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

• ClinicalTrials.gov Identifier: NCT02279433
• Recruitment Status: Completed
• First Posted: October 31, 2014
• Last Update Posted: September 22, 2020
• Sponsor: AnHeart Therapeutics Inc.
• Information provided by (Responsible Party): AnHeart Therapeutics Inc.

Tracking Information

• First Submitted Date: October 15, 2014
• First Posted Date: October 31, 2014
• Last Update Posted Date: September 22, 2020
• Study Start Date: September 2014
• Actual Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 18, 2020)

• Part 1: Number of participants with dose-limiting toxicities [ Time Frame: within 21 days following the first dose of treatment ]
• Tumor response [ Time Frame: up to 2 years ]
  Tumor response will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.

Original Primary Outcome Measures (submitted: October 28, 2014)

• Part 1: Number of participants with dose-limiting toxicities [ Time Frame: 21 days following the first dose of treatment ]
• Part 2: Tumor response [ Time Frame: Every 9 weeks from enrollment up to 2 years ]
  Tumor response will be assessed using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.

Current Secondary Outcome Measures (submitted: September 18, 2020)

• Maximum concentration (Cmax) for DS-6051a [ Time Frame: At Days 1 and 15 of Cycle 1 (21 days) ]
• Time to maximum concentration (Tmax) for DS-6051a [ Time Frame: At Days 1 and 15 of Cycle 1 (21 days) ]
• 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) ]
• Change from baseline in QTc interval [ Time Frame: within 2 years ]
  ECGs performed to assess QTc interval (ms) at baseline and on study treatment and at the end of treatment visit.

Original Secondary Outcome Measures (submitted: October 28, 2014)

• Composite of plasma exposure parameters of DS-6051a [ Time Frame: At Days 1 and 15 of Cycle 1 ]
  Maximum concentration (Cmax), time to maximum plasma concentration (Tmax), and area under the concentration-time curve from time zero to t (AUC0-t) for DS-6051a (a free base form of DS-6051b) will be assessed on Days 1 and 15 of Cycle 1.
• Changes in QTc interval [ Time Frame: At screening, Days 1, 2, 8, and 15 of Cycle 1, Days 1, 8, and 15 of Cycle 2, Days 1 and 15 of Cycle 3, Day 1 of Cycle 4 and thereafter, and within 2 days after the last dose of treatment ]
  ECGs performed to assess QTc interval (ms) at baseline and on study treatment and at the end of treatment visit.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• Brief Summary: 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.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Solid Tumors

Intervention

Drug: DS6051b

DS-6051b 50 mg and 200 mg capsules for oral administration

Other Names:

• Investigational product
• DS-6051a (a free base of 6051b)

Study Arms

Experimental: DS-6051b

DS-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.

Intervention: Drug: DS6051b

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 18, 2020): 46
• Original Estimated Enrollment (submitted: October 28, 2014): 70
• Actual Study Completion Date: March 2019
• Actual Primary Completion Date: March 2019 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02279433
• Other Study ID Numbers: DS6051-A-U101
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: AnHeart Therapeutics Inc.
• Study Sponsor: AnHeart Therapeutics Inc.
• Collaborators: Not Provided

Investigators

• Study Director: Study Director Oncology; AnHeart Therapeutics Inc.

• PRS Account: AnHeart Therapeutics Inc.
• Verification Date: July 2020