title: SU2C phase Ib study of paclitaxel and MK-2206 in advanced solid tumors and metastatic breast cancer.
abstract: BACKGROUND
  There is preclinical synergism between taxanes and MK-2206. We aim to determine the maximum tolerated dose, safety, and activity of combining MK-2206 and paclitaxel in metastatic cancer.
  
  
  METHODS
  Patients received weekly doses of paclitaxel at 80mg/m2 on day 1, followed by MK-2206 orally on day 2 escalated at 90mg, 135mg, and 200mg. Treatment continued until progression, excessive toxicity, or patient request. Blood and tissue were collected for pharmacokinetic and pharmacodynamics markers. A cycle consisted of three weeks of therapy. Dose-limiting toxicity (DLT) was defined as unacceptable toxicity during the first cycle. All statistical tests were two-sided.
  
  
  RESULTS
  Twenty-two patients were treated, nine in dose escalation and 13 in dose expansion. Median age was 55 years. Median number of cycles was four. Dose escalation was completed with no DLT. CTCAE Grade 3 or higher adverse events were fatigue (n = 2), rash (n = 2), hyperglycemia (n = 1), and neutropenia (n = 7). Four patients in the expansion phase required MK-2206 dose reduction. Phase II recommended dose was established as paclitaxel 80mg/m2 weekly on day 1, and MK-2206 135mg weekly on day 2. Paclitaxel systemic exposure was similar in the presence or absence of MK-2206. Plasma MK-2206 concentrations were similar to data from previous phase I monotherapy. There was a statistically significant decrease in expression of pAKT S473 (P = .01) and pAKT T308 (P = .002) after therapy. PI3K/AKT/mTOR downregulation in tumor tissues and circulating markers did not correlate with tumor response or clinical benefit. There were five objective responses, and nine patients had stable disease.
  
  
  CONCLUSIONS
  MK-2206 was well tolerated with paclitaxel. Preliminary antitumor activity was documented.
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Ana M
authors: AM
authors: Gonzalez-Angulo
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Ian
authors: I
authors: Krop
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Argun
authors: A
authors: Akcakanat
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Huiqin
authors: H
authors: Chen
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Shuying
authors: S
authors: Liu
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Yisheng
authors: Y
authors: Li
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Kirk S
authors: KS
authors: Culotta
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Emily
authors: E
authors: Tarco
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Sarina
authors: S
authors: Piha-Paul
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Stacy
authors: S
authors: Moulder-Thompson
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Vivianne
authors: V
authors: Velez-Bravo
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Aysegul A
authors: AA
authors: Sahin
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Laurence A
authors: LA
authors: Doyle
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Kim-Anh
authors: KA
authors: Do
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Eric P
authors: EP
authors: Winer
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Gordon B
authors: GB
authors: Mills
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD).
authors: Razelle
authors: R
authors: Kurzrock
authors: Departments of Breast Medical Oncology (AMGA, SL, SMT), Systems Biology (AMGA, GBM), Biostatistics (HC, YL, K-AD), Experimental Therapeutics (KSC), Investigational Cancer Therapeutics (AA, ET, SPP, VV-B, FMB), Pathology (AAS) and Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Hematology-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA (IK, EPW); Division of Hematology-Oncology, University of California, San Diego, CA (RK); Cancer Therapy Evaluation Program, NIH/National Cancer Institute, Rockville, MD (LAD). fmeric@mdanderson.org.
authors: Funda
authors: F
authors: Meric-Bernstam
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology*; D004334:Drug Administration Schedule; D003875:Drug Eruptions / Q000209:etiology; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology*; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D017239:Paclitaxel