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

• ClinicalTrials.gov Identifier: NCT04115306
• Recruitment Status: Recruiting
• First Posted: October 4, 2019
• Last Update Posted: August 23, 2021
• Sponsor: Phoenix Molecular Designs
• Information provided by (Responsible Party): Phoenix Molecular Designs

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Metastatic Breast Cancer; Triple Negative Breast Cancer	Drug: PMD-026	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 14, 2019
• Estimated Primary Completion Date: February 2022
• Estimated Study Completion Date: February 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: PMD-026; Oral PMD-026 (dose: 25 - 1000 mg), given daily until disease progression or unacceptable toxicity	Drug: PMD-026; Oral RSK1-4 inhibitor

Outcome Measures

Primary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: Through study completion, an average of 12 weeks ]
   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.
2. Maximum tolerated dose (MTD) of PMD-026 [ Time Frame: Up to 21 days ]
   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.
3. Recommended Phase 2 Dose (RP2D) of PMD-026 [ Time Frame: Up to 14 months ]
   The RP2D will be determined following the determination of the MTD and an overall assessment of safety as determined by the Safety Committee.
4. Efficacy in Patients [ Time Frame: 6 weeks ]
   Anti-tumor activity (efficacy) will be assessed in all patients.

Secondary Outcome Measures :

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

Other Outcome Measures:

1. RSK2 Expression [ Time Frame: 6 weeks ]
   RSK2 expression will be evaluated in breast cancer tissue through immunohistochemistry (IHC).
2. PMD-026 Activity in Tissue [ Time Frame: 6 weeks ]
   PMD-026 activity will be evaluated in Lehmann subtypes in breast cancer tissue.
3. RSK2 Expression and Response [ Time Frame: 12 weeks ]
   The relationship between RSK2 expression and response will be evaluated following RSK2 IHC and disease assessments.
4. PMD-026 pharmacodynamics and RSK signaling [ Time Frame: 2 weeks ]
   PMD-026 pharmacodynamics will be evaluated on RSK signaling.

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:

1. Signed informed consent
2. Age ≥ 18 years
3. ECOG Performance Status ≤ 2
4. [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
5. [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
6. [Part 1 - Dose Escalation] Evaluable or measurable disease by RECISTv1.1
7. [Part 2 - Dose Expansion] Measurable disease by RECISTv1.1

8. Adequate laboratory parameters including:

   1. Absolute Neutrophil Count (ANC) ≥ 1500/mm^3
   2. Platelets ≥ 100,000/mm^3
   3. AST/SGOT ≤ 2.5 x ULN (≤ 5 x ULN if known liver involvement)
   4. ALT/SGPT ≤ 2.5 x ULN (≤ 5 x ULN if known liver involvement)
   5. Total bilirubin ≤ 1.5 x ULN (unless diagnosis of Gilbert's syndrome in which case < 3.0 times ULN)
   6. Serum creatinine ≤ 1.5 x ULN or estimated GFR ≥ 60 mL/min

9. If residual treatment related toxicity from prior therapy:

   1. Treatment related toxicity resolved to at least Grade 1 (alopecia excepted), or
   2. Treatment related toxicity resolved to at least Grade 2 with prior approval of the Medical Monitor
10. Available archival or fresh tumor tissue (Formalin-fixed paraffin-embedded [FFPE])
11. [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
12. [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
13. [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
14. [Females] If of childbearing potential, the patient must have a negative serum pregnancy test

Exclusion Criteria:

1. ≤ 14 days from prior chemotherapy, biological or investigational therapy
2. Use of any medications known to result in a prolongation of the QT/QTc interval
3. Use of any medication that is a strong inducer or substrate of cytochrome P450 3A
4. Use of any medications that is a substrate of BCRP
5. Use of any medication that is a substrate of MATE2K
6. ≤ 28 days from prior irradiation (including therapeutic radioisotopes such as strontium 89)
7. ≤ 7 days from limited field irradiation for palliation
8. ≤ 28 days from major surgical procedures
9. ≤ 7 days from minor surgical procedures (no waiting period required following central catheter placement)
10. Central nervous system metastases, unless appropriately treated and neurologically stable for ≥ 28 days
11. Known history of leptomeningeal metastases
12. Uncontrolled bacterial, viral, or fungal infection (s) requiring systemic therapy
13. Pregnant or currently breast-feeding
14. Known Hepatitis B or Hepatitis C infection
15. Known HIV-positive with CD4+ cell counts < 350 cells/uL
16. Known HIV-positive with a history of an AIDS-defining opportunistic infection

17. History of clinically significant cardiovascular abnormalities including:

    1. Congestive heart failure (NYHA classification ≥ 3 in within 6 months of first dose of PMD-026
    2. Unstable angina pectoris
    3. Myocardial infarction within 12 months of study entry
    4. Arrhythmias requiring continued treatment (controlled atrial fibrillation allowed)
    5. QTcF interval > 460 msec (using Fridericia's formula)
18. 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)
19. 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)
20. 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
21. Other known active cancer(s) likely to require treatment in the next year that would impact the assessment of any study endpoints
22. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol

Contacts and Locations

Contacts

Contact: Phoenix Molecular Designs; 604-674-1796; clinical@phoenixmd.ca

Locations

United States, Arizona

Banner MD Anderson Cancer Center; Recruiting

Gilbert, Arizona, United States, 85234

Contact: Alex Latorre, BSN, RN 480-256-5412 jose.latorre@bannerhealth.com

The University of Arizona Cancer Center; Recruiting

Tucson, Arizona, United States, 85724

Contact: Alexia Demitsas, MS 520-694-9089 ademitsas@email.arizona.edu

United States, California

University of California, Los Angeles (UCLA); Recruiting

Los Angeles, California, United States, 90095

Contact: Hiromi Yagi 310-998-4747 hyagi@mednet.ucla.edu

University of California, San Diego (UCSD); Recruiting

San Diego, California, United States, 92093

Contact: Mitch Wodrich 858-822-4343 mwodrich@health.ucsd.edu

Contact: Sauntee Braddock 858-534-8248 sbraddock@health.ucsd.edu

United States, Florida

Florida Cancer Specialists & Research Institute; Recruiting

Sarasota, Florida, United States, 34232

Contact: Judy Wang, MD 941-377-9993 jswang@flcancer.com

Moffitt Cancer Center; Recruiting

Tampa, Florida, United States, 33612

Contact: Jerry Owens 813-745-8304 jerry.owens@moffitt.org

United States, New York

Columbia University; Recruiting

New York, New York, United States, 10032

Contact: Brianne Bodin bb2895@cumc.columbia.edu

United States, Ohio

Ohio State University; Recruiting

Columbus, Ohio, United States, 43210

Contact: Robert Wesolowski, M.D. Robert.Wesolowski@osumc.edu

United States, Texas

South Texas Accelerated Research Therapeutics; Recruiting

San Antonio, Texas, United States, 78229

Contact: Isabel Jimenez, RN, MSN 210-593-5265 isabel.jimenez@startsa.com

Sponsors and Collaborators

Phoenix Molecular Designs

More Information

• Responsible Party: Phoenix Molecular Designs
• ClinicalTrials.gov Identifier: NCT04115306
• Other Study ID Numbers: PMD-026-1-001
• First Posted: October 4, 2019
• Last Update Posted: August 23, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Phoenix Molecular Designs:

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

Additional relevant MeSH terms:

Breast Neoplasms; Triple Negative Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases