients already had brain metastases at the start of the study or not.

Patients without brain metastases live longer

Patients without brain metastases who received nintedanib in combination with docetaxel lived longer than study participants who were only treated with docetaxel (median: 13.5 versus 10.3 months). This results in an indication of a minor added benefit of nintedanib.

Although diarrhoea was more frequent in patients receiving nintedanib, this disadvantage does not challenge the survival advantage. Therefore, overall an indication remains of a minor added benefit for patients without brain metastases.

More symptoms in patients with brain metastases

Nintedanib in lung cancer: Added benefit depends on disease severity  

Pertuzumab plus trastuzumab and docetaxel has competitive advantages in efficacy over our current proprietary clinical gold-standard treatment...

In continuation of my update docetaxel

"Pertuzumab plus trastuzumab and docetaxel has competitive advantages in efficacy over our current proprietary clinical gold-standard treatment, trastuzumab plus docetaxel," said Decision Resources Analyst Amy Duva"l. 

Decision Resources' analysis of the breast cancer drug market also finds that Roche/Genentech/Chugai's Trastuzumab-DM1 (T-DM1) is likely to initially enter later-lines of treatment before receiving approval for the first-line setting, which means it will gain use across all lines of therapy, fragmenting its patient share across lines of treatment and restricting its uptake in the first-line setting. 

Additionally, according to insights from interviewed thought-leaders, pertuzumab plus trastuzumab and docetaxel and T-DM1 plus pertuzumab have demonstrated the potential to increase patients' overall survival, which has not been improved by drug-treatment since the approval of trastuzumab over a decade ago. 

Findings also reveal that the overall breast cancer drug market declined from $10 billion in 2010 to $9.3 billion in 2011 in the United States, France, Germany, Italy, Spain, the United Kingdom and Japan. Decision Resources forecasts that the market will increase from $9.3 billion in 2011 to $10.8 billion in 2020. Significant declines in sales, due to generic and biosimilar price erosion and a substantial reduction in the prescribing of Roche/Genentech/Chugai's Avastin, particularly in the U.S., will be offset by the launch and uptake of premium-priced emerging therapies, particularly in the metastatic HER2-positive setting. 

Ref : http://decisionresources.com/News-and-Events/Press-Releases/Breast-Cancer-Drug-Market-020212

LUME-Lung 1 shows QoL, symptoms benefits

LUME-Lung 1 (Nintedanib + docetaxel) trial patients’ reports of symptoms and health-related quality of life (HRQoL) support the use of second-line nintedanib for the treatment of advanced non-small-cell lung cancer (NSCLC).

Initial findings from the phase III trial demonstrated that the angiokinase inhibitor plus docetaxel offered significantly better progression-free survival for patients with advanced NSCLC, including subpopulations with adenocarcinoma, than placebo plus docetaxel, explain Silvia Novello (University of Turin, Italy) and co-authors in theEuropean Journal of Cancer.

For the current study, the team used a battery of tests to compare patient-reported outcomes on day 1 of each 21-day treatment cycle, at the end of treatment and at the first follow-up visit for the two treatment groups.

Over 80% of the 655 nintedanib-treated patients and 659 of controls completed the European Organisation for Research and Treatment of Cancer Core QoL Questionnaire and its lung cancer supplement, with 70% doing so at the end of treatment.

Baseline health and QoL were comparable for the nintedanib and placebo groups with relatively good scores and a low burden of lung cancer-specific symptoms, such as cough and pain.

The patient groups also had comparable time to deterioration for cough, pain and dyspnoea, although patients given nintedanib had a significantly shorter time to development of the gastrointestinal symptoms of nausea, vomiting, diarrhoea and decreased appetite.

Similarly, the 322 patients with adenocarcinoma histology given nintedanib alongside docetaxel had a similar time to deterioration of lung cancer symptoms as the 336 given placebo, with a small benefit in global health and QoL with nintedanib detected but this did not reach significance.

Ref : http://www.ejcancer.com/article/S0959-8049(14)01139-3/fulltext

LUME-Lung 1 shows QoL, symptoms benefits

Possible New Combination Chemotherapy for Patients with Advanced Prostate Cancer

For more than a decade, oncologists using cytotoxic chemotherapy to treat patients with advanced metastatic castration-resistant prostate cancer (mCRPC) have relied on the sequential use of single agent taxanes such as docetaxel and cabazitaxel. For example, docetaxel is commonly used as the "first-line" therapy, while cabazitaxel is used as the "second-line" therapy. A role for combination therapy using two or more chemotherapy agents at the same time has not been well studied. This week, however, results of a clinical trial presented at the American Society of Clinical Oncology meeting by researchers at The University of Texas MD Anderson Cancer Center may change the perspective on a role for combination chemotherapy in advanced disease.

 Carboplatin  Cabazitaxel   Docetaxel

The study compared the effectiveness of cabazitaxel alone versus cabazitaxel combined with carboplatin -- a type of platinum chemotherapy -- in patients with metastatic castrate-resistant prostate cancer (mCRPC). To date, 160 men have been randomized to treatment with either the single or dual chemotherapy drug regimen. Each patient received up to 10 cycles of chemotherapy.

To monitor the effects of treatment, MD Anderson researchers tracked several variables including Progression Free Survival, as well as changes in blood levels of prostate-specific antigen (PSA) and bone-specific alkaline phosphatase (BAP, a marker of prostate cancer in bone cells). In addition, safety and toxicity were monitored for both patient groups.

Analysis and comparison of the data demonstrated that median PFS was significantly longer for patients receiving combination versus single agent chemotherapy (6.7 months vs 4.4 months, respectively, p = 0.01). Furthermore, reductions in both PSA and BAP were greater for the combination therapy group. PSA reductions greater than 50 percent occurred 60 percent of the time with combined chemotherapy vs. 44 percent with the single drug. PSA reductions greater than 90 percent occurred 28 percent of the time with two chemotherapy drugs vs. 20 percent with one. In addition, BAP reductions greater than 50 percent for combination vs. single drug were 63 percent and 25 percent respectively.

Side effects, such as fatigue, anemia and neutropenia were comparable for both the single-drug regimen and two-drug regimen. In addition, there were no significant toxicity events.

"We believe cabazitaxel-carboplatin combination chemotherapy may become the clinical standard for advanced prostate cancer once additional safety, efficacy and overall survival data is generated," explained Paul Corn, M.D., Ph.D., an associate professor of genitourinary medical oncology at MD Anderson. "Dr. Ana Aparicio's lab is currently developing tumor-specific biomarkers to identity patients with an aggressive variant of prostate cancer most likely to benefit from this approach."

Possible New Combination Chemotherapy for Patients with Advanced Prostate Cancer 

Capecitabine combination therapy reduces early breast cancer recurrence...

Capecitabine, is an orally-administered chemo therapeutic agent used in the treatment of metastatic breast and colorectal cancers.

Mode of action :

Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to form 5-fluorouracil. Its being used (& FDA approved) in the treatment of adjuvant in colorectal cancer, metastatic colorectal cancer and Metastatic breast cancer - used in combination with docetaxel, after failure of anthracycline-based treatment. Also as monotherapy, if the patient has failed paclitaxel-based treatment, and if anthracycline-based treatment has either failed or cannot be continued for other reasons.

Recently, Finnish Breast Cancer Group and published in The Lancet Oncology shows women at intermediate to high-risk of early breast cancer recurrence who received capecitabine as part of their chemotherapy regimen had a 34% reduction in the risk of the disease returning or death, compared with those taking the chemotherapy combination regimen without capecitabin. The pre-planned three-year interim analysis of a randomised, prospective trial compared adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for the treatment of early breast cancer with the standard, non-capecitabine regimen (docetaxel, epirubicin, cyclophosphamide and fluorouracil). The analysis also found that patients taking the capecitabine-containing regimen were significantly less likely to have their cancer spread (distant metastasis) to another part of the body (a 36% reduction in risk was observed). This is the first phase III randomised trial to report efficacy of capecitabine combination therapy in the adjuvant treatment of early breast cancer.

Though capecitabine, has already been shown to be effective in patients with advanced breast cancer, but the most important conclusion the researchers have arrived is "capecitabine-containing regimen in the early stages of breast cancer may offer survival benefits for women".....

Source :http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970307-9/fulltext

Cabazitaxel improves survival in patients with metastatic hormone-refractory prostate cancer....

Cabazitaxel (see structure), is an orally bioavailable semi-synthetic  derivative of the natural taxoid 10-deacetylbaccatin III with potential antineoplastic activity. Cabazitaxel binds to and stabilizes tubulin, resulting in the inhibition of microtubule depolymerization and cell division, cell cycle arrest in the G2/M phase, and the inhibition of tumor cell proliferation. Unlike other taxane compounds, this agent is a poor substrate for the membrane-associated, multidrug resistance (MDR), P-glycoprotein (P-gp) efflux pump and may be useful for treating multidrug-resistant tumors. In addition, cabazitaxel penetrates the blood-brain barrier (BBB).

Sanofi-aventis recently announced results from a Phase 3 trial which demonstrated cabazitaxel plus prednisone/prednisolone significantly improved overall survival and progression-free survival in patients with metastatic (advanced) hormone-refractory prostate cancer whose disease progressed following treatment with docetaxel-based chemotherapy. 

TROPIC (trial) was designed to assess patients with metastatic hormone-refractory prostate cancer whose disease had progressed following treatment with docetaxel-based chemotherapy. Results showed that the combination of cabazitaxel and prednisone/prednisolone significantly reduced the risk of death by 30%.

Researchers are  happy with these compelling results  and  hope that these results will provide new options and hope for patients with serious diseases, such as metastatic hormone-refractory prostate cancer.....

Ref : http://en.sanofi-aventis.com/binaries/20100304_Asco_GU_en_tcm28-27547.pdf

GenSpera plans to initiate G-202 Phase II trial in prostate cancer

 We know that, a Mediterranean plant (see pic), Thapsia garganica, a simple weed, is the original source of G202. For millennia, the plant has been known to be poisonous to animals; in the days of desert caravans, it was called the “death carrot” for the unfortunate fate awaiting any camel that ingested it. Researchers at the Johns Hopkins Kimmel Cancer Center in the US and their Danish collaborators hoped to harness the toxicity of the plant in a controlled way that could be used to treat cancer in people.

They did so by taking apart the toxic compound, thapsigargin, produced by the plant and altering its chemical structure. The resulting prodrug, G202, is not active until it comes into contact with a particular protein produced by certain tumors. This prostate-specific membrane antigen (PMSA) is released by cells lining the outside of prostate and other tumors. Samuel Denmeade, the study’s lead author, uses the image of a hand grenade. The presence of PMSA essentially “pulls the pin” of the G202 grenade. In its active form, the drug is able to kill not only the tumor, but the blood vessels that provide it with nutrients.

A recent study of  G202,  looked at the effects of the drug on human prostate tumors grown in mice, and compared it to docetaxel, a chemotherapy drug already in use. G202 clearly came out on top, reducing by half the size of seven out of nine tumors; docetaxel achieved the same effect on only one out of eight tumors. Similar results for G202 were also seen in experiments with human breast, kidney and bladder cancer.

These promising results encouraged doctors to test the safety of G202 in a phase I clinical trial, involving 29 cancer patients at advanced stages of the disease.  

Now its  good news that,......

GenSpera plans to initiate G-202 Phase II trial in prostate cancer

Synta announces results from ganetespib Phase 2b trial on NSCLC

In continuation of my update on Ganetespib....

"The preliminary results from GALAXY indicate that the addition of ganetespib to docetaxel is well tolerated and may improve outcomes in patients compared to docetaxel alone," said Dr. Ramalingam, a Principal Investigator of the study. "This includes promising improvements in survival seen across the broad adenocarcinoma population as well as in key predefined patient populations. A well-tolerated combination regimen that extends survival associated with salvage therapy in NSCLC will meet a much awaited need to improve the current standard of care."

As per the CEO's statement "the objective of the interim analysis was to identify the best choice of patient population and trial design for transitioning to the Phase 3 stage of the study. The broad-based activity seen in the results presented  support advancing into the Phase 3 stage in alladenocarcinoma patients. The results have yielded a rich data set which we are using to optimize and de-risk the Phase 3 stage of the program. We are hopeful that this next stage of development will lead to a new treatment option for patients fighting this devastating disease."

Enrollment completion of the Phase 2b stage of the GALAXY trial and the transition to the Phase 3 stage are expected later this year. Based on current assumptions, the Company anticipates that Phase 3 will enroll approximately 500 adenocarcinoma patients, with overall survival as a primary endpoint. Biomarker findings and other patient selection and treatment experience from the Phase 2b stage will be incorporated into the design of the Phase 3 stage. An announcement with additional Phase 3 details is anticipated later this year, following discussion with regulatory agencies.  

Ref : http://www.syntapharma.com/documents/Ganetespib_GALAXY_ESMO_2012_Poster.pdf

Synta announces results from ganetespib Phase 2b trial on NSCLC

DECT trial shows combination of epirubicin and trastuzumab improves outcomes in breast cancer patients

In continuation of my update on epirubicin 

The study entitled "A phase II neoadjuvant sequential regimen of docetaxel followed by high-dose epirubicin in combination with cyclophosphamide administered concurrently with trastuzumab. The DECT trial" has recently appeared in the Journal of Cell Physiology, an international, per-reviewed journal focused on cancer-related issues. The authors belong to a multidisciplinary Italian-American team with a long and productive history of collaboration with Prof. Antonio Giordano, Director of the Sbarro Institute for Cancer Research of Philadelphia, Temple University Pennsylvania, USA and the Department of Medicine Surgery and Neuroscience at University of Siena.

 epirubicin

"The use of trastuzumab, a monoclonal antibody targeting the HER2 receptor, has dramatically improved the prognosis of the subgroup of breast cancer patients whose tumors overexpress this specific receptor. One of the greatest challenges in these patients has been combining trastuzumab with extremely effective drugs such as anthracyclines at the cost of an acceptable toxicity. Initial evidence seemed to discourage this approach due to the high-rate of cardiotoxicity, i.e., 27%, reported in the pivotal phase III trial of metastatic breast cancer from Slamon and colleagues. Subsequent studies have partly downsized these results. Yet, several doubts have remained concerning the combined use of these drugs. The DECT trial was design to further address this key question. We also used the data from this randomized trial to interpret treatment efficacy in light of hormonal and metabolic determinants, including the expression of estrogen and progesterone receptors and body mass index," says Prof. Antonio Giordano.

"We enrolled 45 HER2-positive breast cancer patients with locally advanced or operable HER2-positive disease to test the efficacy and toxicity of epirubicin combined with trastuzumab. We observed an exceptionally high rate of responses, particularly in the subgroup of patients with inflammatory disease, and no relevant toxicity, including cardiotoxicity. In addition, some specific disease-and patient-related features were associated with better outcomes. More specifically, the highest chances of optimal response were associated with the lack of hormone receptors and higher BMI," says Dr. Maddalena Barba, researcher at the Regina Elena National Cancer Institute of Rome.

"Although current guidelines discourage from the concurrent use of trastuzumab and anthracyclines in HER2-positive breast cancer, we challenged once more the available evidence by administering a less cardiotoxic anthracycline, i.e., epirubicin at a high dose. The results obtained were remarkable in terms of efficacy and absolutely encouraging in terms of toxicity. In addition, our finding on BMI may deserve further investigation in future studies of HER2-positive breast cancer. The goal we pursue is to define the HER2-positive patient profile which better matches with the highest efficacy at the price of an absolutely acceptable toxicity, including cardiotoxicity," clarifies and concludes Prof. Giordano, a renowned expert in breast cancer.

Results from Morphotek’s farletuzumab Phase III combination study on ovarian cancer

In continuation of my update on carboplatin and a taxane

Morphotek^® Inc., a wholly-owned subsidiary of Eisai Inc., announced top-line results from a Phase III study of its investigational agent farletuzumab (MORAb-003) in combination with carboplatin and a taxane in patients with platinum-sensitive epithelial ovarian cancer in first relapse. 

The study found that farletuzumab in combination with carboplatin and a taxane did not meet the study's primary endpoint of progression-free survival (PFS). The post hoc exploratory analysis showed, however, a trend toward improved PFS in some patient subsets and further analysis is ongoing.

The preliminary safety analysis indicated that the most commonly reported adverse events were those known to be associated with the study chemotherapy agents. Additionally, some immune-mediated events were observed with farletuzumab.

After further analysis of these clinical results, the company will determine a new development strategy based on discussion with external experts and relevant health authorities. In the double-blind, placebo-controlled study, 1,100 patients were enrolled to receive standard-of-care (carboplatin and a taxane [paclitaxel or docetaxel]) chemotherapy and were randomized to three parallel groups to receive one of two different dose levels of farletuzumab or placebo.

"While we are disappointed with these results, we know that ovarian cancer is a difficult disease to treat successfully," says Dr. Nicholas Nicolaides , President and CEO of Morphotek. "Morphotek remains committed to research to understand the potential role of farletuzumab in ovarian and other types of cancer."......

Results from Morphotek’s farletuzumab Phase III combination study on ovarian cancer

New anti-cancer drugs plus chemo for breast cancer shows promise: Study

 New anti-cancer drugs plus chemo for breast cancer shows promise: Study...

ABT-737

  

                                                        


Docetaxel

Positive phase II clinical results of abiraterone (for advanced prostate cancer)....

We know that,  Abiraterone (discovered and developed at the Institute of Cancer Research in London, see structure) is a drug under investigation for use in hormone-refractory prostate cancer (prostate cancer not responding to treatment with antiandrogens). Abiraterone acts  by blocking the formation of testosterone by inhibiting CYP17A1 (CYP450c17), an enzyme also known as 17α-hydroxylase/17,20 lyase.  This enzyme is involved in the formation of DHEA and androstenedione, which may ultimately be metabolized into testosterone.

 

The latest trial, which was led by the ICR and the Royal Marsden  NHS Foundation Trust, is the first to investigate the drug in men with such advanced prostate cancer.

A total of 47 men were recruited for the trial, all of whom had late-stage castration-resistant prostate cancer, which means that their disease was advanced and their tumors were no longer responsive to androgen deprivation therapy. In almost all cases, the men's cancer had spread to their bones. All of the participants had already received hormone therapy and the chemotherapy drug docetaxel, but were no longer responding to those treatments. By the end of the study period, researchers found that around three-quarters of men had experienced a drop in levels of prostate specific antigen (PSA), which is often raised in men with prostate cancer and can be used to measure disease activity.

 In around half of the men,  PSA levels fell by at least 50 per cent, while three-quarters of participants also had a drop in the number of tumor cells circulating in their blood. Three years after the start of the trial, five of the patients were still taking abiraterone and benefitting from the treatment. Lead researcher Dr Alison Reid, also from the ICR and the Royal Marsden, noted that "abiraterone shrank or stabilised men's cancers for an average of almost six months, which is a very impressive result with only mild side-effects". 

Though the initial results are exciting, the researchers conclude that there's a lot more work needed to establish what abiraterone's place will be in treating men with prostate cancer....

Ref :http://info.cancerresearchuk.org/news/archive/cancernews/2010-02-16-New-drug-shows-promise-for-advanced-prostate-cancer-patients