A Open-Label, Multiple Ascending Dose Study of DS-3078a, an Oral TORC1/2 Kinase Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo Inc.
ClinicalTrials.gov Identifier:
NCT01588678
First received: April 26, 2012
Last updated: May 20, 2014
Last verified: May 2014
  Purpose

DS-3078a will be evaluated as a single agent in subjects with advanced solid tumor malignancies or lymphomas refractory to standard treatment or for which no standard treatment is available.


Condition Intervention Phase
Advanced Solid Tumor
Lymphoma
Drug: DS-3078a
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics 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-3078a, an Oral TORC1/2 Kinase Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas

Resource links provided by NLM:


Further study details as provided by Daiichi Sankyo Inc.:

Primary Outcome Measures:
  • Maximum tolerated dose [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    To determine the maximum tolerated dose (MTD) and tentative recommended Phase 2 dose (RP2D) of DS 3078a


Secondary Outcome Measures:
  • determine the Cmax profile of DS 3078a [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    determine the Cmax (maximum concentration) of DS-3078a administered under fed and unfed conditions

  • effect on glucose metabolism [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    determine the effect of DS-3078a on glucose metabolism by measuring serum glucose and C peptide

  • assess pharmacodynamic effects tumor glucose uptake [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    assess the pharmacodynamic effects of DS 3078a by determining tumor glucose uptake using (18F) fluorodeoxyglucose positron emission tomography (FDG-PET)

  • assess tumor response [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    assess tumor response to DS-3078a in subjects with advanced non-Hodgkin lymphomas or advanced solid tumor types in which the mammalian target of rapamycin (mTOR) signaling pathway is frequently activated

  • assess pharmacodynamic effects v-akt murine thymoma viral oncogene [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    assess the pharmacodynamic effects of DS 3078a by measuring v-akt murine thymoma viral oncogene homolog 1 (Akt) phosphorylation in platelet rich plasma (PRP)

  • determine the AUC of DS 3078a [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    determine the Area under the concentration versus time curve (AUC) of DS-3078a administered under fed and unfed conditions

  • determine the Tmax of DS 3078a [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    determine the time of maximum concentyration (Tmax) of DS-3078a administered under fed and unfed conditions

  • determine the terminal half-life of DS 3078a [ Time Frame: 3 years ] [ Designated as safety issue: No ]
    determine the terminal half-life (T1/2) of DS-3078a administered under fed and unfed conditions


Enrollment: 32
Study Start Date: April 2012
Estimated Study Completion Date: June 2014
Estimated Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DS-3078a

Part 1 - Dose escalation of DS-3078a to determine the maximum tolerated dose (MTD) will be guided by the modified continuous reassessment method (mCRM) using a Bayesian logistic regression model (BLRM) following escalation with overdose control (EWOC) principle.

Before starting mCRM, initial dose escalation will proceed following an accelerated titration in which single subjects will be enrolled into sequential dose levels with a dose increment of up to 100% from the previous dose.

Upon completion of Part 1 with established MTD and tentative recommended phase 2 dose (RP2D), the Dose Expansion (Part 2) will begin with the intention of further assessing the safety and tolerability of DS-3078a, confirming the RP2D, determining the Pharmacodynamic response in tumor samples, and evaluating preliminary efficacy of DS-3078a in subjects.

Drug: DS-3078a
DS-3078a will be administered as oral capsules once daily and will be supplied in 5, 20, 50, and 150 mg capsules.

Detailed Description:

This is a Phase 1, open-label study of DS-3078a to assess safety and tolerability, identify the maximum tolerated dose (MTD) and tentative recommended phase 2 dose (RP2D), and assess pharmacokinetic and pharmacodynamic properties in subjects with advanced solid tumor malignancies or lymphomas. The study will include 2 parts: Dose Escalation and Dose Expansion.

  Eligibility

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

Inclusion Criteria:

  • A pathologically or cytologically documented advanced solid tumor or lymphoma that has relapsed from or is refractory to standard treatment or for which no standard treatment is available.
  • Men or women >=18 years old.
  • Eastern Cooperative Oncology Group (ECOG) performance status =<1
  • Have adequate bone marrow function, defined as:

    • Platelet count >=100 x 10^9/L for solid tumors and >=75 x 10^9/L for lymphomas,
    • Hemoglobin level >=9.0 g/dL, and ANC >=1.5 x 10^9/L for solid tumors and >=1.0 x 10^9/L for lymphomas.
  • Have adequate renal function, defined as:

Creatinine clearance >=60 mL/min, or creatinine =<1.5 x ULN.

  • Have adequate hepatic function, defined as:

    • AST/ALT levels =<3 x ULN (=<5 x ULN if liver metastases are present) and
    • Bilirubin =<1.5 x ULN.
  • Have adequate blood clotting function, defined as prothrombin time and activated partial thromboplastin time =<1.5 x ULN.
  • 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/Ethics Committee-approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study specific procedures or tests.

For Part 2

  • A pathologically or cytologically documented advanced solid tumor or non-Hodgkin lymphoma, with measurable disease based on RECIST 1.1 or revised IWG criteria, that is refractory to standard treatment. The solid tumor types that will be included in the study are of the following kinds in which the mTOR signaling is frequently activated: endometrial, prostate, breast, gastric, cervical,ovarian, or neuroendocrine cancers, soft-tissue sarcoma, squamous cell NSCLC,renal cell carcinoma or other tumor types approved by the Sponsor.
  • Agree to undergo pre- and post-treatment tumor biopsies.

Exclusion Criteria:

  • History of primary central nervous system malignancies
  • Gastrointestinal diseases that could affect the absorption of DS-3078a in the opinion of the Investigator
  • Subjects with a fasting glucose >126 mg/dL (>7 mmol/L)
  • History of diabetes mellitus (type 1 or 2) or glycosylated hemoglobin >7.0% at screening
  • Positive test for hepatitis B surface antigen or hepatitis C antibody
  • Recipient of live vaccine within 1 month of or during study drug treatment
  • Use of chronic systemic corticosteroids (use of nasal or inhaled steroids is permitted)
  • Subjects requiring daily supplemental oxygen
  • Recipient of an allogenic stem cell or bone marrow transplant
  • Presence of 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.
  • Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE v4 grade =<1 or baseline.
  • 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.
  • Therapeutic radiation 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 inhibitors or inducers of cytochrome P450 3A4 and P glycoprotein
  • 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 3078a
  • Prolongation of corrected QT interval by Fridericia's method (QTcF) at rest, where the mean QTcF interval is >450 msec based on triplicate electrocardiogram (ECG)
  • Pregnant or breastfeeding
  • Substance abuse or medical, psychological, or social conditions that, in the opinion of the Investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results

For Part 2

  • Subjects who have had prior treatment with an mTOR catalytic site inhibitor or dual PI3K/mTOR inhibitor (including, but not limited to, OSI-027, INK128, ADZ8055,AZD2014, WYE12513, PP242, BEZ-235, DS-7423, XL765, GDC-0980, SF1126, GSK2126458, PF4691502, and PF05212384) will be disqualified from entering the study.
  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: NCT01588678

Locations
United States, Texas
South Texas Accelerated Research Therapeutics
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Daiichi Sankyo Inc.
  More Information

No publications provided

Responsible Party: Daiichi Sankyo Inc.
ClinicalTrials.gov Identifier: NCT01588678     History of Changes
Other Study ID Numbers: DS3078-A-U101
Study First Received: April 26, 2012
Last Updated: May 20, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Daiichi Sankyo Inc.:
endometrial
prostate
breast
gastric
cervical
ovarian
neuroendocrine cancers
soft-tissue sarcoma
squamous cell NSCLC
renal cell carcinoma
non-Hodgkin lymphoma

Additional relevant MeSH terms:
Lymphoma
Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on July 24, 2014