Phase 1b Study of Pidnarulex and Trastuzumab Deruxtecan in Patients With HER2 Expressing Solid Tumors

Plain English Summary

Testing the Safety of the Combination of Anti-Cancer Drugs CX-5461 (Pidnarulex) and Trastuzumab Deruxtecan (T-DXd) for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Solid Tumors and Breast Cancer is a Phase 1 clinical trial sponsored by National Cancer Institute (NCI) studying Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Invasive Breast Carcinoma, Locally Advanced Breast Carcinoma, Metastatic Breast Carcinoma, Metastatic HER2-Low Breast Carcinoma, Metastatic HER2-Positive Breast Carcinoma, Metastatic Hormone Receptor-Positive Breast Carcinoma, Metastatic Malignant Solid Neoplasm, Metastatic Triple-Negative Breast Carcinoma. This trial tests a new combination of drugs to treat HER2-positive breast cancer and other solid tumors. It's for patients with HER2-positive breast cancer or other solid tumors that have spread to other parts of the body. Participants will receive infusions of the drugs and have regular blood tests and scans. Other treatments like chemotherapy, targeted therapy, or hormonal therapy can be used before joining the trial. The trial aims to enroll 36 participants.

Official Summary

This phase I trial tests the safety, side effects, and best dose of pidnarulex in combination with trastuzumab deruxtecan in treating patients with breast cancer and other solid tumors that express varying levels of a protein called HER2 and that has spread from where it first started (primary site) to other places in the body (metastatic), that cannot be removed by surgery (unresectable), or that has spread to nearby tissue or lymph nodes (locally advanced). Pidnarulex is an enzyme inhibitor that causes cell death and prevents tumor cell growth. Trastuzumab deruxtecan is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive tumor cells in a targeted way and delivers deruxtecan to kill them. Giving pidnarulex in combination with trastuzumab deruxtecan may be safe, tolerable and/or effective in treating patients with metastatic, unresectable, or locally advanced HER2-expressing breast cancer or other solid tumors.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible patients must be at least 18 years old and have HER2-positive breast cancer or other solid tumors that have spread. Patients must have had at least one prior line of cytotoxic chemotherapy and must not have progressed on a prior anthracycline in the metastatic setting. Participants must have measurable disease and a performance status of ≤ 2 (Karnofsky ≥ 60%). Patients with known cardiac disease or a history of treatment with cardiotoxic agents must have a clinical risk assessment of cardiac function. This trial is studying Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Invasive Breast Carcinoma, Locally Advanced Breast Carcinoma, Metastatic Breast Carcinoma, Metastatic HER2-Low Breast Carcinoma, Metastatic HER2-Positive Breast Carcinoma, Metastatic Hormone Receptor-Positive Breast Carcinoma, Metastatic Malignant Solid Neoplasm, Metastatic Triple-Negative Breast Carcinoma, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures will help determine the maximum tolerated dose and the safety of the drug combination, which is crucial for patients. The specific primary outcome measures are: Maximum tolerated dose (dose escalation phase) (Up to completion of dose-escalation); Incidence of adverse events with drug combination at the recommended phase 2 dose (dose expansion phase) (Up to 3 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial is important as it aims to fill a treatment gap for HER2-expressing solid tumors, offering a potentially safer and more effective combination of drugs. This research targets Anatomic Stage III Breast Cancer AJCC v8, Anatomic Stage IV Breast Cancer AJCC v8, Invasive Breast Carcinoma, Locally Advanced Breast Carcinoma, Metastatic Breast Carcinoma, Metastatic HER2-Low Breast Carcinoma, Metastatic HER2-Positive Breast Carcinoma, Metastatic Hormone Receptor-Positive Breast Carcinoma, Metastatic Malignant Solid Neoplasm, Metastatic Triple-Negative Breast Carcinoma, where improved treatment options are needed.

Investor Insight

The market for HER2-targeted therapies is large, with strong competition, but this trial could potentially lead to a new approved treatment, making it an attractive investment opportunity. Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about your eligibility and the potential risks and benefits of participating in the trial. You will receive infusions of the drugs and have regular blood tests and scans. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 36 participants

Interventions

• PROCEDURE: Biopsy Procedure — Undergo biopsy
• PROCEDURE: Biospecimen Collection — Undergo collection of blood samples
• PROCEDURE: Echocardiography Test — Undergo ECHO
• PROCEDURE: Multigated Acquisition Scan — Undergo MUGA
• DRUG: Pidnarulex — Given IV

Primary Outcomes

• Maximum tolerated dose (dose escalation phase) (Up to completion of dose-escalation)
• Incidence of adverse events with drug combination at the recommended phase 2 dose (dose expansion phase) (Up to 3 years)

Secondary Outcomes

• Tumor response rate (Up to 3 years)
• Plasma concentrations of CX-5461 (pidnarulex) and trastuzumab deruxtecan (Cycle (C) 1 day (D) 1, C1D8, C1D10, C1D15, C2D1, C2D8, C2D10, C2D15 (cycle length = 21 days))
• Markers of deoxyribonucleic acid (DNA) damage repair (DDR) (At baseline and on-treatment)

Full Eligibility Criteria

Inclusion Criteria:

* DOSE ESCALATION PHASE ONLY: Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
* DOSE EXPANSION PHASE ONLY: Participants must have histologically or cytologically confirmed invasive breast cancer, with either locally advanced or metastatic disease
* Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of CX-5461 (pidnarulex) in combination with T-DXd in patients \< 18 years of age, children are excluded from this study
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
* Absolute neutrophil count (ANC) ≥ 1,500/mcL

  * No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment
* Platelets ≥ 100,000/mcL

  * No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment
* Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) (or ≤ 2 × institutional ULN in patients with documented Gilbert's syndrome)
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 3 × institutional ULN (or ≤ 5 × ULN in patients with liver metastases)
* International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN
* Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m\^2 (using the Cockcroft-Gault equation for participants with creatinine levels above institutional ULN)
* Patients must have had at least one prior line of cytotoxic chemotherapy. Patients can have received an unlimited number of additional lines of chemotherapy, targeted therapy, biologic therapy, or hormonal therapy. Patients must not have progressed on a prior anthracycline in the metastatic setting. Receipt of anthracycline in the (neo)adjuvant setting is allowed, provided that disease recurrence occurred later than 6 months after the completion of treatment
* Prior poly (ADP-ribose) polymerase (PARP) inhibition is allowed
* No specific germline mutation is required
* DOSE ESCALATION PHASE ONLY:

  * HER2-positive (IHC 3+) solid cancers,
  * HR+ HER2 positive/low/ultralow breast cancer or triple negative breast cancer (TNBC) HER2-low breast cancer, with HER2 positive defined by the current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines,
  * HER2-low, with HER2-low defined as IHC 2+/in situ hybridization (ISH)-, IHC 1+/ISH-, or IHC 1+/ISH untested
* DOSE EXPANSION PHASE ONLY:

  * Either the primary invasive tumor and/or the metastasis must be:

    * HER2-low, with HER2-low defined as IHC 2+/ISH-, IHC 1+/ISH-, or IHC 1+/ISH untested. Any estrogen receptor (ER) and progesterone receptor (PR) expression is permitted but must be known, or
    * HR+ HER2-ultralow defined as IHC 0 with membrane staining
* Participants must have at least one lesion that is not within a previously radiated field that is measurable per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Bone lesions are not considered measurable by definition. Biopsy of the lesion that will be used for disease evaluation (measurable disease) is not allowed in the dose expansion portion of this study
* Peripheral neuropathy grade ≤ 1
* Patients must have left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within 28 days before randomization/enrollment
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
* Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
* Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
* Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
* Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better
* Patients with a prior or concurrent malignancy whose 

Trial Locations

• Dana-Farber - Harvard Cancer Center LAO, Boston, Massachusetts, United States

Frequently Asked Questions

Related Conditions

• Anatomic Stage III Breast Cancer AJCC v8
• Anatomic Stage IV Breast Cancer AJCC v8
• Invasive Breast Carcinoma
• Locally Advanced Breast Carcinoma
• Metastatic Breast Carcinoma
• Metastatic HER2-Low Breast Carcinoma
• Metastatic HER2-Positive Breast Carcinoma
• Metastatic Hormone Receptor-Positive Breast Carcinoma
• Metastatic Malignant Solid Neoplasm
• Metastatic Triple-Negative Breast Carcinoma

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