Clinical Trials /

A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b

NCT02279433

Description:

DS-6051b is an orally administered inhibitor of the tyrosine kinases (ROS1) and neurotropic tyrosine kinase receptors (NTRK). This phase 1 first-in-human study evaluates safety and tolerability of DS-6051b in cancer subjects and identify a recommended phase 2 dose (RP2D). In addition, this study will also assess the pharmacokinetic (PK)/pharmacodynamic (PD) profiles and preliminary efficacy of DS-6051b.

Related Conditions:
  • Colorectal Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A First-in-human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-6051b
  • Official Title: A Phase 1/1B Multi-Center, Non Randomized, Open-Label, Multiple Dose First-In-Human Study Of DS-6051b, An Oral ROS1 And NTRK Inhibitor, In Subjects With Metastatic and/or Unresectable Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: DS6051-A-U101
  • NCT ID: NCT02279433

Conditions

  • Solid Tumors

Interventions

DrugSynonymsArms
DS6051bInvestigational product, DS-6051a (a free base of 6051b)DS-6051b

Purpose

DS-6051b is an orally administered inhibitor of the tyrosine kinases (ROS1) and neurotropic tyrosine kinase receptors (NTRK). This phase 1 first-in-human study evaluates safety and tolerability of DS-6051b in cancer subjects and identify a recommended phase 2 dose (RP2D). In addition, this study will also assess the pharmacokinetic (PK)/pharmacodynamic (PD) profiles and preliminary efficacy of DS-6051b.

Detailed Description

      The Dose Escalation part (Part 1) of this study will evaluate safety and tolerability, and
      determine the tentative RP2D. Plasma exposure of DS-6051a and the exposure - QT interval
      prolongation relationship will also be assessed. Approximately 30 subjects with advanced
      solid tumors harboring ROS1 or NTRK1, NTRK2, or NTRK3 rearrangement, neuroendocrine
      carcinoma, or with advanced solid tumors and tumor-induced pain will be enrolled.

      The Food Effect (FE) part of this study is to determine the effect of food on the PK of
      DS-6051a following administration of a single oral dose of DS-6051b. The safety and
      tolerability of DS-6051b administered with or without food will also be assessed.

      After the safety profile of DS-6051b is adequately evaluated, the Dose Expansion part (Part
      2) will be initiated to further assess the safety and tolerability, and preliminarily
      evaluate the efficacy of DS-6051b at the tentative RP2D. Approximately 40 cancer subjects
      carrying a ROS1 or NTRK1, NTRK2, or NTRK3 rearrangement will be enrolled.
    

Trial Arms

NameTypeDescriptionInterventions
DS-6051bExperimentalDS-6051b is orally administered as 50 mg and 200 mg capsules once daily on Days 1 to 21 of a 21-day cycle. Dose escalation in Part 1 will continue until tentative Recommended Part 2 Dose (RP2D) is determined. In Part 2 participants will receive the RP2D.
  • DS6051b

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or cytologically confirmed diagnosis of advanced solid tumors that have
             relapsed from or are refractory to standard treatment or for which no standard
             treatment is available

          2. Part 1 Dose Escalation subjects must meet 1 of the following criteria:

               -  Solid tumors with documented ROS1, NTRK1, NTRK2, or NTRK3 rearrangement

               -  Neuroendocrine tumors

               -  Solid tumors with tumor-induced pain

          3. Part 2 Dose Expansion subjects must meet 1 of the following criteria:

               -  NSCLC with documented ROS1, NTRK1, NTRK2, or NTRK3 rearrangement

               -  k-RAS wild-type CRC with documented NTRK1, NTRK2, or NTRK3 rearrangement

               -  Other solid tumors with documented ROS1, NTRK1, NTRK2, or NTRK3 rearrangement

               -  Pulmonary LCNEC;

          4. Male or female ≥18 years of age

          5. Eastern Cooperative Oncology Group performance status 0 to 1

          6. Adequate organ function

          7. Adequate blood clotting function

          8. Women of childbearing potential must have a negative pregnancy test

          9. Willingness to provide archival tumor samples

         10. Other inclusion criteria may apply

        Exclusion Criteria:

          1. Hematological malignancies

          2. Known positive HIV infection, or active hepatitis B or C infection

          3. Comorbidity that would interfere with therapy

          4. Receipt of an allogeneic bone marrow or allogeneic stem cell transplant

          5. Concomitant medical condition that would increase the risk of toxicity, in the opinion
             of the Investigator or Sponsor

          6. History of myocardial infarction and unstable angina within 6 months before study drug
             treatment; symptomatic congestive heart failure (Congestive Heart Failure New York
             Heart Association Class III or IV); congenital long QT syndrome; or ventricular
             arrhythmias defined as grade ≥2 according to NCI CTCAE, v4

          7. Clinically active primary central nervous system tumors or brain metastases with the
             exception of subjects with glioblastoma multiform that carry ROS1 rearrangement

          8. Unresolved toxicities from previous anticancer therapy

          9. Systemic treatment with anticancer therapy within 3 weeks before study drug treatment

         10. Therapeutic radiation therapy or major surgery within 4 weeks before study drug
             treatment or palliative radiation therapy within 2 weeks before study drug treatment

         11. Participation in a therapeutic clinical study within 3 weeks for biological
             treatments, and within 2 weeks or 5 half-lives, whichever is longer, for small
             molecule agents, before study drug treatment

         12. Concomitant treatment with strong inhibitors or inducers of CYP3A4 and P-glycoprotein

         13. Clinically significant malabsorption syndrome or other gastrointestinal disease that
             would impact drug absorption

         14. QTcF values higher than 450 ms at screening

         15. Breastfeeding

         16. Other exclusion criteria may apply
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Number of participants with dose-limiting toxicities
Time Frame:within 21 days following the first dose of treatment
Safety Issue:
Description:Tumor response will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.

Secondary Outcome Measures

Measure:Maximum concentration (Cmax) for DS-6051a
Time Frame:At Days 1 and 15 of Cycle 1 (21 days)
Safety Issue:
Description:
Measure:Time to maximum concentration (Tmax) for DS-6051a
Time Frame:At Days 1 and 15 of Cycle 1 (21 days)
Safety Issue:
Description:
Measure:Area under the concentration-time curve from time zero to t (AUC0-t) for DS-6051a
Time Frame:At Days 1 and 15 of Cycle 1 (21 days)
Safety Issue:
Description:
Measure:Change from baseline in QTc interval
Time Frame:within 2 years
Safety Issue:
Description:ECGs performed to assess QTc interval (ms) at baseline and on study treatment and at the end of treatment visit.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:AnHeart Therapeutics Inc.

Trial Keywords

  • Neoplasms
  • Lung Neoplasms
  • Colorectal Neoplasms
  • Neuroendocrine Tumors
  • Pancreatic Neoplasms

Last Updated

September 22, 2020