149 results on '"Haluska, Frank G."'
Search Results
102. Phase 2 Study of the g209-2M Melanoma Peptide Vaccine and Low-Dose Interleukin-2 in Advanced Melanoma
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Roberts, John D, primary, Niedzwiecki, Donna, additional, Carson, William E, additional, Chapman, Paul B, additional, Gajewski, Thomas F, additional, Ernstoff, Marc S, additional, Hodi, F Stephen, additional, Shea, Christopher, additional, Leong, Stanley P, additional, Johnson, Jeffrey, additional, Zhang, Dongsheng, additional, Houghton, Alan, additional, and Haluska, Frank G, additional
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- 2006
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103. Immunization Using Autologous Dendritic Cells Pulsed with the Melanoma-Associated Antigen gp100-Derived G280-9V Peptide Elicits CD8+ Immunity
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Linette, Gerald P., primary, Zhang, Dongsheng, additional, Hodi, F. Stephen, additional, Jonasch, Eric P., additional, Longerich, Simonne, additional, Stowell, Christopher P., additional, Webb, Iain J., additional, Daley, Heather, additional, Soiffer, Robert J., additional, Cheung, Amy M., additional, Eapen, Sara G., additional, Fee, Sharon V., additional, Rubin, Krista M., additional, Sober, Arthur J., additional, and Haluska, Frank G., additional
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- 2005
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104. Melanoma of unknown primary: experience at Massachusetts General Hospital and Dana-Farber Cancer Institute
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Katz, Kenneth A., primary, Jonasch, Eric, additional, Hodi, F. Stephen, additional, Soiffer, Robert, additional, Kwitkiwski, Kimberly, additional, Sober, Arthur J., additional, and Haluska, Frank G., additional
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- 2005
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105. Treatment of Melanoma with 5-Fluorouracil or Dacarbazine In Vitro Sensitizes Cells to Antigen-Specific CTL Lysis through Perforin/Granzyme- and Fas-Mediated Pathways
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Yang, Sixun, primary and Haluska, Frank G., additional
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- 2004
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106. Antimelanoma Activity of CTL Generated from Peripheral Blood Mononuclear Cells After Stimulation with Autologous Dendritic Cells Pulsed with Melanoma gp100 Peptide G209-2M Is Correlated to TCR Avidity
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Yang, Sixun, primary, Linette, Gerald P., additional, Longerich, Simonne, additional, and Haluska, Frank G., additional
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- 2002
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107. Phase II Study of Paclitaxel and Carboplatin for Malignant Melanoma
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Hodi, F. Stephen, primary, Soiffer, Robert J., additional, Clark, Jeffrey, additional, Finkelstein, Dianne M., additional, and Haluska, Frank G., additional
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- 2002
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108. Interferon in Oncological Practice: Review of Interferon Biology, Clinical Applications, and Toxicities
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Jonasch, Eric, primary and Haluska, Frank G., additional
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- 2001
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109. HLA-A2.1/Kb Transgenic Murine Dendritic Cells Transduced with an Adenovirus Encoding Human gp100 Process the Same A2.1-Restricted Peptide Epitopes as Human Antigen-Presenting Cells and Elicit A2.1-Restricted Peptide-Specific CTL
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Yang, Sixun, primary, Linette, Gerald P., additional, Longerich, Simonne, additional, Roberts, Bruce L., additional, and Haluska, Frank G., additional
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- 2000
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110. Mutational analysis of the CDK-4 gene in human pancreatic endocrine tumors
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Tsao, Hensin, primary, Gaspard, John P., additional, Haluska, Frank G., additional, and Chung, Daniel C., additional
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- 2000
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111. In Vitro Priming with Adenovirus/gp100 Antigen-Transduced Dendritic Cells Reveals the Epitope Specificity of HLA-A*0201-Restricted CD8+ T Cells in Patients with Melanoma
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Linette, Gerald P., primary, Shankara, Srinivas, additional, Longerich, Simonne, additional, Yang, Sixun, additional, Doll, Rhonda, additional, Nicolette, Charles, additional, Preffer, Frederic I., additional, Roberts, Bruce L., additional, and Haluska, Frank G., additional
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- 2000
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112. Analysis of human transcriptomes
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Velculescu, Victor E, primary, Madden, Stephen L, additional, Zhang, Lin, additional, Lash, Alex E, additional, Yu, Jian, additional, Rago, Carlo, additional, Lal, Anita, additional, Wang, Clarence J, additional, Beaudry, Gary A, additional, Ciriello, Kristin M, additional, Cook, Brian P, additional, Dufault, Michael R, additional, Ferguson, Anne T, additional, Gao, Yuhong, additional, He, Tong-Chuan, additional, Hermeking, Heiko, additional, Hiraldo, Siewleng K, additional, Hwang, Paul M, additional, Lopez, Marissa A, additional, Luderer, Hilary F, additional, Mathews, Brynna, additional, Petroziello, Joseph M, additional, Polyak, Kornelia, additional, Zawel, Leigh, additional, Zhang, Wen, additional, Zhang, Xiaoming, additional, Zhou, Wei, additional, Haluska, Frank G, additional, Jen, Jin, additional, Sukumar, Saraswati, additional, Landes, Gregory M, additional, Riggins, Gregory J, additional, Vogelstein, Bert, additional, and Kinzler, Kenneth W, additional
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- 1999
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113. Identification and Mutation Analysis ofDOC-1R,a DOC-1 Growth Suppressor-Related Gene
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Zhang, Xue, primary, Tsao, Hensin, additional, Tsuji, Takanori, additional, Minoshima, Shinsei, additional, McBride, Jim, additional, Majewski, Paul, additional, Todd, Randy, additional, Shimizu, Nobuyoshi, additional, Wong, David T.W., additional, Housman, David E., additional, and Haluska, Frank G., additional
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- 1999
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114. Lack of phospholipase A2 mutations in neuroblastoma, melanoma and colon-cancer cell lines
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Haluska, Frank G., primary, Thiele, Carol, additional, Goldstein, Alisa, additional, Tsao, Hensin, additional, Benoit, Eric P., additional, and Housman, David, additional
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- 1997
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115. Surgical Management of Primary Cutaneous Melanomas of the Hands and Feet
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Tseng, Jennifer F., primary, Tanabe, Kenneth K., additional, Gadd, Michele A., additional, Cosimi, A. Benedict, additional, Malt, Ronald A., additional, Haluska, Frank G., additional, Mihm, Martin C., additional, Sober, Arthur J., additional, and Souba, Wiley W., additional
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- 1997
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116. Mutations of the CDKN2/p16INK4 gene in Australian melanoma kindreds
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Walker, Graeme, primary, Hussussian, Christopher, additional, Flores, José F., additional, Glendening, Michael J., additional, Haluska, Frank G., additional, Dracopoli, Nicholas C., additional, Hayward, Nicholas K., additional, and Fountain, Jane W., additional
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- 1995
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117. A phase 1 study of oral ridaforolimus in pediatric patients with advanced solid tumors
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Pearson, Andrew D.J., Federico, Sara M., Aerts, Isabelle, Hargrave, Darren R., DuBois, Steven G., Iannone, Robert, Geschwindt, Ryan D., Wang, Ruixue, Haluska, Frank G., Trippett, Tanya M., and Geoerger, Birgit
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phase I-III trials_pediatric cancers ,phase I-III trials_sarcoma/soft-tissue malignancies ,ridaforolimus ,mTOR ,pharmacokinetics - Abstract
Purpose Ridaforolimus is an investigational, potent, selective mTOR inhibitor. This study was conducted to determine the recommended phase 2 dose (RP2D), maximum tolerated dose, safety, pharmacokinetics, and antitumor activity of oral ridaforolimus in children with advanced solid tumors. Experimental Design In this phase 1, multicenter, open-label study in children aged 6 to <18 years with advanced solid tumors, ridaforolimus was administered orally for 5 consecutive days/week in 28-day cycles until progression, unacceptable toxicity, or consent withdrawal. Dose started at 22 mg/m2 and increased to 28 mg/m2 and 33 mg/m2, followed by expansion at the RP2D. Results: Twenty patients were treated; 18 were evaluable for dose-limiting toxicities. One dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in 1 patient at 33 mg/m2. Dose escalation concluded at 33 mg/m2; the maximum tolerated dose was not determined. The most common treatment-related adverse events (frequency ≥40%) were manageable grade 1–2 stomatitis, thrombocytopenia, hypertriglyceridemia, increased alanine aminotransferase, fatigue, hypercholesterolemia, anemia, and increased aspartate aminotransferase. Ridaforolimus exposure at 28 mg/m2 and 33 mg/m2 exceeded adult target levels. The RP2D for oral ridaforolimus in children was defined as 33 mg/m2. Four patients received at least 4 cycles; 2 with pineoblastoma and diffuse intrinsic pontine glioma had stable disease for 12 and 46 cycles, respectively. Conclusions: Ridaforolimus is orally bioavailable and well tolerated in children with advanced solid tumors. The RP2D (33 mg/m2, 5 days/week) exceeds the adult RP2D. The favorable toxicity and pharmacokinetic profiles may allow for combination therapy, a promising therapeutic option in pediatric malignancies.
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- 2016
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118. Graft-versus-Host Disease Associated with Transfusion of Blood from Unrelated HLA-Homozygous Donors
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Shivdasani, Ramesh A., primary, Haluska, Frank G., additional, Dock, Nancy L., additional, Dover, Jeffrey S., additional, Kineke, Elise J., additional, and Anderson, Kenneth C., additional
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- 1993
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119. Variable breakpoints in Burkitt lymphoma cells with chromosomal t(8; 14) translocation separate c-myc and the IgH locus up to several hundred kb
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Joos, Stefan, primary, Falk, Martin H., additional, Lichter, Peter, additional, Haluska, Frank G., additional, Henglein, Berthold, additional, Lenoir, Gilbert M., additional, and Bornkamm, Georg W., additional
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- 1992
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120. A Pivotal Phase 2 Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 12-Month Follow-up of the PACE Trial
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Cortes, Jorge E., Kim, Dong-Wook, Pinilla-Ibarz, Javier, le Coutre, Philipp, Paquette, Ron, Chuah, Charles, Nicolini, Franck E, Apperley, Jane, Khoury, H. Jean, Talpaz, Moshe, DiPersio, John F., DeAngelo, Daniel J., Abruzzese, Elisabetta, Rea, Delphine, Baccarani, Michele, Muller, Martin C, Gambacorti-Passerini, Carlo, Wong, Stephane, Lustgarten, Stephanie, Rivera, Victor M., Clackson, Tim, Turner, Christopher D., Haluska, Frank G, Guilhot, Francois, Deininger, Michael W., Hochhaus, Andreas, Hughes, Timothy, Goldman, John M, Shah, Neil, and Kantarjian, Hagop M
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- 2012
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121. Adjuvant High-Dose Interferon Alfa-2b in Patients with High-Risk Melanoma.
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Jonasch, Eric, Kumar, Uday N., Linette, Gerald P., Hodi, F. Stephen, Soiffer, Robert J., Ryan, Bonita F., Sober, Arthur J., Mihm, Martin C., Tsao, Hensin, Langley, Richard G., Cosimi, Benedict A., Gadd, Michele A., Tanabe, Kenneth K., Souba, Wiley, Haynes, Harley A., Barnhill, Raymond, Osteen, Robert, and Haluska, Frank G.
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ADJUVANT treatment of cancer ,MELANOMA ,INTERFERONS ,ANTINEOPLASTIC agents ,HEPATOTOXICOLOGY - Abstract
We performed an analysis of toxicity and survival in stage III melanoma patients receiving adjuvant interferon alfa-2b (IFN). This was a retrospective single-arm analysis of 40 patients with stage III melanoma who received (IFN) administered at maximum tolerated doses of 20 mU/m²/day intravenously (IV) for 1 month and 10 mU/m² three times per week subcutaneously (SC) for 48 weeks. Toxicity in our series is comparable to that experienced in the Eastern Cooperative Oncology Group (ECOG) 1684 trial, except for higher rates of dose-limiting myelosuppression and hepatotoxicity. All 40 patients experienced constitutional symptoms, but only 14/40 (35%) experienced grade 3 to 4 symptoms. Of the 40 patients, 36 (90%) experienced neurologic symptoms, but only seven (17.5%) experienced grade 3 to 4 neurotoxicity. Two patients stopped treatment because of severe psychiatric symptoms; one patient attempted suicide, and a psychosis developed in another. Thirty-nine (97.5%) patients experienced myelosuppression; 31 (77.5%) developing grade 3 to 4 myelosuppression. Hepatotoxicity was evident in 39 (97.5%) patients, and 26 (65%) experienced grade 3 to 4 hepatotoxicity. Three patients (7.5%) experienced mild renal toxicity. At a median follow-up of 27 months from initiation of therapy, there have been 19 relapses (47.5% disease-free survival [DFS]) and 10 deaths (75% OS) resulting from progression of disease. The DFS compares with the treatment arm in ECOG 1684 at 27 months, but overall survival is higher in our series of patients at the same time point. In a single program setting, IFN can be administered with similar side effects and outcome profiles seen in multi-institutional studies. Modifications in the induction regimen resulted in notably higher hematologic and hepatic toxicities but did not preclude administering further therapy and did not result in increased attrition rate among patients: only nine patients (22.5%) had their treatment stopped as a result of IFN-related toxicity. In comparison, 26% of patients had to have their treatment discontinued because of toxicity in ECOG 1684. [ABSTRACT FROM AUTHOR]
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- 2000
122. ONCOGENE ACTIVATION BY CHROMOSOME TRANSLOCATION IN HUMAN MALIGNANCY.
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Haluska, Frank G., Tsujimoto, Yoshihide, and Croce, Carlo M.
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GENETICS , *CHROMOSOMES , *BURKITT'S lymphoma , *CHROMOSOMAL translocation , *MOLECULAR biology , *ONCOGENES - Abstract
Presents oncogene activation by chromosome translocation in human malignancy. Molecular analysis of Burkitt's lymphoma translocation; Mechanisms of oncogene activation of chromosome translocation; Site involved in the majority of the Burkitt's lymphoma translocation.
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- 1987
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123. Molecular Mechanisms of Chromosome Translocation in Human B- and T-cell Neoplasiaa.
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HALUSKA, FRANK G. and CROCE, CARLO M.
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- 1987
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124. The t(8;14) breakpoint of the EW 36 undifferentiated lymphoma cell line lies 5' of MYC in a region prone to involvement in endemic Burkitt's lymphomas.
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Haluska, Frank G., Tsujimoto, Yoshihide, and Croce, Carlo M.
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- 1988
125. The t(8; 14) chromosomal translocation occurring in B-cell malignancies results from mistakes in V-D-J joining.
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Haluska, Frank G., Finver, Sheldon, Tsujimoto, Yoshihide, and Croce, Carlo M.
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- 1986
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126. More clues to gene rearrangements
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HALUSKA, FRANK G., primary and CROCE, CARLO M., additional
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- 1987
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127. Mechanisms of chromosome translocation in B- and T-cell neoplasia
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Haluska, Frank G., primary, Tsujimoto, Yoshihide, additional, and Croce, Carlo M., additional
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- 1987
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128. p380-8A 1.8 SaSs, a single copy clone 5′ of c-mycat 8q24 which recognizes an SstI polymorphism
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Haluska, Frank G., primary, Huebner, Kay, additional, and Croce, Carlo M., additional
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- 1987
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129. Experimental Gypsy Moth (Lymantria dispar) Ophthalmia Nodosa
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Haluska, Frank G., Puliafito, Carmen A., Henriquez, Antonio, and Albert, Daniel M.
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• Ophthalmia nodosa is the nodular granulomatous inflammatory response of ocular tissue to caterpillar hairs. We experimentally simulated this condition by surgically implanting gypsy moth hairs in the rabbit cornea. We were not, however, able to produce ophthalmia nodosa solely by placing cilia in the rabbit culde-sac. The experimentally induced inflammation closely resembled human ophthalmia nodosa in both its clinical and histopathologic features.
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- 1983
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130. Molecular Responses with Ponatinib in Patients with Philadelphia Chromosome Positive (Ph+) Leukemia: Results From the PACE Trial
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Hochhaus, Andreas, Kim, Dong-Wook, Pinilla-Ibarz, Javier, le Coutre, Philipp, Paquette, Ronald, Chuah, Charles, Nicolini, Franck E., Apperley, Jane, Khoury, H. Jean, Talpaz, Moshe, DiPersio, John F., DeAngelo, Daniel, Abruzzese, Elisabetta, Rea, Delphine, Baccarani, Michele, Muller, Martin C, Gambacorti-Passerini, Carlo, Wong, Stephane, Lustgarten, Stephanie, Rivera, Victor M., Clackson, Tim, Turner, Christopher D., Haluska, Frank G, Guilhot, Francois, Deininger, Michael W., Hughes, Timothy P., Goldman, John M, Shah, Neil, Kantarjian, Hagop M., and Cortes, Jorge E.
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Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the TKI resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML), or Ph+ acute lymphoblastic leukemia (Ph+ ALL) were evaluated in a pivotal phase 2, international, open-label clinical trial (PACE).To evaluate the patterns of molecular response in patients treated with ponatinib in the PACE trial.The PACE trial enrolled 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I BCR-ABL mutation. Patients were assigned to 1 of 6 cohorts according to disease phase (CP-CML, AP-CML, or BP-CML/Ph+ ALL), R/I to dasatinib or nilotinib, and presence of T315I. Mutation and molecular response analyses were performed at a single central laboratory. Molecular responses are reported on the International Scale (BCR-ABLIS; b2a2/b3a2 [p210] transcript only): major molecular response (MMR), ≤0.1%; MR4, ≤0.01%; MR4.5, ≤0.0032%. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 21] months).The median age was 59 (18 to 94) years. The median time from initial diagnosis to start of ponatinib was 6 (0.3 to 28) years. 96% had received prior imatinib, 84% dasatinib, 65% nilotinib; 8% received 1, 39% received 2, and 53% received all 3 prior approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. BCR-ABL mutations were detected in 55% of all patients at baseline: 22.9% T315I only, 26.5% mutations other than T315I, 5.8% mutations in addition to T315I. The most common mutations were T315I (29%), F317L (8%), E255K (4%), F359V (4%), and G250E (3%). Baseline BCR-ABL transcript levels were >10% in 74% (74% in CP-CML) and >1% to ≤10% in 14% (20% in CP-CML). No patients entered the study in MMR. The best response to the most recent dasatinib or nilotinib containing regimen was MMR or better in 4% (3% in CP-CML).Molecular response rates by cohort are shown below for CP-CML and AP-CML. Deep molecular responses, including MR4.5, were observed in both disease phases. Of 16 BP-CML and 3 Ph+ ALL patients with the b2a2/b3a2 transcript and baseline and post-baseline bone marrow assessments, 5 BP-CML and 0 Ph+ ALL patients achieved MMR. In CP-CML, MMR rates for the most frequent mutations other than T315I were 41% F317L, 50% E255K, 31% F359V, 38% G250E. Subgroup analyses in CP-CML indicated significant differences in the MMR rate for patients with T315I only (56%; p<0.001) and mutations in addition to T315I (50%; p=0.0216) vs. no mutation (21%), and for T315I only vs. mutations other than T315I (34%; p=0.0237). These differences are likely due to younger age (median 51 vs. 61 years) and exposure to fewer prior TKIs (median 2 vs. 3) in CP-CML patients with T315I vs. those without T315I. In CP-CML, 53% maintained or achieved BCR-ABLIS ≤10% by 3 months, with a trend towards higher rates in patients receiving fewer prior approved TKIs (1: 81%; 2: 61%; 3: 45%). The MMR rate (cumulative) in CP-CML improved over time: 13% by 3 months, 24% by 6 months, 28% by 9 months. The median time to MMR for CP-CML patients achieving MMR was 6 (2 to 17) months. CP-CML patients with MMR had an estimated probability of remaining in MMR at 6 months and 1 year of 87% and 84%, respectively (Kaplan-Meier). Ponatinib was generally well-tolerated. Data with a minimum follow-up of 12 months will be presented.Ponatinib treatment led to significant and deep molecular responses in this heavily pretreated population. In CP-CML, the MMR rate was ∼10-fold higher than that reported with the most recent dasatinib or nilotinib treatment.Hochhaus: ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kim:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, NOVARTIS PHARMA, BRISTOL MYERS SQUIBB, PFIZER: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy; Pfizer: Research Funding; ARIAD: Research Funding; BMS: Research Funding; Novartis: Research Funding. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding.
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- 2012
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131. Efficacy and Safety of Ponatinib According to Prior Approved Tyrosine Kinase Inhibitor (TKI) Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CP-CML): Results From the PACE Trial
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Kim, Dong-Wook, Cortes, Jorge E., Pinilla-Ibarz, Javier, le Coutre, Philipp, Paquette, Ronald, Chuah, Charles, Nicolini, Franck E., Apperley, Jane, Khoury, H. Jean, Talpaz, Moshe, DiPersio, John F., DeAngelo, Daniel, Abruzzese, Elisabetta, Rea, Delphine, Baccarani, Michele, Muller, Martin C, Gambacorti-Passerini, Carlo, Wong, Stephane, Lustgarten, Stephanie, Rivera, Victor M., Clackson, Tim, Turner, Christopher D., Haluska, Frank G, Guilhot, Francois, Deininger, Michael W., Hochhaus, Andreas, Hughes, Timothy P., Goldman, John M, Shah, Neil, and Kantarjian, Hagop M.
- Abstract
Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the uniformly TKI-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with CP-CML were evaluated in a pivotal phase 2, international, open-label clinical trial.This prospectively defined analysis was performed to evaluate the impact that previous exposure to approved TKIs had on the efficacy and safety of ponatinib treatment among patients with CP-CML.The PACE trial enrolled 449 patients, including 270 patients with CP-CML. Enrolled patients were required to be resistant or intolerant (R/I) to dasatinib or nilotinib, or they had to have the T315I mutation at baseline. Patients with CP-CML were assigned to 1 of 2 cohorts: R/I (N=203) or T315I (N=64). Three patients were post-imatinib and did not have T315I at baseline; they were treated but not assigned to a cohort. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 19] months). The efficacy and safety of ponatinib according to prior approved TKI therapy (imatinib, dasatinib, nilotinib) is presented for the total CP-CML (N=270) population.The median age of CP-CML patients was 60 (18 to 94) years. Median time from initial diagnosis to start of ponatinib was 7 (0.5 to 27) years. Patients were heavily pretreated: 97% had received prior imatinib, 80% dasatinib, 68% nilotinib; 7% of patients had received 1 prior approved TKI, 40% 2 prior approved TKIs, 53% all 3 prior approved TKIs; 60% had received ≥3 prior approved/investigational TKIs. In patients previously treated with dasatinib or nilotinib (N=256), 84% had a history of resistance and 16% were purely intolerant to dasatinib or nilotinib.At the time of analysis, 66% of patients remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%) and progressive disease (7%). Response rates according to the number of prior approved TKIs are shown in the table below. Patients receiving fewer prior approved TKIs had higher response rates. The difference in MCyR rate was statistically significant for patients previously treated with 1 vs. 3 approved TKIs (p=0.003) and for patients previously treated with 2 vs. 3 approved TKIs (p=0.011). Differences in MMR rates were not statistically significant. Of patients achieving MCyR, 98% of patients receiving 2 prior approved TKIs and 83% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MCyR at 1 year. Of patients achieving MMR, 86% of patients receiving 2 prior approved TKIs and 80% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MMR at 1 year. Kaplan-Meier estimates were not calculable for patients receiving 1 prior TKI. The most common treatment-related AEs according to number of prior approved TKIs (1, 2, 3, respectively) were thrombocytopenia (32%, 38%, 44%), rash (37%, 37%, 39%), dry skin (37%, 36%, 39%), abdominal pain (21%, 26%, 28%), and headache (26%, 28%, 19%). Rash, dry skin, abdominal pain, and headache were generally grade 1 or 2 in severity. Thrombocytopenia was typically reported early in treatment and was manageable with or without dose reductions and/or dose interruptions.Ponatinib has substantial activity in patients with CP-CML, with higher response rates and improved tolerability observed in patients receiving fewer prior approved TKIs. Data with a minimum follow-up of 12 months will be presented.Kim: Novartis, BMS, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Pfizer: Research Funding; BMS: Research Funding; Novartis: Consultancy, Research Funding; ARIAD: Research Funding.
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- 2012
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132. Multivariate Analyses of the Clinical and Molecular Parameters Associated with Efficacy and Safety in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Treated with Ponatinib in the PACE Trial
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Mauro, Michael J., Cortes, Jorge E., Kim, Dong-Wook, Pinilla-Ibarz, Javier, le Coutre, Philipp, Paquette, Ronald, Chuah, Charles, Nicolini, Franck E., Apperley, Jane, Khoury, H. Jean, Talpaz, Moshe, DiPersio, John F., DeAngelo, Daniel J, Abruzzese, Elisabetta, Rea, Delphine, Baccarani, Michele, Muller, Martin C, Gambacorti-Passerini, Carlo, Wong, Stephane, Dorer, David J., Knickerbocker, Ronald Keith, Rivera, Victor M., Clackson, Tim, Turner, Christopher D., Haluska, Frank G, Guilhot, Francois, Deininger, Michael W., Hochhaus, Andreas, Hughes, Timothy, Goldman, John M, Shah, Neil, and Kantarjian, Hagop M.
- Abstract
Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in a phase 2, international, open-label clinical trial (PACE). These multivariate analyses explored the impact of dose intensity and several prognostic and predictive factors on clinical responses, adverse events (AEs), and laboratory changes.Enrolled patients were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I BCR-ABL mutation at baseline. A total of 267 chronic phase (CP), 83 accelerated phase (AP), and 94 blast phase (BP) CML/Ph+ ALL patients were assigned to 1 of 6 cohorts according to disease phase (CP-, AP-, or BP-CML/Ph+ ALL), R/I to dasatinib or nilotinib, and presence of T315I. Three CP-CML and 2 AP-CML patients were treated, but not assigned to a cohort (post-imatinib, did not have T315I at baseline); these patients were excluded from efficacy analyses and included in safety analyses. For the purposes of the efficacy multivariate analyses, AP-CML, BP-CML, and Ph+ ALL patients were combined. The baseline covariates analyzed were age, time since diagnosis, number of prior TKIs, presence or absence of the T315I mutation, neutrophil and platelet counts, and weight. The primary efficacy outcome analyzed was major cytogenetic response (MCyR) in CP-CML and major hematologic response (MaHR) for all other patients. The safety outcomes analyzed were the following AEs: pancreatitis, elevated lipase, alanine aminotransferase (ALT) increase, aspartate aminotransferase (AST) increase, rash, neutropenia, thrombocytopenia, arthralgia, and hypertriglyceridemia. The impact on neutrophils, platelets, bilirubin, ALT, AST, creatinine, lipase, and triglycerides was also examined. Binary event outcomes were analyzed using logistic regression models. Data values over time were analyzed using linear mixed effects models. Laboratory values were log-transformed. Data as of 27 April 2012 were used in these analyses.Median baseline characteristics of the CP-CML R/I and T315I cohorts, respectively, were: 61 vs 51 yrs of age, 8 vs 5 yrs since initial diagnosis, 3 vs 2 prior TKIs. The median dose intensity for the CP-CML R/I and T315I cohorts was 30 and 39 mg/day, respectively. In general, other baseline characteristics were balanced between these 2 cohorts. Multivariate analysis found statistically significant associations between MCyR and increasing dose intensity (mg/day) (p<0.0001) and decreasing age (p=0.046) in CP-CML. Despite the finding that CP-CML patients with the T315I mutation had a higher response rate than those without the T315I mutation (MCyR 70% vs 49%), presence of T315I was not a significant prognostic factor for response after adjusting for other covariates (p>0.2). This was likely because patients with T315I received a greater dose intensity, were younger, and were previously treated with fewer TKIs.The probability of achieving MaHR in patients with AP-CML, BP-CML, and Ph+ ALL increased with increasing dose intensity (p<0.001) and with higher numbers of baseline platelets (p=0.0046). As in CP-CML, similar trends in baseline characteristics were observed, and the presence of the T315I mutation was not a significant prognostic factor for MaHR.In all patients, the probability of AEs (pancreatitis, lipase increase, ALT and AST increase, thrombocytopenia, neutropenia, arthralgia, and rash) increased with increasing dose intensity. Hypertriglyceridemia was trend level associated with dose intensity (p=0.054). Presence of T315I was associated with a lower risk of thrombocytopenia (p<0.0001) and neutropenia (p=0.005) after adjustment for dose intensity and the other factors. In general, younger age, less time since diagnosis, and fewer prior TKIs were associated with a lower probability of AEs.These findings suggest that dose intensity and factors related to extent of disease and prior treatment were most predictive of effectiveness and tolerance of ponatinib. T315I was not a significant prognostic factor for efficacy or safety after adjustment for other factors, with the exception of thrombocytopenia and neutropenia; patients with T315I had lower predicted rates of these AEs after adjustment for dose intensity and other factors in the reduced models.Off Label Use: Ponatinib - non FDA approved (experimental) compound. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis : Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers-Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Bristol Myers-Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Dorer:ARIAD: Employment, Equity Ownership. Knickerbocker:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:Novartis: Consultancy; Bristol Myers-Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding. Kantarjian:Pfizer: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding.
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- 2012
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133. p380-8A 1.8 SaSs, a single copy clone 5′ of c-myc at 8q24 which recognizes an SstI polymorphism.
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Haluska, Frank G., Huebner, Kay, and Croce, Carlo M.
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- 1987
134. PTEN signaling pathways in melanoma.
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Wu, Heng, Goel, Vikas, and Haluska, Frank G
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PHOSPHATASES , *CANCER , *GLIOBLASTOMA multiforme , *PROTEINS , *CELL cycle - Abstract
Phosphatase and tensin homolog deleted in from chromosome ten (PTEN), initially also known as mutated in multiple advanced cancers or TGF-?-regulated and epithelia cell-enriched phosphatase, is a tumor suppressor gene that is mutated in a large fraction of human melanomas. A broad variety of human cancers carry PTEN alterations, including glioblastomas, endometrial, breast, thyroid and prostate cancers. The PTEN protein has at least two biochemical functions: it has both lipid phosphatase and protein phosphatase activity. The lipid phosphatase activity of PTEN decreases intracellular PtdIns(3,4,5)P3 level and downstream Akt activity. Cell-cycle progression is arrested at G1/S, mediated at least partially through the upregulation of the cyclin-dependent kinase inhibitor p27. In addition, agonist-induced apoptosis is mediated by PTEN, through the upregulation of proapoptotic machinery involving caspases and BID, and the downregulation of antiapoptotic proteins such as Bcl2. The protein phosphatase activity of PTEN is apparently less central to its involvement in tumorigenesis. It is involved in the inhibition of focal adhesion formation, cell spreading and migration, as well as the inhibition of growth factor-stimulated MAPK signaling. Therefore, the combined effects of the loss of PTEN lipid and protein phosphatase activity may result in aberrant cell growth and escape from apoptosis, as well as abnormal cell spreading and migration. In melanoma, PTEN loss has been mostly observed as a late event, although a dose-dependent loss of PTEN protein and function has been implicated in early stages of tumorigenesis as well. In addition, loss of PTEN and oncogenic activation of RAS seem to occur in a reciprocal fashion, both of which could cooperate with CDKN2A loss in contribution to melanoma tumorigenesis.Oncogene (2003) 22, 3113-3122. doi:10.1038/sj.onc.1206451 [ABSTRACT FROM AUTHOR]
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- 2003
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135. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: ?nal 5-year results of the phase 2 PACE trial.
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Cortes, Jorge E., Dong-Wook Kim, Pinilla-Ibarz, Javier, le Coutre, Philipp D., Paquette, Ronald, Chuah, Charles, Nicolini, Franck E., Apperley, Jane F., Khoury, H. Jean, Talpaz, Moshe, DeAngelo, Daniel J., Abruzzese, Elisabetta, Rea, Delphine, Baccarani, Michele, MŠller, Martin C., Gambacorti-Passerini, Carlo, Lustgarten, Stephanie, Rivera, Victor M., Haluska, Frank G., and Guilhot, François
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LYMPHOBLASTIC leukemia treatment , *DASATINIB , *TREATMENT of chronic myeloid leukemia , *ARTERIAL occlusions , *THROMBOCYTOPENIA - Abstract
Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome--positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n 5 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ‡90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440. [ABSTRACT FROM AUTHOR]
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- 2018
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136. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial.
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Gettinger, Scott N, Bazhenova, Lyudmila A, Langer, Corey J, Salgia, Ravi, Gold, Kathryn A, Rosell, Rafael, Shaw, Alice T, Weiss, Glen J, Tugnait, Meera, Narasimhan, Narayana I, Dorer, David J, Kerstein, David, Rivera, Victor M, Clackson, Timothy, Haluska, Frank G, and Camidge, David Ross
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NON-small-cell lung carcinoma , *CANCER treatment , *ANAPLASTIC lymphoma kinase , *MEDICATION safety , *GENE rearrangement , *GENETIC mutation , *THERAPEUTICS , *CLINICAL trials , *COMPARATIVE studies , *GENES , *HETEROCYCLIC compounds , *LUNG cancer , *LUNG tumors , *RESEARCH methodology , *MEDICAL cooperation , *ORGANOPHOSPHORUS compounds , *RESEARCH , *TRANSFERASES , *EVALUATION research , *PROTEIN kinase inhibitors - Abstract
Background: Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK-rearranged NSCLC.Methods: In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK-rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30-300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK-rearranged NSCLC (cohort 1), crizotinib-treated ALK-rearranged NSCLC (cohort 2), EGFRT790M-positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01449461.Findings: Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 [58%] with ALK-rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. four (100% [95% CI 40-100]) of four patients in cohort 1 had an objective response, 31 (74% [58-86]) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% [4-41]) of 18 did in cohort 4, and five (83% [36-100]) of six did in cohort 5. 51 (72% [60-82]) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response (44 [62% (50-73)] had a confirmed objective response). All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response (100% [63-100]). Three (50% [95% CI 12-88]) of six patients in cohort 5 had an intracranial response. The most common grade 3-4 treatment-emergent adverse events across all doses were increased lipase concentration (12 [9%] of 137), dyspnoea (eight [6%]), and hypertension (seven [5%]). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten [7%]), pneumonia (nine [7%]), and hypoxia (seven [5%]). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression.Interpretation: Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg).Funding: ARIAD Pharmaceuticals. [ABSTRACT FROM AUTHOR]- Published
- 2016
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137. Impact of dose intensity of ponatinib on selected adverse events: Multivariate analyses from a pooled population of clinical trial patients.
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Dorer, David J., Knickerbocker, Ronald K., Baccarani, Michele, Cortes, Jorge E., Hochhaus, Andreas, Talpaz, Moshe, and Haluska, Frank G.
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TREATMENT of chronic myeloid leukemia , *PROTEIN-tyrosine kinase inhibitors , *ADVERSE health care events , *DOSE-effect relationship in pharmacology , *VENOUS thrombosis risk factors , *LOGISTIC regression analysis , *THERAPEUTICS - Abstract
Ponatinib is approved for adults with refractory chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia, including those with the T315I BCR-ABL1 mutation. We pooled data from 3 clinical trials (N = 671) to determine the impact of ponatinib dose intensity on the following adverse events: arterial occlusive events (cardiovascular, cerebrovascular, and peripheral vascular events), venous thromboembolic events, cardiac failure, thrombocytopenia, neutropenia, hypertension, pancreatitis, increased lipase, increased alanine aminotransferase, increased aspartate aminotransferase, rash, arthralgia, and hypertriglyceridemia. Multivariate analyses allowed adjustment for covariates potentially related to changes in dosing or an event. Logistic regression analysis identified significant associations between dose intensity and most events after adjusting for covariates. Pancreatitis, rash, and cardiac failure had the strongest associations with dose intensity (odds ratios >2). Time-to-event analyses showed significant associations between dose intensity and risk of arterial occlusive events and each subcategory. Further, these analyses suggested that a lag exists between a change in dose and the resulting change in event risk. No significant association between dose intensity and risk of venous thromboembolic events was evident. Collectively, these findings suggest a potential causal relationship between ponatinib dose and certain adverse events and support prospective investigations of approaches to lower average ponatinib dose intensity. [ABSTRACT FROM AUTHOR]
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- 2016
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138. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial.
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Lipton, Jeffrey H, Chuah, Charles, Guerci-Bresler, Agnès, Rosti, Gianantonio, Simpson, David, Assouline, Sarit, Etienne, Gabriel, Nicolini, Franck E, le Coutre, Philipp, Clark, Richard E, Stenke, Leif, Andorsky, David, Oehler, Vivian, Lustgarten, Stephanie, Rivera, Victor M, Clackson, Timothy, Haluska, Frank G, Baccarani, Michele, Cortes, Jorge E, and Guilhot, François
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TREATMENT of chronic myeloid leukemia , *CHRONIC myeloid leukemia , *ARTERIAL occlusions , *DRUG efficacy , *IMATINIB , *PROTEIN-tyrosine kinase inhibitors , *NEUTROPENIA , *PATIENTS , *ANTINEOPLASTIC agents , *CHROMOSOME abnormalities , *COMPARATIVE studies , *DRUG side effects , *HETEROCYCLIC compounds , *IMIDAZOLES , *RESEARCH methodology , *MEDICAL cooperation , *PROGNOSIS , *PROTEINS , *RESEARCH , *RESEARCH funding , *EVALUATION research , *RANDOMIZED controlled trials , *TREATMENT effectiveness , *KAPLAN-Meier estimator - Abstract
Background: Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia.Methods: The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805.Findings: Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib.Interpretation: The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established.Funding: ARIAD Pharmaceuticals. [ABSTRACT FROM AUTHOR]- Published
- 2016
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139. Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients.
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Deininger, Michael W., Hodgson, J. Graeme, Shah, Neil P., Cortes, Jorge E., Dong-Wook Kim, Nicolini, Franck E., Talpaz, Moshe, Baccarani, Michele, Müller, Martin C., Jin Li, Parker, Wendy T., Lustgarten, Stephanie, Clackson, Tim, Haluska, Frank G., Guilhot, Francois, Kantarjian, Hagop M., Soverini, Simona, Hochhaus, Andreas, Hughes, Timothy P., and Rivera, Victor M.
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TREATMENT of chronic myeloid leukemia , *DRUG resistance , *ANTINEOPLASTIC agents , *GENETIC mutation , *PROTEIN-tyrosine kinases - Abstract
BCR-ABL1 kinase domain mutations can confer resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In preclinical studies, clinically achievable concentrations of the third-generation BCR-ABL1 TKI ponatinib inhibit T315I and all other single BCR-ABL1mutants except T315M, which generates a single amino acid exchange, but requires 2 sequential nucleotide exchanges. In addition, certain compound mutants (containing ≥2 mutations in cis) confer resistance. Initial analyses based largely on conventional Sanger sequencing (SS) have suggested that the preclinical relationship betweenBCR-ABL1mutation status andponatinib efficacy is generally recapitulated in patients receiving therapy. Thus far, however, such analyses have been limited by the inabilityofSStodefinitively identifycompoundmutationsormutationsrepresentinglessthan ~20%of total alleles (referred to as "low-levelmutations"), aswell as limited patient follow-up. Here we used next-generation sequencing (NGS) to define the baseline BCR-ABL1 mutation status of 267 heavily pretreated chronic phase (CP)-CML patients from the PACE trial, and used SS to identify clonally dominant mutants that may have developed on ponatinib therapy (30.1 months median follow-up). Durable cytogenetic and molecular responses were observed irrespective of baseline mutation status and included patients with compound mutations. No single or compoundmutation was identified that consistently conferred primary and/or secondary resistance to ponatinib in CP-CML patients. Ponatinib is effective in CP-CML irrespective of baseline mutation status. [ABSTRACT FROM AUTHOR]
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- 2016
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140. Loss of ARF Sensitizes Transgenic BRAFV600E Mice to UV-Induced Melanoma via Suppression of XPC.
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Chi Luo, Jinghao Sheng, Hu, Miaofen G., Haluska, Frank G., Cui, Rutao, Zhengping Xu, Tsichlis, Philip N., Guo-Fu Hu, and Hinds, Philip W.
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CANCER research , *GENETICS , *GENETIC mutation , *MELANOMA , *ONCOGENES - Abstract
Both genetic mutations and UV irradiation (UVR) can predispose individuals to melanoma. Although BRAFV600E is the most prevalent oncogene in melanoma, the BRAFV600E mutant is not sufficient to induce tumors in vivo. Mutation at the CDKN2A locus is another melanoma-predisposing event that can disrupt the function of both p16INK4a and ARF. Numerous studies have focused on the role of p16INK4a in melanoma, but the involvement of ARF, a well-known p53 activator, is still controversial. Using a transgenic BRAFV600E mouse model previously generated in our laboratory, we report that loss of ARF is able to enhance spontaneous melanoma formation and cause profound sensitivity to neonatal UVB exposure. Mechanistically, BRAFV600E and ARF deletion synergize to inhibit nucleotide excision repair by epigenetically repressing XPC and inhibiting the E2F4/DP1 complex. We suggest that the deletion of ARF promotes melanomagenesis not by abrogating p53 activation but by acting in concert with BRAFV600E to increase the load of DNA damage caused by UVR. [ABSTRACT FROM AUTHOR]
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- 2013
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141. Ponatinib in Refractory Philadelphia Chromosome–Positive Leukemias.
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Cortes, Jorge E., Kantarjian, Hagop, Shah, Neil P., Bixby, Dale, Mauro, Michael J., Flinn, Ian, O'Hare, Thomas, Hu, Simin, Narasimhan, Narayana I., Rivera, Victor M., Clackson, Tim, Turner, Christopher D., Haluska, Frank G., Druker, Brian J., Deininger, Michael W.N., and Talpaz, Moshe
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PROTEIN-tyrosine kinase inhibitors , *MYELOID leukemia , *LYMPHOBLASTIC leukemia , *HEMATOLOGY , *ADVERSE health care events , *TOXICOLOGY , *LEUKEMIA treatment , *PATIENTS - Abstract
Background: Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors. Methods: In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140). Results: Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response. Conclusions: Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.) [ABSTRACT FROM PUBLISHER]
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- 2012
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142. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients.
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Hodi, F. Stephen, Butler, Marcus, Oble, Darryl A., Seiden, Michael V., Haluska, Frank G., Kruse, Andrea, MacRae, Suzanne, Nelson, Marybeth, Canning, Christine, Lowy, Israel, Korman, Alan, Lautz, David, Russell, Sara, Jaklitsch, Michael T., Ramaiya, Nikhil, Chen, Teresa C., Neuberg, Donna, Allison, James P., Mihm, Martin C., and Dranoff, Glenn
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ANTINEOPLASTIC agents , *T cells , *CANCER patients , *TUMOR immunology , *IMMUNOLOGY - Abstract
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) functions as a negative regulator of endogenous and vaccine-induced antitumor immunity. The administration of fully human anti-CTLA-4 blocking monoclonal antibodies to advanced-cancer patients increases immune-mediated tumor destruction in some subjects. Nonetheless, patients that respond also frequently manifest serious inflammatory pathologies, raising the possibility that the therapeutic and toxic effects of CTLA-4 blockade might be linked. Here we show that periodic infusions of anti-CTLA-4 antibodies after vaccination with irradiated, autologous tumor cells engineered to secrete GM-CSF (GVAX) generate clinically meaningful antitumor immunity without grade 3 or 4 toxicity in a majority of metastatic melanoma patients. The application of this sequential immunotherapy to advanced ovarian carcinoma patients also revealed that tumor destruction and severe inflammatory pathology could be dissociated, although further refinements are required to increase clinical responses and to minimize toxicity in this population. The extent of therapy-induced tumor necrosis was linearly related to the natural logarithm of the ratio of intratumoral CD8+ effector T cells to FoxP3+ regulatory T cells (Tregs) in posttreatment biopsies. Together, these findings help clarify the immunologic and clinical effects of CTLA-4 antibody blockade in previously vaccinated patients and raise the possibility that selective targeting of antitumor Tregs may constitute a complementary strategy for combination therapy. [ABSTRACT FROM AUTHOR]
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- 2008
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143. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients.
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Hodi, F. Stephen, Mihm, Martin C., Soiffer, Robert J., Haluska, Frank G., Butler, Marcus, Seiden, Michael V., Davis, Thomas, Henry-Spires, Rochele, MacRae, Suzanne, Willman, Ann, Padera, Robert, Jaklitsch, Michael T., Shankar, Sridhar, Chen, Teresa C., Korman, Alan, Allison, James P., and Dranoff, Glenn
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T cells , *BONE metastasis - Abstract
A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cellular and humoral responses, thereby effectuating tumor destruction in some cases. The attenuation of T cell activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further limits the potency of tumor immunity. In murine systems, the administration of antibodies that block CTLA-4 function inhibits the growth of moderately immunogenic tumors and, in combination with cancer vaccines, increases the rejection of poorly immunogenic tumors, albeit with a loss of tolerance to normal differentiation antigens. To gain a preliminary assessment of the biologic activity of antagonizing CTLA-4 function in humans, we infused a CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three of three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two of two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous granulocytemacrophage colony-stimulating factor-secreting tumor cells. MDXCTLA4 did not elicit tumor necrosis in four of four metastatic melanoma patients previously immunized with defined melanosomal antigens. No serious toxicities directly attributable to the antibody were observed, although five of seven melanoma patients developed T cell reactivity to normal melanocytes. These findings suggest that CTLA-4 antibody blockade increases tumor immunity in some previously vaccinated cancer patients. [ABSTRACT FROM AUTHOR]
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- 2003
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144. Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib.
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Lynch, Thomas J., Bell, Daphne W., Sordella, Raffaella, Gurubhagavatula, Sarada, Okimoto, Ross A., Brannigan, Brian W., Harris, Patricia L., Haserlat, Sara M., Supko, Jeffrey G., Haluska, Frank G., Louis, David N., Christiani, David C., Settleman, Jeff, and Haber, Daniel A.
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CANCER patients - Abstract
Background: Most patients with non–small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. Methods: We searched for mutations in the EGFR gene in primary tumors from patients with non–small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. Results: Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non–small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. Conclusions: A subgroup of patients with non–small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib. N Engl J Med 2004;350:2129-39. [ABSTRACT FROM AUTHOR]
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- 2004
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145. Phase II Study of Ponatinib in Advanced Gastrointestinal Stromal Tumors: Efficacy, Safety, and Impact of Liquid Biopsy and Other Biomarkers.
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George S, von Mehren M, Fletcher JA, Sun J, Zhang S, Pritchard JR, Hodgson JG, Kerstein D, Rivera VM, Haluska FG, and Heinrich MC
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- Biomarkers, Humans, Imidazoles, Liquid Biopsy, Mutation, Protein Kinase Inhibitors adverse effects, Proto-Oncogene Proteins c-kit genetics, Antineoplastic Agents adverse effects, Circulating Tumor DNA genetics, Gastrointestinal Stromal Tumors drug therapy, Gastrointestinal Stromal Tumors genetics, Gastrointestinal Stromal Tumors pathology, Pyridazines adverse effects
- Abstract
Purpose: The purpose of this study is to evaluate ponatinib for advanced gastrointestinal stromal tumors (GIST)., Patients and Methods: This single-arm phase II trial enrolled patients with metastatic and/or unresectable GIST with failure of prior tyrosine kinase inhibitor (TKI) treatment into two cohorts based on presence or absence of KIT exon 11 (ex11) primary mutations. Patients initially received ponatinib 45 mg once daily. Following a temporary clinical hold in October 2013, dose reductions were implemented to reduce risk of arterial occlusive events (AOE). Primary endpoint was 16-week clinical benefit rate (CBR) in KIT ex11-positive cohort. KIT mutations in circulating tumor DNA (ctDNA) were assessed., Results: Forty-five patients enrolled (30 KIT ex11-positive and 15 KIT ex11-negative); median follow-up was 14.7 and 13.6 months, respectively, as of August 1, 2016. Sixteen-week CBR was 36% (KIT ex11-positive; primary endpoint) and 20% (KIT ex11-negative). ctDNA analyses (n = 37) demonstrated strong concordance of primary KIT mutations between plasma and tumor. At least two secondary mutations were detected in 35% of patients overall and 54% of KIT ex11-positive patients. Changes from baseline in mutated ctDNA levels were consistent with clinical activity. Ponatinib was ineffective in patients with KIT exon 9 primary mutations. Resistance was associated with emergence of V654A. AOEs and venous thromboembolic events occurred in three and two patients, respectively. Six patients died; two deaths (pneumonia and pulmonary embolism) were considered possibly ponatinib-related., Conclusions: Ponatinib demonstrated activity in advanced GIST, particularly in KIT ex11-positive disease. ctDNA analysis confirmed heterogeneous resistance mutations in TKI-pretreated advanced GIST. Safety was consistent with previous studies., (©2022 The Authors; Published by the American Association for Cancer Research.)
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- 2022
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146. Southwest Oncology Group S0008: a phase III trial of high-dose interferon Alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of cancer and leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group.
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Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, and Sondak VK
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Child, Cisplatin administration & dosage, Cisplatin adverse effects, Dacarbazine administration & dosage, Dacarbazine adverse effects, Female, Humans, Interferon alpha-2, Interferon-alpha adverse effects, Interferons administration & dosage, Interferons adverse effects, Interleukin-2 administration & dosage, Interleukin-2 adverse effects, Male, Melanoma mortality, Middle Aged, Recombinant Proteins adverse effects, Recombinant Proteins therapeutic use, Vinblastine administration & dosage, Vinblastine adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Interferon-alpha therapeutic use, Melanoma drug therapy
- Abstract
Purpose: High-dose interferon (IFN) for 1 year (HDI) is the US Food and Drug Administration-approved adjuvant therapy for patients with high-risk melanoma. Efforts to modify IFN dose and schedule have not improved efficacy. We sought to determine whether a shorter course of biochemotherapy would be more effective., Patients and Methods: S0008 (S0008: Chemotherapy Plus Biological Therapy in Treating Patients With Melanoma) was an Intergroup phase III trial that enrolled high-risk patients (stage IIIA-N2a through IIIC-N3), randomly assigning them to receive either HDI or biochemotherapy consisting of dacarbazine, cisplatin, vinblastine, interleukin-2, IFN alfa-2b (IFN-α-2b) and granulocyte colony-stimulating factor given every 21 days for three cycles. Coprimary end points were relapse-free survival (RFS) and overall survival (OS)., Results: In all, 432 patients were enrolled. Grade 3 and 4 adverse events occurred in 57% and 7% of HDI patients and 36% and 40% of biochemotherapy patients, respectively. At a median follow-up of 7.2 years, biochemotherapy improved RFS (hazard ratio [HR], 0.75; 95% CI, 0.58 to 0.97; P = .015), with a median RFS of 4.0 years (95% CI, 1.9 years to not reached [NR]) versus 1.9 years for HDI (95% CI, 1.2 to 2.8 years) and a 5-year RFS of 48% versus 39%. Median OS was not different (HR, 0.98; 95% CI, 0.74 to 1.31; P = .55), with a median OS of 9.9 years (95% CI, 4.62 years to NR) for biochemotherapy versus 6.7 years (95% CI, 4.5 years to NR) for HDI and a 5-year OS of 56% for both arms., Conclusion: Biochemotherapy is a shorter, alternative adjuvant treatment for patients with high-risk melanoma that provides statistically significant improvement in RFS but no difference in OS and more toxicity compared with HDI., (© 2014 by American Society of Clinical Oncology.)
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- 2014
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147. A multicenter, first-in-pediatrics, phase 1, pharmacokinetic and pharmacodynamic study of ridaforolimus in patients with refractory solid tumors.
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Gore L, Trippett TM, Katzenstein HM, Boklan J, Narendran A, Smith A, Macy ME, Rolla K, Narashimhan N, Squillace RM, Turner CD, Haluska FG, and Nieder M
- Subjects
- Adolescent, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Child, Child, Preschool, Female, Humans, Male, Neoplasms diagnosis, Sirolimus adverse effects, Sirolimus pharmacokinetics, Sirolimus therapeutic use, TOR Serine-Threonine Kinases antagonists & inhibitors, Treatment Outcome, Neoplasms drug therapy, Sirolimus analogs & derivatives
- Abstract
Purpose: Ridaforolimus (MK-8669, AP23573) is a potent and selective mammalian target of rapamycin (mTOR) inhibitor. Preclinically, ridaforolimus displays antiproliferative activity against a variety of human tumors in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents. Antitumor activity has been confirmed in adults. This phase I study determined the safety, pharmacological, biologic, and toxicity profiles of ridaforolimus in pediatric patients with refractory malignancies., Experimental Design: Eligible children ages 1 to 18 years with advanced solid tumors were enrolled in a 3 + 3 dose escalation design, to determine the safety, tolerability, and maximum tolerated dose (MTD)/dose-limiting toxicity (DLT) of ridaforolimus. Toxicities, pharmacokinetics, and pharmacodynamics were characterized., Results: Fifteen patients were treated. No DLT was observed at any dose level tested; therefore, an MTD was not identified. Most adverse events were mild to moderate; the most common grades 3 and 4 adverse events were hematologic, including thrombocytopenia and anemia. Nonhematologic adverse events were mostly electrolyte disturbances. The observed pharmacokinetic profile of ridaforolimus in children was consistent with that previously showed in adults. Pharmacodynamic confirms that the dose range tested has pharmacological/pharmacodynamic activity. Forty percent of patients achieved stable disease including four of six with central nervous system tumors and two of eight with sarcomas., Conclusions: This first-in-pediatrics study shows that the second-generation mTOR inhibitor ridaforolimus is well tolerated in heavily pretreated children with refractory solid tumors. No DLTs were observed over the dose range tested. Ridaforolimus may represent a therapeutic option for use in pediatric malignancies., (©2013 AACR.)
- Published
- 2013
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148. Analysis of the potential effect of ponatinib on the QTc interval in patients with refractory hematological malignancies.
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Sonnichsen D, Dorer DJ, Cortes J, Talpaz M, Deininger MW, Shah NP, Kantarjian HM, Bixby D, Mauro MJ, Flinn IW, Litwin J, Turner CD, and Haluska FG
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- Adult, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Electrocardiography, Female, Humans, Imidazoles administration & dosage, Imidazoles blood, Imidazoles therapeutic use, Male, Middle Aged, Models, Biological, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors blood, Protein Kinase Inhibitors therapeutic use, Pyridazines administration & dosage, Pyridazines blood, Pyridazines therapeutic use, Heart drug effects, Hematologic Neoplasms drug therapy, Imidazoles adverse effects, Long QT Syndrome chemically induced, Protein Kinase Inhibitors adverse effects, Pyridazines adverse effects
- Abstract
Purpose: Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial., Methods: Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points. Electrocardiographic parameters, including QTc interval, were measured, and 11 morphological analyses were conducted. Central tendency analyses of ECG parameters were performed using time-point and time-averaged approaches. All patients with at least 2 baseline ECGs and 1 on-treatment ECG were included in the analyses. Patients with paired ECGs and plasma samples were included in the pharmacokinetic/pharmacodynamic analysis to examine the relationship between ponatinib plasma concentration and change from baseline in QT intervals., Results: Thirty-nine patients at the 30-, 45-, and 60-mg dose levels were included in the central tendency and morphological analyses. There was no significant effect on cardiac repolarization, as evidenced by non-clinically significant mean QTcF changes from baseline of -10.9, -3.6, and -5.0 ms for the 30-, 45-, and 60-mg dose levels, respectively. The morphological analysis revealed 2 patients with atrial fibrillation and 2 with T wave inversion. Seventy-five patients were included in the pharmacokinetic/pharmacodynamic analysis across all dose levels. The slope of the relationship for QTcF versus plasma ponatinib concentration was not positive (-0.0171), indicating no exposure-effect relationship., Conclusions: Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.
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- 2013
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149. Therapeutic targets in melanoma: map kinase pathway.
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Haluska FG and Ibrahim N
- Subjects
- Drug Therapy, Combination, Humans, Melanoma genetics, Mitogen-Activated Protein Kinase Kinases genetics, Mutation, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms genetics, ras Proteins antagonists & inhibitors, ras Proteins genetics, Melanoma drug therapy, Melanoma enzymology, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Skin Neoplasms drug therapy, Skin Neoplasms enzymology
- Abstract
Recent progress in our understanding of the genetic alterations that occur in the pathogenesis of melanoma provides exciting opportunities for therapy. The most important signaling pathways in melanoma lie downstream of NRAS: the RAS-BRAF-MAPK pathway. A great deal of attention has been focused on the high mutation rate in the BRAF oncogene, which approaches 60%, because BRAF itself is an appealing drug substrate and because of the central contribution of BRAF function to melanoma development that the mutation rate signifies. Agents that specifically target BRAF, such as sorafenib, as well as new molecules that function both upstream and downstream of BRAF, are being actively investigated.
- Published
- 2006
- Full Text
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