Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer
Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer Introduction Key Melanoma Clinical Trials Smo SONIDEGIB* Extracellular PKC CDK4/6 Inhibitor AEB071 Porcupine LGK974 MEK BINIMETINIB** Mitogen-Activated Protein Kinase Inhibitor RAF ENCORAFENIB†† CDK4/6 LEE011† Nuclear membrane Tumor cell membrane THE PIPELINE OF NOVARTIS ONCOLOGY – SKIN CANCER Protein Kinase C (PKC) Inhibitor Sonidegib is also known as LDE225 ** Binimetinib (also known as MEK162 or ARRY-162) is licensed from Array BioPharma Inc. † LEE011 was discovered in collaboration with Astex †† Encorafenib is also known as LGX818 * Porcupine Inhibitor Intracellular 2012-2013 Skin Cancer Statistics (US Estimates) New cases Deaths Melanoma (2013)1 76,690 9,480 Nonmelanoma (2012)2 >2,000,000 <1,000 Raf Kinase Inhibitor Cancer type Smoothened Inhibitor Novartis Oncology currently has Phase II and III trials underway using both single agent and combination therapy for the treatment of various types of skin cancer, most notably, basal cell carcinoma and mutated metastatic melanoma. Two Phase I trials for the treatment of uveal melanoma are also ongoing. Skin Cancer Clinical Studies MOA data is based on in vitro/in vivo data. Clinical benefit is unknown. All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available. © 2014 Novartis 3/14 G-PIP-1083440 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 References Novartis Pharma AG CH-4002 Basel Switzerland Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer NCT01763164 Introduction A randomized Phase III, open label, multicenter, two-arm study comparing the efficacy of binimetinib (MEK162) versus dacarbazine in patients with advanced unresectable or metastatic NRAS mutation-positive melanoma3 NOW ENROLLING previously untreated or progressed on or after prior first-line immunotherapy for metastatic disease NEMO (NCT01763164) COLUMBUS (NCT01909453) Study design: 3 Mitogen-Activated Protein Kinase Inhibitor Prescreening to centrally confirm NRAS Q61 mutation RANDOMIZATION 2:1 Key secondary endpoint: Compare overall survival (OS) in both treatment arms 1000 mg/m2 q3w n = 131 Additional secondary endpoints compare MEK162 and dacarbazine in terms of: Smoothened Inhibitor • Overall response rate (ORR) defined as complete response (CR), or partial response (PR) • Time to objective response and duration of response • Disease control rate calculated as a proportion of patients achieving a best overall response of CR, PR or stable disease (SD) • Safety • Quality of life Raf Kinase Inhibitor Compare the progression-free survival (PFS) in both treatment arms by blinded independent review committee (BIRC) Protein Kinase C (PKC) Inhibitor dacarbazine 45 mg bid n = 262 Primary endpoint: Porcupine Inhibitor Stratification by stage (IIIC, IVM 1a, IVM 1b vs IVM 1c), ECOG performance status (0 vs 1), and prior immunotherapy (yes vs no) binimetinib (MEK162) CDK4/6 Inhibitor Patients with advanced unresectable or metastatic melanoma (N = 393) Key Melanoma Clinical Trials Study population: Adult patients with centrally-confirmed NRAS mutation-positive melanoma who are Binimetinib (MEK162) is an investigational compound. Efficacy and safety have not been established. There is no guarantee that binimetinib (MEK162) will become commercially available. Skin Cancer Clinical Studies MOA data is based on in vitro/in vivo data. Clinical benefit is unknown. All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available. © 2014 Novartis 3/14 G-PIP-1083440 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 References Novartis Pharma AG CH-4002 Basel Switzerland Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer NCT01909453 Introduction A Phase III randomized, 3-arm, open label, multicenter study of encorafenib (LGX818) Plus binimetinib (MEK162) and encorafenib (LGX818) monotherapy compared with vemurafenib in patients with unresectable or metastatic BRAF V600 mutant melanoma5 NOW ENROLLING BRAF V600 mutant cutaneous melanoma NEMO (NCT01763164) COLUMBUS (NCT01909453) Study design:5 Mitogen-Activated Protein Kinase Inhibitor Randomization 1:1:1 Stratification by stage (IIIB, IIIC, IVM1a, IVM1b, vs IVM1c) ECOG performance status (0 vs 1) Prior first-line immunotherapy (yes vs no) encorafenib (LGX818) 300 mg qd n=300 Additional secondary endpoints include: Raf Kinase Inhibitor Progression-free survival (PFS) of encorafenib plus • PFS of encorafenib plus binimetinib vs encorafenib binimetinib and/or encorafenib monotherapy compared monotherapy with vemurafenib • Time to objective response (TTR) • Duration of response (DOR) Key secondary endpoint: • Safety and tolerability of encorafenib plus binimetinib Overall survival (OS) between study arms of encorafenib and binimetinib monotherapy plus binimetinib and encorafenib monotherapy versus • Pharmacokinetics of encorafenib and binimetinib vemurafenib • Objective response rate (ORR), disease control rate (DCR), patient-reported outcomes (PRO) Protein Kinase C (PKC) Inhibitor Primary endpoint: vemurafenib 960 mg bid n=300 Porcupine Inhibitor Combination encorafenib (LGX818) + binimetinib (MEK162) 450 mg qd + 45 mg bid n=300 CDK4/6 Inhibitor Pre-screening to centrally confirm BRAF V600E or V600K mutation Key Melanoma Clinical Trials Study population: Adult patients with histologically confirmed, locally advanced, unresectable or metastatic Smoothened Inhibitor Encorafenib (LGX818) and binimetinib (MEK162) are investigational compounds. Their efficacy and safety have not been established. There is no guarantee that encorafenib (LGX818) and binimetinib (MEK162) will become commercially available. Skin Cancer Clinical Studies MOA data is based on in vitro/in vivo data. Clinical benefit is unknown. All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available. © 2014 Novartis 3/14 G-PIP-1083440 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 References Novartis Pharma AG CH-4002 Basel Switzerland Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer Malignancies Introduction Tumor cell membrane Key Melanoma Clinical Trials CDK4/6 Inhibitor Mitogen-Activated Protein Kinase Inhibitor CDK4/6 INHIBITOR stimulation, activation of the major signal transduction pathways (including MAPK and Pi3K pathways) leads to an increased abundance of D-cyclins, which associate with CDK4/6, resulting in Rb phosphorylation and activation of E2F transcription factors. This series of events allows cells to undergo DNA replication and proliferate.6,7 • Approximately, 80% of human neoplasms maintain functional Rb and have aberrations that increase the • LEE011* • An orally available, selective inhibitor of CDK4/6 kinases, which prevents phosphorylation of Rb and G1 arrest in cancer cell lines.29,33 Protein Kinase C (PKC) Inhibitor CDK4/6 activity (e.g. translocation and amplification of D-cyclins, amplification of CDK4/6 and inactivation of p16). In addition, Rb-positive cancers driven by activated oncogenes that are upstream regulators of D-cyclins, including K-RAS mutation and phosphatase and tensin homolog (PTEN) deletion, are expected to be dependent on CDK4/6 activity for growth.6,7 Porcupine Inhibitor • CDK4/6 control cell cycle progression by regulating the activity of Retinoblastoma protein (Rb). Upon mitogen • In in vitro and in vivo tumor models, has been shown active in cancers harboring aberrations • LEE011 is currently in Phase Ib/II studies in melanoma. Raf Kinase Inhibitor that increase CDK4/6 activity, including those directly linked to the kinases as well as activating alterations in the upstream regulators.29,33 • NCT01781572: A Phase Ib/II, multicenter, open-label, study of LEE011in combination with binimetinib (MEK162)** in patients with NRAS mutant melanoma23 (LGX818) in adult patients with BRAF mutant melanoma24 • NCT01820364: Phase II, multicenter, open-label study of single-agent encorafenib (LGX818) followed by a rational combination with agents after progression on encorafenib (LGX818), in adult patients with locally advanced or metastatic BRAF V600 melanoma31 Smoothened Inhibitor • NCT01777776: A Phase Ib/II, multicenter, study of LEE011 in combination with encorafenib *LEE011 was discovered in collaboration with Astex. Skin Cancer Clinical Studies **Binimetinib (also known as MEK162 or ARRY-162) is licensed from Array BioPharma Inc. MOA data is based on in vitro/in vivo data. Clinical benefit is unknown. All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available. © 2014 Novartis 3/14 G-PIP-1083440 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 References Novartis Pharma AG CH-4002 Basel Switzerland Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer Malignancies Introduction Tumor cell membrane Key Melanoma Clinical Trials BINIMETINIB (MEK162) CDK4/6 Inhibitor • Mitogen-activated ERK kinases 1 and 2 (MEK1 and MEK2) play roles in cancer cell proliferation, apoptosis, and Mitogen-Activated Protein Kinase Inhibitor MITOGEN-ACTIVATED PROTEIN KINASE (MAPK) INHIBITOR metastasis. MEK1 and MEK2 are components of the RAS/RAF/MEK/ERK signaling pathway.8,9 pancreatic, colon, lung and thyroid cancers.8 • Mutations of BRAF are associated with selective sensitivity to MEK inhibition when compared to either ‘wild-type’ cells or cells harboring a RAS mutation8,9 • Binimetinib (MEK162)* Porcupine Inhibitor • It is hypothesized that aberrant signaling of the RAS/RAF/MEK/ERK pathway could be a driving factor in melanoma, • An oral, selective allosteric MAPK kinase (MEK) inhibitor9 • NEMO - NCT01763164: Randomized Phase III, open label, multicenter, two-arm study comparing the efficacy of binimetinib (MEK162) versus dacarbazine in patients with advanced unresectable or metastatic NRAS mutation-positive melanoma3 Protein Kinase C (PKC) Inhibitor • Phase I, II and III studies as a single agent and in combination therapy in melanoma are ongoing • NCT01781572: A Phase Ib/II, multicenter, open-label, study of LEE011** in combination with binimetinib (MEK162) in adult patients with NRAS mutant melanoma23 in adult patients with metastatic uveal melanoma30 • COLUMBUS - NCT01909453: Raf Kinase Inhibitor • NCT01801358: A Phase Ib/II, open-label, multicenter study of AEB071 and binimetinib (MEK162) A Phase III randomized, three-arm, open label, multicenter study of encorafenib (LGX818) plus binimetinib (MEK162) and encorafenib (LGX818) monotherapy compared with vemurafenib in patients with unresectable or metastatic BRAF V600 mutant melanoma5 in combination with binimetinib (MEK162) in adult patients with BRAF V600 - dependent advanced solid tumors32 Smoothened Inhibitor • NCT01543698: A Phase Ib/II, multicenter, open-label, dose escalation study of encorafenib (LGX818) Binimetinib (also known as MEK162 or ARRY-162) is licensed from Array BioPharma Inc. ** LEE011 was discovered in collaboration with Astex * Skin Cancer Clinical Studies MOA data is based on in vitro/in vivo data. Clinical benefit is unknown. All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available. © 2014 Novartis 3/14 G-PIP-1083440 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 References Novartis Pharma AG CH-4002 Basel Switzerland Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer Malignancies Introduction Key Melanoma Clinical Trials CDK4/6 Inhibitor Mitogen-Activated Protein Kinase Inhibitor • The Wnt pathway regulates cellular proliferation, migration, morphology, apoptosis, differentiation, and stem cell self-renewal.9,10 Dysregulation of the Wnt pathway is known to play a role in the development of a variety of malignancies, including melanoma, breast cancer, and squamous cell carcinoma.11-13 • Interaction between Wnt ligands and the co-receptors Frizzled and low-density lipoprotein receptor-related • Wnt ligands require post-translational palmitoylation in order to be secreted.8,11 An enzyme that is involved in regulating this process is Porcupine, a membrane bound O-acyltransferase enzyme, which plays a role for palmitoylation of Wnt ligands.10,13 Protein Kinase C (PKC) Inhibitor protein 5/6 (LRP5/6) initiates the canonical Wnt pathway. Activation of this pathway prevents proteosomal degradation of ß-catenin.11 ß-catenin translocates to the nucleus where it interacts with the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to activate specific Wnt-target genes.11 Porcupine Inhibitor PORCUPINE INHIBITOR • LGK974 • NCT01351103: A Phase I, open-label, dose-escalation study of oral LGK974 in patients with Raf Kinase Inhibitor • Oral, selective small molecule inhibitor of Porcupine4 • A Phase I study of LGK974 in patients with melanoma or lobular breast cancer is currently ongoing malignancies dependent on Wnt ligands25 Smoothened Inhibitor Skin Cancer Clinical Studies MOA data is based on in vitro/in vivo data. Clinical benefit is unknown. All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available. © 2014 Novartis 3/14 G-PIP-1083440 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 References Novartis Pharma AG CH-4002 Basel Switzerland Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer Malignancies Introduction Key Melanoma Clinical Trials CDK4/6 Inhibitor Mitogen-Activated Protein Kinase Inhibitor • PKC is a mediator of B-cell receptor (BCR)-NF-κB activation as it phosphorylates CARD11 of the CARD11Bcl10-MALT1 (CBM) signaling complex. The CBM complex then activates the I kappa B kinase (IKK) complex, leading to the translocation of NF-κB to the nucleus and expression of its target genes.14 Isoforms of PKC have been shown to play a role in cellular signaling, proliferation, differentiation, migration, and apoptosis.15 Porcupine Inhibitor PROTEIN KINASE (PKC) INHIBITOR • Two Gα proteins, GNAQ and GNA11, are constitutively activated in the majority of blue nevi and melanomas of • In vivo, mutant GNAQ and GNA11 transform melanocytes and induce rapid tumor growth in mice when introduced into immortalized murine melanocytes.16,18 • AEB071 • NCT01402440: An open label, single-arm, Phase I study of AEB071 (a protein kinase C inhibitor) in patients with CD79-mutant diffuse large B-cell lymphoma26 Raf Kinase Inhibitor • Oral, PKC inhibitor active for isoforms of PKC15 • Phase I and II studies using AEB071 are underway Protein Kinase C (PKC) Inhibitor the uvea.14 GPCRs are recognized for their role in stimulating growth and malignant transformation, and the signaling from these receptors can be mediated by PKC.17 • NCT01430416: Phase I study of AEB071, an oral protein kinase C inhibitor, in patients with metastatic uveal melanoma27 in adult patients with metastatic uveal melanoma30 * Binimetinib (also known as MEK162 or ARRY-162) is licensed from Array BioPharma Inc. Smoothened Inhibitor • NCT01801358: A Phase Ib/II, open-label, multicenter study of AEB071 and binimetinib (MEK162)* Skin Cancer Clinical Studies MOA data is based on in vitro/in vivo data. Clinical benefit is unknown. All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available. © 2014 Novartis 3/14 G-PIP-1083440 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 References Novartis Pharma AG CH-4002 Basel Switzerland Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer Malignancies Introduction ENCORAFENIB (LGX818) Key Melanoma Clinical Trials CDK4/6 Inhibitor • The RAF protein is a component of mitogen-activated protein kinase (MAPK) signal transduction pathway, which controls proliferation, differentiation, and apoptosis in mammalian cells through RAS, RAF, and extracellular-signal-regulated kinase (ERK) kinase (MEK).19 • There are three isoforms of RAF: A-RAF, B-RAF, and C-RAF.17 Activating mutations of B-RAF have been identified • Selective RAF inhibitors have demonstrated activity in tumor cell lines harboring the B-RAFV600 mutation in preclinical models.20 • Encorafenib (LGX818) • Oral, selective B-Raf inhibitor • In preclinical studies, suppresses the RAF-MEK-ERK pathway in tumor cells expressing B-RAFV600 in wild-type B-RAF tumor cells Porcupine Inhibitor in multiple cancers, most notably in melanomas but also in colorectal cancer, serous borderline ovarian cancer, and papillary thyroid carcinomas.19,20 The most common B-RAF mutation is V600E which accounts for 90% of all cancer causing B-RAF mutations.20,21 Mitogen-Activated Protein Kinase Inhibitor RAF KINASE INHIBITOR except 4 B-RAF mutation • Phase I, II and III studies are underway, including encorafenib (LGX818) alone and in combination with other targeted therapies • NCT01436656: Phase I, multicenter, open-label, dose-escalation study of oral encorafenib (LGX818) Protein Kinase C (PKC) Inhibitor • Evaluated in melanoma, colorectal cancer, and other advanced solid tumors in patients harboring the in adult patients with locally advanced or metastatic B-RAF mutant melanoma28 • NCT01777776: Phase Ib/II, multicenter, study of LEE011* in combination with encorafenib (LGX818) • NCT01820364: Phase II, multicenter, open-label study of single-agent encorafenib (LGX818) followed by a rational combination with agents after progression on encorafenib (LGX818), in adult patients with locally advanced or metastatic BRAF V600 melanoma31 Raf Kinase Inhibitor in adult patients with BRAF mutant melanoma24 • COLUMBUS - NCT01909453: A Phase III randomized, three-arm, open-label, multicenter • NCT01543698: A Phase Ib/II, multicenter, open-label, dose escalation study of LGX818 in combination with binimetinib (MEK162)** in adult patients with B-RAFV600 - dependent advanced solid tumors32 Smoothened Inhibitor study of encorafenib (LGX818) plus binimetinib (MEK162) and encorafenib (LGX818) monotherapy compared with vemurafenib in patients with unresectable or metastatic BRAF V600 mutant melanoma5 *LEE011 was discovered in collaboration with Astex. **Binimetinib (also known as MEK162 or ARRY-162) is licensed from Array BioPharma Inc. Skin Cancer Clinical Studies MOA data is based on in vitro/in vivo data. Clinical benefit is unknown. All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available. © 2014 Novartis 3/14 G-PIP-1083440 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 References Novartis Pharma AG CH-4002 Basel Switzerland Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer Malignancies Introduction SONIDEGIB (LDE225) Hh Ptch CDK4/6 Inhibitor Sufu Key Melanoma Clinical Trials Tumor cell membrane Smo Gli Gli Mitogen-Activated Protein Kinase Inhibitor INCREASED APOPTOSIS DECREASED PROLIFERATION • Smo is a GPCR-like (G protein-coupled receptor) molecule that positively regulates Hh signal transduction, a signaling pathway that plays a role in the development and homeostasis in organs and tissues22 Protein Kinase C (PKC) Inhibitor • Genetic activation of the Hh pathway at or upstream of Smo is linked to tumorigenesis of several cancers22 • Sonidegib (LDE225) • Selective Smo inhibitor4 • Sonidegib (LDE225) is currently in a Phase II trial in advanced basal cell carcinoma • NCT01327053: Phase II, randomized double-blind study of efficacy and safety of two dose levels of Porcupine Inhibitor SMOOTHENED (SMO) INHIBITOR sonidegib (LDE225) in patients with locally advanced or metastatic basal cell carcinoma34 Raf Kinase Inhibitor Smoothened Inhibitor Skin Cancer Clinical Studies MOA data is based on in vitro/in vivo data. Clinical benefit is unknown. All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available. © 2014 Novartis 3/14 G-PIP-1083440 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 References Novartis Pharma AG CH-4002 Basel Switzerland Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer Malignancies SKIN CANCER CLINICAL STUDIES Phase I encorafenib (LGX818) CDK4/6 inhibitor LEE011 PKC inhibitor AEB071 Porcupine inhibitor LGK974 Smoothend inhibitor sonidegib (LDE225) CDK4/6 Inhibitor RAF kinase inhibitor Mitogen-Activated Protein Kinase Inhibitor binimetinib (MEK162) Phase III Key Melanoma Clinical Trials Mitogen-activated protein kinase inhibitor Phase II Introduction Class For more information about study design or enrollment: • For countries outside the United States, please contact your local Novartis Oncology Medical Representative • United States residents can call our clinical trials hotline at 1-800-340-6843 • Visit www.clinicaltrials.gov Porcupine Inhibitor HOW TO GET CLINICAL TRIAL INFORMATION Protein Kinase C (PKC) Inhibitor Raf Kinase Inhibitor Smoothened Inhibitor Skin Cancer Clinical Studies All compounds are either investigational or studied in new indications. Efficacy and safety have not been established. There is no guarantee that they will become commercially available. © 2014 Novartis 3/14 G-PIP-1083440 Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936-1080 References Novartis Pharma AG CH-4002 Basel Switzerland Targeting Hematological Novartis Oncology Pipeline: Targeting Skin Cancer REFERENCES 2. http://www.cancer.gov/cancertopics/types/skin. Accessed February 13, 2014. 3. National Institutes of Health (NIH). ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01763164. Introduction 1. http://www.cancer.gov/cancertopics/types/melanoma. Accessed February 13, 2014. Updated January 14, 2014. Accessed February 13, 2014. 4. Novartis, data on file. 5. National Institutes of Health (NIH). ClinicalTrials.gov. http://www.clinicaltrials.gov/ct2/show/NCT01909453. 6. Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta. 2002 Mar 14;1602(1):73–87. 7. Shapiro GI. 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