Phase 1/1b Study of Oral PMD-026 in Patients With Metastatic Breast Cancer and Metastatic Triple Negative Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to test the safety and tolerability of PMD-026 in patients with metastatic breast cancer and triple negative breast cancer. PMD-026 is a targeted oral agent designed to kill tumor cells in metastatic breast cancer and triple negative breast cancer.

Detailed Description
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This study will evaluate the safety and tolerability of PMD-026 using an accelerated titration design to define the MTD in metastatic breast cancer, followed by an expansion at the RP2D in triple negative breast cancer. All patients will receive daily oral doses of PMD-026 until either disease progression or unacceptable toxicity. Patients will have disease assessments initially after 6 weeks of treatment, and every 9 weeks thereafter. Patients enrolled to the Dose Escalation Phase must have histologically or cytologically diagnosed metastatic breast cancer that has progressed on or after standard of care therapy. Patients enrolled to the Dose Expansion Phase must have histologically or cytologically diagnosed metastatic triple negative breast cancer from initial diagnosis (ER/PgR <1%, HER2 negative) that has progressed on or after standard of care therapy. All patients must provide tumor tissue (archival preferred) prior to study entry. A subset (N=12) of patients in Part 2 of the study will participate in a 1- week evaluation of the effect of food on PMD-026 oral absorption. PMD-026 is an oral, reversible small molecule inhibitor of RSK1-4 with high selectivity for RSK2. High levels of RSK2 expression have been associated with worse overall survival in breast cancer. Inhibiting RSK2 may inhibit growth of breast cancer.

Official Title
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Phase 1/1b Multicenter, Open-Label, First-in-Human Dose Escalation and Dose Expansion Study to Assess Safety and Tolerability of Orally Administered PMD-026 in Patients With Metastatic Breast Cancer With Expansion in Metastatic Triple Negative Breast Cancer

Conditions
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Metastatic Breast Cancer, Triple Negative Breast Cancer

Intervention / Treatment
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* Drug: PMD-026


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent Age ≥ 18 years ECOG Performance Status ≤ 2 [Part 1 - Dose Escalation] Histologically or cytologically diagnosed metastatic breast cancer that has progressed on or after standard of care therapy and for which no standard of care therapy is available that would confer clinical benefit [Part 2 - Dose Expansion] Histologically or cytologically diagnosed metastatic triple-negative breast cancer with <1% expression of ER and PR and negative for HER2 (either 0 or 1+ by IHC or IHC 2+ and fluorescence in situ hybridization (FISH) negative) from the time of initial diagnosis that has progressed on or after standard of care therapy and for which no standard of care therapy is available that would confer clinical benefit [Part 1 - Dose Escalation] Evaluable or measurable disease by RECISTv1.1 [Part 2 - Dose Expansion] Measurable disease by RECISTv1.1 Adequate laboratory parameters including: Absolute Neutrophil Count (ANC) ≥ 1500/mm^3 Platelets ≥ 100,000/mm^3 AST/SGOT ≤ 2.5 x ULN (≤ 5 x ULN if known liver involvement) ALT/SGPT ≤ 2.5 x ULN (≤ 5 x ULN if known liver involvement) Total bilirubin ≤ 1.5 x ULN (unless diagnosis of Gilbert's syndrome in which case < 3.0 times ULN) Serum creatinine ≤ 1.5 x ULN or estimated GFR ≥ 60 mL/min If residual treatment related toxicity from prior therapy: Treatment related toxicity resolved to at least Grade 1 (alopecia excepted), or Treatment related toxicity resolved to at least Grade 2 with prior approval of the Medical Monitor Available archival or fresh tumor tissue (Formalin-fixed paraffin-embedded [FFPE]) [Females] The patient must be postmenopausal, surgically sterile, or agree to use adequate contraception (adequate as determined by the PI - may include abstinence) throughout the study and for a least 30 days following the last dose of PMD-026 [Males] The patient must be surgically sterile or must agree to use adequate contraception (adequate as determined by the PI - may include abstinence) throughout the study and for at least 30 days following the last dose of PMD-026 [Males] The patient must agree to refrain from donating sperm throughout the study and for at least 30 days following the last dose of PMD-026 [Females] If of childbearing potential, the patient must have a negative serum pregnancy test Exclusion Criteria: ≤ 14 days from prior chemotherapy, biological or investigational therapy Use of any medications known to result in a prolongation of the QT/QTc interval Use of any medication that is a strong inducer or substrate of cytochrome P450 3A Use of any medications that is a substrate of BCRP Use of any medication that is a substrate of MATE2K ≤ 28 days from prior irradiation (including therapeutic radioisotopes such as strontium 89) ≤ 7 days from limited field irradiation for palliation ≤ 28 days from major surgical procedures ≤ 7 days from minor surgical procedures (no waiting period required following central catheter placement) Central nervous system metastases, unless appropriately treated and neurologically stable for ≥ 28 days Known history of leptomeningeal metastases Uncontrolled bacterial, viral, or fungal infection (s) requiring systemic therapy Pregnant or currently breast-feeding Known Hepatitis B or Hepatitis C infection Known HIV-positive with CD4+ cell counts < 350 cells/uL Known HIV-positive with a history of an AIDS-defining opportunistic infection History of clinically significant cardiovascular abnormalities including: Congestive heart failure (NYHA classification ≥ 3 in within 6 months of first dose of PMD-026 Unstable angina pectoris Myocardial infarction within 12 months of study entry Arrhythmias requiring continued treatment (controlled atrial fibrillation allowed) QTcF interval > 460 msec (using Fridericia's formula) Presence of active gastrointestinal disease or other condition that is expected to interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥ 2, and malabsorption syndrome) Inadequately controlled hypertension defined as systolic blood pressure >180 mmHg or diastolic blood pressure >100 mmHg (patients with values above these levels must have their blood pressure controlled prior to starting treatment) Serious active infection at the time of treatment, or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment Other known active cancer(s) likely to require treatment in the next year that would impact the assessment of any study endpoints Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PMD-026<br>Oral PMD-026 (dose: 25 - 1000 mg), given daily until disease progression or unacceptable toxicity | Drug: PMD-026<br>* Oral RSK1-4 inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Toxicities will be assessed in each patient by tracking the occurrence of graded Adverse Events (AEs). AEs will be graded according to the National Cancer Institute Common Terminology for Adverse Events (NCI CTCAE) v5.0. | Through study completion, an average of 12 weeks | 
| Maximum tolerated dose (MTD) of PMD-026 | The MTD will be defined as the dose level at which no more than one of six patients experiences a dose limiting toxicity (DLT) after 21 days of treatment have occurred, with the next higher dose having at least 2 of 3 or 2 of 6 patients experiencing a DLT. | Up to 21 days | 
| Recommended Phase 2 Dose (RP2D) of PMD-026 | The RP2D will be determined following the determination of the MTD and an overall assessment of safety as determined by the Safety Committee. | Up to 14 months | 
| Efficacy in Patients | Anti-tumor activity (efficacy) will be assessed in all patients. | 6 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Concentration | The plasma concentration will be measured as part of pharmacokinetic (PK) testing. | 24 hours | 
| Time to Response | The time to response will be evaluated by disease assessments. | 6 weeks | 
| Duration of Response | The duration of response will be evaluated by disease assessments from time of first response (CR or PR) to time of disease progression. | 6 weeks | 
| Effect of food on PMD-026 PK | The effect of food on plasma concentration will be measured as part of pharmacokinetic (PK) testing. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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invasive breast cancer, ER-negative breast cancer, PR-negative breast cancer, HER2-negative breast cancer, triple negative breast cancer, Triple-Negative Breast Cancer, TNBC, Breast cancer, Breast malignancy, breast malignancies, metastatic breast cancer, Metastatic TNBC, Metastatic Triple-Negative Breast Cancer, Metastatic Triple Negative Breast Cancer, advanced breast cancer, solid tumor, late stage breast cancer/late-stage breast cancer