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Safety and Tolerability of DS-7423 in Subjects With Advanced Solid Malignant Tumors

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ClinicalTrials.gov Identifier: NCT01364844
Recruitment Status : Completed
First Posted : June 3, 2011
Last Update Posted : February 25, 2014
Information provided by (Responsible Party):

Study Description
Brief Summary:

This will be a Phase 1, open-label study of DS-7423 to assess its safety and tolerability, identify a RP2D, (recommended Phase 2 Dose) and assess its Pharmacokinetics (PK) (what your body does to process the drugs and how your body gets them out of your system.) and pharmacodynamics (PDy) (Pharmacodynamics is a study of what a drug does to your body) properties in subjects with advanced solid malignant tumors. This study will include 2 parts: part 1-Dose Escalation and part 2-Dose Expansion.

Study Hypothesis: DS-7423 will be safe and tolerable, and will exhibit acceptable PK and PDy properties in subjects with advanced solid malignant tumors for whom standard therapy has failed or for whom no standard therapy exists.

Condition or disease Intervention/treatment Phase
Solid Tumor Colorectal Cancer Endometrial Cancer Drug: DS-7423 Phase 1

Detailed Description:
Part 1 : Dose-escalation of DS-7423 to determine maximum tolerated dose (MTD) in subjects with advanced solid tumors Part 2 : Dose Expansion: The purpose of Part 2 of this clinical research study is to confirm the safety and tolerability of the MTD of DS-7423 identified in Part 1, and measure the effects of DS-7423 on your cancer. Part 2 will be conducted in subjects with advanced colorectal or endometrial cancer.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Multiple-Escalating-Dose Study of DS-7423, an Orally Administered Dual PI3K/mTOR Inhibitor, in Subjects With Advanced Solid Tumors
Study Start Date : July 2011
Primary Completion Date : November 2013
Study Completion Date : November 2013
Arms and Interventions

Arm Intervention/treatment
Experimental: DS7423 Drug: DS-7423
oral capsule 1mg, 8mg, 48mg, and 80mg strengths administered once daily

Outcome Measures

Primary Outcome Measures :
  1. Adverse Events [ Time Frame: 30 days after last dose ]
    All adverse events will be graded according to the NCI-CTCAE, version 4.0

Secondary Outcome Measures :
  1. Plasma pharmacokinetics of DS-7423 [ Time Frame: Cycle 1 - days 1, 2, 8, and 15; Cycle 2 - day 1; end of study ]
    The various pharmacokinetic parameters will be calculated from plasma concentrations of DS-7423 using non-compartmental analyses.

  2. Effects of DS-7423 on glucose metabolism [ Time Frame: Cycle 1 Days 1, 2, and 15; and end-of-study ]
    The effects of DS-7423 on glucose metabolism will be determined by measuring glucose and C-peptide levels

  3. Pharmacodynamic effects of DS-7423 in surrogate tissues [ Time Frame: Cycle 1 Days 1, 2, and 15 ]
    The pharmacodynamic effects of DS-7423 will be determined by measuring phosphorylation of Akt in platelet-rich plasma

  4. Pharmacodynamic effects of DS-7423 in tumors [ Time Frame: Baseline and Cycle 1 Day 4 ]
    The pharmacodynamic effects of DS-7423 will be determined by measuring tumor glucose uptake using (18F) fluorodeoxyglucose-positron emission tomography

  5. Part 2 - Objective response rate in subjects with advanced colorectal and endometrial cancer [ Time Frame: Baseline and every 2 cycles of treatment for the first 8 cycles and then every 3 cycles thereafter until study drug discontinuation ]
    Objective response rate = the sum of complete response [CR] and partial response [PR] rates as measured using Response Evaluation Criteria in Solid Tumors (RECIST) criteria Version 1.1

  6. Part 2 - Pharmacodynamic effects of DS-7423 in tumors [ Time Frame: Baseline and Cycle 1 Day 15 ]
    The pharmacodynamic effects of DS-7423 in tumors will be determined by measuring Akt, ribosomal protein S6 (S6), and proline-rich Akt substrate, 40 kDA (PRAS40) phosphorylation in pre- and posttreatment tumor biopsies

Eligibility Criteria

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • A pathologically documented advanced solid malignant tumor refractory to standard treatment or for which no standard treatment is available
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Have adequate bone marrow function, defined as:

Platelet count >= 100 X 10^9/L Hemoglobin (Hb) level >= 9.0 g/dL ANC >= 1.5 X 10^9/L - Have adequate renal function, defined as: Creatinine clearance >= 60 mL/min, as calculated using the modified Cockroft Gault equation, ([{140 - age in yrs} x {actual weight in kg}] divided by [{72 x serum creatinine in mg/dL} multiply by 0.85 if female]), or creatinine =< 1.5 X ULN

- Have adequate hepatic function, defined as: AST/ALT levels =< 3 X ULN (if liver metastases are present, =< 5 X ULN) Bilirubin =< 1.5 X ULN

- Have adequate blood clotting function, defined as: Prothrombin time and activated partial thromboplastin time =< 1.5 X ULN

  • Subjects should be able to provide written informed consent, comply with protocol visits and procedures, be able to take oral medication, and not have any active infection or chronic comorbidity that would interfere with therapy
  • Subjects (male and female) of childbearing potential must agree to use double-barrier contraceptive measures or avoid intercourse during the study and for 90 days after the last dose of study drug
  • Subjects must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects) and must sign and date an Institutional Review Board (IRB) approved informed consent form (ICF) (including Health Insurance Portability and Accountability Act (HIPAA) authorization, if applicable) before performance of any study-specific procedures or tests
  • Subjects must be willing to provide available preexisting diagnostic or resected tumor samples, such as formalin-fixed paraffin-embedded sections. Providing fresh tumor biopsy is optional for subjects in dose escalation cohorts. Pre- and posttreatment biopsies are optional for all the subjects in Dose Escalation cohorts but required for those in Dose Expansion cohorts

Additional Inclusion Criteria for Part 2 (Dose Expansion)

  • A pathologically documented advanced colorectal or endometrial cancer, with measurable disease based on RECIST criteria, Version 1.1, that is refractory to standard treatment
  • Agree to undergo pre- and posttreatment tumor biopsies

Exclusion Criteria:

  • History of second malignancy and primary central nervous system malignancies, except adequately treated nonmelanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated, with no evidence of disease for >= 3 years
  • Gastrointestinal diseases that could affect the absorption of DS-7423
  • Subjects with a fasting glucose > 126 mg/dL (> 7 mmol/L)
  • History of diabetes mellitus (Type I or II) or hemoglobin A1c (HbA1c) > 7.0%
  • Tested positive for hepatitis B or C serological markers (HBsAg or antiHCV)
  • Recipient of live vaccine within 1 month of or during study drug treatment
  • Concomitant use of chronic systemic corticosteroids
  • Subjects requiring daily supplemental oxygen
  • Recipient of a stem cell or bone marrow transplant
  • Has a concomitant medical condition that would increase the risk of toxicity, in the opinion of the investigator or sponsor
  • Clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 4 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (2 weeks for stereotactic radiotherapy)
  • Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI CTCAE, Version 4.0, grade =< 1 or baseline. Subjects with chronic grade 2 toxicities may be eligible per the discretion of the investigator or sponsor (eg, grade 2 chemotherapy-induced neuropathy)
  • Systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or hormonal therapy within 3 weeks before study drug treatment; or treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment; or treatment with small-molecule targeted agents within 2 weeks, or 5 half-lives before study drug treatment, whichever is longer. Previous and concurrent use of hormone replacement therapy, the use of gonadotropin-releasing hormone modulators for prostate cancer, and the use of somatostatin analogs for neuroendocrine tumors are permitted if such therapy has not been changed within 60 days before study drug treatment
  • Therapeutic radiation therapy or major surgery within 4 weeks before study drug treatment or palliative radiation therapy within 2 weeks before study drug treatment
  • Participation in a clinical study within 3 weeks (2 weeks or 5 half-lives, whichever is longer, for small-molecule targeted agents) before study drug treatment, or current participation in other investigational procedures
  • Concomitant treatment with strong inducers or strong inhibitors of cytochrome P450 (CYP) 3A4/5, and CYP2C8
  • Prolongation of corrected QT interval by Fridericia's method (QTcF) at rest, where the mean QTcF interval is > 450 millisecond (ms) for males and > 470 ms for females based on triplicate ECG
  • Pregnant or breastfeeding
  • Substance abuse or medical, psychological, or social conditions that may, in the opinion of the investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results
  • Prior NCI CTCAE, Version 4.0, grade 3/4 toxicity from a dual phosphatidylinositol 3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor (including, but not limited to, BEZ-235, XL765, GDC-0980, SF1126, GSK2126458, PF4691502, and PF05212384), requiring dose reduction and/or study discontinuation

Additional Exclusion Criteria for Part 2 (Dose Expansion)

- Prior treatment with a dual PI3K/ mTOR inhibitor (including, but not limited to, BEZ-235, XL765, GDC-0980, SF1126, GSK2126458, PF4691502, and PF05212384)

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01364844

United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Tennessee
Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
Daiichi Sankyo, Inc.
More Information

Responsible Party: Daiichi Sankyo, Inc.
ClinicalTrials.gov Identifier: NCT01364844     History of Changes
Other Study ID Numbers: DS7423-A-U101
First Posted: June 3, 2011    Key Record Dates
Last Update Posted: February 25, 2014
Last Verified: February 2014

Additional relevant MeSH terms:
Colorectal Neoplasms
Endometrial Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Uterine Diseases
Genital Diseases, Female