Trastuzumab Deruxtecan and Lovastatin in HER2-low and Ultralow Advanced or Metastatic Breast Cancer

Phase II Trial Evaluating Trastuzumab Deruxtecan and Lovastatin in HER2-low and Ultralow Advanced or Metastatic Breast Cancer (MBC)

The purpose of this study is to evaluate use of lovastatin, a drug that may lower CAV-1 levels, in order to increase HER2 expression on cells and enhance the uptake and efficacy of trastuzumab deruxtecan (T-DXd) in HER2-low and ultralow advanced metastatic breast cancer. Trastuzumab deruxtecan (T-DXd) is an FDA approved antibody drug conjugate for HER2-low and ultralow breast cancer and lovastatin is a cholesterol lowering agent.

Study Overview

• Status: Not yet recruiting
• Conditions: Breast Cancer; Advanced Breast Cancer; Metastatic Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab deruxtecan; Drug: Lovastatin

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Andrew A Davis, MD; Phone Number: 314-362-5740; Email: aadavis@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
      • Contact: Andrew A Davis, MD; Phone Number: 314-362-5740; Email: aadavis@wustl.edu
      • Principal Investigator: Andrew A Davis, MD
      • Sub-Investigator: Patricia Pereira, PhD
      • Sub-Investigator: Jingqin Rosy Luo, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed HER2 low (IHC 1+ or 2+ with negative in-situ hybridization) or ultralow (IHC 0 with incomplete/faint membrane staining in >0 but ≤10% of tumor cells) breast cancer. Patients may be advanced/unresectable or metastatic.
• Patients must have received no more than 1 prior line of chemotherapy (e.g. capecitabine). There is no limit on the prior number of endocrine-based therapies for patients with hormone-receptor positivity.
• Measurable disease per RECIST 1.1.
• At least 18 years of age.
• ECOG performance status ≤ 2

• Adequate bone marrow and organ function as defined below:

  • Absolute neutrophil count ≥ 1.5 K/cumm
  • Platelets ≥ 100 K/cumm
  • Hemoglobin ≥ 9.0 g/dL
  • Total bilirubin ≤ 1.5 x IULN
  • AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
  • Creatinine clearance > 30 mL/min by Cockcroft-Gault
• The effects of T-DXd and lovastatin on the developing human fetus are unknown. For this reason, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 7 months after the last dose of either study drug. Should a woman become pregnant or suspect she is pregnant while participating in this study or should a man suspect he has fathered a child, s/he must inform her treating physician immediately.
• Patients must have left ventricular ejection fraction (LVEF) of ≥50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before C1D-1.
• Agreement to adhere to Lifestyle Considerations throughout study duration
• Ability to understand and willingness to sign an IRB approved written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

Exclusion Criteria:

• Prior treatment with T-DXd or other topoisomerase I ADC including sacituzumab govitecan, datopotamab deruxtecan, or investigational ADCs with topoisomerase I payloads.
• Prior statin use within 7 days prior to C1D-1.
• Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade ≤1 or baseline. Participants with chronic grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Study PI or designee (e.g., grade 2 chemotherapy-induced neuropathy).
• Prior or concurrent malignancy whose natural history has the potential to interfere with the safety or efficacy assessment of the investigational regimen. Patients with prior or concurrent malignancy that does NOT meet that definition are eligible for this trial
• Currently receiving any other investigational agents, or receipt of any investigational agents within 3 weeks or 5 half-lives, whichever is shorter, prior to C1D-1.
• Receipt of chemotherapy, immunotherapy, endocrine therapy, or other systemic anticancer therapy within 3 weeks or 5 half-lives, whichever is shorter, prior to C1D-1.
• Patients with untreated brain metastases. Patients with treated brain metastases are allowed if post-treatment brain-imaging after CNS-directed therapy shows no evidence of progression, and patients are not taking steroids to control edema or other symptoms.
• A history of allergic reactions attributed to compounds of similar chemical or biologic composition to T-DXd, lovastatin, or other agents used in the study.
• Patients with clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli within three months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e. Rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy.
• Patients with a history of non-infectious ILD/pneumonitis that required steroids or has current ILD/pneumonitis. Patients with a history of infectious ILD/pneumonitis should be discussed with the study PI.
• Prior intolerance to statin therapy, defined as intolerable muscle symptoms or significant transaminitis elevation (>3x ULN) or CK elevation (>5x ULN) attributed to statin therapy within the last 2 years prior to C1D-1.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or clinically significant cardiac arrhythmia.
• History or current significant cardiovascular disease, stroke, severe dyslipidemia, or vascular disorders that require continuous statin dosing. Uncertain cases should be discussed with the study PI for clarification of eligibility.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of C1D1.
• HIV-infected if not on effective anti-retroviral therapy with undetectable viral load for 6 months. Patients with HIV who are receiving effective anti-retroviral therapy and have had an undetectable viral load for at least 6 months are eligible. HIV testing not required in the absence of known history of infection.
• Evidence of chronic hepatitis B virus (HBV) that is detectable on suppressive therapy. Patients with evidence of chronic HBV infection with undetectable HBV viral load on suppressive therapy are eligible. HBV testing not required in the absence of known history of infection.
• History of hepatitis C virus (HCV) infection that has not been cured or that has a detectable viral load. Patients with a history of HCV that has been treated and cured are eligible. Patients with HCV infection who are currently on treatment and have an undetectable HCV viral load are eligible. HCV testing not required in the absence of known history of infection.
• Use of strong inhibitors of CYP3A4 within 5 half-lives of the medication prior to C1D-1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Safety Lead In: Trastuzumab Deruxtecan (T-DXd) + Lovastatin; T-DXd will be administered at a standard dose intravenously (IV) every 3 weeks and lovastatin will be administered orally at 20 mg with doses approximately 12 hours and 30 minutes before each cycle of T-DXd. Patients will be assessed for unacceptable toxicities during the first two treatment cycles.10 patients enrolled in either the safety lead-in or enrolled after the safety lead-in is completed will undergo a pre- and on-treatment biopsy for pharmacodynamic assessment.	Drug: Trastuzumab deruxtecan; Standard of care trastuzumab deruxtecan is administered at a starting dose of 5.4 mg/kg intravenously every 3 weeks according to package guidelines. The first infusion is administered over 90 minutes, and subsequent infusions may be administered over 30 minutes if prior infusions were well tolerated.; Other Names: Enhertu; T-DXd; Drug: Lovastatin; Lovastatin is provided in 10 mg and 20mg tablets for oral administration. It will be taken approximately 12 hours and 10 minutes before each T-DXd cycle.; Other Names: Mevacor; Altoprev; Altocor
Experimental: Standard dose: T-DXd + Lovastatin; T-DXd will be administered at a standard dose intravenously (IV) every 3 weeks and lovastatin will be administered orally at 20 mg with doses approximately 12 hours and 30 minutes before each cycle of T-DXd. 10 patients enrolled in either the safety lead-in or enrolled after the safety lead-in is completed will undergo a pre- and on-treatment biopsy for pharmacodynamic assessment.	Drug: Trastuzumab deruxtecan; Standard of care trastuzumab deruxtecan is administered at a starting dose of 5.4 mg/kg intravenously every 3 weeks according to package guidelines. The first infusion is administered over 90 minutes, and subsequent infusions may be administered over 30 minutes if prior infusions were well tolerated.; Other Names: Enhertu; T-DXd; Drug: Lovastatin; Lovastatin is provided in 10 mg and 20mg tablets for oral administration. It will be taken approximately 12 hours and 10 minutes before each T-DXd cycle.; Other Names: Mevacor; Altoprev; Altocor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR is defined as the proportion of patients who achieve complete response (CR) or partial response (PR) according to RECIST v1.1. CR is defined as disappearance of all target lesions. Disappearance of all non-target lesions and normalization of tumor marker level. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.	Start of treatment through end of treatment (estimated total time 12 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	PFS is defined from treatment start date to date of progression or date of death due to any cause or date of last follow up, whichever is earlier. PFS will be analyzed by the Kaplan-Meier method. Progressive disease (PD) is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).	Start of treatment to date of progression, death, or date of last follow up whichever is earlier (total estimated time to be 24 months)
Overall Survival (OS)	OS is defined from start of treatment to date of death due to any cause or last date of follow up. OS will be analyzed by the Kaplan-Meier method.	Start of treatment to date of progression, death, or date of last follow up (total estimated time to be 24 months)
Safety lead-in only: Rate of unacceptable toxicities	Unacceptable toxicities are assessed according to CTCAE v6.0 and specified in study protocol.	Start of treatment to completion of Cycle 2 (each cycle is 3 weeks in length, estimated total time 6 weeks)
Number and type of adverse events (AEs)	AEs assessed according to CTCAE v6.0.	Start of treatment through 30 days post last dose of either study treatment, whichever is later (estimated total time 13 months)

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Andrew A Davis, MD, Washington University School of Medicine

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Estimated): August 31, 2026
• Primary Completion (Estimated): August 31, 2030
• Study Completion (Estimated): August 31, 2031

Study Registration Dates

• First Submitted: May 21, 2026
• First Submitted That Met QC Criteria: May 29, 2026
• First Posted (Actual): June 2, 2026

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 29, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Antibody drug conjugate; HER2 low; HER2 ultralow
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Lovastatin; trastuzumab deruxtecan
• Other Study ID Numbers: 26-x146

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes