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.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Solid Tumors	Drug: DS6051b	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Study Start Date: September 2014
• Actual Primary Completion Date: March 2019
• Actual Study Completion Date: March 2019

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: DS6051b; DS-6051b 50 mg and 200 mg capsules for oral administration; Other Names: Investigational product; DS-6051a (a free base of 6051b)

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Maximum concentration (Cmax) for DS-6051a [ Time Frame: At Days 1 and 15 of Cycle 1 (21 days) ]
2. Time to maximum concentration (Tmax) for DS-6051a [ Time Frame: At Days 1 and 15 of Cycle 1 (21 days) ]
3. 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) ]
4. 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.

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, Arizona

HonorHealth Research Institute

Scottsdale, Arizona, United States, 85258

United States, California

Chao Family Comprehensive Cancer Center of

Orange, California, United States, 92868

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Dana Farber Cancer Inst.

Boston, Massachusetts, United States, 02215

United States, New York

New York University

New York, New York, United States, 10016

United States, Texas

South Texas Accelerated Research Therapeutics

San Antonio, Texas, United States, 78229

Sponsors and Collaborators

AnHeart Therapeutics Inc.

Investigators

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

More Information

• Responsible Party: AnHeart Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT02279433
• Other Study ID Numbers: DS6051-A-U101
• First Posted: October 31, 2014
• Last Update Posted: September 22, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by AnHeart Therapeutics Inc.:

Neoplasms; Lung Neoplasms; Colorectal Neoplasms; Neuroendocrine Tumors; Pancreatic Neoplasms