Abstract
Background: BRAF inhibitors are effective against selected BRAF V600 -mutated tumors. Preclinical data suggest that BRAF inhibition in conjunction with chemotherapy has increased therapeutic activity. Methods: Patients with advanced cancers and BRAF mutations were enrolled into a dose-escalation study (3+3 design) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Results: Nineteen patients with advanced cancers and BRAF mutations were enrolled and received vemurafenib (480-720 mg orally twice a day), carboplatin (area under the curve [AUC] 5-6 intravenously every 3 weeks), and paclitaxel (100-135 mg/m 2 intravenously every 3 weeks). The MTD was not reached, and vemurafenib at 720 mg twice a day, carboplatin at AUC 5, and paclitaxel at 135 mg/m 2 were the last safe dose levels. DLTs included a persistent grade 2 creatinine elevation (n = 1), grade 3 transaminitis (n = 1), and grade 4 thrombocytopenia (n = 1). Non–dose-limiting toxicities that were grade 3 or higher and occurred in more than 2 patients included grade 3/4 neutropenia (n = 5), grade 3/4 thrombocytopenia (n = 5), grade 3 fatigue (n = 4), and grade 3 anemia (n = 3). Of the 19 patients, 5 (26%; all with melanoma) had a partial response (PR; n = 4) or complete response (CR; n = 1); these responses were mostly durable and lasted 3.1 to 54.1 months. Of the 13 patients previously treated with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, 4 (31%) had a CR (n = 1) or PR (n = 3). Patients not treated with prior platinum therapy had a higher response rate than those who did (45% vs 0%; P =.045). Conclusions: The combination of vemurafenib, carboplatin, and paclitaxel is well tolerated and demonstrates encouraging activity, predominantly in patients with advanced melanoma and BRAF V600 mutations, regardless of prior treatment with BRAF and/or MEK inhibitors.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 463-472 |
| Number of pages | 10 |
| Journal | Cancer |
| Volume | 125 |
| Issue number | 3 |
| DOIs | |
| State | Published - Feb 1 2019 |
Keywords
- BRAF mutation
- carboplatin
- paclitaxel
- vemurafenib
ASJC Scopus subject areas
- Oncology
- Cancer Research
MD Anderson CCSG core facilities
- Clinical and Translational Research Center
- Clinical Trials Office
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In: Cancer, Vol. 125, No. 3, 01.02.2019, p. 463-472.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Phase 1 study of the combination of vemurafenib, carboplatin, and paclitaxel in patients with BRAF-mutated melanoma and other advanced malignancies
AU - Bhatty, Minny
AU - Kato, Shumei
AU - Piha-Paul, Sarina A.
AU - Naing, Aung
AU - Subbiah, Vivek
AU - Huang, Helen J.
AU - Karp, Daniel D.
AU - Tsimberidou, Apostolia M.
AU - Zinner, Ralph G
AU - Hwu, Wen-Jen
AU - Javle, Milind
AU - Patel, Sapna P.
AU - Hu, Mimi I.
AU - Varadhachary, Gauri R.
AU - Conley, Anthony P.
AU - Ramzanali, Nishma M.
AU - Holley, Veronica R.
AU - Kurzrock, Razelle
AU - Meric-Bernstam, Funda
AU - Kwang Chae, Young
AU - Kim, Kevin B.
AU - Falchook, Gerald S.
AU - Janku, Filip
N1 - Funding Information: Apostolia M. Tsimberidou reports a research grant from Foundation Medicine during the conduct of the study. Anthony P. Conley reports personal fees from Novartis Pharmaceuticals, Nektar Therapeutics, and Ignyta, Inc, outside the submitted work. Filip Janku has research support from Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, Piqur, Symphogen, and Upsher-Smith Laboratories; is on the scientific advisory boards of Guardant Health, IFM Therapeutics, Synlogic, and Deciphera; is a paid consultant for Trovagene and Immunomet; and has ownership interests in Trovagene. Funding Information: This study was supported by the National Center for Advancing Translational Sciences (UL1 TR000371), the National Institutes of Health through MD Anderson’s Cancer Center Support Grant (P30 CA016672), the Sidney Kimmel Foundation for Cancer Research (to Filip Janku), and the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy (to Filip Janku). Funding Information: Minny Bhatty: Data collection, data analysis, and manuscript writing and approval. Shumei Kato: Data collection, data analysis, and manuscript writing and approval. Sarina A. Piha-Paul: Provision of study materials or patients and manuscript writing and approval. Aung Naing: Provision of study materials or patients and manuscript writing and approval. Vivek Subbiah: Provision of study materials or patients and manuscript writing and approval. Helen J. Huang: Data collection, data analysis, and manuscript writing and approval. Daniel D. Karp: Provision of study materials or patients and manuscript writing and approval. Apostolia M. Tsimberidou: Provision of study materials or patients and manuscript writing and approval. Ralph G. Zinner: Provision of study materials or patients and manuscript writing and approval. Wen-Jen Hwu: Provision of study materials or patients and manuscript writing and approval. Milind Javle: Provision of study materials or patients and manuscript writing and approval. Sapna P. Patel: Provision of study materials or patients and manuscript writing and approval. Mimi I. Hu: Provision of study materials or patients and manuscript writing and approval. Gauri R. Varadhachary: Provision of study materials or patients and manuscript writing and approval. Anthony P. Conley: Provision of study materials or patients and manuscript writing and approval. Nishma M. Ramzanali: Data collection and manuscript writing and approval. Veronica R. Holley: Data collection and manuscript writing and approval. Razelle Kurzrock: Conception and design and manuscript writing and approval. Funda Meric-Bernstam: Provision of study materials or patients and manuscript writing and approval. Young Kwang Chae: Conception and design and manuscript writing and approval. Kevin B. Kim: Conception and design and manuscript writing and approval. Gerald S. Falchook: Conception and design, provision of study materials or patients, and manuscript writing and approval. Filip Janku: Conception and design, data collection, data analysis, provision of study materials or patients, manuscript writing and approval, and responsibility for the overall content. Apostolia M. Tsimberidou reports a research grant from Foundation Medicine during the conduct of the study. Anthony P. Conley reports personal fees from Novartis Pharmaceuticals, Nektar Therapeutics, and Ignyta, Inc, outside the submitted work. Filip Janku has research support from Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, Piqur, Symphogen, and Upsher-Smith Laboratories; is on the scientific advisory boards of Guardant Health, IFM Therapeutics, Synlogic, and Deciphera; is a paid consultant for Trovagene and Immunomet; and has ownership interests in Trovagene. This study was supported by the National Center for Advancing Translational Sciences (UL1 TR000371), the National Institutes of Health through MD Anderson?s Cancer Center Support Grant (P30 CA016672), the Sidney Kimmel Foundation for Cancer Research (to Filip Janku), and the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy (to Filip Janku). This was an open-label, nonrandomized, 3+3 dose-escalation phase 1 study of the combination of vemurafenib, carboplatin, and paclitaxel in patients with BRAF-mutated advanced cancers (NCT01636622). The primary endpoints were to establish the regimen?s MTD or recommended phase 2 dose and to evaluate its dose-limiting toxicities (DLTs) and safety. The secondary endpoints were to evaluate early signals of efficacy such as the response rate. The study was performed at The University of Texas MD Anderson Cancer Center. The study protocol was approved by MD Anderson?s institutional review board. All patients provided written informed consent before starting study-related procedures. Eligible patients had a histologically or cytologically confirmed diagnosis of a refractory advanced solid tumor harboring a BRAF mutation detected in a Clinical Laboratory Improvement Amendments?approved laboratory, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (version 1.1), and had been off prior systemic cancer therapies for at least 3 weeks (in the case of chemotherapy) or 5 half-lives (in the case of biologic treatments except for BRAF inhibitors, which required no washout). Other inclusion criteria included a QTc interval < 500 milliseconds; an Eastern Cooperative Oncology Group performance status of 0 to 2; and adequate bone marrow, liver, and renal function (total bilirubin level ? 2 ? upper limit of normal [ULN]; aspartate aminotransferase and alanine aminotransferase levels ? 2.5 ? ULN or, if liver metastasis was present, ? 5 ? ULN; serum creatinine level ? 2 ? ULN; platelet count > 75,000/mL; absolute neutrophil count > 1000/mL; and hemoglobin level >8.0 g/dL). Treatment dose levels are given in Table. Vemurafenib (480-720 mg) was given orally twice daily for 21 days and was started the evening of the day after the administration of paclitaxel (100-135 mg/m2) and carboplatin (area under the curve [AUC] 5-6). Paclitaxel and carboplatin were given intravenously on day 1 of the 21-day cycle until disease progression or unacceptable toxicity. Safety was assessed with the National Cancer Institute?s Common Terminology Criteria for Adverse Events (version 4), and DLTs were evaluated during the first 21 days of therapy. Abbreviations: AST, aspartate aminotransferase; AUC, area under the curve; bid, twice a day; DLT, dose-limiting toxicity; iv, intravenously; po, by mouth. DLTs were treatment-related grade 3 or higher hemolytic anemia; grade 4 thrombocytopenia; grade 3 or higher febrile neutropenia; grade 4 neutropenia lasting longer than 7 consecutive days; a grade 3 creatinine elevation; a grade 3 elevation of bilirubin, alanine aminotransferase, or aspartate aminotransferase; any other grade 3 nonhematologic toxicity leading to treatment interruption for longer than 7 consecutive days; any grade 4 nonhematologic toxicity; any intolerable grade 2 or 3 nonhematologic toxicity requiring a dose reduction for the second cycle of treatment; and any treatment-related adverse events resulting in a treatment delay longer than 7 consecutive days during cycle 1. The therapy response was assessed according to the Response Evaluation Criteria in Solid Tumors (version 1.1) with computed tomography and magnetic resonance imaging performed at the baseline and then every 2 weeks. This was an open-label, nonrandomized, 3+3 dose-escalation phase 1 study of the combination of vemurafenib, carboplatin, and paclitaxel in patients with BRAF-mutated advanced cancers (NCT01636622). The primary endpoints were to establish the regimen?s MTD or recommended phase 2 dose and to evaluate its dose-limiting toxicities (DLTs) and safety. The secondary endpoints were to evaluate early signals of efficacy such as the response rate. The study was performed at The University of Texas MD Anderson Cancer Center. The study protocol was approved by MD Anderson?s institutional review board. All patients provided written informed consent before starting study-related procedures. Eligible patients had a histologically or cytologically confirmed diagnosis of a refractory advanced solid tumor harboring a BRAF mutation detected in a Clinical Laboratory Improvement Amendments?approved laboratory, had measurable disease according to the Response Evaluation Criteria in Solid Tumors (version 1.1), and had been off prior systemic cancer therapies for at least 3 weeks (in the case of chemotherapy) or 5 half-lives (in the case of biologic treatments except for BRAF inhibitors, which required no washout). Other inclusion criteria included a QTc interval < 500 milliseconds; an Eastern Cooperative Oncology Group performance status of 0 to 2; and adequate bone marrow, liver, and renal function (total bilirubin level ? 2 ? upper limit of normal [ULN]; aspartate aminotransferase and alanine aminotransferase levels ? 2.5 ? ULN or, if liver metastasis was present, ? 5 ? ULN; serum creatinine level ? 2 ? ULN; platelet count > 75,000/mL; absolute neutrophil count > 1000/mL; and hemoglobin level >8.0 g/dL). Treatment dose levels are given in Table. Vemurafenib (480-720 mg) was given orally twice daily for 21 days and was started the evening of the day after the administration of paclitaxel (100-135 mg/m2) and carboplatin (area under the curve [AUC] 5-6). Paclitaxel and carboplatin were given intravenously on day 1 of the 21-day cycle until disease progression or unacceptable toxicity. Safety was assessed with the National Cancer Institute?s Common Terminology Criteria for Adverse Events (version 4), and DLTs were evaluated during the first 21 days of therapy. Abbreviations: AST, aspartate aminotransferase; AUC, area under the curve; bid, twice a day; DLT, dose-limiting toxicity; iv, intravenously; po, by mouth. DLTs were treatment-related grade 3 or higher hemolytic anemia; grade 4 thrombocytopenia; grade 3 or higher febrile neutropenia; grade 4 neutropenia lasting longer than 7 consecutive days; a grade 3 creatinine elevation; a grade 3 elevation of bilirubin, alanine aminotransferase, or aspartate aminotransferase; any other grade 3 nonhematologic toxicity leading to treatment interruption for longer than 7 consecutive days; any grade 4 nonhematologic toxicity; any intolerable grade 2 or 3 nonhematologic toxicity requiring a dose reduction for the second cycle of treatment; and any treatment-related adverse events resulting in a treatment delay longer than 7 consecutive days during cycle 1. The therapy response was assessed according to the Response Evaluation Criteria in Solid Tumors (version 1.1) with computed tomography and magnetic resonance imaging performed at the baseline and then every 2 weeks. Whole blood was collected in ethylenediaminetetraacetic acid?containing tubes and was centrifuged and spun twice within 2 hours to yield plasma. The QIAamp circulating nucleic acid kit (Qiagen, Valencia, California) was used to isolate cfDNA according to the manufacturer?s instructions. At least 8 ng (if available) of unamplified cfDNA was tested with a droplet digital polymerase chain reaction (ddPCR) BRAFV600E mutation?specific assay and/or multiplex BRAFV600 screening kit (Bio-Rad, Pleasanton, California) to distinguish the wild-type allele from the 3 most common mutations (BRAFV600E, BRAFV600K, and BRAFV600R); with a multiplex ddPCR KRASG12/G13 screening kit (Bio-Rad) to distinguish the wild-type allele from the 7 most common mutations (KRASG12A, KRASG12C, KRASG12D, KRASG12R, KRASG12S, KRASG12V, and KRASG13D); with a multiplex ddPCR NRASG12/G13 screening kit (Bio-Rad) to distinguish the wild-type allele from the 8 most common mutations (NRASG12A, NRASG12C, NRASG12D, NRASG12S, NRASG12V, NRASG13D, NRASG13R, and NRASG13V); and with a multiplex ddPCR NRASQ61 screening kit (Bio-Rad) to distinguish the wild-type allele from the 5 most common mutations (NRASQ61K, NRASQ61L, NRASQ61R, NRASQ61H 183A>T, and NRASQ61H 183A>C) with the QX200 ddPCR system (Bio-Rad) according to the manufacturer?s standard protocol. The lower limit of detection was an approximately 0.2% mutant allele frequency for the multiplexed screening assay and a <0.1% mutant allele frequency per single well for the mutation-specific assays. The PFS duration was defined as the time from the initiation of systemic therapy to the date of disease progression or death from any cause. The overall survival (OS) duration was defined as the time from the initiation of systemic therapy to the date of death or last follow-up. The Kaplan-Meier method was used to estimate PFS and OS, and a log-rank test was used to compare PFS or OS among patient subgroups. All tests were 2-sided, and P values <.05 were considered statistically significant. Statistical analyses were performed with the SPSS 21 software program (SPSS, Chicago, Illinois). Publisher Copyright: © 2018 American Cancer Society
PY - 2019/2/1
Y1 - 2019/2/1
N2 - Background: BRAF inhibitors are effective against selected BRAF V600 -mutated tumors. Preclinical data suggest that BRAF inhibition in conjunction with chemotherapy has increased therapeutic activity. Methods: Patients with advanced cancers and BRAF mutations were enrolled into a dose-escalation study (3+3 design) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Results: Nineteen patients with advanced cancers and BRAF mutations were enrolled and received vemurafenib (480-720 mg orally twice a day), carboplatin (area under the curve [AUC] 5-6 intravenously every 3 weeks), and paclitaxel (100-135 mg/m 2 intravenously every 3 weeks). The MTD was not reached, and vemurafenib at 720 mg twice a day, carboplatin at AUC 5, and paclitaxel at 135 mg/m 2 were the last safe dose levels. DLTs included a persistent grade 2 creatinine elevation (n = 1), grade 3 transaminitis (n = 1), and grade 4 thrombocytopenia (n = 1). Non–dose-limiting toxicities that were grade 3 or higher and occurred in more than 2 patients included grade 3/4 neutropenia (n = 5), grade 3/4 thrombocytopenia (n = 5), grade 3 fatigue (n = 4), and grade 3 anemia (n = 3). Of the 19 patients, 5 (26%; all with melanoma) had a partial response (PR; n = 4) or complete response (CR; n = 1); these responses were mostly durable and lasted 3.1 to 54.1 months. Of the 13 patients previously treated with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, 4 (31%) had a CR (n = 1) or PR (n = 3). Patients not treated with prior platinum therapy had a higher response rate than those who did (45% vs 0%; P =.045). Conclusions: The combination of vemurafenib, carboplatin, and paclitaxel is well tolerated and demonstrates encouraging activity, predominantly in patients with advanced melanoma and BRAF V600 mutations, regardless of prior treatment with BRAF and/or MEK inhibitors.
AB - Background: BRAF inhibitors are effective against selected BRAF V600 -mutated tumors. Preclinical data suggest that BRAF inhibition in conjunction with chemotherapy has increased therapeutic activity. Methods: Patients with advanced cancers and BRAF mutations were enrolled into a dose-escalation study (3+3 design) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Results: Nineteen patients with advanced cancers and BRAF mutations were enrolled and received vemurafenib (480-720 mg orally twice a day), carboplatin (area under the curve [AUC] 5-6 intravenously every 3 weeks), and paclitaxel (100-135 mg/m 2 intravenously every 3 weeks). The MTD was not reached, and vemurafenib at 720 mg twice a day, carboplatin at AUC 5, and paclitaxel at 135 mg/m 2 were the last safe dose levels. DLTs included a persistent grade 2 creatinine elevation (n = 1), grade 3 transaminitis (n = 1), and grade 4 thrombocytopenia (n = 1). Non–dose-limiting toxicities that were grade 3 or higher and occurred in more than 2 patients included grade 3/4 neutropenia (n = 5), grade 3/4 thrombocytopenia (n = 5), grade 3 fatigue (n = 4), and grade 3 anemia (n = 3). Of the 19 patients, 5 (26%; all with melanoma) had a partial response (PR; n = 4) or complete response (CR; n = 1); these responses were mostly durable and lasted 3.1 to 54.1 months. Of the 13 patients previously treated with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, 4 (31%) had a CR (n = 1) or PR (n = 3). Patients not treated with prior platinum therapy had a higher response rate than those who did (45% vs 0%; P =.045). Conclusions: The combination of vemurafenib, carboplatin, and paclitaxel is well tolerated and demonstrates encouraging activity, predominantly in patients with advanced melanoma and BRAF V600 mutations, regardless of prior treatment with BRAF and/or MEK inhibitors.
KW - BRAF mutation
KW - carboplatin
KW - paclitaxel
KW - vemurafenib
UR - http://www.scopus.com/inward/record.url?scp=85055952073&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055952073&partnerID=8YFLogxK
U2 - 10.1002/cncr.31812
DO - 10.1002/cncr.31812
M3 - Article
C2 - 30383888
AN - SCOPUS:85055952073
SN - 0008-543X
VL - 125
SP - 463
EP - 472
JO - Cancer
JF - Cancer
IS - 3
ER -