Safety, Tolerability, and Pharmacokinetic (PK) Study of DHES0815A in Participants With Human Epidermal Growth Factor Receptor (HER)2-Positive Breast Cancer

NCT03451162 | Completed Phase 1 Results FDA Drug

• 1 other identifier: GO39869
• Study Type: interventional
• Target: 14
• Locations: 2 countries
• Sites: 5

Brief Summary

This first-in-human, Phase 1, open-label, multicenter, dose-escalation study will evaluate the safety, tolerability, and PK of DHES0815A as a single agent in participants with advanced and/or metastatic HER2-positive breast cancer for whom established treatment has proven ineffective or intolerable or is unavailable. The study may include a dose-expansion cohort (based on an ongoing assessment of the totality of data obtained in this study) to further assess safety, tolerability, PK, and preliminary anti-tumor activity.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (5)

• Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) With Severity Determined as Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0

  AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. SAE is any AE that is fatal, is life threatening, requires or prolongs inpatient hospitalization, results in persistent/significant disability/incapacity and is congenital anomaly/birth defect. Severity of AEs were graded per NCI CTCAE v4.0. Grade 1: Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2: Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living; Grade 3: Severe/medically significant, but not immediately life-threatening: hospitalization/prolongation of hospitalization indicated; disabling/limiting self-care activities of daily living; Grade 4: Life-threatening consequences/urgent intervention indicated; Grade 5: Death related to AE.

  From Day 1 to end of study (up to approximately 39 months)

• Number of Participants With Dose-limiting Toxicity (DLT)

  DLT=any one events occurring during DLT assessment window: ≥15% decrease from baseline in left ventricular ejection fraction (LVEF)/≥10% decrease to \<50% LVEF; Grade ≥ 3 non-hematologic toxicity; Grade ≥4 neutropenia (absolute neutrophil count \<500 cells/microliters \[μL\]) lasting \<7 days; Grade ≥3 febrile neutropenia; Grade ≥4 anemia; Grade ≥4 thrombocytopenia; Grade 3 thrombocytopenia associated with clinically significant bleeding; Any increase in hepatic transaminase (ALT or AST) \>3\*baseline in combination with either an increase in direct bilirubin \>2\*upper limit of normal/clinical jaundice, in absence of cholestasis/other contributory factors. NCI CTCAE v4.0. was used to grade these events.Grade1: Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; Grade2: Moderate; minimal, local/non-invasive intervention indicated;Grade3: Severe/medically significant, but not immediately life-threatening;Grade4: Life-threatening consequences/urgent intervention indicated.

  From Day 1 up to Day 21

• Duration of Treatment

  Treatment duration was calculated from the first dose of study drug to the last dose of study drug administration.

  From Day 1 up to last dose of study drug (up to approximately 39 months)

• Total Cumulative Dose

  From Day 1 up to last dose of study drug (up to approximately 39 months)

• Change From Baseline in LVEF as Assessed by Echocardiogram (ECHO) or Multiple-Gated Acquisition (MUGA) Scan

  LVEF is the fraction of blood (in percent) pumped out of the heart's left ventricular chamber with each heartbeat and is a measure of cardiac output for the heart. Baseline LVEF value and the change from baseline to the worst value in LVEF measurement were reported. LVEF was measured by ECHO or MUGA scan.

  Baseline, end of Cycle 1, Days 15-21 of Cycles 2, 4, and 6, and every four cycles thereafter up to the study discontinuation visit (up to approximately 39 months)

Secondary Outcomes (6)

• Concentration of DHES0815A Total Antibody

  Pre-dose and 30 minutes (min) post-dose on Day 1 Cycles 1-4; 4 hour (h) post-dose on Day 1 Cycle1; post-dose on Days 2, 3, 11, 17 Cycle 1; post-dose on Days 8 and 15 Cycles 1-4; study discontinuation visit (up to approx. 39 months) (Cycle length=21 days)

• Concentration of Plasma Conjugated Pyrrolo [2,1-c] [1,4] Benzodiazepine Monoamide (PDB-MA)

  Pre-dose and 30 minutes (min) post-dose on Day 1 Cycles 1-4; 4 hour (h) post-dose on Day 1 Cycle1; post-dose on Days 2, 3, 11, 17 Cycle 1; post-dose on Days 8 and 15 Cycles 1-4; study discontinuation visit (up to approx. 39 months) (Cycle length=21 days)

• Concentration of Plasma Unconjugated PDB-MA

  Pre-dose and 30 minutes (min) post-dose on Day 1 Cycles 1-4; 4 hour (h) post-dose on Day 1 Cycle1; post-dose on Days 2, 3, 11, 17 Cycle 1; post-dose on Days 8 and 15 Cycles 1-4; study discontinuation visit (up to approx. 39 months) (Cycle length=21 days)

• Number of Participants With Objective Response Assessed According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

  From start of treatment until confirmation of CR or PR (up to approximately 39 months)

• Duration of Response (DoR) Assessed According to RECIST v1.1

  From the initial CR or PR to the time of PD or death, whichever occurs first (up to approximately 39 months)

Study Arms (2)

Dose Escalation Cohort: DHES0815A

EXPERIMENTAL

Participants will receive DHES0815A in escalating doses in the dose-escalation cohort of the study. Participants will receive additional infusions of DHES0815A on Day 1 of subsequent cycles provided that they meet the protocol specified criteria for acceptable toxicity and ongoing clinical benefit.

Drug: DHES0815A

Dose Expansion Cohort: DHES0815A

EXPERIMENTAL

Participants will be treated at or below the Maximum Tolerated Dose (MTD) of DHES0815A (based on the review of the totality of the data) to obtain additional safety, tolerability, PK, and anti-tumor activity data.

Drug: DHES0815A

Interventions

DHES0815A DRUG

DHES0815A will be administered via intravenous (IV) infusion on Day 1 of each 21-day cycle.

Dose Escalation Cohort: DHES0815A; Dose Expansion Cohort: DHES0815A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Measurable disease by RECIST v1.1 with at least one measurable target lesion
• Locally advanced or metastatic HER2-positive breast cancer that has relapsed or is refractory to established therapies
• Adequate hematologic and end-organ function
• For dose-expansion cohort only: no more than two prior systemic chemotherapy-containing regimens in the advanced/metastatic setting (excluding trastuzumab emtansine, which is considered a targeted cytotoxic agent)

You may not qualify if:

• Treatment with chemotherapy, hormonal therapy (except hormone replacement therapy, oral contraceptives), immunotherapy, biologic therapy, radiation therapy (except palliative radiation to bony metastases), or herbal therapy as cancer therapy within 4 weeks prior to initiation of DHES0815A
• History of exposure to the protocol specified doses of anthracyclines
• Pregnancy, lactation, or breastfeeding
• Major surgical procedure within 4 weeks prior to Day 1
• Evidence of a significant uncontrolled concomitant disease of the nervous system, pulmonary, autoimmune, renal, hepatic, endocrine, or gastrointestinal disorders; or a serious non-healing wound or fracture
• Known active bacterial, viral, fungal, mycobacterial, or other infection
• Clinically significant history of liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis
• Untreated or active central nervous system (CNS) metastases
• Cardiopulmonary dysfunction, including inadequate left ventricular ejection function at baseline, less than 50% by either echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA)
• QT interval corrected through use of Fridericia's formula (QTcF) \> 470 milliseconds (ms)

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (5)

Yale Cancer Center

New Haven, Connecticut, 06520, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 11101, United States

Location

Sarah Cannon Research Institute

Nashville, Tennessee, 37203, United States

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Related Publications (1)

• Lewis GD, Li G, Guo J, Yu SF, Fields CT, Lee G, Zhang D, Dragovich PS, Pillow T, Wei B, Sadowsky J, Leipold D, Wilson T, Kamath A, Mamounas M, Lee MV, Saad O, Choeurng V, Ungewickell A, Monemi S, Crocker L, Kalinsky K, Modi S, Jung KH, Hamilton E, LoRusso P, Krop I, Schutten MM, Commerford R, Sliwkowski MX, Cho E. The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results. Nat Commun. 2024 Jan 11;15(1):466. doi: 10.1038/s41467-023-44533-z.

  PMID: 38212321 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

DHES0815A

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800 821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 16, 2018
• First Posted: March 1, 2018
• Study Start: April 17, 2018
• Primary Completion: July 16, 2021
• Study Completion: July 16, 2021
• Last Updated: August 5, 2024
• Results First Posted: August 5, 2024

Record last verified: 2024-02

Locations

US (4); KR (1)