biochemotherapy | Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Posts Tagged ‘biochemotherapy’

1:45PM 11/12/2014 – Panel Discussion – Oncology @10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

Posted in Academic Publishing, Conference Coverage with Social Media, Personalized and Precision Medicine & Genomic Research, Scientific & Biotech Conferences: Press Coverage, tagged #endcancer, #meded, anti-cancer therapy, Big data, biochemotherapy, Bioinformatics, Chemogenomics, genomic drug development, genomics, health outcomes research, Huntsman Intermountain, MD Anderson Cancer center, medical education, Medical Ethics, oncology, Personalized medicine, Targeted therapy on November 12, 2014| Leave a Comment »

1:45PM 11/12/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

Reporter: Aviva Lev-Ari, PhD, RN

REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston http://pharmaceuticalintelligence.com

1:45 p.m. Panel Discussion – Oncology

Oncology

There has been a remarkable transformation in our understanding of the molecular genetic basis of cancer and its treatment during the past decade or so. In depth genetic and genomic analysis of cancers has revealed that each cancer type can be sub-classified into many groups based on the genetic profiles and this information can be used to develop new targeted therapies and treatment options for cancer patients. This panel will explore the technologies that are facilitating our understanding of cancer, and how this information is being used in novel approaches for clinical development and treatment.

Oncology

Opening Speaker & Moderator:

Lynda Chin, M.D.
Department Chair, Department of Genomic Medicine
MD Anderson Cancer Center @MDAnderson #endcancer

Who pays for personalized medicine?
potential of Big data, analytics, Expert systems, so not each MD needs to see all cases, Profile disease to get same treatment
business model: IP, Discovery, sharing, ownership — yet accelerate therapy
security of healthcare data
segmentation of patient population
management of data and tracking innovations
platforms to be shared for innovations
study to be longitudinal,
How do we reconcile course of disease with personalized therapy
phenotyping the disease vs a Patient in wait for cure/treatment

Panelists:

Roy Herbst, M.D., Ph.D. @DrRoyHerbstYale

Ensign Professor of Medicine and Professor of Pharmacology;
Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital @YaleCancer

Development new drugs to match patient, disease and drug – finding the right patient for the right Clinical Trial

match patient to drugs
partnerships: out of 100 screened patients, 10 had the gene, 5 were able to attend the trial — without the biomarker — all 100 patients would participate for the WRONG drug for them (except the 5)
patients wants to participate in trials next to home NOT to have to travel — now it is in the protocol
Annotated Databases – clinical Trial informed consent – adaptive design of Clinical Trial vs protocol
even Academic MD can’t read the reports on Genomics
patients are treated in the community — more training to MDs
Five companies collaborating – comparison of 6 drugs in the same class
if drug exist and you have the patient — you must apply personalized therapy

Lincoln Nadauld, M.D., Ph.D.
Director, Cancer Genomics, Huntsman Intermountain Cancer Clinic @lnadauld @intermountain

@Stanford, all patients get Tumor profiles Genomic results, interpretation – deliver personalized therapy
Outcomes from Genomics based therapies
Is survival superior
Targeted treatment – Health economic impact is cost lower or not for same outcome???
genomic profiling of tumors: Genomic information changes outcome – adverse events lower
Path ways and personalized medicine based on Genomics — integration not yet been worked out

Question by Moderator: Data Management

Platform development, clinical knowledge system,
build consortium of institutions to share big data – identify all patients with same profile

See more at http://personalizedmedicine.partners.org/Education/Personalized-Medicine-Conference/Program.aspx#sthash.qGbGZXXf.dpuf

In focus: Melanoma therapeutics

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, FDA Regulatory Affairs, Human Immune System in Health and in Disease, Molecular Genetics & Pharmaceutical, Pharmaceutical Analytics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, tagged Aldesleukin, American Cancer Society, angiogenesis, biochemotherapy, BRAF, Chemotherapy, Clinical Trials, Dacarbazine, Eastern Cooperative Oncology Group, ECOG, FDA, gp100, IFN-gamma, IFN-α-2b, IL-2, Immunotherapy, Interferon gamma, Interleukin-2, Ipilimumab, Jak3, MAPK, Melanoma, metastatic, OS, overall survival, PFS, progression-free survival, Proleukin, response rate, RR, Temozolomide, Therapy, vaccine, VEGFR, Vemurafenib, Yervoy on March 8, 2013| 5 Comments »

In focus: Melanoma therapeutics

Author and Curator: Ritu Saxena, Ph.D.

In the last post of Melanoma titled “In focus: Melanoma Genetics”, I discussed the clinical characteristics and the genetics involved in Melanoma. This post would discuss melanoma therapeutics, both current and novel.

According to the American Cancer Society, more than 76,000 new cases and more than 9100 deaths from melanoma were reported in the United States in 2012[1] Melanoma develops from the malignant transformation of melanocytes, the pigment-producing cells that reside in the basal epidermal layer in human skin. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate.

Melanoma therapeutics

Surgical treatment of cutaneous melanoma employs specific surgical margins depending on the depth of invasion of the tumor and there are specific surgical treatment guidelines of primary, nodal, and metastatic melanoma that surgeons adhere to while treatment. Melanoma researchers have been focusing on developing adjuvant therapies for that would increase the survival post-surgery.

Chemotherapy

Among traditional chemotherapeutic agents, only dacarbazine is FDA approved for the treatment of advanced melanoma (Eggermont AM and Kirkwood JM, Eur J Cancer, Aug 2004;40(12):1825-36). Dacarbazine is a triazene derivative and alkylates and cross-links DNA during all phases of the cell cycle, resulting in disruption of DNA function, cell cycle arrest, and apoptosis. Currently, 17 clinical trials are underway to test the efficacy and effectiveness of dacarbazine against melanoma as either a single agent or in combination chemotherapy regimens with other anti-cancer chemotherapeutic agents such as cisplatin, paclitaxel. Temozolomide is a triazene analog of dacarbazine and is approved for the treatment of malignant gliomas. At physiologic pH, it is converted to a short-lived active cytotoxic compound, monomethyl triazeno imidazole carboxamide (MTIC). MTIC methylates DNA at the O6 and N7 positions of guanine, resulting in inhibition of DNA replication. Unlike dacarbazine, which is metabolized to MITC only in the liver, temozolomide is metabolized to MITC at all sites. Temozolomide is administered orally and penetrates well into the central nervous system. Temozolomide is being tested in many combination regimens for patients with melanoma metastatic to the brain (Douglas JG and Margolin K, Semin Oncol, Oct 2002;29(5):518-24).

Immunotherapy

Melanoma and the immune system are closely related. Hence, immunotherapy has been explored in the treatment of the disease. The two most widely investigated immunotherapy drugs for melanoma are Interferon (IFN)-alpha and Interleukin-2 (IL-2).

The role of IFNalpha-2b in the adjuvant therapy of patients with localized melanoma at high risk for relapse was established by the results of three large randomized trials conducted by the US Intergroup; all three trials demonstrated an improvement in relapse-free survival and two in overall survival. One of these trials, a large randomized multicenter trial performed by the Eastern Cooperative Oncology Group (ECOG), in high-risk melanoma patients showed significant improvements in relapse-free and overall survival with adjuvant IFN-α-2b therapy, compared with standard observation (ECOG 1684). The results of the study led to FDA approval of IFN-α-2b for treatment of melanoma. This study was performed on patients with deep primary tumors without lymph node involvement and node-positive melanomas. In other studies, little antitumor activity has been demonstrated in IFN-α-2b–treated metastatic stage IV melanoma.

Recombinant IL-2 showed an overall response rate of 15-20% in metastatic melanoma and was capable of producing complete and durable remissions in about 6% of patients treated. Based upon these data, the US FDA has approved the use of high-dose IL-2 for the therapy of patients with metastatic melanoma. Aldesleukin (Brand name: Proleukin) is a recombinant analog of the endogenous cytokine interleukin-2 (IL-2). It binds to and activates the IL-2 receptor (IL-2R), followed by heterodimerization of the IL-2R beta and gamma(c) cytoplasmic chains; activation of Jak3; and phosphorylation of tyrosine residues on the IL-2R beta chain, resulting in an activated receptor complex (NCI). The activated complex recruits several signaling molecules that act as substrates for regulatory enzymes associated with the complex. It is administered intravenously and stimulates lymphokine-activating killer (LAK) cells, natural killer (NK) cells and the production of cytokines such as gamma interferon (nm|OK). Several clinical trials are currently underway using Aldesleukin to determine the efficacy of combination treatment in melanoma patients.

Another anti-cancer immunotherapeuty-based mechanism involved inhibition of inhibitory signal of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a molecule on T-cells that plays a critical role in regulating natural immune responses. Ipilimumab (Brand name: Yervoy) was by FDA for melanoma treatment. It is a human monoclonal antibody (MAb) T-cell potentiator that specifically blocks CTLA-4. It is approved for inoperable advanced (Stage III) or metastatic (Stage IV) melanoma in newly diagnosed or previously treated patients (nm|OK). The approval, March 25, 2011, was based on a randomized (3:1:1) double-blind double-dummy clinical trial (MDX010-20) in patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment for melanoma. Patients were randomly assigned to receive either ipilimumab, 3 mg/kg intravenously, in combination with the tumor vaccine (n=403); ipilimumab plus vaccine placebo (n=137); or tumor vaccine with placebo (n=136). Patients treated with ipilimumab alone had a median overall survival (OS) of 10 months while those treated with tumor vaccine had a median OS of 6 months. The trial also demonstrated a statistically significant improvement in OS for patients treated with the combination of ipilimumab plus tumor vaccine compared with patients treated with tumor vaccine alone. For more information on the trial, check the clinical trials website, www.clinicaltrials.gov

Signaling pathway inhibitors

Approximately 90% of BRAF gene mutations involve valine (V) to glutamic acid (E) mutation at number 600 residue (V600E). The resulting oncogene product, BRAF (V600E) kinase is highly active and exhibits elevated MAPK pathway. The BRAF(V600E) gene mutation occurs in approximately 60% of melanomas indicating that it could be therapeutically relevant. Vemurafenib (Brand name: Zelboraf) is a novel small-molecule inhibitor of BRAF (V600E) kinase. It selectively binds to the ATP-binding site and inhibits the activity of BRAF (V600E) kinase. Vemurafebib inhibits over active MAPK pathway by inhibiting the mutated BRAF kinase, thereby reducing tumor cell proliferation (NCI). Encouraging results of phase III randomized, open-label, multicenter trial were reported recently at the 2011 ASCO meeting (Chapman PB, et al, ASCO 2011, Abstract LBA4). The trial compared the novel BRAF inhibitor vemurafenib with dacarbazine in patients with BRAF-mutated melanoma. Previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for BRAF mutation were randomized (1:1) to vemurafenib or dacarbazine. The response rate (RR) was significantly high (48.4%) in vemurafenib treated patients as compared to 5.5% in dacarbazine among the 65% of patients evaluable for RR to date. In addition, vemurafenib was associated with significantly improved OS and PFS compared to dacarbazine in patients with previously untreated BRAF (V600E) mutation bearing patients with metastatic melanoma.

Biochemotherapy

Biochemothreapy combine traditional chemotherapy with immunotherapies, such as IL-2 and IFN-α-2b. These combination therapies seemed promising in phase II trials, however, seven large studies failed to show statistically significant increased overall survival rates for various biochemotherapy regimens in patients with stage IV metastasis (Margolin KA, et al, Cancer, 1 Aug 2004;101(3):435-8). Owing to inconsistent results of the available studies with regard to benefit including RR, OS and progression time, and consistently high toxicity rates, clinical practice guideline do not recommend biochemotherapy for the treatment of metastatic melanoma (Verma S, et al, Curr Oncol, April 2008; 15(2): 85–89).

Vaccines

The use of therapeutic vaccines is an ongoing area of research, and clinical trials of several types of vaccines (whole cell, carbohydrate, peptide) are being conducted in patients with intermediate and late-stage melanoma. Vaccines are also being tested in patients with metastatic melanoma to determine their immune effects and to define their activity in combination with other immunotherapeutic agents such as IL-2 or IFNalpha (Agarwala S, Am J Clin Dermatol, 2003;4(5):333-46). In fact, recently investigators at the Indiana University Health Goshen Center for Cancer Care (Goshen, IN) conducted a randomized, multicenter phase III trial involving 185 patients with stage IV or locally advanced stage III cutaneous melanoma. The patients were assigned into treatment groups with IL-2 alone or with vaccine (gp100) followed by IL-2. The vaccine-IL-2 group had a significantly improved OR as compared to the IL-2-only group (16% Vs. 6%) and longer progression free survival (2.2 months Vs. 1.6 months). The median overall survival was also longer in the vaccine-interleukin-2 group than in the interleukin-2-only group (17.8 months Vs. 11.1 months). Thus, a combination of vaccine and immunotherapy showed a better response rate and longer progression-free survival than with interleukin-2 alone in patients with advanced melanoma (Schwartzentruber DJ, et al, N Engl J Med, 2 Jun 2011;364(22):2119-27).

Which Treatment When?

Earlier, there were essentially two main options for patients suffering from advanced melanoma, dacarbazine and IL-2. Dacarbazine, a chemotherapeutic agent produces modest improvements in survival or symptomatic benefits in most patients. Interleukin-2 -based drugs, on the other hand, induce long-term remissions in a small group of patients but are highly toxic. Recently, FDA approved ipilimumab and vemurafenib for patients with metastatic melanoma. Apart from these, therapies are also aiming at starving the tumor by inhibiting angiogenesis or depleting nutrients essential for cancer growth. Of the antiangiogenic compounds, VEGFR inhibitors SU5416 and AG-013736 demonstrated broad-spectrum antitumor activity in mice bearing xenografts of human cancer cell lines originating from various tissues, including melanoma. In addition, several trials are currently underway to test the efficacy of the drugs in combination. In the future, personalized medicine-based recommendations of novel and existing drugs for melanoma patients might be the way to go.

Reference: