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To: scaram(o)uche who wrote (1826)3/22/2012 3:07:22 PM
From: ariadough
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10 openings this month alone 3 today

http://www.ariad.com/wt/tertiarypage/careers_opportunities

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From: Biomaven3/23/2012 11:13:24 AM
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As I've said before, the FLT3 opportunity in AML could be very significant. Up to now drugs that have targeted this mutation have been very disappointing (for unclear reasons), but ponatinib has the best shot at changing that picture:

Br J Haematol. 2012 Mar 13. doi: 10.1111/j.1365-2141.2012.09085.x. [Epub ahead of print]
Ponatinib may overcome resistance of FLT3-ITD harbouring additional point mutations, notably the previously refractory F691I mutation.
Zirm E, Spies-Weisshart B, Heidel F, Schnetzke U, Böhmer FD, Hochhaus A, Fischer T, Scholl S.
SourceDepartment of Haematology/Oncology, Clinic for Internal Medicine II, Jena University Hospital, Jena.


AbstractFms-like tyrosine kinase (FLT3) mutations are the most frequent mutations in patients with acute myeloid leukaemia (AML) that confer a poor prognosis. Constitutively active FLT3-ITD (internal tandem duplications) mutations define a promising target for therapeutic approaches using small molecule inhibitors. However, several point mutations of the FLT3 tyrosine kinase domain (FLT3-TKD) have been identified to mediate resistance towards FLT3 tyrosine kinase inhibitors (FLT3-TKI), including secondary mutations of FLT3. We investigated the cellular effects of the recently characterised FLT3-TKI ponatinib (AP24534) on murine myeloid cells transfected with FLT3-ITD with or without additional point mutations of the FLT3-TKD including the (so far) multi-resistant F691I mutation. Ponatinib effectively induced apoptosis not only in the parental FLT3-ITD cell line but also in all stably transfected subclones harbouring additional FLT3-TKD point mutations (N676D, F691I or G697R). These observations correlated with a strong inhibition of FLT3-ITD and its downstream targets STAT5, AKT and ERK1/2 upon ponatinib incubation, as determined by Western blotting. We conclude that ponatinib represents a promising FLT3-TKI that should be further investigated in clinical trials. The targeted therapy of FLT3-ITD-positive AML with ponatinib might be associated with a lower frequency of secondary resistance caused by acquired FLT3-TKD mutations.

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From: scaram(o)uche3/23/2012 1:31:06 PM
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blogger's review of recent stuff, mechs. of crizotinib resistance.....

pharmastrategyblog.com

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To: Biomaven who wrote (1828)3/24/2012 9:03:31 AM
From: iandy
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To: Biomaven who wrote (1828)3/24/2012 9:21:16 AM
From: iandy
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Ariad announced the initial results of their small trial of AML patients over 7 months ago.

biospace.com

Do you think this indication should have moved further along in clinical development by now?

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From: ariadough3/27/2012 10:22:23 AM
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Ariad Pharmaceuticals ( ARIA) and Merck ( MRK)
Monday, April 2, 2012 (1:00 pm)
Vorinostat abrogates ridaforolimus-induced activation of Akt in synovial sarcoma cells: A possible rationale for their synergism
Background: Curative treatments for patients with metastatic synovial sarcoma (SS) do not exist and such patients have a poor prognosis. Previously, we demonstrated that the combination of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat exhibited synergism in a variety of cell lines. Here, we explore whether the Akt pathway is potentially involved in mediating the synergistic effects of ridaforolimus and vorinostat.
Conclusions: The combination of ridaforolimus and vorinostat demonstrates in vitro synergism in SS as well as in a variety of other tumor types. The addition of vorinostat prevented ridaforolimus-induced Akt activation, a possible mechanism of resistance to mTOR inhibition. Adding HDAC inhibition to mTOR inhibitors may be a route to circumvent Akt-mediated resistance to mTOR inhibitors. Our results also indicate that this combination may demonstrate broad anti-neoplastic activity.

**(Our opinion) These pre-clinical findings could provide the thesis for a potential positive outcome in the current Phase 1 study " A Phase I Study of Ridaforolimus and Vorinostat in Patients With Advanced Renal Cell Carcinoma ([url=http://seekingalpha.com/symbol/rcc]RCC)"[/url]

Monday, April 2, 2012 (8:00 am)
Response biomarkers to IGF1R and mTOR inhibitor combination therapy in ovarian carcinoma
Ovarian cancer, the sixth most frequent cause of cancer death among women in the developed world, is a heterogeneous disease characterized by a diverse set of genetic alterations. These factors underscore the need for more effective treatment options accompanied by biomarker strategies to identify patients who will have a greater likelihood to respond to novel therapy. A combination strategy to target the PI3K pathway with the mTOR inhibitor ridaforolimus and anti-IGF1R antibody dalotuzumab is currently undergoing clinical development. Previous translational work has suggested that low RAS activity, as determined by a RAS gene expression signature score, and high levels of IGF1R pathway activation may enrich for response to this combination therapy. Ranking of tumors in the Moffitt tumor database with a low RAS and high IGF profile suggested that ER+ breast and ovarian cancers are enriched for these putative response biomarkers. Consistent with these observations, clinical responses were noted for several ER+ breast or ovarian cancer patients in a Phase I trial for ridaforolimus and dalotuzumab combination therapy. To provide further support for low RAS and high IGF as response biomarkers, the anti-tumor activity of ridaforolimus and dalotuzumab was assessed in 12 patient derived primary ovarian cancer xenograft models developed at START. These models have been extensively characterized by the South Texas Accelerated Research and Therapeutics (START) group for response to standard of care drugs, and the status of many commonly mutated genes in ovarian cancer. Molecular analyses of these tumors suggest that they represent a diverse cross section of ovarian cancer. Similarly, responses to ridaforolimus and dalotuzumab combination therapy ranged from minimal to significant regression. Importantly, the responsive tumor models were associated with a low RAS gene signature and a moderate to high IGF expression level. Tumors with KRAS mutations or a high RAS gene score were generally resistant to therapy. These results support the further development of low RAS and high IGF as enrichment biomarkers for ridaforolimus and dalotuzumab combination therapy in ovarian carcinoma.

**(Our opinion) These pre-clinical findings could provide the thesis for a potential positive outcome in two current human studies: Phase II "A Study of Ridaforolimus (MK-8669) in Combination With Dalotuzumab (MK-0646) Compared to Standard of Care Treatment in Estrogen Receptor Positive Breast Cancer Patients" and Phase 1 "A Study of Dalotuzumab + MK-2206, Dalotuzumab + MK-0752, and Dalotuzumab + MK-8669 Combination Therapies in Participants With Advanced Cancer"

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From: ariadough3/28/2012 8:50:44 AM
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i have been looking for weeks now to see what i can find about ap26113 and how it penetrates the blood brain barrier. in the latest report from rachel that seems to be the key for 113.

in her earlier report i did find this----However, improved penetration across the blood brain barrier to limit brain
disease progression and increased potency against common mutations suggest
Xalkori should be very beatable on PFS. These data will take time to generate.
ALK positive lung cancer


i think this is very very important moving forward and why we will see 113 benefit many of these patients. and perhaps keep the cancer from the brain.

thoughts

dough

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From: ariadough4/2/2012 10:54:29 AM
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News release




View printer-friendly version
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ARIAD Presents New Preclinical Data on Ponatinib and AP26113
Both Tyrosine Kinase Inhibitors Overcome Drug Resistance Due to “Gatekeeper” Mutations Of Multiple Oncogenic Targets

CAMBRIDGE, Mass. & CHICAGO--(BUSINESS WIRE)--Apr. 2, 2012-- ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced the presentation of new preclinical data on its investigational pan-BCR-ABL inhibitor, ponatinib, and its investigational dual EGFR-ALK inhibitor, AP26113, at the American Association for Cancer Research Annual Meeting in Chicago. Both drug candidates, discovered using ARIAD’s structure-based drug design platform, are potent inhibitors of multiple “gatekeeper” mutations that have been shown to confer clinical resistance to other targeted cancer medicines.

The first study, “Ponatinib, a potent pan-BCR-ABL inhibitor, retains activity against gatekeeper mutants of FLT3, RET, KIT, PDGFR and FGFR1,” was presented yesterday and shows that ponatinib overcomes resistant gatekeeper mutations well beyond BCR-ABL -- the drug’s target in chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) -- in other clinically relevant tyrosine kinase targets.

The preclinical research conducted by ARIAD scientists assessed the activity of ponatinib using cell lines expressing activated forms of FLT3, RET, KIT, PDGFR and FGFR1, each a kinase target associated with a specific tumor type. Ponatinib potently inhibited the activity of these kinases and maintained potent activity against gatekeeper variants that have been shown to cause resistance to other tyrosine kinase inhibitors in acute myeloid leukemia, medullary thyroid cancer, gastrointestinal stromal tumor (GIST) and rare forms of leukemia driven by these tyrosine kinases.

“Ponatinib was designed to block the abnormal tyrosine kinase, BCR-ABL, which drives CML and Ph+ALL,” said Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer of ARIAD. “The structural design feature that allows ponatinib to evade the BCR-ABL T315I gatekeeper mutation also enables the molecule to overcome analogous mutations in its other kinase targets. We are actively working with academic collaborators to set up clinical trials aimed at determining the potential role of ponatinib in these additional forms of drug-resistant cancer.”

A second abstract, “AP26113 is a dual ALK/EGFR inhibitor: Characterization against EGFR T790M in cell and mouse models of NSCLC,” will be presented today and describes the activity of AP26113, a dual inhibitor of EGFR and ALK, to overcome gatekeeper mutations of these targets. This preclinical research further confirms that AP26113 is a potent, reversible inhibitor of the T790M gatekeeper mutation of epidermal growth factor receptor (EGFR). Activated EGFR occurs in approximately 250,000 lung cancer patients worldwide, and the single T790M mutation accounts for over 50 percent of resistance to tyrosine kinase inhibitors in these patients who have limited treatment options available.

This poster also presents, for the first time, preclinical data demonstrating that AP26113 potently inhibits non-small cell lung cancer (NSCLC) cell lines that express an activating translocation of the ROS1 tyrosine kinase. Such ROS1 mutations have recently been identified as a feature of approximately two percent of all NSCLC, representing another area for further investigation of AP26113 in NSCLC patients in need of better therapeutic choices


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From: ariadough4/3/2012 12:00:27 PM
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biomaven i know you have commented on this before but i thought it was worth reposting as some may have not saw this before.

pnas.org

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From: ariadough4/4/2012 4:15:49 PM
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No Study Results Posted
Related Studies



Ponatinib - Frontline for Chronic Myeloid Leukemia (CML) in Chronic Phase (CP)
This study is not yet open for participant recruitment.
Verified April 2012 by M.D. Anderson Cancer Center
First Received on April 2, 2012. No Changes Posted
Sponsor: Collaborator: Information provided by (Responsible Party): ClinicalTrials.gov Identifier:
M.D. Anderson Cancer Center
Ariad Pharmaceuticals
M.D. Anderson Cancer Center
NCT01570868


Purpose

The goal of this clinical research study is to learn if ponatinib can help to control chronic myeloid leukemia (CML) in chronic phase. The safety of this drug will also be studied.

Ponatinib is designed to block the function of BCR-ABL, which is the abnormal protein responsible for causing leukemia in certain cells.




ConditionInterventionPhase
Leukemia
Drug: Ponatinib
Phase II


Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Ponatinib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase


Resource links provided by NLM:

MedlinePlus related topics: Cancer Chronic Myeloid Leukemia Leukemia
U.S. FDA Resources



Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures: Complete Cytogenetic Response (CCyR) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
The binary indicator of complete cytogenetic remission measured from start of therapy to 6 months, denoted by CCR6. Method of Kaplan and Meier21 used to estimate the unadjusted distributions of time to toxicity, duration of CCR, and the times to transformation to accelerated phase or blastic phase chronic myeloid leukemia (CML).




Secondary Outcome Measures: Time to Toxicity [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
Time to toxicity (T) defined as any grade 3 or 4 drug-related non-hematologic adverse event that has not resolved to grade 2 or less after 6 weeks of optimal therapeutic management, or drug-related toxicity of any grade that in the opinion of the investigator prevents further therapy with ponatinib. Secondary outcomes include duration of complete cytogenic response (CCR), time to transformation to accelerated phase or blastic phase chronic myeloid leukemia (CML), and major molecular response (MMR). Time to toxicity monitored using the Bayesian method of Thall, et al.



Estimated Enrollment: 50
Study Start Date: September 2012
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
Experimental: Ponatinib
Patients receive ponatinib at a dose of 45 mg orally, once daily. If a dose is missed or vomited, the next dose should not be increased to account for missing a dose. Total duration of therapy 3 to 5 years.
Drug: Ponatinib
Starting dose: 45 mg by mouth once daily.
Other Name: AP24534


Detailed Description:
Study Drug Administration:

You will take ponatinib by mouth 1 time every day while you are on study with about a cup (8 ounces) of water. You should not eat within 2 hours before or after taking the drug. You will complete a study diary in which you will record the date and time that you take the study drug each time. If you miss any doses, you will also note this in the study diary. Bring this diary to every study visit, as described below.

Study Visits:

The tests and procedures for this study have a wide range of time in which they can be done. In general, your schedule of study visits will be as follows:

Weekly in Month 1 Monthly in Year 1 Three (3) to 4 times in Year 2 Two (2) to 3 times in every year after that The study staff will help you schedule your study visits. The following tests and procedures will be performed:

Every 1-2 weeks for the first 4 weeks, then every 4-6 weeks for the first year, then every 3-4 months for the next year, then every 4-6 months after that, blood (about 1/2 tablespoon) will be drawn for routine tests. Every 3 months for the first year, you will have an ECG. Every 3 months for the first year, then every 6-12 months after that, you will have a physical exam. Every 3-4 months for the first year, then every 6-12 months after that, blood (about 2 teaspoons) will be drawn to measure levels of leukemia cells in your body. Every 3-4 months for the first year, then every 6-12 months for the next 2 years, then every 2-3 years after that, you will have a bone marrow aspirate for genetic testing and to check the status of the disease. Length of Participation:

You may continue taking the study drug for up to 5 years. You will be taken off study early if intolerable side effects occur, if the disease gets worse, or if you are unable to follow study directions.

Your participation on the study will be over when you have completed the follow-up visit/call.

Follow-Up:

If you leave the study, you will be called or you will come to the clinic within 30 days to learn about any side effects or symptoms you may be having. If you are called, this call will last about 2-3 minutes.

This is an investigational study. Ponatinib is not FDA approved or commercially available. It is currently being used for research purposes only.

Up to 50 patients will take part in this study. All will be enrolled at MD Anderson.






Eligibility


Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No

Criteria
Inclusion Criteria:

Diagnosis of Ph-positive (by cytogenetics or FISH) or Bcr-ABL-positive (by PCR) CML in early chronic phase CML (i.e., time from diagnosis </= 6 months). Except for hydroxyurea, patients must have received no or minimal prior therapy, defined as </=1 month of prior IFN- (with or without ara-C) and/or an FDA-approved tyrosine kinase inhibitor (e.g, dasatinib, nilotinib). Age >/=18 years Eastern Cooperative Oncology Group (ECOG) performance of 0-2. Adequate end organ function, defined as the following: total bilirubin <1.5 * ULN, SGPT <2.5 * upper limit of normal (ULN),creatinine clearance (CrCl) >/= 30 mL/min at screening (calculation according to Cockroft & Gault formula). Patients must sign an informed consent indicating they are aware of the investigational nature of this study, in keeping with the policies of the hospital. Women of pregnancy potential must practice an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control. Adequate forms of contraception are barrier methods (e.g., condoms, diaphragm), oral, depo provera, or injectable contraceptives, intrauterine devices, spermicidal jelly or foam, abstinence, and tubal ligation. Women and men must continue birth control for the duration of the trial & at least 3 months after the last dose of study drug. **continued from above: All WOCBP MUST have a negative serum or urine pregnancy test within 7 days prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study. Exclusion Criteria:

New York Heart Association (NYHA) cardiac class 3-4 heart disease Cardiac Symptoms: Patients meeting the following criteria are not eligible: Unstable angina or myocardial infarction within 3 months; Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec) on both the Fridericia and Bazett's correction; Symptomatic congestive heart failure within 3 months prior to first dose of ponatinib (NYHA class III or IV). Patients with active, uncontrolled psychiatric disorders including: psychosis, major depression, and bipolar disorders. Pregnant or breast-feeding women are excluded. Patients with history of pancreatitis. Patients in late chronic phase (i.e., time from diagnosis to treatment >6 months), or blast phase are excluded. The definitions of CML phases are as follows: A. Early chronic phase: time from diagnosis to therapy </= 6 months; B. Late chronic phase: time from diagnosis to therapy > 6 months; C. Blastic phase: presence of 30% blasts or more in the peripheral blood or bone marrow; D. Accelerated phase CML: presence of any of the following features: Peripheral or marrow blasts 15% or more; Peripheral or marrow basophils 20% or more; Thrombocytopenia < 100 * 10(9)/L unrelated to therapy; Documented extramedullary blastic disease outside liver or spleen. **continued from above: E. Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome has been historically been included as a criterion for accelerated phase. However, patients with clonal evolution as the only criterion of accelerated phase have a significantly better prognosis, and when present at diagnosis may not impact the prognosis at all. Thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study.



Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01570868


Contacts
Contact: Jorge Cortes, MD 713-794-5783


Locations
United States, Texas
UT MD Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030

Sponsors and Collaborators
M.D. Anderson Cancer Center
Ariad Pharmaceuticals

Investigators
Principal Investigator: Jorge Cortes, MD UT MD Anderson Cancer Center



More Information

Additional Information:
UT MD Anderson Cancer Center Website

No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01570868 History of Changes
Other Study ID Numbers: 2012-0074
Study First Received: April 2, 2012
Last Updated: April 2, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Ponatinib
AP24534
Leukemia
Chronic Myeloid Leukemia
CML
Chronic Phase
Cytogenetic response
CCyR
Major molecular response
MMR
Complete molecular response
CMR


Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases


ClinicalTrials.gov processed this record on April 03, 2012

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