MC# 22-01 - A Phase I, Open-Label, Multicenter, Dose Escalation Study of PRT2527 in Patients with Advanced Solid Tumors

  • Agent(s): PRT2527
  • Disease Type(s): Breast, Prostate, Sarcoma, Solid Tumor, Lung-NSCLC
  • Phase(s): I
  • Drug Classification(s): Small Molecule, Targeted Therapy
  • Molecular Target(s): CDK9
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Mechanism of Action

PRT2527 is a potent and highly selective inhibitor of cyclin-dependent kinase 9 (CDK9).  CDK9 is a member of the CDK family, which is an important group of proteins involved in the control of the cell cycle.  CDK9 is a key regulator of ribonucleic acid (RNA) transcription.

Purpose

In this study, the sponsor and investigators want to learn:

  • How much of PRT2527 can be given with an acceptable level of side effects
  • The effects of PRT2527 (good and bad)
  • How much of PRT2527 is absorbed into the blood and how fast it is removed
Inclusion Criteria
  1. Tumor Types Under Study:
    • Selected sarcomas (Ewing sarcoma of bone or soft tissue; Synovial sarcoma; Myxoid/round cell liposarcoma) with a gene fusion (e.g., EWS-FLI1, EWSR1, etc.)
      • Relapsed / refractory Ewing sarcoma of bone or soft tissue; Synovial sarcoma; Myxoid/round cell liposarcoma.
      • Tumor must display a gene fusion (e.g., EWS-FLI1, EWSR1, etc.).
      • Must have been treated with at least one systemic treatment regimen.
        Note: Next Generation Sequencing report from a validated clinical laboratory or 3rd party vendor must be submitted prior to enrollment for confirmation of eligibility.
    • Castrate Resistant Prostate Cancer
      • Metastatic or locally confined but inoperable, pathologically confirmed adenocarcinoma of the prostate that is castrate resistant, castration-resistant prostate cancer is defined by disease progression despite castrate levels of testosterone (serum testosterone below 50 ng/dL) and may present as either a continuous rise in serum prostate-specific antigen levels, the progression of pre-existing disease, and/or the appearance of new metastases.
      • Patients must also have received at least one prior anti-androgen therapy, either concurrent or sequentially with initial androgen deprivation therapy and progressed on such therapy.
    • Hormone Positive, HER2 Negative Breast Cancer
      • Patients must have histologically confirmed incurably recurrent and / or metastatic disease.
      • ER+/Her2- invasive ductal or invasive lobular carcinoma (ER >1% regardless of PR status, and HER2 negative as per ASCO/CAP guidelines).
      • Must have failed ≥ two prior lines of therapy; at least one prior regimen must have included treatment with a CDK 4/6 inhibitor, with progression on such therapy.
    • Advanced Non-Small Cell Lung Cancer
      • Patients must have histologically confirmed, locally advanced or metastatic disease.
      • Patients must have failed ≥ 2 prior lines of therapy.
    • MYC Amplified Solid Tumors
      • Tumor must display MYC overexpression and / or MYC gene amplification.
      • Patients must have been treated with at least one systemic treatment regimen for relapsed / refractory disease.
      • Note: Genomic sequencing or IHC or FISH report from a validated clinical laboratory or 3rd party vendor must be submitted prior to enrollment for confirmation of eligibility.
  2. Patients who are ≥ 18 years of age.
  3. Must have measurable disease per RECIST 1.1; patients with prostate cancer may have evaluable disease.
  4. Must have an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1.
  5. Must have adequate hepatic function as evidenced by:
    1. AST and ALT levels ≤ 3.0 x ULN (≤ 5 x ULN for patients with liver metastases)
    2. Total bilirubin < 1.5 x ULN for reference lab or direct bilirubin < 1.5 x ULN if total bilirubin ≥ 1.5 x ULN (exceptions can be made for subjects with Gilbert’s syndrome or other causes of unconjugated hyperbilirubinemia following consultation with Sponsor).
  6. All patients must have adequate renal function as evidenced by a calculated creatinine clearance of ≥ 50 mL/min according to the Cockcroft-Gault equation.
  7. Recent lab values (within 14 days prior to Week 1 Day 1) meet the following criteria:
    1. Absolute neutrophil count of > 1.5 x 103/μL;
    2. Platelet count ≥ 75,000/μL;
    3. Hemoglobin ≥ 9.0 g/dL (RBC transfusions may be used to meet HGB criteria).
  8. All patients must provide a tumor tissue sample from a core or excisional/surgical biopsy (fine needle aspirates are not acceptable) to send to the central laboratory for biomarker analysis. Archival samples from up to 10 years prior are acceptable, as are newly obtained biopsies.
  9. With the exception of alopecia, all patients must have recovered from the effects of any prior cancer related therapy, radiotherapy or surgery (toxicity from prior therapy is not greater than Grade 1).
    NOTE: Patients who have residual toxicity > Grade 1 from prior immunotherapy (e.g., adrenal insufficiency) but are managed with a stable dose of maintenance replacement therapies may be included.
  10. Female patients of childbearing potential must have a negative pregnancy test (urine / serum) within 7 days of the start of treatment.
  11. All female patients of childbearing potential who are heterosexually active and male patients with female sexual partners of childbearing potential must agree to use a highly effective method of contraception (e.g., oral contraceptives, double-barrier methods such as a condom and a diaphragm, intrauterine device) during the study and for 90 days following the last dose of study medication, or to abstain from sexual intercourse for this time; a woman not of childbearing potential is one who has undergone bilateral oophorectomies or who is post-menopausal, defined as the absence of menstrual periods for 12 consecutive months.
  12. Have a life expectancy of at least 3 months at the time of informed consent.
Exclusion Criteria
  1. Patients with known hypersensitivity to any of the components of PRT2527
  2. Patients with primary malignancies of the CNS, or who have uncontrolled CNS metastases, including impending spinal cord compression.
    NOTE: Patients with controlled CNS metastases must show radiographic stability for three months prior to starting the study. Those patients on a low dose of steroids, must have maintained their current dose unchanged, for at least 3 months.
  3. Patients who are pregnant or lactating.
  4. Have a corrected QT interval (using Fridericia's correction formula) (QTcF) of > 480 msec from prior or baseline Screening ECG.
  5. Patients known to be HIV positive. Patients who are HIV+ and who are on anti-viral therapy with undetectable viral load are eligible. If HIV status is unknown, specific screening is not required.
  6. Patients with known active hepatitis B or C. Patients with hepatitis C on anti-viral therapy with undetectable viral levels are not excluded. If hepatitis status is unknown, specific screening is not required.
  7. Patients who have active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy, including known, active COVID-19.
  8. Patients with uncontrolled intercurrent illnesses or psychiatric illness/social situations that would limit compliance with study requirements or render the patient at high risk during study participation.
  9. Subjects who have impaired cardiac function or clinically significant cardiac disease. History of congestive heart failure (CHF), greater than New York Heart Association (NYHA) Class III, uncontrolled unstable arrhythmia, myocardial infarction within the past 6 months prior to Week 1 Day 1.
  10. Presence of chronic inflammatory bowel disease (e.g., ulcerative colitis, Crohn’s disease).
  11. Patients who require treatment with strong inhibitors or inducers of CYP3A4.
  12. Prior exposure to a CDK9 inhibitor.
  13. History of another primary malignancy, with the exception of:
    1. Malignancy treated with curative intent with no known active disease for > 2 years prior to study start, and who has not received any anti-cancer treatment in the last 2 years;
    2. Locally excised non-melanoma skin cancer without evidence of disease (e.g., squamous cell or basal cell carcinoma of the skin);
    3. Adequately treated carcinoma in situ without evidence of disease (e.g., cervical or ductal carcinoma in situ).
  14. Patients who have severe chronic obstructive pulmonary disease with hypoxemia (Defined as resting O2 saturation of ≤ 90% breathing room air).
  15. Patients who have undergone major surgery within 2 weeks prior to Week 1 Day 1.(Consult with Sponsor for questions on whether surgery is considered major). Minorsurgeries such as biopsies or port placement are allowed).
  16. Patients who have had chemotherapy, biologic therapy, targeted therapy, immunotherapy,extended-field radiotherapy, or investigational agents within 5 half-lives or 28 days(whichever is shorter) prior to administration of the first dose of study drug on Week 1 Day 1.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT05159518

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Re: MC# 22-01