PALOMA3 supports palbociclib use in advanced breast cancer

In continuation of my update on palbociclib... 

Advanced breast cancer patients who have failed prior endocrine treatment may receive a progression-free survival (PFS) benefit if palbociclib is added to fulvestrant, a phase III trial indicates.

The advantage accorded by the small-molecule inhibitor of CDK4 and CDK6 was irrespective of the menopausal status of the women, the team reports in The New England Journal of Medicine.

The research was concurrently presented at the annual meeting of the American Society of Clinical Oncology, held in Chicago, Illinois, USA.

The double-blind PALOMA3 trial comprised women with advanced breast cancer positive for oestrogen and/or progesterone hormone receptors but negative for epidermal growth factor receptor 2 who had progressed or relapsed during endocrine therapy.

PALOMA3 supports palbociclib use in advanced breast cancer

ASCO 2015: AMGEN presents new data evaluating less-frequent dosing of kyprolis for multiple myeloma patients

Amgen announced the initiation of the ARROW trial, a global Phase 3 study evaluating the benefit of Kyprolis®(carfilzomib) for Injection administered once-weekly with dexamethasone versus the current U.S. Food and Drug Administration (FDA) approved twice-weekly administration schedule in patients with relapsed and refractory multiple myeloma who have received prior treatment with bortezomib and an immunomodulatory agent (IMiD). The trial was initiated based on results from the Phase 1/2 CHAMPION study, which were presented (abstract no. 8527) at the 51stAnnual Meeting of the American Society of Clinical Oncology (ASCO) on Sunday, May 31 at 8:00 a.m. CT.

Results from the Phase 1 and 2 portions of CHAMPION were presented for 104 patients (Phase 1, n=15; Phase 2, n=89) with relapsed or refractory multiple myeloma who had received one to three prior treatment regimens at the determined maximum tolerated dose (MTD) of 20/70 mg/m2. In the Phase 2 portion of the study, the overall response rate (ORR; defined as the percentage of patients achieving a partial response or better) was 77 percent. The clinical benefit rate (CBR; defined as the percentage of patients with minimal response or better) was 84 percent; the median time to response for patients who achieved a partial response or better was 1.6 months (range, 0.7-7.2); Kaplan-Meier median duration of response (DOR) was 15 months (95 percent CI 9-not estimable); and the Kaplan-Meier median progression-free survival (PFS) was 10.6 months (95 percent CI 9.0-16.1).

ASCO 2015: AMGEN presents new data evaluating less-frequent dosing of kyprolis for multiple myeloma patients

Combining targeted drug with chemotherapy offers longer life to b-cell cancer patients

Because of the significant benefit found in combining the targeted drug ibrutinib with standard chemotherapy for relapsed chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), an interim analysis has closed the international HELIOS phase III clinical trial.

Ibrutinib

Led by Mayo Clinic, researchers found that ibrutinib and chemotherapy (bendamustine and rituximab, known as BR) reduced the risk of death or cancer progression by almost 80 percent in patients with previously treated CLL or SLL, compared to use of BR alone.

The announcement was made at a press briefing at the 2015 meeting of the American Society of Clinical Oncology by HELIOS' senior investigator Asher Chanan-Khan, M.D., professor of medicine and chair of Hematology & Oncology, Mayo Clinic Cancer Center in Jacksonville, Florida.

"This finding represents a significant advancement in the management and treatment of this leukemia," says Dr. Chanan-Khan. "Although CLL remains incurable, this new regimen offers longer disease control and a decreased risk of relapse for our patients."

The HELIOS study -- which enrolled 578 patients from centers around the world -- was the first to compare, head-to-head, chemo immunotherapy alone to chemo immunotherapy plus a targeted drug in patients with CLL.

Combining targeted drug with chemotherapy offers longer life to b-cell cancer patients 

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 

Targeted drug can ‘diminish the suffering’ of myelofibrosis

Investigators further found that pacritinib could be used safely in patients with myelofibrosis who have thrombocytopenia, a life-threating loss of blood platelets that can lead to deadly bleeding. The only currently approved therapy for myelofibrosis   ruxolitinib   is not recommended in patients who have severe thrombocytopenia.

 Pacritinib  Ruxolitinib

Ruben A. Mesa, M.D., chair of Hematology and Medical Oncology at Mayo Clinic in Arizona, will present these results at a press conference held during the 2015 American Society of Clinical Oncology (ASCO) annual meeting in Chicago.

"Use of pacritinib can alleviate the burden and diminish the suffering that this cancer causes," says Dr. Mesa. "For many of the patients who used it, pacritinib is a very good drug. The agent was significantly superior to other medical treatments.

"It is too early to know if pacritinib has an impact on survival, but that is clearly our expectation," he adds.

Mayo researchers led by Dr. Mesa were also part of a phase 2 trial that found pacritinib offered significant benefit in treating the disorder.

Myelofibrosis is a chronic bone-marrow disorder that can lead to lowering of blood counts, scarring in the bone marrow, severe symptoms and enlargement of the spleen. Myelofibrosis can be life threatening for afflicted patients because of the debilitation the disease causes and/or progression to acute leukemia, Dr. Mesa says.

Myelofibrosis is one of three blood cancers classified as myeloproliferative neoplasms (MPNs), and MPN affects about 350,000 people in the U.S., he says.

In this study, two-thirds of the 327 patients with primary and secondary myelofibrosis were treated with pacritinib. The other one-third were treated with best available therapy (BAT), but were able to cross over to use of pacritinib if their cancer was largely nonresponsive. BAT was chosen by the patient's physician, but did not include ruxolitinib because many patients were not eligible for it due to existing thrombocytopenia.

Pacritinib, an oral drug, is known as a JAK2/FLT3 inhibitor. JAK2 is a protein that acts like an on-off growth switch in blood cells.

"The JAK2 pathway is abnormally turned on in patients, which leads to this chronic leukemia. This drug turns off that switch," Dr. Mesa says.

PERSIST-1 investigators found that medium duration of treatment on the study was 16-plus months, and that by six months, spleen size was reduced in 25 percent of evaluable patients treated with pacritinib compared to 6 percent in the BAT group. Almost 80 percent of BAT patients crossed over to use of pacritinib, and 21 percent of all pacritinib patients had achieved a reduction in spleen volume of 35 percent or more. Symptoms of the cancer were reduced in more than 46 percent of pacritinib-treated patients compared to 9 percent in patients given BAT.

Targeted drug can ‘diminish the suffering’ of myelofibrosis 

Promising preliminary results for AKB-9778 in diabetic macular oedema

AKB-9778, a small molecule competitive inhibitor of vascular endothelial-protein tyrosine phosphatase (VE-PTP), has a good safety and efficacy profile in patients with diabetic macular oedema, suggests a preliminary dose-escalation study. 

By blocking VE-PTP, AKB-9778 promotes the activation of Tie2, a protein involved in the regulation of vascular permeability, explain the researchers. In preclinical studies, AKB-9778 has been shown to suppress vascular leakage as well as neovascularisation of the retina and choroid, they add.

In this phase Ib trial, four groups of six patients were treated with open-label AKB-9778 self-administered twice daily via subcutaneous injections at doses of 5.0 mg, 15.0 mg, 22.5 mg or 30.0 mg for 4 weeks.

Participants treated with the higher 22.5 mg and 30.0 mg doses, but not those given the 5.0 mg and 15.0 mg doses, experienced headache, dizziness and vasovagal events such as presyncope or syncope – adverse events that are consistent with the anticipated vasodilatory activity of AKB-9778, say the researchers.

“Modest decreases” in resting systolic blood pressure were also observed in the 22.5 mg and 30.0 mg groups, they report, adding that these effects and the adverse events were “transient” and “generally resolved” shortly after dosing.

At 4 weeks, best-corrected visual acuity (BCVA) improved from intake in the 15.0 mg, 22.5 mg and 30.0 mg groups; of 18 participants, 10 achieved an improvement of five to 10 letters, one improved by 11 letters and two by over 15 letters.

Moreover, seven patients who received AKB-9778 at doses of 15.0 mg or more showed decreases in study eye central subfield thickness (CST) from baseline, with reductions of over 100 μm in five patients and of 50 to 100 μm in two patients.

Promising preliminary results for AKB-9778 in diabetic macular oedema

JAK2 inhibitor ruxolitinib shows promise in treating CMML patients

In continuation of my update on Ruxolitinib

Chronic myelomonocytic leukemia (CMML) is a rare type of myelodysplastic, myeloproliferative neoplasm characterized by increased numbers of peripheral monocytes and less than 20 percent blasts. CMML has few treatment options and patients only survive on average for 12 to 24 months. Preclinical studies suggest that JAK2 inhibitors may be an effective treatment option for CMML. Eric Padron, M.D., assistant member of the Malignant Hematology Program at Moffitt Cancer Center will report on the first phase 1 study of the JAK2 inhibitor ruxolitinib in CMML patients at the 2015 American Society of Clinical Oncology Annual Meeting in Chicago.

The Moffitt team and their collaborators performed a dose-escalation study of ruxolitinib in 19 CMLL patients. Ruxolitinib displayed minimal toxicity, with no dose-limiting toxicities observed and only one grade 3 or higher adverse event.

Efficacy data suggest that ruxolitinib is a promising treatment option for CMML patients. Out of fifteen patients who were evaluable for response, 3 displayed hematologic improvement and 1 patient had a partial response. Nine of the patients entered the trial with an enlarged spleen, and 5 of these patients had a greater than 50 percent reduction in their spleen size.

Ruxolitinib may be particularly beneficial for patients who have B symptoms, as 10 out of 11 patients with disease related symptoms had a clinically meaningful or complete resolution of their symptoms.

The researchers determined a phase 2 recommended dose of 20 mg twice a day, and a phase 2 study of ruxolitinib in CMML patients is planned.

JAK2 inhibitor ruxolitinib shows promise in treating CMML patients

Metformin can reduce risk of open-angle glaucoma in people with diabetes

In continuation of my update on metformin

Taking the medication metformin hydrochloride was associated with reduced risk of developing the sight-threatening disease open-angle glaucoma in people with diabetes, according to a study published online by JAMA Ophthalmology.

Medications that mimic caloric restriction such as metformin can reduce the risk of some late age-onset disease. It is unknown whether these caloric mimetic drugs affect the risk of age-associated eye diseases such as macular degeneration, diabetic retinopathy, cataract or glaucoma.

Researcher Julia E. Richards, Ph.D., of the University of Michigan, Ann Arbor, and co-authors examined metformin use and the risk of open-angle glaucoma (OAG) using data from a large U.S. managed care network from 2001 through 2010.

Of 150,016 patients with diabetes, 5,893 (3.9 percent) developed OAG. Throughout the study period, 60,214 patients (40.1 percent) filled at least one metformin prescription; 46,505 (31 percent) filled at least one sulfonylurea prescription; 35,707 (23.8 percent) filled at least one thiazolidinedione prescription; 3,663 (2.4 percent) filled at least one meglitinide prescription; and 33,948 (22.6 percent) filled at least one insulin prescription. Some patients filled prescriptions for multiple medications.

Metformin can reduce risk of open-angle glaucoma in people with diabetes

Amgen announces AMG 416 Phase 3 results for treatment of secondary hyperparathyroidism in CKD patients

Amgen announced THE pooled data from two pivotal Phase 3, global, randomized, placebo-controlled trials evaluating AMG 416, a novel calcimimetic, for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease (CKD) receiving hemodialysis. Both studies met the primary endpoint, demonstrating that a greater proportion of patients in the AMG 416 groups achieved a greater than 30 percent reduction in parathyroid hormone (PTH) during the Efficacy Assessment Phase compared with placebo. The data were presented today at the 52nd ERA-EDTA Congress in London.

"Secondary hyperparathyroidism is a complex and challenging condition that can be difficult to manage, as it may require patients to take demanding drug regimens multiple times a day," said John Cunningham, lead author of the studies, professor of Nephrology at the University College London Medical School and consultant physician at The Royal Free Hospital, London. "Providing patients with chronic kidney disease on hemodialysis with a calcimimetic that can be administered intravenously on the same schedule as dialysis has the potential to fulfill an unmet need in this patient population."

AMG 416 is a novel calcimimetic agent in clinical development for the treatment of SHPT in patients with CKD who are receiving hemodialysis. In the registrational programs, AMG 416 is administered intravenously at the end of dialysis. AMG 416 acts by binding to and activating the calcium-sensing receptor on the parathyroid gland, thereby causing decreases in PTH. Sustained elevations in PTH are known to lead to significant clinical consequences for patients with CKD.

In the two Phase 3 placebo-controlled studies, an aggregate of 1,023 patients with moderate-to-severe SHPT (PTH greater than 400 pg/mL) on hemodialysis were randomized to receive intravenous AMG 416 or placebo three times a week. The primary endpoint of both studies was the proportion of patients achieving greater than 30 percent reduction in PTH during the Efficacy Assessment Phase, defined as weeks 20 through 27. Secondary endpoints included the proportion of patients with PTH less than or equal to 300 pg/mL, and percent reductions in PTH, albumin adjusted calcium (cCa), phosphate (P) and cCa x P. In the AMG 416 group, 74.7 percent of patients achieved a greater than 30 percent reduction from baseline in PTH compared with 8.9 percent in the placebo arm.

Amgen announces AMG 416 Phase 3 results for treatment of secondary hyperparathyroidism in CKD patients

Study expands understanding of the production of ET-743 compound

In continuation of my update on Trabectedin

For decades, scientists have known that ET-743, a compound extracted from a marine invertebrate called a mangrove tunicate, can kill cancer cells. The drug has been approved for use in patients in Europe and is in clinical trials in the U.S.

Scientists suspected the mangrove tunicate, which is a type of a sea squirt, doesn't actually make ET-743. But the precise origins of the drug, which is also known as trabectedin, were a mystery.

By analyzing the genome of the tunicate along with the microbes that live inside it using advanced sequencing techniques, researchers at the University of Michigan were able to isolate the genetic blueprint of the ET-743's producer--which turns out to be a type of bacteria called Candidatus Endoecteinascidia frumentensis.

The findings greatly expand understanding of the microbe and of how ET-743 is produced, the researchers reported online May 27 in the journal Environmental Microbiology. They're optimistic that the insights will help make it possible to culture the bacteria in the laboratory without its host.

"These symbiotic microbes have long been thought to be the true sources of many of the natural products that have been isolated from invertebrates in the ocean and on the land. But very little is known about them because we're not able to get most of them to grow in a laboratory setting," said study senior author David Sherman, the Hans W. Vahlteich Professor of Medicinal Chemistry in the College of Pharmacy and a faculty member of the U-M Life Sciences Institute, where his lab is located.

"Currently, many of these compounds can only be harvested in small amounts from host animals, which is unsustainable from an economic and environmental perspective," said Michael Schofield, one of two first authors on the study and a member of the Sherman lab before she graduated from U-M this spring. "Our hope is that understanding the genomes of these micro-organisms and the chemical reactions that occur inside of them will provide new avenues to economical and sustainable production of the medicinal molecules they make."

ET-743 is currently made using a complicated, partially synthetic process.

"A major challenge of sequencing genomes from samples containing a mixture of different organisms is figuring out which DNA sequences go with which organisms. We used bioinformatic approaches that allowed us to tease that apart," said Sunit Jain, a bioinformatics specialist in the U-M Department of Earth and Environmental Sciences, and the study's other first author.

Study expands understanding of the production of ET-743 compound