Trial record 1 of 1 for:    DS2248-A-U101
Previous Study | Return to List | Next Study

A Study of DS-2248, in Subjects With Advanced Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2014 by Daiichi Sankyo Inc.
Sponsor:
Collaborator:
Daiichi Sankyo Development Ltd
Information provided by (Responsible Party):
Daiichi Sankyo Inc.
ClinicalTrials.gov Identifier:
NCT01288430
First received: February 1, 2011
Last updated: January 6, 2014
Last verified: January 2014
  Purpose

This phase 1 clinical trial is intended to understand the safety and tolerability of a new anticancer drug in subjects with advanced solid tumors. The patients who qualify for the study will receive a once daily dose of the drug taken by mouth and will undergo several tests to measure the drug in the blood and to understand the safety, tolerability and any effect of the drug on the tumor. The antitumor effect of the drug is not known in human.


Condition Intervention Phase
Solid Tumors
Non-small Cell Lung Carcinoma
Drug: DS-2248
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Multiple-Ascending-Dose Study of DS-2248, an Orally Bioavailable Heat Shock Protein 90 Inhibitor, in Subjects With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Daiichi Sankyo Inc.:

Primary Outcome Measures:
  • Objective response rate [ Time Frame: Baseline to not more than 6 months ] [ Designated as safety issue: No ]
    Objective response rate = the sum of complete response [CR] and partial response [PR] rates


Secondary Outcome Measures:
  • Progression-free survival [ Time Frame: Baseline to not more than 6 months ] [ Designated as safety issue: No ]
    Tumor response will be evaluated every 2 cycles using Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, if measurable tumors are available. Computed tomography (CT) and/or magnetic resonance imaging (MRI) should be used for tumor assessment unless another modality of disease assessment is necessary for the lesions.

  • Study Part 1 - Determine the plasma pharmacokinetics of DS-2248 [ Time Frame: Cycle 1 (Days 1, 2, 8, 15); Cycles 2, 3, (Days 1, 8, 15) ] [ Designated as safety issue: No ]
    The various pharmacokinetic parameters will be calculated from plasma concentrations of DS-2248 using non-compartmental analyses.

  • Study Part 2 - Determine the plasma pharmacokinetics of DS-2248 [ Time Frame: Day 1 for Cycle 3 and subsequent cycles ] [ Designated as safety issue: No ]
    The various pharmacokinetic parameters will be calculated from plasma concentrations of DS-2248 using non-compartmental analyses.

  • Disease control rate [ Time Frame: Baseline to not more than 6 months ] [ Designated as safety issue: No ]
    Disease control rate (DCR) = the sum of complete response rate, partial response rate, and stable disease (SD) rate for a minimum of 12 weeks

  • Response duration [ Time Frame: Baseline to not more than 6 months ] [ Designated as safety issue: No ]
  • Duration of stable disease [ Time Frame: Baseline to not more than 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 88
Study Start Date: March 2011
Estimated Study Completion Date: March 2015
Estimated Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DS-2248

Study Part 1: DS-2248 oral capsule(s) of increasing strength in a dose escalation study in subjects with advanced solid tumors, administered once daily in 21-day cycles, with no interruption between cycles if no unacceptable treatment-related toxicity or tumor progression is observed.

Study Part 2: DS-2248 oral capsule(s) dose of 4.5 mg/m2, in subjects with non-small cell lung cancer who have developed acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors or whose tumors carry an ALK translocation and are resistant to ALK inhibitor therapy, administered once daily in 21 day-cycles, with no interruption between cycles if no unacceptable treatment-related toxicity or tumor progression are observed.

Drug: DS-2248
Oral capsules, of various strengths (1, 5 , 20 ,or 50 milligrams), once daily during 21-day cycles, until unacceptable treatment-related toxicity or tumor progression are observed.

Detailed Description:

The study will be conducted in two parts. Part 1 is a dose escalation study in which subjects in each cohort will be given increasing doses of the study drug until a maximum tolerated dose (MTD) or maximum administered dose (MAD) is determined as the recommended phase 2 dose (RP2D). The drug will be administered as oral capsules once daily in 21 day cycles, with no interruption between cycles if no unacceptable treatment-related toxicity or tumor progression are observed.

After determining the RP2D, Part 2 of the study, which is a dose expansion study will begin in which subjects with advanced non-small cell lung cancer who developed acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI), erlotinib, gefitinib, afatinib (and others) or whose tumors carry an ALK translocation and are resistant to ALK inhibitor therapy, will be treated with DS-2248 at RP2D. The drug will be administered as oral capsules once daily in 21 day cycles, with no interruption between cycles if no unacceptable treatment-related toxicity or tumor progression are observed.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

    • Platelet count ≥100x10^9/L or more.
    • Hemoglobin (Hb) level ≥9.0 g/dL.
    • Absolute neutrophil count ≥1.5 x 10^9/L.
  4. Have adequate renal function, defined as:

    - Creatinine clearance ≥60 mL/min, as calculated using the modified Cockcroft-Gault equation AND creatinine ≤1.5 times upper limit of normal(ULN).

  5. Have adequate hepatic function, defined as:

    • Aspartate aminotransferase (AST) levels ≤3 times ULN (if liver metastases are present, ≤5x ULN)
    • Alanine aminotransferase (ALT) levels ≤3x ULN (if liver metastases are present, ≤5x ULN
    • Bilirubin ≤1.5x ULN
  6. Have adequate blood clotting function, defined as:

    - Prothrombin time and activated partial thromboplastin time ≤1.5x ULN

  7. 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 co-morbidity that would interfere with therapy.
  8. Subjects (male and female) of childbearing/reproductive 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. If female and of childbearing potential, must have a negative result of a pregnancy test (serum or urine)within 72 hours prior to initiating study treatment. Surgically sterile individuals and postmenopausal females are considered not having child-bearing potential.
  9. 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 approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study-specific procedures or tests.
  10. Subjects must be willing to provide pre-existing diagnostic or resected tumor samples, such as formalin-fixed paraffin-embedded sections, if available. Providing fresh pre-treatment tumor biopsy is optional for subjects in dose escalation cohorts and in dose expansion Stage 1. Post-treatment biopsies are optional for all the subjects in the study (dose escalation and dose expansion cohorts).

Additional Inclusion Criteria for Part 2 (Dose Expansion)

  1. Pathologically documented stage IIIB/IV non-small cell lung cancer.
  2. Measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST) criteria, Version 1.1.
  3. Subjects must meet 1 of the following 3 criteria in order to be included in Part 2:

    1. Acquired resistance to reversible Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor (EGFR-TKI), which should meet the following criteria:

      • Previous treatment with single-agent therapy (erlotinib, gefitinib, afatinib or others).
      • Either of the following: A tumor that harbors an EGFR mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) -OR- Prior objective clinical benefit from EGFR-TKI, as evidenced by complete response (CR), partial response (PR), or stable disease (SD) ≥6 months as defined by RECIST or World Health Organization criteria.
      • Systemic progression of disease as defined by RECIST or WHO criteria while treatment with gefitinib, erlotinib, afatinib or others.
      • No intervening therapy other than EGFR-TKIs (erlotinib, gefitinib, afatinib or others) after progression on an EGFR-TKI.
      • Pre-treatment biopsy (performed via bronchoscopy or imaging guidance) for molecular testing of the tumor is desired but not mandatory for enrollment in Stage 1. However, pre-treatment biopsy within 21 days prior to the first day of treatment is required for enrollment in Stage 2.
    2. Presence of ALK fusion gene in the tumor demonstrated by FISH and the subject has acquired resistance to ALK inhibitor therapy.

Exclusion Criteria:

  1. History of second malignancies or primary central nervous system malignancies, except adequately treated non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated, with no evidence of disease for ≥3 years.
  2. Gastrointestinal diseases that could affect the absorption of DS-2248.
  3. Subjects with peptic ulcer disease requiring on-going treatment with pH-modifiers
  4. Subjects with history of inflammatory bowel disease.
  5. Subjects with retinal or uveal diseases including macular degeneration with central vision loss, retinal detachment, diabetic retinopathy, and uveitis.
  6. Recipient of a stem cell or bone marrow transplant.
  7. Has a concomitant medical condition that would increase the risk of toxicity, in the opinion of the Investigator or Sponsor.
  8. 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).
  9. Has unresolved toxicities from previous anti-cancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (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 (e.g., Grade 2 chemotherapy-induced neuropathy).
  10. Systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or hormonal therapy (except megestrol acetate as supportive care) 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 Tyrosine Kinase Inhibitors within 7 days for erlotinib and afatinib and 10 days for gefitinib before study drug treatment. 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.
  11. Therapeutic radiation therapy or major surgery within 4 weeks before study drug treatment or palliative radiation therapy within 2 weeks before study drug treatment.
  12. Participation in a clinical drug study within 3 weeks for small-molecule TKIs before study drug treatment, or current participation in other investigational procedures.
  13. Concomitant treatment with potent inducers or potent inhibitors of cytochrome P450 3A4 (CYP3A4).
  14. Concomitant treatment with a medication known to cause renal tubular damage or reduce renal perfusion at the dose administered, including aminoglycosides, amphotericin B, pentamidine, nonsteroidal anti-inflammatory drugs, and zoledronate.
  15. Corrected QT interval (QTc by Bazett's formula) prolongation at rest, where the mean QTc interval is >450 msec based on triplicate ECG.
  16. Pregnant or breastfeeding.
  17. 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.
  18. Less than 1 week since using systemically acting drugs that increase gastric pH, such as H2-blockers and proton pump inhibitors. Antacids should be avoided within 48 hours of the first dose of DS-2248.
  19. Use of St. John's Wort (hypericin) is not permitted for 30 days before and during the study. Foods or beverages containing grapefruit should be avoided within 48 hours before and during the study.

Additional Exclusion Criteria for Part 2 (Dose Expansion)

  1. Prior treatment with Hsp90 inhibitors
  2. Intervening therapy after progression on an EGFR-TKI (erlotinib, gefitinib, afatinib or others), unless re-treated with EGFR-TKI.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01288430

Contacts
Contact: Jennifer L. Cutter, PhD 513-579-9911 ext 2526 j.cutter@medpace.com

Locations
United States, California
Recruiting
Duarte, California, United States
Recruiting
Loma Linda, California, United States
Recruiting
Orange, California, United States
United States, Florida
Recruiting
Orlando, Florida, United States
United States, Indiana
Recruiting
Indianapolis, Indiana, United States
United States, Michigan
Completed
Detroit, Michigan, United States
United States, Oregon
Recruiting
Portland, Oregon, United States
United States, Texas
Completed
San Antonio, Texas, United States
United States, Washington
Recruiting
Seattle, Washington, United States
Sponsors and Collaborators
Daiichi Sankyo Inc.
Daiichi Sankyo Development Ltd
  More Information

No publications provided

Responsible Party: Daiichi Sankyo Inc.
ClinicalTrials.gov Identifier: NCT01288430     History of Changes
Other Study ID Numbers: DS2248-A-U101, 2011-002666-21
Study First Received: February 1, 2011
Last Updated: January 6, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Daiichi Sankyo Inc.:
Heat shock protein 90
Advanced solid tumors
Non-small cell lung carcinoma
Epidermal growth factor receptor
Tyrosine kinase inhibitor acquired resistance
Non-small cell lung carcinoma with acquired resistance to erlotinib, gefitinib, afatinib or others.

Additional relevant MeSH terms:
Neoplasms
Carcinoma
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms

ClinicalTrials.gov processed this record on September 30, 2014