A Phase Ib/II Study Evaluating Navitoclax After Failure of Hypomethylating Agent and Venetoclax for Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome

What's the purpose of this trial?

This phase Ib/II trial tests the safety, side effects, and best dose of navitoclax in combination with venetoclax and decitabine in treating patients with higher risk myelodysplastic syndrome (MDS) that has come back after initial treatment or was not responsive to initial treatment. This study will also look at the effectiveness of the treatment combination and patient's quality of life while on these medications. Navitoclax is an oral drug that works as an inhibitor of the BCL-2 family of proteins, which are often overly expressed in a wide variety of cancers and are linked to tumor drug resistance. This drug blocks some of the enzymes that keep cancer cells from dying. Venetoclax is an oral drug that works as an inhibitor of BCL-2 proteins that works very similarly to navitoclax by blocking the action of a certain proteins in the body that helps cancer cells survive which helps to kill cancer cells. Decitabine is an intravenous drug. It is a hypomethylating agent which means it interferes with deoxyribonucleic acid (DNA) methylation. DNA methylation is a major factor that regulates gene expression in cells, and an increase in DNA methylation can block the genes that regulate cell division and growth. When these genes are blocked the overall result allows or promotes cancer as there is no control over cell growth. Decitabine stops cells from making DNA and may kill cancer cells. Participation in this trial may improve the understanding of both chemotherapy response in MDS and mechanisms of resistance to current therapies.

This trial is currently open and accepting patients.

What will happen during the trial?

You may be able to join this trial if you:

The following criteria is a partial list of reasons why patients may be eligible to participate in this clinical trial. Further evaluation with a medical professional is required.

  • Inclusion Criteria:
    • Provide signed and dated informed consent form
    • Willing to comply with all study procedures and be available for the duration of the study
    • Male or female, aged 18 years or older
    • Must have myelodysplastic syndrome with IPSS-R(1) of at least 3 and have been previously treated with HMA (azacitidine or decitabine) and venetoclax for at least 2 cycles. Patients in the phase I portion of the trial may be enrolled if they have not received venetoclax with HMA therapy.
    • Prior hematopoietic stem cell transplant will be allowed if 90 or more days has passed since the date of transplant to day 1 of cycle 1 and patients are no longer taking immunosuppressive agents.
    • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2 [See Appendix B for details.]
    • Must be able to swallow pills whole.
    • Adequate renal function, defined as creatinine clearance ≥ 40 mL/min, calculated with the use of the 24-hour creatinine clearance or modified Cockcroft-Gault equation.
    • Adequate hepatic function, defined as:AST or
      • ALT ≤ 2.5x ULN
      • Total bilirubin ≤ 1.5x ULN (or ≤ 3x ULN for patients with documented Gilbert syndrome)
      • Coagulation: activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤ 1.5 × ULN
    • A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
      • Not a woman of childbearing potential (WOCBP)
      • A WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment. Approved methods are detailed below.
      • Hormonal Methods: levonorgestrel-releasing intrauterine system (e.g., Mirena®), implants, hormone shot or injection, combined pill, Minipill, Patch
    • If not surgically sterile, male patients must be willing to practice at least one of the following highly effective methods of birth control for at least their partner's menstrual cycle before and for 120 days after study drug administration. Approved methods are detailed below. Surgically sterile male patients may practice birth control measures at their own discretion.
      • Two of the following Barrier/Intrauterine Methods: Male or female condom with or without spermicide, cap, diaphragm, or sponge with spermicide, copper T intrauterine device
      • Hormonal Methods: levonorgestrel-releasing intrauterine system (e.g., Mirena®), implants, hormone shot or injection, combined pill, Minipill, Patch
      • Barrier/intrauterine methods combined with hormonal methods

Exclusion Criteria:

  • Active, uncontrolled systemic infection. Patients on prophylactic antibiotics are NOT excluded.
  • Uncontrolled HIV, HBV, or HVC infections defined as detectable viral load
  • History of any active malignancy within the past 2 years prior to screening, with the exception of:
    • Adequately treated carcinoma in situ of the uterine cervix
    • Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
    • Asymptomatic prostate
  • Subject requiring a medication that interferes with coagulation or platelet function except for low dose aspirin (up to 100 mg daily) and prophylactic dose low molecular weight heparin (LMWH). Subjects prescribed these medications prior to enrollment should discontinue at least 3 days prior to C1D1. If they are not able to discontinue these medications, subjects will be excluded.
  • WBC >25,000 cells/microL. Hydroxyurea therapy to reduce WBC count prior to enrollment is NOT excluded.
  • Malabsorption syndrome or other condition precluding enteral medication administration.
  • Subjects treated concomitantly with CYP2C8 substrates, CYP2C9 substrates, CYP3A inhibitors, CYP3A inducers and P-glycoprotein inhibitors are allowed. Venetoclax dosing must be adjusted as per sections 5.4.2 and 5.8.2.
  • Pregnancy or lactation or intending to become pregnant during the study.
  • Known allergic reactions to components of the study product(s)
  • Treatment with another investigational drug or other intervention within 2 weeks of planned C1D1.

Additional Trial Information

Phase 1/2

Enrollment: 37 patients (estimated)

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Sidney Kimmel Cancer Center Thomas Jefferson University

Philadelphia, PA

Open and Accepting
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