Details

Details

Title An Open-Label, Single-Arm, Phase 2 Study of Mocetinostat in Selected Patients with Inactivating Alterations of Acetyltransferase Genes in Previously Treated Locally Advanced or Metastatic Urothelial Carcinoma.

IRB METH1814

CC 14-1292

Hospital Main Campus

Phase Phase 2

Disease Bladder, Genitourinary, Urothelial

Drug Mocetinostat

Description

Description

Primary Objective
  • To determine the efficacy of mocetinostat in patients with locally advanced, unresectable or metastatic urothelial carcinoma who have inactivating mutations or deletions involving CREBBP and/or EP300 gene loci in their tumor tissue.
Secondary Objectives
  • To evaluate the safety and tolerability of mocetinostat in the selected population.
  • To evaluate secondary efficacy endpoints with mocetinostat treatment in the selected population.
  • To assess the Pharmacokinetics (PK) of mocetinostat in the selected population.
Exploratory Objectives
  • To assess clinical activity endpoints with mocetinostat treatment in the exploratory cohort.
  • To assess the correlation of other genetic alterations occurring simultaneously with CREBBP and/or EP300 with mocetinostat treatment response and resistance.
  • To assess the mechanisms of acquired resistance to mocetinostat in a selected population.
  • To assess circulating tumor DNA (ctDNA) for:
    • Sensitivity of ctDNA assay for detection and quantification of CREBBP and/or EP300 gene alterations;
    • Change in ctDNA burden during therapy, including correlation with disease response; and
    • Change in ctDNA genetic alteration status in responders at the time of disease progression.
Inclusion Criteria

Inclusion Criteria

  1. Histologically confirmed urothelial (transitional cell) carcinoma with metastatic disease or with unresectable, locally advanced disease.
  2. Received prior chemotherapy which included a platinum agent. Therapy may have been administered in the peri-operative or metastatic setting. In the case of peri-operative treatment, disease progression or relapse must have occurred within 1 year of the last date of treatment.
  3. Analysis of tumor tissue using a Sponsor pre-approved method and laboratory that demonstrates an inactivating mutation or deletion of the CREBBP and/or EP300 genes. If eligibility is established using a local laboratory, tumor specimens and/or DNA should be available for retrospective sequencing in the central laboratory selected by the Sponsor. In the event that the minimum amount of tumor specimen is not available for central review and a new biopsy is not safe, enrollment must be approved by the Sponsor.
  4. Measurable disease, as per RECIST version 1.1 (Appendix 4).
  5. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (Appendix 1).
  6. Adequate bone marrow and organ function demonstrated by:
    • Absolute neutrophil count ≥ 1,000/mm3 (≥ 1.0 x 109/L)
    • Platelet count ≥ 75,000/mm3 (≥ 100 x 109/L)
    • Hemoglobin ≥ 8 g/dL
    • Deleted in Amendment #1, International Normalized Ratio (INR) ≤ 1.5
    • Serum creatinine:
      • patient weight > 120 lbs, ≤ 1.5 x ULN or calculated creatinine clearance ≥ 30 cc/min
      • patient weight ≤ 120 lbs, ≤1.5 x ULN and calculated or measured creatinine clearance ≥ 30 cc/min
    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x Upper Limit of Normal (ULN), or ≤ 5.0 x ULN for patients with documented liver metastases.
    • Total bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN for patients with Gilbert Syndrome.
  7. ≥ 18 years of age.
  8. Able to swallow and retain oral medication.
  9. Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment.
  10. Completed informed consent process, including signing IRB/EC-approved informed consent form.
  11. Willing to comply with clinical trial instructions and requirements.
Exclusion Criteria

Exclusion Criteria

  1. Previous or current treatment with an HDAC inhibitor (except prior valproic acid for seizures.
  2. Most recent prior cancer therapy (e.g., chemotherapy, radiation therapy, or investigational agent) discontinued ≤3 weeks before first dose date (6 weeks for nitrosourea, antibodies or mitomycin-C).
  3. Absence of recovery from the adverse effects of prior therapy at the time of enrollment to ≤ Grade 2 (excluding alopecia).
  4. Symptomatic or uncontrolled brain metastases. Patients with symptoms suggestive of brain metastases must undergo screening CT or MRI scan of the brain. For patients with history of brain metastases, time elapsed since last cranial radiation must be at least 4 weeks, and last steroid treatment must be at least 2 weeks.
  5. Impaired cardiac function including any of the following:
    • Current or history of a small, moderate or large pericardial effusion, and/or hemodynamic compromise due to pericardial effusion of any size (definitions are provided in Table 10). Minimal or trivial pericardial effusion is not excluded.
    • Significant cardiac abnormalities such as unstable angina pectoris, myocardial infarction within 6 months, congestive heart failure ≥ NYHA Class 3, symptomatic or uncontrolled atrial fibrillation.
    • Prolonged QTc interval (> 480 msec).
    • Presence of unstable atrial fibrillation (ventricular response rate > 100 beats per minute).
    • Left ventricular ejection fraction (LVEF) < 40%.
    • History of pericarditis.
    • Pericardial or epicardial metastases.
    • Other clinically significant heart disease.
  6. Need for treatment with warfarin or coumarin derivatives. Use of other anticoagulants is at investigator discretion and should be based on best medical practice.
  7. Concomitant medication known to cause prolonged QT which cannot be discontinued or changed to a different medication prior to enrollment (Appendix 2).
  8. Known or suspected presence of another malignancy that could be mistaken for metastatic urothelial carcinoma during disease assessments.
  9. Need for treatment with gastric pH modifying medications including proton pump inhibitors and/or H2 antagonist medications. Patients may switch to use of antacids.
  10. Other concurrent severe and/or uncontrolled medical condition that would, in the investigator's judgment, contraindicate his/her participation in the clinical study (e.g. chronic pancreatitis, active chronic hepatitis, etc.)
  11. Known human immunodeficiency virus (HIV) seropositivity.
  12. Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented within the screening period prior start of study drug.
  13. Breast-feeding or planning to breast feed during the study or within 30 days after study treatment.
  14. Known hypersensitivity to any of the excipients of mocetinostat.
  15. Any uncontrolled inter-current illness, active or uncontrolled infection.
  16. Any serious illness, medical condition, or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with the patient's participation in the study, or with the interpretation of the results.