1,519 results on '"Janku, Filip"'
Search Results
2. BRAF v600E–mutant cancers treated with vemurafenib alone or in combination with everolimus, sorafenib, or crizotinib or with paclitaxel and carboplatin (VEM-PLUS) study
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Nelson, Blessie Elizabeth, Roszik, Jason, Janku, Filip, Hong, David S., Kato, Shumei, Naing, Aung, Piha-Paul, Sarina, Fu, Siqing, Tsimberidou, Apostolia, Cabanillas, Maria, Busaidy, Naifa Lamki, Javle, Milind, Byers, Lauren Averett, Heymach, John V., Meric-Bernstam, Funda, and Subbiah, Vivek
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- 2023
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3. First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations
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Janku, Filip, Kim, Tae Min, Iyer, Gopakumar, Spreafico, Anna, Elez, Elena, de Jonge, Maja, Yamamoto, Noboru, van der Wekken, Anthonie J., Ascierto, Paolo Antonio, Maur, Michela, Marmé, Frederik, Kiladjian, Jean-Jacques, Basu, Sumit, Baffert, Fabienne, Buigues, Amparo, Chen, Chi, Cooke, Vesselina, Giorgetti, Elisa, Kim, Jaeyeon, McCarthy, Fiona, Moschetta, Michele, and Dummer, Reinhard
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- 2024
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4. Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or Progressive Glioma; Results of a First-in-Human Phase I TrialVorasidenib in Recurrent or Progressive Glioma
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Mellinghoff, Ingo K, Penas-Prado, Marta, Peters, Katherine B, Burris, Howard A, Maher, Elizabeth A, Janku, Filip, Cote, Gregory M, de la Fuente, Macarena I, Clarke, Jennifer L, Ellingson, Benjamin M, Chun, Saewon, Young, Robert J, Liu, Hua, Choe, Sung, Lu, Min, Le, Kha, Hassan, Islam, Steelman, Lori, Pandya, Shuchi S, Cloughesy, Timothy F, and Wen, Patrick Y
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Neurosciences ,Orphan Drug ,Cancer ,Brain Cancer ,Brain Disorders ,Clinical Research ,Clinical Trials and Supportive Activities ,Rare Diseases ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Brain Neoplasms ,Diamines ,Disease Progression ,Female ,Glioma ,Humans ,Isocitrate Dehydrogenase ,Male ,Middle Aged ,Mutation ,Neoplasm Recurrence ,Local ,Pyridines ,Young Adult ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeLower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (IDH1/IDH2). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.Patients and methodsWe conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant IDH1/2 (mIDH1/2) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.ResultsVorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.ConclusionsVorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing mIDH LGG.
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- 2021
5. Perspectives in immunotherapy: meeting report from the “Immunotherapy Bridge” (December 4th–5th, 2019, Naples, Italy)
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Ascierto, Paolo A, Butterfield, Lisa H, Campbell, Katie, Daniele, Bruno, Dougan, Michael, Emens, Leisha A, Formenti, Silvia, Janku, Filip, Khleif, Samir N, Kirchhoff, Tomas, Morabito, Alessandro, Najjar, Yana, Nathan, Paul, Odunsi, Kunle, Patnaik, Akash, Paulos, Chrystal M, Reinfeld, Bradley I, Skinner, Heath D, Timmerman, John, and Puzanov, Igor
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Immunization ,Vaccine Related ,Cancer ,Good Health and Well Being ,Biomarkers ,Tumor ,Humans ,Immunotherapy ,Italy ,Medical Oncology ,Melanoma ,Checkpoint inhibitors ,Combination therapy ,Biomarkers ,Tumor microenvironment ,Vaccine ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Over the last few years, numerous clinical trials and real-world experience have provided a large amount of evidence demonstrating the potential for long-term survival with immunotherapy agents across various malignancies, beginning with melanoma and extending to other tumours. The clinical success of immune checkpoint blockade has encouraged increasing development of other immunotherapies. It has been estimated that there are over 3000 immuno-oncology trials ongoing, targeting hundreds of disease and immune pathways. Evolving topics on cancer immunotherapy, including the state of the art of immunotherapy across various malignancies, were the focus of discussions at the Immunotherapy Bridge meeting (4-5 December, 2019, Naples, Italy), and are summarised in this report.
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- 2021
6. Successful treatment of non-Langerhans cell histiocytosis with the MEK inhibitor trametinib: a multicenter analysis
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Aaroe, Ashley, Kurzrock, Razelle, Goyal, Gaurav, Goodman, Aaron M., Patel, Harsh, Ruan, Gordon, Ulaner, Gary, Young, Jason, Li, Ziyi, Dustin, Derek, Go, Ronald S., Diamond, Eli L., and Janku, Filip
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- 2023
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7. Safety and Efficacy of Vorinostat Plus Sirolimus or Everolimus in Patients with Relapsed Refractory Hodgkin Lymphoma
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Janku, Filip, Park, Haeseong, Call, S Greg, Madwani, Kiran, Oki, Yasuhiro, Subbiah, Vivek, Hong, David S, Naing, Aung, Velez-Bravo, Vivianne M, Barnes, Tamara G, Hagemeister, Fredrick B, Falchook, Gerald S, Karp, Daniel D, Wheler, Jennifer J, Piha-Paul, Sarina A, Garrido-Laguna, Ignacio, Shpall, Elizabeth J, Fayad, Luis E, Neelapu, Sattva S, Meric-Bernstam, Funda, Kurzrock, Razelle, and Fanale, Michelle A
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Clinical Research ,Clinical Trials and Supportive Activities ,Lymphoma ,Rare Diseases ,Transplantation ,Hematology ,Cancer ,Evaluation of treatments and therapeutic interventions ,6.2 Cellular and gene therapies ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Brentuximab Vedotin ,Dose-Response Relationship ,Drug ,Drug-Related Side Effects and Adverse Reactions ,Everolimus ,Female ,Hematopoietic Stem Cell Transplantation ,Histone Deacetylase Inhibitors ,Histone Deacetylases ,Hodgkin Disease ,Humans ,Male ,Middle Aged ,Recurrence ,Sirolimus ,Stem Cell Transplantation ,TOR Serine-Threonine Kinases ,Vorinostat ,Young Adult ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposePreclinical and early clinical data suggested that combining histone deacetylase (HDAC) and mTOR inhibitors can synergistically inhibit Hodgkin lymphoma.Patients and methodsDuring the dose-escalation study (ClinicalTrials.gov number: NCT01087554) with the HDAC inhibitor vorinostat and the mTOR inhibitor sirolimus (V+S), a patient with Hodgkin lymphoma refractory to nine prior therapies demonstrated a partial response (PR) lasting for 18.5 months, which promoted additional enrollment of patients with Hodgkin lymphoma as well as exploration of an alternative combination of vorinostat and mTOR inhibitor everolimus (V+E).ResultsA total of 40 patients with refractory Hodgkin lymphoma received V+S (n = 22) or V+E (n = 18). Patients received a median of five prior therapies, including brentuximab (n = 39), autologous stem cell transplantation (n = 26), and allogeneic stem cell transplantation (n = 12). The most frequent grade ≥3 treatment-related adverse event was thrombocytopenia in 55% and 67% of patients treated with V+S and V+E, respectively. Complete response was reported in 6 (27%) patients treated with V+S and 2 (11%) patients treated with V+E, and PR was reported in 6 patients (27%) treated with V+S and 4 (22%) patients treated with V+E (objective response rate of 55% and 33%, respectively). In summary, combined HDAC and mTOR inhibition had encouraging activity in heavily pretreated patients with relapsed/refractory Hodgkin lymphoma and warrants further investigation.ConclusionsCombined HDAC and mTOR inhibition has salutary activity in patients with relapsed refractory Hodgkin lymphoma and warrants further investigation.
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- 2020
8. Ivosidenib in Isocitrate Dehydrogenase 1–Mutated Advanced Glioma
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Mellinghoff, Ingo K, Ellingson, Benjamin M, Touat, Mehdi, Maher, Elizabeth, De La Fuente, Macarena I, Holdhoff, Matthias, Cote, Gregory M, Burris, Howard, Janku, Filip, Young, Robert J, Huang, Raymond, Jiang, Liewen, Choe, Sung, Fan, Bin, Yen, Katharine, Lu, Min, Bowden, Chris, Steelman, Lori, Pandya, Shuchi S, Cloughesy, Timothy F, and Wen, Patrick Y
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Brain Cancer ,Neurosciences ,Clinical Trials and Supportive Activities ,Clinical Research ,Cancer ,Genetics ,Rare Diseases ,Orphan Drug ,Brain Disorders ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adult ,Aged ,Antineoplastic Agents ,Brain Neoplasms ,Dose-Response Relationship ,Drug ,Enzyme Inhibitors ,Female ,Glioma ,Glycine ,Humans ,Isocitrate Dehydrogenase ,Male ,Middle Aged ,Mutation ,Pyridines ,Young Adult ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeDiffuse gliomas are malignant brain tumors that include lower-grade gliomas (LGGs) and glioblastomas. Transformation of low-grade glioma into a higher tumor grade is typically associated with contrast enhancement on magnetic resonance imaging. Mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in most LGGs (> 70%). Ivosidenib is an inhibitor of mutant IDH1 (mIDH1) under evaluation in patients with solid tumors.MethodsWe conducted a multicenter, open-label, phase I, dose escalation and expansion study of ivosidenib in patients with mIDH1 solid tumors. Ivosidenib was administered orally daily in 28-day cycles.ResultsIn 66 patients with advanced gliomas, ivosidenib was well tolerated, with no dose-limiting toxicities reported. The maximum tolerated dose was not reached; 500 mg once per day was selected for the expansion cohort. The grade ≥ 3 adverse event rate was 19.7%; 3% (n = 2) were considered treatment related. In patients with nonenhancing glioma (n = 35), the objective response rate was 2.9%, with 1 partial response. Thirty of 35 patients (85.7%) with nonenhancing glioma achieved stable disease compared with 14 of 31 (45.2%) with enhancing glioma. Median progression-free survival was 13.6 months (95% CI, 9.2 to 33.2 months) and 1.4 months (95% CI, 1.0 to 1.9 months) for the nonenhancing and enhancing glioma cohorts, respectively. In an exploratory analysis, ivosidenib reduced the volume and growth rates of nonenhancing tumors.ConclusionIn patients with mIDH1 advanced glioma, ivosidenib 500 mg once per day was associated with a favorable safety profile, prolonged disease control, and reduced growth of nonenhancing tumors.
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- 2020
9. First-in-human study of IM156, a novel potent biguanide oxidative phosphorylation (OXPHOS) inhibitor, in patients with advanced solid tumors
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Janku, Filip, Beom, Seung-Hoon, Moon, Yong Wha, Kim, Tae Won, Shin, Young G., Yim, Dong-Seok, Kim, Gun Min, Kim, Hyo Song, Kim, Sun Young, Cheong, Jae-Ho, Lee, Young Woo, Geiger, Barb, Yoo, Sanghee, Thurston, Archie, Welsch, Dean, Rudoltz, Marc S., and Rha, Sun Young
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- 2022
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10. First-in-Man Phase I Trial of the Selective MET Inhibitor Tepotinib in Patients with Advanced Solid Tumors
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Falchook, Gerald S, Kurzrock, Razelle, Amin, Hesham M, Xiong, Wenyuan, Fu, Siqing, Piha-Paul, Sarina A, Janku, Filip, Eskandari, Ghazaleh, Catenacci, Daniel V, Klevesath, Manfred, Bruns, Rolf, Stammberger, Uz, Johne, Andreas, Bladt, Friedhelm, Friese-Hamim, Manja, Girard, Pascal, Bawab, Samer El, and Hong, David S
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Clinical Research ,Rare Diseases ,Clinical Trials and Supportive Activities ,Cancer ,Orphan Drug ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adult ,Aged ,Aged ,80 and over ,Dose-Response Relationship ,Drug ,Female ,Humans ,Male ,Maximum Tolerated Dose ,Middle Aged ,Nausea ,Neoplasms ,Patient Safety ,Piperidines ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins c-met ,Pyridazines ,Pyrimidines ,Tissue Distribution ,Treatment Outcome ,Vomiting ,Young Adult ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeTepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and methodsPatients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsOne hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.ConclusionsTepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.
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- 2020
11. Ultrasensitive detection of BRAF V600E mutations in circulating tumor DNA of patients with metastatic thyroid cancer
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Gouda, Mohamed A., Ong, Emily, Huang, Helen J., McPhaul, Laron W., Yoon, Steve, Janku, Filip, and Gianoukakis, Andrew G.
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- 2022
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12. Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: Results of a single-center, multi-arm phase Ib study
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Thein, Kyaw Z., Karp, Daniel D., Tsimberidou, Apostolia, Gong, Jing, Sulovic, Selma, Shah, Jatin, Milton, Denái R., Hong, David S., Janku, Filip, McQuinn, Lacey, Stephen, Bettzy A., Colen, Rivka, Carter, Brett W., Yap, Timothy A., Piha-Paul, Sarina A., Fu, Siqing, Meric-Bernstam, Funda, and Naing, Aung
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- 2022
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13. Molecular Profiling of Tumor Tissue and Plasma Cell-Free DNA from Patients with Non-Langerhans Cell Histiocytosis
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Janku, Filip, Diamond, Eli L, Goodman, Aaron M, Raghavan, Vaijayanthi Kandadai, Barnes, Tamara G, Kato, Shumei, Abdel-Wahab, Omar, Durham, Benjamin H, Meric-Bernstam, Funda, and Kurzrock, Razelle
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Rare Diseases ,Cancer ,Clinical Research ,Adolescent ,Adult ,Aged ,Cell-Free Nucleic Acids ,Early Detection of Cancer ,Erdheim-Chester Disease ,Female ,Genomics ,High-Throughput Nucleotide Sequencing ,Histiocytosis ,Sinus ,Humans ,Leukemia ,Myeloid ,Male ,Middle Aged ,Mitogen-Activated Protein Kinases ,Mutation ,Polymerase Chain Reaction ,Proto-Oncogene Proteins B-raf ,Young Adult ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
The BRAF V600E mutation and BRAF inhibitor responsiveness characterize ∼50% of patients with the non-Langerhans cell histiocytosis (non-LCH) Erdheim-Chester disease (ECD). We interrogated the non-LCH molecular landscape [ECD, n = 35; Rosai-Dorfman disease (RDD), n = 3; mixed ECD/RDD, n = 1] using BRAF V600E PCR and/or next-generation sequencing [tissue and cell-free DNA (cfDNA) of plasma and/or urine]. Of 34 evaluable patients, 17 (50%) had the BRAF V600E mutation. Of 31 patients evaluable for non-BRAF V600E alterations, 18 (58%) had ≥1 alteration and 12 putative non-BRAF V600E MAPK pathway alterations: atypical BRAF mutation; GNAS, MAP2K1, MAP2K2, NF1, and RAS mutations; RAF1 or ERBB2 amplifications; LMNA-NTRK1 (TRK inhibitor-sensitive) and CAPZA2-BRAF fusions. Four patients had JAK2, MPL ASXL1, U2AF1 alterations, which can correlate with myeloid neoplasms, a known ECD predisposition, and one developed myelofibrosis 13 months after cfDNA testing. Therefore, our multimodal comprehensive genomics reveals clinically relevant alterations and suggests that MAPK activation is a hallmark of non-LCH.
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- 2019
14. ACTR-31. PHASE 1 STUDY OF AG-881, AN INHIBITOR OF MUTANT IDH1 AND IDH2: RESULTS FROM THE RECURRENT/PROGRESSIVE GLIOMA POPULATION
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Mellinghoff, Ingo, Penas-Prado, Marta, Peters, Katherine, Cloughesy, Timothy, Burris, Howard, Maher, Elizabeth, Janku, Filip, Cote, Gregory, De La Fuente, Macarena, Clarke, Jennifer, Steelman, Lori, Le, Kha, Xu, Huansheng, Sonderfan, Alison, Hummel, Diana, Schoenfeld, Steven, Yen, Katharine, Pandya, Shuchi, and Wen, Patrick
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Neurosciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Abstract INTRODUCTION: Isocitrate dehydrogenase 1 and 2 mutations (mIDH1/2) occur in >70% of low-grade gliomas and secondary glioblastomas, and lead to genetic and epigenetic dysregulation, promoting tumorigenesis. AG-881 is an oral, potent, brain-penetrant inhibitor of mIDH1/2 under phase 1 clinical evaluation in gliomas and other solid tumors. Here we present clinical data from the glioma population. METHODS Patients with recurrent/progressive mIDH1/2 glioma received AG-881 daily in continuous 28-day cycles. A Bayesian model was used for dose escalation. Dose-limiting toxicity (DLT) definition: Grade 3 AG-881-related adverse event (AE) in Cycle 1 or by sponsor designation. Blood samples were collected for pharmacokinetic (PK)/pharmacodynamic (PD) evaluations. MRI response every 8 weeks by RANO and RANO-LGG criteria. RESULTS As of 28Mar2018, 52 patients with glioma had received AG-881 and 17 (32.7%) remained on treatment. Grade 2/3 = 90.4%; median age = 42.5 years; IDH1/2: 48/3; median no. prior therapies = 2 (range 1–6). Five initial dose levels tested: 25mg (n=6), 50mg (n=5), 100mg (n=10), 200mg (n=14), and 300mg (n=5). To confirm safety and PK, a 10mg dose level was tested (n=6) and 6 additional patients enrolled in the 50mg cohort. Common (>20%) AEs across glioma patients regardless of attribution: ALT increased (44.2%), AST increased (38.5%), headache (34.6%), fatigue (30.8%), nausea (26.9%), seizure (21.2%). Five patients experienced DLTs at 100mg: Grade 2 ALT/AST that resolved to Grade 1 with dose modification (n=4) or discontinuation (n=1). Among the evaluable glioma population: 2% minor response, 75% stable disease, 21% progressive disease, and 2% missing as best overall response. CONCLUSION: Maximum tolerated dose/recommended phase 2 dose was not reached by Bayesian model; clinical team recommendation was to proceed with doses
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- 2018
15. Clinical characteristics and outcomes of phase I cancer patients with CCNE1 amplification: MD Anderson experiences
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Yao, Shuyang, Meric-Bernstam, Funda, Hong, David, Janku, Filip, Naing, Aung, Piha-Paul, Sarina Anne, Tsimberidou, Apostolia Maria, Karp, Daniel, Subbiah, Vivek, Yap, Timothy Anthony, Ahnert, Jordi Rodon, Pant, Shubham, Dumbrava, Ecaterina E Ileana, Wathoo, Chetna, Campbell, Erick, Yu, Lihou, Yamamura, Yuko, and Fu, Siqing
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- 2022
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16. Challenges and opportunities associated with the MD Anderson IMPACT2 randomized study in precision oncology
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Vo, Henry Hiep, Fu, Siqing, Hong, David S., Karp, Daniel D., Piha-Paul, Sarina, Subbiah, Vivek, Janku, Filip, Naing, Aung, Yap, Timothy A., Rodon, Jordi, Ajani, Jaffer A., Cartwright, Carrie, Johnson, Amber, Song, I-Wen, Beck, Jennifer, Kahle, Michael, Nogueras-Gonzalez, Graciela M., Miller, Vincent, Chao, Calvin, Vining, David J., Berry, Donald A., Meric-Bernstam, Funda, and Tsimberidou, Apostolia-Maria
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- 2022
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17. Patient-reported symptom burden in patients with rare cancers receiving pembrolizumab in a phase II Clinical Trial
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Mendoza, Tito R., Hong, David S., Peterson, Christine B., Stephen, Bettzy, Dumbrava, Ecaterina, Pant, Shubbam, Tsimberidou, Apostolia Maria, Yap, Timothy Anthony, Sheshadri, Ajay, Altan, Mehmet, George, Goldy, Castillo, Lilibeth, Rodriguez, Enedelia, Gong, Jing, Subbiah, Vivek, Janku, Filip, Fu, Siqing, Piha-Paul, Sarina A., Ahnert, Jordi Rodon, Karp, Daniel D., Cleeland, Charles, Meric-Bernstam, Funda, and Naing, Aung
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- 2022
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18. Validation of Prognostic Scores in Patients With Metastatic Urothelial Cancer Enrolling in Phase I Targeted Therapy or Next Generation Immunotherapy Trials
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Alhalabi, Omar, Hahn, Andrew W., Msaouel, Pavlos, Meric-Bernstam, Funda, Wilson, Nathaniel, Naing, Aung, Piha-Paul, Sarina, Janku, Filip, Pant, Shubham, Yap, Timothy A, Hong, David S, Fu, Siqing, Karp, Daniel, Beltran, Kimberly, Campbell, Erick, Le, Hung, Campbell, Matthew T., Shah, Amishi, Tannir, Nizar M., Siefker-Radtke, Arlene, Gao, Jianjun, Roszik, Jason, and Subbiah, Vivek
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- 2022
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19. First-in-human evaluation of the novel mitochondrial complex I inhibitor ASP4132 for treatment of cancer
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Janku, Filip, LoRusso, Patricia, Mansfield, Aaron S., Nanda, Rita, Spira, Alexander, Wang, Tianli, Melhem-Bertrandt, Amal, Sugg, Jennifer, and Ball, Howard A.
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- 2021
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20. Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi‐arm phase Ib study
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Thein, Kyaw Zin, Piha-Paul, Sarina A., Tsimberidou, Apostolia, Karp, Daniel D., Janku, Filip, Zarifa, Abdulrazzak, Shah, Jatin, Milton, Denái R., Bean, Stacie, McQuinn, Lacey, Gong, Jing, Colen, Rivka, Carter, Brett W., Subbiah, Vivek, Ogbonna, Deby C., Pant, Shubham, Meric-Bernstam, Funda, and Naing, Aung
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- 2021
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21. Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in patients with advanced cancers
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Sen, Shiraj, Kato, Shumei, Agarwal, Rishi, Piha-Paul, Sarina, Hess, Kenneth, Karp, Daniel, Janku, Filip, Fu, Siqing, Naing, Aung, Pant, Shubham, Falchook, Gerald, Tang, Chad, Wu, Xifeng, Ye, Yuanqing, Tsimberidou, Apostolia, Subbiah, Vivek, Kurzrock, Razelle, Byers, Lauren, Westin, Shannon, Lim, JoAnn, Bean, Stacie, Bass, Allison, Nguyen, Ly, Meric-Bernstam, Funda, and Hong, David
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Clinical Trials and Supportive Activities ,Rare Diseases ,Clinical Research ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,6.2 Cellular and gene therapies ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Albumins ,Antineoplastic Combined Chemotherapy Protocols ,Bevacizumab ,Deoxycytidine ,Drug Administration Schedule ,Female ,Humans ,Male ,Maximum Tolerated Dose ,Middle Aged ,Neoplasms ,Paclitaxel ,Polymorphism ,Genetic ,Treatment Outcome ,Vascular Endothelial Growth Factor A ,Young Adult ,Gemcitabine ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundWe performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab-paclitaxel in patients with advanced solid tumours.MethodsPatients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed.ResultsThe study enrolled 110 patients who had undergone a median of 3 prior lines of therapy. The median age was 60 years (range, 17-85 years), and 55 patients (50%) had gemcitabine-refractory disease. We observed 3 dose-limiting toxicities during dose escalation and 3 DLTs in expansion cohorts. Dose escalation to 150 mg/m2 nab-paclitaxel and 15 mg/kg bevacizumab with 1000 mg/m2 of gemcitabine was well tolerated with no MTD. One patient with gemcitabine-refractory peritoneal papillary carcinoma had a complete response, 13 patients (13%) had partial responses, and 54 patients (52%) had stable disease ≥12 weeks. Exploratory VEGF single nucleotide polymorphism (SNP) analysis was performed on 13 patients.ConclusionsThe combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. Based on this study, the recommended phase 2 dose is gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2, and bevacizumab 15 mg/kg. VEGF polymorphism data should be evaluated in future bevacizumab-based trials.
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- 2018
22. Phosphatidylinositol 3-Kinase α–Selective Inhibition With Alpelisib (BYL719) in PIK3CA-Altered Solid Tumors: Results From the First-in-Human Study
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Juric, Dejan, Rodon, Jordi, Tabernero, Josep, Janku, Filip, Burris, Howard A, Schellens, Jan HM, Middleton, Mark R, Berlin, Jordan, Schuler, Martin, Gil-Martin, Marta, Rugo, Hope S, Seggewiss-Bernhardt, Ruth, Huang, Alan, Bootle, Douglas, Demanse, David, Blumenstein, Lars, Coughlin, Christina, Quadt, Cornelia, and Baselga, José
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Breast Cancer ,Patient Safety ,6.1 Pharmaceuticals ,6.2 Cellular and gene therapies ,Evaluation of treatments and therapeutic interventions ,Administration ,Oral ,Adult ,Aged ,Aged ,80 and over ,Breast Neoplasms ,Class I Phosphatidylinositol 3-Kinases ,Dose-Response Relationship ,Drug ,Drug Administration Schedule ,Female ,Humans ,Middle Aged ,Thiazoles ,Treatment Outcome ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
Purpose We report the first-in-human phase Ia study to our knowledge ( ClinicalTrials.gov identifier: NCT01219699) identifying the maximum tolerated dose and assessing safety and preliminary efficacy of single-agent alpelisib (BYL719), an oral phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor. Patients and Methods In the dose-escalation phase, patients with PIK3CA-altered advanced solid tumors received once-daily or twice-daily oral alpelisib on a continuous schedule. In the dose-expansion phase, patients with PIK3CA-altered solid tumors and PIK3CA-wild-type, estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer received alpelisib 400 mg once daily. Results One hundred thirty-four patients received treatment. Alpelisib maximum tolerated doses were established as 400 mg once daily and 150 mg twice daily. Nine patients (13.2%) in the dose-escalation phase had dose-limiting toxicities of hyperglycemia (n = 6), nausea (n = 2), and both hyperglycemia and hypophosphatemia (n = 1). Frequent all-grade, treatment-related adverse events included hyperglycemia (51.5%), nausea (50.0%), decreased appetite (41.8%), diarrhea (40.3%), and vomiting (31.3%). Alpelisib was rapidly absorbed; half-life was 7.6 hours at 400 mg once daily with minimal accumulation. Objective tumor responses were observed at doses ≥ 270 mg once daily; overall response rate was 6.0% (n = 8; one patient with endometrial cancer had a complete response, and seven patients with cervical, breast, endometrial, colon, and rectal cancers had partial responses). Stable disease was achieved in 70 (52.2%) patients and was maintained > 24 weeks in 13 (9.7%) patients; disease control rate (complete and partial responses and stable disease) was 58.2%. In patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative breast cancer, median progression-free survival was 5.5 months. Frequently mutated genes (≥ 10% tumors) included TP53 (51.3%), APC (23.7%), KRAS (22.4%), ARID1A (13.2%), and FBXW7 (10.5%). Conclusion Alpelisib demonstrated a tolerable safety profile and encouraging preliminary activity in patients with PIK3CA-altered solid tumors, supporting the rationale for selective PI3Kα inhibition in combination with other agents for the treatment of PIK3CA-mutant tumors.
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- 2018
23. A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors
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Janku, Filip, primary, Choong, Grace M., additional, Opyrchal, Mateusz, additional, Dowlati, Afshin, additional, Hierro, Cinta, additional, Rodon, Jordi, additional, Wicki, Andreas, additional, Forster, Martin D., additional, Blagden, Sarah P., additional, Yin, Jun, additional, Reid, Joel M., additional, Muller, Helene, additional, Cmiljanovic, Natasa, additional, Cmiljanovic, Vladimir, additional, and Adjei, Alex A., additional
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- 2024
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24. Incorporating Circulating Biomarkers into Clinical Trials
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Janku, Filip, Yap, Timothy A., editor, Rodon, Jordi, editor, and Hong, David S., editor
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- 2020
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25. Pembrolizumab in Patients with Refractory Cutaneous Squamous Cell Carcinoma: A Phase II Trial
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Ferrarotto, Renata, Sousa, Luana G., Qing, Yun, Kaya, Diana, Stephen, Bettzy, Jain, Dipti, Bell, Diana, Pant, Shubham, Tsimberidou, Apostolia M., Janku, Filip, Blumenschein, George, Glisson, Bonnie S., Ahnert, Jordi Rodon, Piha-Paul, Sarina A., Lee, J. Jack, Wong, Michael K., Lu, Charles, Meric-Bernstam, Funda, and Naing, Aung
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- 2021
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26. Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours
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Rodon, Jordi, Argilés, Guillem, Connolly, Roisin M., Vaishampayan, Ulka, de Jonge, Maja, Garralda, Elena, Giannakis, Marios, Smith, David C., Dobson, Jason R., McLaughlin, Margaret E., Seroutou, Abdelkader, Ji, Yan, Morawiak, Jennifer, Moody, Susan E., and Janku, Filip
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- 2021
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27. A Phase 1/1b Study Evaluating Trametinib Plus Docetaxel or Pemetrexed in Patients With Advanced Non–Small Cell Lung Cancer
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Gandara, David R, Leighl, Natasha, Delord, Jean-Pierre, Barlesi, Fabrice, Bennouna, Jaafar, Zalcman, Gerald, Infante, Jeffrey R, Reckamp, Karen L, Kelly, Karen, Shepherd, Frances A, Mazieres, Julien, Janku, Filip, Gardner, Olivia S, Mookerjee, Bijoyesh, Wu, Yuehui, Cox, Donna S, Schramek, Dan, Peddareddigari, Vijay, Liu, Yuan, D'Amelio, Anthony M, and Blumenschein, George
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Lung ,Clinical Research ,Lung Cancer ,Cancer ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adenocarcinoma ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Carcinoma ,Large Cell ,Carcinoma ,Non-Small-Cell Lung ,Carcinoma ,Squamous Cell ,Docetaxel ,Female ,Follow-Up Studies ,Humans ,Lung Neoplasms ,Male ,Middle Aged ,Neoplasm Staging ,Pemetrexed ,Prognosis ,Pyridones ,Pyrimidinones ,Survival Rate ,Taxoids ,Trametinib ,MEK inhibitor ,NSCLC ,KRAS mutations ,Cardiorespiratory Medicine and Haematology ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
ObjectivesThis two-part study evaluated trametinib, a MEK1/2 inhibitor, in combination with anticancer agents. Inhibition of MEK, a downstream effector of KRAS, demonstrated preclinical synergy with chemotherapy in KRAS-mutant NSCLC cell lines. Part 1 of this study identified recommended phase 2 doses of trametinib combinations. Part 2, reported herein, evaluated the safety, tolerability, pharmacokinetics, and efficacy of trametinib combinations in patients with NSCLC with and without KRAS mutations.MethodsPhase 1b evaluated trametinib plus docetaxel with growth factor support (trametinib, 2.0 mg once daily, and docetaxel, 75 mg/m2 every 3 weeks) or pemetrexed (trametinib, 1.5 mg once daily, and pemetrexed, 500 mg/m2 every 3 weeks). Eligibility criteria for the expansion cohorts included metastatic NSCLC with measurable disease, known KRAS mutation status, Eastern Cooperative Oncology Group performance status of 1 or lower, and no more than two prior regimens.ResultsThe primary end point of overall response rate (ORR) was met for both combinations. A confirmed partial response (PR) was observed in 10 of the 47 patients with NSCLC who received trametinib plus docetaxel (21%). The ORR was 18% (four PRs in 22 patients) in those with KRAS wild-type NSCLC versus 24% (six PRs in 25 patients) in those with KRAS-mutant NSCLC. Of the 42 patients with NSCLC treated with trametinib plus pemetrexed, six (14%) had a PR; the ORR was 17% (four of 23) in patients with KRAS-mutated NSCLC versus 11% (two of 19) in KRAS wild-type NSCLC. Adverse events-most commonly diarrhea, nausea, and fatigue-were manageable.ConclusionsTrametinib-plus-chemotherapy combinations were tolerable. Clinical activity exceeding the ORRs previously reported with docetaxel or pemetrexed alone in KRAS-mutated NSCLC and meeting prespecified criteria was observed.
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- 2017
28. Phase 1 trial of ADI-PEG20 plus cisplatin in patients with pretreated metastatic melanoma or other advanced solid malignancies
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Yao, Shuyang, Janku, Filip, Subbiah, Vivek, Stewart, John, Patel, Sapna Pradyuman, Kaseb, Ahmed, Westin, Shannon Neville, Naing, Aung, Tsimberidou, Apostolia Maria, Hong, David, Piha-Paul, Sarina Anne, Shi, Nai, Johnston, Amanda, Bomalaski, John, and Fu, Siqing
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- 2021
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29. Phase I dose-escalation study of the mTOR inhibitor sirolimus and the HDAC inhibitor vorinostat in patients with advanced malignancy
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Park, Haeseong, Garrido-Laguna, Ignacio, Naing, Aung, Fu, Siqing, Falchook, Gerald S, Piha-Paul, Sarina A, Wheler, Jennifer J, Hong, David S, Tsimberidou, Apostolia M, Subbiah, Vivek, Zinner, Ralph G, Kaseb, Ahmed O, Patel, Shreyaskumar, Fanale, Michelle A, Velez-Bravo, Vivianne M, Meric-Bernstam, Funda, Kurzrock, Razelle, and Janku, Filip
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Cancer ,Hematology ,Lymphoma ,Orphan Drug ,Clinical Research ,Rare Diseases ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Antineoplastic Combined Chemotherapy Protocols ,Female ,Histone Deacetylase Inhibitors ,Humans ,Hydroxamic Acids ,Male ,Maximum Tolerated Dose ,Middle Aged ,Neoplasms ,Sirolimus ,TOR Serine-Threonine Kinases ,Vorinostat ,Young Adult ,phase I ,sirolimus ,vorinostat ,mTOR ,HDAC ,Oncology and carcinogenesis - Abstract
Preclinical models suggest that histone deacetylase (HDAC) and mammalian target of rapamycin (mTOR) inhibitors have synergistic anticancer activity. We designed a phase I study to determine the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of combined mTOR inhibitor sirolimus (1 mg-5 mg PO daily) and HDAC inhibitor vorinostat (100 mg-400 mg PO daily) in patients with advanced cancer. Seventy patients were enrolled and 46 (66%) were evaluable for DLT assessment since they completed cycle 1 without dose modification unless they had DLT. DLTs comprised grade 4 thrombocytopenia (n = 6) and grade 3 mucositis (n = 1). Sirolimus 4 mg and vorinostat 300 mg was declared RP2D because MTD with sirolimus 5 mg caused significant thrombocytopenia. The grade 3 and 4 drug-related toxic effects (including DLTs) were thrombocytopenia (31%), neutropenia (8%), anemia (7%), fatigue (3%), mucositis (1%), diarrhea (1%), and hyperglycemia (1%). Of the 70 patients, 35 (50%) required dose interruption or modification and 61 were evaluable for response. Partial responses were observed in refractory Hodgkin lymphoma (-78%) and perivascular epithelioid tumor (-54%), and stable disease in hepatocellular carcinoma and fibromyxoid sarcoma. In conclusion, the combination of sirolimus and vorinostat was feasible, with thrombocytopenia as the main DLT. Preliminary anticancer activity was observed in patients with refractory Hodgkin lymphoma, perivascular epithelioid tumor, and hepatocellular carcinoma.
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- 2016
30. Identification of KRASG12C Mutations in Circulating Tumor DNA in Patients With Cancer
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Thein, Kyaw Z., Biter, Amadeo B., Banks, Kimberly C., Duda, Andrew W., Saam, Jennifer, Roszik, Jason, Janku, Filip, Skoulidis, Ferdinandos, Heymach, John V., Kopetz, Scott, Meric-Bernstam, Funda, and Hong, David S.
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- 2022
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31. Longitudinal Monitoring of Circulating Tumor DNA to Predict Treatment Outcomes in Advanced Cancers
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Gouda, Mohamed A., Huang, Helen J., Piha-Paul, Sarina A., Call, S. Greg, Karp, Daniel D., Fu, Siqing, Naing, Aung, Subbiah, Vivek, Pant, Shubham, Dustin, Derek J., Tsimberidou, Apostolia M., Hong, David S., Rodon, Jordi, Meric-Bernstam, Funda, and Janku, Filip
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- 2022
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32. Hormonal modulation of ESR1 mutant metastasis
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Gu, Guowei, Tian, Lin, Herzog, Sarah K., Rechoum, Yassine, Gelsomino, Luca, Gao, Meng, Du, Lili, Kim, Jin-Ah, Dustin, Derek, Lo, Hin Ching, Beyer, Amanda R., Edwards, David G., Gonzalez, Thomas, Tsimelzon, Anna, Huang, Helen J., Fernandez, Natalie M., Grimm, Sandra L., Hilsenbeck, Susan G., Liu, Dan, Xu, Jun, Alaniz, Alyssa, Li, Shunqiang, Mills, Gordon B., Janku, Filip, Kittler, Ralf, Zhang, Xiang H. -F., Coarfa, Cristian, Foulds, Charles E., Symmans, W. Fraser, Andò, Sebastiano, and Fuqua, Suzanne A. W.
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- 2021
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33. Presence of both alterations in FGFR/FGF and PI3K/AKT/mTOR confer improved outcomes for patients with metastatic breast cancer treated with PI3K/AKT/mTOR inhibitors
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Wheler, Jennifer J, Atkins, Johnique T, Janku, Filip, Moulder, Stacy L, Stephens, Philip J, Yelensky, Roman, Valero, Vicente, Miller, Vincent, Kurzrock, Razelle, and Meric-Bernstam, Funda
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Breast Cancer ,Biotechnology ,Pediatric Research Initiative ,Good Health and Well Being ,FGFR ,PI3K ,breast cancer ,next-generation sequencing - Abstract
There is limited data on co-expression of FGFR/FGR amplifications and PI3K/ AKT/mTOR alterations in breast cancer. Tumors from patients with metastatic breast cancer referred to our Phase I Program were analyzed by next generation sequencing (NGS). Genomic libraries were selected for all exons of 236 (or 182) cancer-related genes sequenced to average depth of >500× in a CLIA laboratory (Foundation Medicine, Cambridge, MA, USA) and analyzed for all classes of genomic alterations. We report genomic profiles of 112 patients with metastatic breast cancer, median age 55 years (range, 27-78). Twenty-four patients (21%) had at least one amplified FGFR or FGF. Fifteen of the 24 patients (63%) also had an alteration in the PI3K/ AKT/mTOR pathway. There was no association between alterations in FGFR/FGF and PI3K/AKT/mTOR (P=0.49). Patients with simultaneous amplification in FGFR/FGF signaling and the PI3K/AKT/mTOR pathway had a higher rate of SD≥6 months/PR/ CR when treated with therapies targeting the PI3K/AKT/mTOR pathway than patients with only alterations in the PI3K/AKT/mTOR pathway (73% vs. 34%; P=0.0376) and remained on treatment longer (6.8 vs. 3.7 months; P=0.053). Higher response rates were seen in patients with simultaneous amplification in FGFR/FGF signaling and alterations in the PI3K/AKT/mTOR pathway who were treated with inhibitors of that pathway.
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- 2016
34. Phase I study of mTORC1/2 inhibitor sapanisertib in combination with metformin in patients with mTOR/AKT/PI3K pathway alterations and advanced solid malignancies.
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Subbiah, Vivek, primary, Coleman, Niamh, additional, Piha-Paul, Sarina A., additional, Tsimberidou, Apostolia M., additional, Janku, Filip, additional, Rodon, Jordi, additional, Pant, Shubham, additional, Dumbrava, Ecaterina E., additional, Fu, Siqing, additional, Hong, David S., additional, Zhang, Shizhen, additional, Sun, Ming, additional, Jiang, Yunfang, additional, Roszik, Jason, additional, Song, Juhee, additional, Yuan, Ying, additional, Meric-Bernstam, Funda, additional, and Naing, Aung, additional
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- 2023
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35. CTNI-76. EFFICACY OF BRAF INHIBITOR PLIXORAFENIB (FORE8394) IN RECURRENT, PRIMARY CENTRAL NERVOUS SYSTEM TUMORS (PCNST)
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de la Fuente, Macarena, primary, Butowski, Nicholas, additional, Taylor, Jennie, additional, Yaeger, Rona, additional, Tsai, Frank Yung-Chin, additional, Janku, Filip, additional, Allen, Carl, additional, Ammakkanavar, Natraj, additional, Michelson, Glenn, additional, Jiang, Ping, additional, Paz, Michael, additional, Tussay-Lindenberg, Alexia, additional, Wang, Kongming, additional, Shepherd, Stacie Peacock, additional, Kline, Irina, additional, Sherman, Eric, additional, and Rodon, Jordi, additional
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- 2023
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36. Multiple gene aberrations and breast cancer: lessons from super-responders
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Wheler, Jennifer J, Atkins, Johnique T, Janku, Filip, Moulder, Stacy L, Yelensky, Roman, Stephens, Philip J, and Kurzrock, Razelle
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Human Genome ,Cancer ,Breast Cancer ,Biotechnology ,Genetics ,Adult ,Anastrozole ,Antineoplastic Combined Chemotherapy Protocols ,Breast Neoplasms ,Class I Phosphatidylinositol 3-Kinases ,Disease-Free Survival ,Everolimus ,Female ,Gene Expression Regulation ,Neoplastic ,High-Throughput Nucleotide Sequencing ,Humans ,Middle Aged ,Mutation ,Neoplasm Proteins ,Nitriles ,Phosphatidylinositol 3-Kinases ,TOR Serine-Threonine Kinases ,Treatment Outcome ,Triazoles ,Breast cancer ,Genomic aberrations ,Next generation sequencing ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Epidemiology - Abstract
BackgroundThe presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes.Case presentationsWe performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2-negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Tumors were analyzed using a targeted next generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Patients received anastrozole (1 g PO daily) and everolimus (5 or 10 mg PO daily). Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Primary breast tissue was available for NGS testing in three of the responders (partial response with progression free survival of 11 and 14 months, respectively; complete response with progression free survival of 9+ months). The following molecular aberrations were observed: PTEN loss by immunohistochemistry, CCDN1 and FGFR1 amplifications, and PRKDC re-arrangement (NGS) (patient #1); PIK3CA and PIK3R1 mutations, and CCDN1, FGFR1, MYC amplifications (patient #2); TP53 mutation, CCNE1, IRS2 and MCL1 amplifications (patient #3). Some (but not all) of these aberrations converge on the PI3K/AKT/mTOR pathway, perhaps accounting for response.ConclusionsPatients with estrogen receptor-positive breast cancer can achieve significant responses on a combination of anastrozole and everolimus, even in the presence of multiple molecular aberrations. Further study of next generation sequencing-profiled tumors for convergence and resistance pathways is warranted.
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- 2015
37. Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial
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How, Jeffrey A., Jazaeri, Amir A., Soliman, Pamela T., Fleming, Nicole D., Gong, Jing, Piha-Paul, Sarina A., Janku, Filip, Stephen, Bettzy, and Naing, Aung
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- 2021
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38. Precision medicine: preliminary results from the Initiative for Molecular Profiling and Advanced Cancer Therapy 2 (IMPACT2) study
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Tsimberidou, Apostolia Maria, Hong, David S., Fu, Siqing, Karp, Daniel D., Piha-Paul, Sarina, Kies, Merrill S., Ravi, Vinod, Subbiah, Vivek, Patel, Sunil M., Tu, Shi-Ming, Janku, Filip, Heymach, John, Johnson, Amber, Cartwright, Carrie, Zhao, Li, Zhang, Jianhua, Berry, Donald A., Vining, David J., Futreal, Andrew, Miller, Vincent A., and Meric-Bernstam, Funda
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- 2021
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39. Associations between the gut microbiome and fatigue in cancer patients
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Hajjar, Joud, Mendoza, Tito, Zhang, Liangliang, Fu, Siqing, Piha-Paul, Sarina A., Hong, David S., Janku, Filip, Karp, Daniel D., Ballhausen, Alexej, Gong, Jing, Zarifa, Abdulrazzak, Peterson, Christine B., Meric-Bernstam, Funda, Jenq, Robert, and Naing, Aung
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- 2021
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40. A novel method for liquid-phase extraction of cell-free DNA for detection of circulating tumor DNA
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Janku, Filip, Huang, Helen J., Pereira, David Y., Kobayashi, Masae, Chiu, Chung Hei, Call, S. Greg, Woodbury, Kristen T., Chao, Felix, Marshak, Daniel R., and Chiu, Ricky Y. T.
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- 2021
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41. Selinexor in combination with standard chemotherapy in patients with advanced or metastatic solid tumors
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Thein, Kyaw Z., Piha-Paul, Sarina A., Tsimberidou, Apostolia, Karp, Daniel D., Janku, Filip, Fu, Siqing, Subbiah, Vivek, Hong, David S., Yap, Timothy A., Shah, Jatin, Milton, Denái R., McQuinn, Lacey, Gong, Jing, Tran, Yanyan, Carter, Brett W., Colen, Rivka, Meric-Bernstam, Funda, and Naing, Aung
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- 2021
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42. Monitoring of Dynamic Changes and Clonal Evolution in Circulating Tumor DNA From Patients With IDH-Mutated Cholangiocarcinoma Treated With Isocitrate Dehydrogenase Inhibitors
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Lapin, Morten, Huang, Helen J., Chagani, Sharmeen, Javle, Milind, Shroff, Rachna T., Pant, Shubham, Gouda, Mohamed A., Raina, Anjali, Madwani, Kiran, Holley, Veronica R., Call, S. Greg, Dustin, Derek J., Lanman, Richard B., Meric-Bernstam, Funda, Raymond, Victoria M., Kwong, Lawrence N., and Janku, Filip
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- 2022
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43. BRAF mutation testing with a rapid, fully integrated molecular diagnostics system
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Janku, Filip, Claes, Bart, Huang, Helen J, Falchook, Gerald S, Devogelaere, Benoit, Kockx, Mark, Bempt, Isabelle Vanden, Reijans, Martin, Naing, Aung, Fu, Siqing, Piha-Paul, Sarina A, Hong, David S, Holley, Veronica R, Tsimberidou, Apostolia M, Stepanek, Vanda M, Patel, Sapna P, Kopetz, E Scott, Subbiah, Vivek, Wheler, Jennifer J, Zinner, Ralph G, Karp, Daniel D, Luthra, Rajyalakshmi, Roy-Chowdhuri, Sinchita, Sablon, Erwin, Meric-Bernstam, Funda, Maertens, Geert, and Kurzrock, Razelle
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Human Genome ,Genetics ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,Good Health and Well Being ,DNA Mutational Analysis ,Formaldehyde ,High-Throughput Nucleotide Sequencing ,Humans ,Melanoma ,Mutation ,Neoplasms ,Paraffin Embedding ,Pathology ,Molecular ,Proto-Oncogene Proteins B-raf ,Real-Time Polymerase Chain Reaction ,Reproducibility of Results ,Skin Neoplasms ,BRAF ,rapid ,integrated ,qPCR ,Oncology and carcinogenesis - Abstract
Fast and accurate diagnostic systems are needed for further implementation of precision therapy of BRAF-mutant and other cancers. The novel IdyllaTMBRAF Mutation Test has high sensitivity and shorter turnaround times compared to other methods. We used Idylla to detect BRAF V600 mutations in archived formalin-fixed paraffin-embedded (FFPE) tumor samples and compared these results with those obtained using the cobas 4800 BRAF V600 Mutation Test or MiSeq deep sequencing system and with those obtained by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory employing polymerase chain reaction-based sequencing, mass spectrometric detection, or next-generation sequencing. In one set of 60 FFPE tumor samples (15 with BRAF mutations per Idylla), the Idylla and cobas results had an agreement of 97%. Idylla detected BRAF V600 mutations in two additional samples. The Idylla and MiSeq results had 100% concordance. In a separate set of 100 FFPE tumor samples (64 with BRAF mutation per Idylla), the Idylla and CLIA-certified laboratory results demonstrated an agreement of 96% even though the tests were not performed simultaneously and different FFPE blocks had to be used for 9 cases. The IdyllaTMBRAF Mutation Test produced results quickly (sample to results time was about 90 minutes with about 2 minutes of hands on time) and the closed nature of the cartridge eliminates the risk of PCR contamination. In conclusion, our observations demonstrate that the Idylla test is rapid and has high concordance with other routinely used but more complex BRAF mutation-detecting tests.
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- 2015
44. Exploring response signals and targets in aggressive unresectable hepatocellular carcinoma: an analysis of targeted therapy phase 1 trials
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Subbiah, Ishwaria M, Falchook, Gerald S, Kaseb, Ahmed O, Hess, Kenneth R, Tsimberidou, Apostolia M, Fu, Siqing, Subbiah, Vivek, Hong, David S, Naing, Aung, Sarina, A Piha-Paul, Akmal, Owais, Janku, Filip, and Kurzrock, Razelle
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Rare Diseases ,Clinical Research ,Clinical Trials and Supportive Activities ,Liver Disease ,Digestive Diseases ,Prevention ,Cancer ,Liver Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Adolescent ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers ,Tumor ,Carcinoma ,Hepatocellular ,Child ,Clinical Trials ,Phase I as Topic ,Disease-Free Survival ,Female ,Humans ,Liver Neoplasms ,Male ,Middle Aged ,Molecular Targeted Therapy ,Multivariate Analysis ,Mutation ,Outcome Assessment ,Health Care ,Prognosis ,Young Adult ,targeted agents ,novel therapeutics ,management ,systemic therapy ,clinical trials ,Oncology and carcinogenesis - Abstract
PurposePatients with advanced hepatocellular carcinoma (HCC) have limited effective therapeutic options. Given the rapid advanced in drug development and emergence of novel agents, we analyzed the characteristics and outcomes of HCC patients treated on early phase trials with an emphasis on targeted therapies.MethodsWe reviewed the records of consecutive HCC patients evaluated in the Phase I Clinical Trials Program at MD Anderson from March 2004.ResultsThirty-nine patients were not treated due to poor performance status (n = 22, 56%) and decision to pursue alternate therapies (n = 10, 27%). Of 61 treated patients (median age, 60 years; median prior therapies, 3), eight patients (13%) attained stable disease lasting ≥6 months; four (7%) had a partial response, mainly with anti-angiogenic or multikinase inhibitors. Median Phase I progression-free survival (PFS) was 2.6 months versus 4.4 months (p 0.019) and 4.1 months (p 0.27) for their first-, and second-line FDA-approved therapy. Molecular analysis showed frequent PTEN loss (10/19 patients, 53%) and P53 mutation (4/4 patients tested). On multivariate analysis, independent factors predicting shorter survival were white ethnicity/race (p 0.031), cirrhosis (p 0.016), and serum sodium (p 0.0013).ConclusionsIn our heavily-pretreated HCC patients, the phase I PFS was comparable to that of 2nd-line therapy, highlighting a potential role for clinical trials after progression on first-line therapy. The response rate (SD>6 months/PR) of 20% was observed with early signals of activity in regimens combining inhibitors of angiogenesis, multiple kinases and mTOR with preliminary molecular analysis revealing prevalence of PTEN loss.
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- 2015
45. Erratum: Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies
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Janku, Filip, Angenendt, Philipp, Tsimberidou, Apostolia M, Fu, Siqing, Naing, Aung, Falchook, Gerald S, Hong, David S, Holley, Veronica R, Cabrilo, Goran, Wheler, Jennifer J, Piha-Paul, Sarina A, Zinner, Ralph G, Bedikian, Agop Y, Overman, Michael J, Kee, Bryan K, Kim, Kevin B, Kopetz, E Scott, Luthra, Rajyalakshmi, Diehl, Frank, Meric-Bernstam, Funda, and Kurzrock, Razelle
- Subjects
Oncology and Carcinogenesis - Abstract
The Abstract is incorrect in PubMed. The corrected Abstract is provided here.
- Published
- 2015
46. Dose-finding study of hepatic arterial infusion of irinotecan-based treatment in patients with advanced cancers metastatic to the liver
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Said, Rabih, Kurzrock, Razelle, Naing, Aung, Hong, David S, Fu, Siqing, Piha-Paul, Sarina A, Wheler, Jennifer J, Janku, Filip, Kee, Bryan K, Bidyasar, Savita, Lim, Joann, Wallace, Michael, and Tsimberidou, Apostolia M
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Digestive Diseases ,Clinical Trials and Supportive Activities ,Clinical Research ,Cancer ,Liver Disease ,6.2 Cellular and gene therapies ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Adult ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,Phytogenic ,Antineoplastic Combined Chemotherapy Protocols ,Bevacizumab ,Camptothecin ,Cetuximab ,Female ,Hepatic Artery ,Humans ,Infusions ,Intra-Arterial ,Infusions ,Intravenous ,Irinotecan ,Liver Neoplasms ,Male ,Maximum Tolerated Dose ,Middle Aged ,Organoplatinum Compounds ,Oxaliplatin ,Liver metastasis ,Phase I trial ,Hepatic arterial infusion ,UGT1A ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Pharmacology and pharmaceutical sciences - Abstract
BackgroundLiver metastases are associated with a poor prognosis. We investigated the use of hepatic arterial infusion (HAI) of irinotecan combination therapy in patients with liver metastases.Patients and methodsPatients with histologically confirmed advanced cancer with liver metastases that was refractory to standard therapy were eligible. A standard "3 + 3" phase I study design was used to determine the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). Three cohorts were evaluated: HAI of irinotecan with systemic intravenous (IV) (a) bevacizumab, (b) oxaliplatin and bevacizumab, or (c) bevacizumab and cetuximab.ResultsFrom October 2009 through December 2013, 98 patients with various tumor types were enrolled (median age, 62 years, range, 34-85; and median number of prior therapies, 4, range, 1-11). In cohorts A and C, dose escalation continued until the highest dose level-considered the MTD-was reached. In cohort B, dose escalation continued until dose level 3, and dose level 2 was considered the MTD. Rates of grade 3/4 adverse events were as follows: diarrhea, 8 %; fatigue, 4 %; neutropenia, 4 %; thrombocytopenia, 2 %; and skin rash, 2 %. Seventy-seven patients were evaluable for response. Partial response was noted in 5 (6.5 %) patients (neuroendocrine cancer, n = 2; CRC, n = 2; NSCLC, n = 1); and stable disease ≥ 6 months in 17 (22.1 %) patients (CRC, n = 13; breast, n = 1; neuroendocrine, n = 1; NSCLC, n = 1; pancreatic, n = 1).ConclusionsHAI irinotecan in combination with bevacizumab; oxaliplatin plus bevacizumab; or cetuximab plus bevacizumab was safe and may be a treatment option for selected patients with advanced cancer and liver involvement.
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- 2015
47. A first-in-human study of AMG 208, an oral MET inhibitor, in adult patients with advanced solid tumors
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Hong, David S, Rosen, Peter, Lockhart, A Craig, Fu, Siqing, Janku, Filip, Kurzrock, Razelle, Khan, Rabia, Amore, Benny, Caudillo, Isaac, Deng, Hongjie, Hwang, Yuying C, Loberg, Robert, Ngarmchamnanrith, Gataree, Beaupre, Darrin M, and Lee, Peter
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Hematology ,Urologic Diseases ,Prostate Cancer ,Cancer ,Clinical Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions ,Administration ,Oral ,Adult ,Aged ,Aged ,80 and over ,Area Under Curve ,Biomarkers ,Tumor ,Dose-Response Relationship ,Drug ,Fatigue ,Female ,Humans ,Hypertension ,Immunohistochemistry ,In Situ Hybridization ,Fluorescence ,Male ,Metabolic Clearance Rate ,Middle Aged ,Nausea ,Neoplasms ,Protein Kinase Inhibitors ,Proto-Oncogene Proteins c-met ,Pyridazines ,Remission Induction ,Treatment Outcome ,Triazoles ,MET ,first-in-human ,solid tumors ,prostate cancer ,small molecule ,Oncology and Carcinogenesis - Abstract
BackgroundThis first-in-human study evaluated AMG 208, a small-molecule MET inhibitor, in patients with advanced solid tumors.MethodsThree to nine patients were enrolled into one of seven AMG 208 dose cohorts (25, 50, 100, 150, 200, 300, and 400 mg). Patients received AMG 208 orally on days 1 and days 4-28 once daily. The primary objectives were to evaluate the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) of AMG 208.ResultsFifty-four patients were enrolled. Six dose-limiting toxicities were observed: grade 3 increased aspartate aminotransferase (200 mg), grade 3 thrombocytopenia (200 mg), grade 4 acute myocardial infarction (300 mg), grade 3 prolonged QT (300 mg), and two cases of grade 3 hypertension (400 mg). The MTD was not reached. The most frequent grade ≥3 treatment-related adverse event was anemia (n = 3) followed by hypertension, prolonged QT, and thrombocytopenia (two patients each). AMG 208 exposure increased linearly with dose; mean plasma half-life estimates were 21.4-68.7 hours. One complete response (prostate cancer) and three partial responses (two in prostate cancer, one in kidney cancer) were observed.ConclusionsIn this study, AMG 208 had manageable toxicities and showed evidence of antitumor activity, particularly in prostate cancer.
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- 2015
48. Challenges and perspective of drug repurposing strategies in early phase clinical trials
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Kato, Shumei, Moulder, Stacy L, Ueno, Naoto T, Wheler, Jennifer J, Meric-Bernstam, Funda, Kurzrock, Razelle, and Janku, Filip
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Orphan Drug ,Prevention ,Cancer ,Clinical Trials and Supportive Activities ,Rare Diseases ,Clinical Research ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,5.9 Resources and infrastructure (treatment development) ,Good Health and Well Being ,Drug repurposing ,cancer ,drug development ,early phase trial - Abstract
Despite significant investments in the development of new agents only 5% of cancer drugs entering Phase I clinical trials are ultimately approved for routine clinical cancer care. Drug repurposing strategies using novel combinations of previously tested anticancer agents could reduce the cost and improve treatment outcomes. At MD Anderson Cancer Center, early phase clinical trials with drug repurposing strategies demonstrated promising outcomes in patients with both rare and common treatment refractory advanced cancers. Despite clinical efficacy advancing drug repurposing strategies in the clinical trial trajectory beyond early phase studies has been challenging mainly due to lack of funding and interest from the pharmaceutical industry. In this review, we delineate our experience and challenges with drug repurposing strategies.
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- 2015
49. Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies
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Janku, Filip, Angenendt, Philipp, Tsimberidou, Apostolia M, Fu, Siqing, Naing, Aung, Falchook, Gerald S, Hong, David S, Holley, Veronica R, Cabrilo, Goran, Wheler, Jennifer J, Piha-Paul, Sarina A, Zinner, Ralph G, Bedikian, Agop Y, Overman, Michael J, Kee, Bryan K, Kim, Kevin B, Kopetz, E Scott, Luthra, Rajyalakshmi, Diehl, Frank, Meric-Bernstam, Funda, and Kurzrock, Razelle
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Clinical Research ,Cancer ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Adult ,Aged ,Aged ,80 and over ,Biomarkers ,Tumor ,Class I Phosphatidylinositol 3-Kinases ,DNA Mutational Analysis ,DNA ,Neoplasm ,Female ,Genes ,erbB-1 ,Humans ,Kaplan-Meier Estimate ,Male ,Middle Aged ,Neoplasms ,Phosphatidylinositol 3-Kinases ,Proto-Oncogene Proteins B-raf ,Proto-Oncogene Proteins p21(ras) ,Young Adult ,EGFR ,BRAF ,KRAS ,PIK3CA ,cell-free DNA ,Oncology and carcinogenesis - Abstract
Cell-free (cf) DNA in the plasma of cancer patients offers an easily obtainable source of biologic material for mutation analysis. Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS, and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures. Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.75, 95% confidence interval [CI] 0.63 - 0.88), in 99% cases for EGFR mutations (kappa = 0.90, 95% CI 0.71- 1.00), in 83% cases for KRAS mutations (kappa = 0.67, 95% CI 0.54 - 0.80) and in 91% cases for PIK3CA mutations (kappa = 0.65, 95% CI 0.46 - 0.85). Patients (n = 41) with > 1% of KRAS mutant cfDNA had a shorter median survival compared to 20 patients with 1% of mutant cfDNA (BRAF, EGFR, KRAS, or PIK3CA) had a shorter median survival compared to 33 patients with
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- 2015
50. Castleman's disease and sarcoidosis, a rare association resulting in a "mixed" response: a case report.
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Mohammed, Anwarullah, Janku, Filip, Qi, Ming, and Kurzrock, Razelle
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Lymph Nodes ,Humans ,Sarcoidosis ,Prednisone ,Antineoplastic Agents ,Antibodies ,Monoclonal ,Positron-Emission Tomography ,Aged ,Male ,Castleman Disease ,Antibodies ,Monoclonal ,Giant Lymph Node Hyperplasia ,Other Medical and Health Sciences ,General & Internal Medicine - Abstract
IntroductionMulticentric Castleman's disease is a rare lymphoproliferative disorder whose hallmark is atypical lymph node hyperplasia. Symptoms can include fever, splenomegaly, and abnormal blood cell counts. High levels of interleukin 6 (IL-6) are observed frequently in this disorder and are believed to drive the disease. Recently, therapies that target interleukin-6 or its receptor have been shown to be effective in Castleman's disease.Case presentationWe report the case of a 76-year-old Caucasian man with aggressive biopsy-proven Castleman's disease who experienced pulmonary and lymph node involvement, as well as fever and weight loss. He was treated with siltuximab, a chimeric anti-interleukin-6 antibody. After 5 months, fluorodeoxyglucose positron emission tomography computed tomography scans showed marked improvement in his lungs, but worsening mediastinal disease, consistent with a mixed response. Biopsy of the mediastinal disease revealed lymphoplasmacytic infiltrate with non-caseating, ill-defined granulomas and scarring consistent with sarcoidosis. Prednisone 50mg by mouth daily was started, which was tapered to 2.0-5.0mg daily. Siltuximab was continued. A subsequent fluorodeoxyglucose positron emission tomography computed tomography scan showed near-complete resolution of lung and mediastinal disease, now ongoing for 3.5+ years without serious adverse events.ConclusionsLymphomas have previously been reported to coexist with sarcoidosis, albeit rarely, but there has been only a single previous case of this type with Castleman's disease. Of importance, early recognition of the presence of sarcoidosis in our patient prevented discontinuation of siltuximab therapy due to "progression". Our experience may also have broader implications in that it suggests that etiology of "mixed responses" should be confirmed by performing biopsies on the progressive tumor.
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- 2015
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