DS-6157a in Participants With Advanced Gastrointestinal Stromal Tumor (GIST)

• ClinicalTrials.gov Identifier: NCT04276415
• Recruitment Status: Completed
• First Posted: February 19, 2020
• Last Update Posted: April 8, 2022
• Sponsor: Daiichi Sankyo, Inc.
• Information provided by (Responsible Party): Daiichi Sankyo, Inc.

Study Description

Brief Summary:

This study will assess the safety, efficacy, and pharmacokinetics of DS-6157a in participants with advanced gastrointestinal stromal tumors (GIST).

Condition or disease	Intervention/treatment	Phase
Gastrointestinal Stromal Tumors	Drug: DS-6157a	Phase 1

Detailed Description:

This study is a two-part, multicenter, open-label, multiple-dose, first-in-human study of the antibody-drug conjugate (ADC) DS-6157a given as a single agent to participants with gastrointestinal stromal tumor (GIST).

This study will include 2 parts:

1. Dose Escalation (Part 1)
2. Dose Expansion (Part 2)

Dose Escalation: Participants with histopathologically documented advanced GIST not amenable to curative therapy may be included in which the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of DS-6157a monotherapy will be determined.

Dose Expansion: Once the RDE(s) is established for DS-6157a (Part 1), enrollment in Dose Expansion (Part 2) will commence in 2 cohorts. Participants with GIST who have progressed on or are intolerant to imatinib (IM) and at least one post-IM treatment will be enrolled in Cohort 1, and participants with GIST who progressed on IM and had not received a post-IM treatment (2nd line) will be enrolled in Cohort 2.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 34 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Subjects With Advanced Gastrointestinal Stromal Tumor
• Actual Study Start Date: May 7, 2020
• Actual Primary Completion Date: March 2, 2022
• Actual Study Completion Date: March 2, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose Escalation: DS-6157a; Participants with advanced gastrointestinal stromal tumor (GIST) who will receive an intravenous infusion of DS-6157a (escalating doses starting at 1.6 mg/kg).	Drug: DS-6157a; Administered as a single agent intravenously (IV) every 3 weeks
Experimental: Dose Expansion: Cohort 1 (3rd line or later) treated at RDE; Participants with advanced gastrointestinal stromal tumor (GIST) who have progressed on or are intolerant to imatinib (IM) and at least one post-IM treatment will receive DS-6157a at the recommended dose for expansion (RDE) based on the Dose Escalation phase.	Drug: DS-6157a; Administered as a single agent intravenously (IV) every 3 weeks
Experimental: Dose Expansion: Cohort 2 (2nd line) treated at RDE; Participants with advanced gastrointestinal stromal tumor (GIST) who have progressed on imatinib (IM) and had not received a post-IM treatment (2nd line) will receive DS-6157a at the recommended dose for expansion (RDE) based on the Dose Escalation phase.	Drug: DS-6157a; Administered as a single agent intravenously (IV) every 3 weeks

Outcome Measures

Primary Outcome Measures :

1. Number of participants with dose-limiting toxicities (DLT) following intravenous administration of DS-6157a in patients with advanced gastrointestinal stromal tumors (GIST) [ Time Frame: Baseline up to 5 years post-treatment ]
2. Summary of most frequently reported (≥10%) treatment-emergent adverse events (TEAEs) following intravenous administration of DS-6157a in patients with advanced gastrointestinal stromal tumors (GIST) [ Time Frame: Baseline up to 5 years post-treatment ]
3. Objective response rate (ORR) following intravenous administration of DS-6157a in patients with advanced gastrointestinal stromal tumors (GIST) (Dose expansion) [ Time Frame: Baseline up to 5 years post-treatment ]
4. Duration of response (DoR) following intravenous administration of DS-6157a in patients with advanced gastrointestinal stromal tumors (GIST) (Dose expansion) [ Time Frame: Baseline up to 5 years post-treatment ]
5. Disease control rate (DCR) following intravenous administration of DS-6157a in patients with advanced gastrointestinal stromal tumors (GIST) (Dose expansion) [ Time Frame: Baseline up to 5 years post-treatment ]
6. Progression-free survival (PFS) following intravenous administration of DS-6157a in patients with advanced gastrointestinal stromal tumors (GIST) (Dose expansion) [ Time Frame: Baseline up to 5 years post-treatment ]

Secondary Outcome Measures :

1. Pharmacokinetic Analysis: Area under the plasma concentration-time curve up to the last quantifiable time (AUClast) for DS-6157a, total anti-GPR20 antibody, and MAAA-1181a following intravenous administration of DS-6157a [ Time Frame: Post Cycle 1 and Cycle 3 doses (each cycle is 21 days) ]
2. Pharmacokinetic Analysis: Area under the plasma concentration-time curve in the dosing interval (AUCtau) for DS-6157a, total anti-GPR20 antibody, and MAAA-1181a following intravenous administration of DS-6157a [ Time Frame: Post Cycle 1 and Cycle 3 doses (each cycle is 21 days) ]
3. Pharmacokinetic Analysis: Time to maximum plasma concentration (Tmax) for DS-6157a, total anti-GPR20 antibody, and MAAA-1181a following intravenous administration of DS-6157a [ Time Frame: Post Cycle 1 and Cycle 3 doses (each cycle is 21 days) ]
4. Pharmacokinetic Analysis: Maximum plasma concentration (Cmax) for DS-6157a, total anti-GPR20 antibody, and MAAA-1181a following intravenous administration of DS-6157a [ Time Frame: Post Cycle 1 and Cycle 3 doses (each cycle is 21 days) ]
5. Pharmacokinetic Analysis: Lowest concentration reached after a single dose (Ctrough) for DS-6157a, total anti-GPR20 antibody, and MAAA-1181a following intravenous administration of DS-6157a [ Time Frame: Post Cycle 1 and Cycle 3 doses (each cycle is 21 days) ]
6. Pharmacokinetic Analysis: Terminal elimination half-life (t1/2) for DS-6157a, total anti-GPR20 antibody, and MAAA-1181a following intravenous administration of DS-6157a [ Time Frame: Post Cycle 1 and Cycle 3 doses (each cycle is 21 days) ]
7. Objective response rate (ORR) following intravenous administration of DS-6157a in participants with advanced gastrointestinal stromal tumors (GIST) (Dose escalation) [ Time Frame: Baseline up to 5 years post-treatment ]
8. Duration of response (DoR) following intravenous administration of DS-6157a in participants with advanced gastrointestinal stromal tumors (GIST) (Dose escalation) [ Time Frame: Baseline up to 5 years post-treatment ]
9. Disease control rate (DCR) following intravenous administration of DS-6157a in participants with advanced gastrointestinal stromal tumors (GIST) (Dose escalation) [ Time Frame: Baseline up to 5 years post-treatment ]
10. Progression-free survival (PFS) following intravenous administration of DS-6157a in participants with advanced gastrointestinal stromal tumors (GIST) (Dose escalation) [ Time Frame: Baseline up to 5 years post-treatment ]
11. Number of participants with anti-drug antibodies against DS-6157a following intravenous administration of DS-6157a in participants with advanced gastrointestinal stromal tumors (GIST) [ Time Frame: Baseline up to 5 years post-treatment ]

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:

• Written informed consent
• At least 20 years old in Japan or 18 years old in other countries at the time of signature of the informed consent form (ICF), following local regulatory requirements
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
• Has histopathologically documented unresectable and/or metastatic GIST meeting the criteria below:

• Dose Escalation (Part 1): Participants should meet one of the following criteria:

  1. (For US sites only) Participants with GIST who have progressed on or are intolerant to imatinib (IM) and at least one post-IM treatment or who are not candidates for post-IM standard of care treatment
  2. (For Japan sites only) Participants with GIST who have received all the existing standard of care treatments or who are not candidates for one or more available post-IM standard of care treatments
  3. Participants with GIST who are not candidates for IM or curative intent surgical treatment (i.e., participants without activating KIT or platelet-derived growth factor receptor alpha (PDGFRa) mutations, with PDGFRa D842V mutations, or are KIT negative by local results)
• Dose Expansion (Part 2) Cohort 1: Participants with GIST who have progressed on or are intolerant to IM and at least one post-IM treatment
• Dose Expansion (Part 2) Cohort 2: Participants with GIST who have progressed on IM and had not received a post-IM treatment (2nd line)
• Consents to provide fresh tumor biopsy tissue samples both before and on DS-6157a treatment for the measurement of GPR20 levels by immunohistochemistry and other biomarkers
• Has a left ventricular ejection fraction (LVEF) ≥50% by either echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) within 28 days before study treatment
• Has at least 1 measurable lesion based on RECIST Version 1.1 as assessed by the Investigator

• Has adequate organ function within 7 days before the start of study treatment, defined as:

  1. Platelet count ≥100,000/mm^3
  2. Hemoglobin ≥8.5 g/dL
  3. Absolute neutrophil count ≥1,500/mm^3
  4. Creatinine clearance ≥50 mL/min
  5. Aspartate aminotransferase ≤3 × upper limit of normal (ULN) (if liver metastases are present, ≤5 × ULN)
  6. Alanine aminotransferase ≤3 × ULN (if liver metastases are present, ≤5 × ULN)
  7. Total bilirubin ≤1.5 × ULN or ≤3.0 × ULN for participants with documented history of Gilbert's Syndrome

• Has an adequate treatment washout period prior to start of study treatment, defined as:

  1. Major surgery: ≥4 weeks (or 2 weeks for minor surgeries)
  2. Radiation therapy: ≥3 weeks (or 2 weeks for palliative radiation excluding pelvic radiation)

  3. Systemic anti-cancer therapy (except for anti-androgen for prostate cancer and bisphosphonate, denosumab, or medroxyprogesterone acetate for bone metastases):

     • Cytotoxic chemotherapy: ≥3 weeks or 5 times the terminal elimination half-life (t½) of the chemotherapeutic agent, whichever is shorter
     • Antibody and antibody-conjugates therapy: ≥3 weeks or 5 times the t½, whichever is longer
     • Prior tyrosine kinase inhibitors (TKIs): washout period from 2 to 21 days depending on the TKI
     • Immunotherapy: ≥4 weeks.
• Male participants with female partners of childbearing potential and female participants of child-bearing potential must agree to use a highly effective form of contraception, or avoid intercourse during and upon completion of the study and for at least 4 months (for males) and for at least 7 months (for females) after the last dose of study drug.

Exclusion Criteria:

• History of an allogeneic bone marrow or solid organ transplant within 3 months before the start of study treatment
• Concomitant treatment with any medication that is classified as having a known risk of Torsades de pointes should be avoided from the start of study treatment through the end of Cycle 3
• Prophylactic administration of granulocyte colony-stimulating factor (G-CSF), filgrastim, pegfilgrastim, erythropoietin, or the transfusion of blood, red blood cells, or platelets within 14 days before the start of treatment and during Cycle 1. Chronic therapy with erythropoietin at stable dose that started at least 14 days before the first dose of DS-6157a may continue.
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, Grade ≤1. Participants with chronic Grade 2 toxicities may be eligible.
• Has spinal cord compression or clinically active central nervous system (CNS) metastases (including brain metastases), defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms
• Has known hypersensitivity to either the drug substances or inactive ingredients in the drug product
• Has a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety, efficacy, or any other assessments of the investigational regimen
• Has a documented history of myocardial infarction or unstable angina within 6 months before study treatment
• Has a medical history of symptomatic congestive heart failure (New York Heart Association classes II-IV) or a serious cardiac arrhythmia requiring treatment
• Has a corrected QT by Fridericia's formula (QTcF), of >470 ms based on the average of triplicate 12-lead electrocardiogram (ECG) per local read
• Has a documented history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required corticosteroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• Has clinically significant pulmonary compromise or requirement for supplemental oxygen
• Has clinically significant corneal disease
• Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Has active human immunodeficiency virus (HIV) infection as determined by plasma HIV RNA viral load.
• Has evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, as manifest by the detectable viral load (HBV-DNA or HCV-RNA, respectively)
• Is a lactating mother (women who are willing to temporarily interrupt breastfeeding will also be excluded), or pregnant as confirmed by pregnancy tests performed within 7 days before study treatment
• Women who plan to become pregnant while in the study and for at least 7 months after the last administration of study treatment
• Men who plan to father a child while in the study and for at least 4 months after the last administration of study treatment
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding diatheses, substance abuse, or other medical condition that would increase the risk of toxicity or interfere with participation of the participant or evaluation of the clinical study

Contacts and Locations

Locations

United States, Massachusetts

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Missouri

Washington University of St. Louis

Saint Louis, Missouri, United States, 63110

United States, Oregon

Oregon Health and Science University

Portland, Oregon, United States, 97239

United States, Texas

MD Anderson

Houston, Texas, United States, 77030

Japan

National Cancer Center Hospital East

Tokyo, Japan, 277-8577

Sponsors and Collaborators

Daiichi Sankyo, Inc.

Investigators

• Study Director: Global Clinical Leader; Daiichi Sankyo, Inc.

More Information

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT04276415
• Other Study ID Numbers: DS6157-A-U101
• First Posted: February 19, 2020
• Last Update Posted: April 8, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)
• Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• URL: https://vivli.org/ourmember/daiichi-sankyo/

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

Keywords provided by Daiichi Sankyo, Inc.:

Gastrointestinal stromal tumors; DS-6157a; Anti-drug antibody conjugate; G-protein coupled receptor 20 (GPR20)

Additional relevant MeSH terms:

Gastrointestinal Stromal Tumors; Neoplasms; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases