A Phase Ib/II Study Evaluating Navitoclax After Failure of Hypomethylating Agent and Venetoclax for Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome
Trial Snapshot
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- Thomas Jefferson University
- Enrollment
- 6
- Locations
- 2
- Primary Endpoint
- Maximally Tolerated Dose (MTD) of Navitoclax in Combination with Venetoclax and Decitabine (Phase I)
Study Overview
Brief Summary
This 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.
Detailed Description
This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2.
PRIMARY OBJECTIVES:
I. To determine the safety profile leading to a recommended phase II dose (RP2D) of navitoclax in combination with venetoclax and decitabine. (Phase I) II. To evaluate the efficacy of combination therapy navitoclax, venetoclax and decitabine in patients with relapsed or refractory high-risk MDS after failure of hypomethylating agent and venetoclax. (Phase II)
SECONDARY OBJECTIVE:
I. To further evaluate the safety profile navitoclax in combination with venetoclax and decitabine. (Phase II)
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
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 Revised International Prognostic Score (IPSS-R) of at least 3 and have been previously treated with hypomethylating agent (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
- •Must be able to swallow pills whole
- •Creatinine clearance >= 40 mL/min, calculated with the use of the 24-hour creatinine clearance or modified Cockcroft-Gault equation
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
- •Total bilirubin =< 1.5 x ULN (or =< 3 x ULN for patients with documented Gilbert syndrome)
- •Coagulation: activated partial thromboplastin time (aPTT) and international normalized ratio (INR) =< 1.5 x 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, registered trademark), 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.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
- •Barrier/intrauterine methods combined with hormonal methods
Exclusion Criteria
- •Active, uncontrolled systemic infection. Patients on prophylactic antibiotics are NOT excluded
- •Uncontrolled human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) 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 C1D
- •If they are not able to discontinue these medications, subjects will be excluded
- •White blood cells (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. Pregnancy or lactation or intending to become pregnant during the study
- •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 cycle 1 day 1 (C1D1)
Arms & Interventions
Treatment (navitoclax, decitabine, venetoclax)
This is a single-center trial of navitoclax, venetoclax and decitabine in adult patients with R/R HR-MDS who have previously failed HMA therapy. This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2. In the phase I dose escalation portion, patients will receive navitoclax in combination with standard dosing of venetoclax and decitabine. The maximally tolerated dose (MTD) will be the recommended phase II dose (RP2D). Previously, navitoclax in combination with venetoclax and chemotherapy in ALL found the MTD to 50mg of nativoclax po.
In the phase II dose expansion portion, patients will receive navitoclax at the RP2D in combination with standard dose venetoclax and decitabine. Patients will continue on treatment with navitoclax, venetoclax and decitabine until relapse, dose-limiting toxicity, availability of alternate therapy or withdrawal of consent.
Intervention: Bone Marrow Biopsy (Procedure)
Treatment (navitoclax, decitabine, venetoclax)
This is a single-center trial of navitoclax, venetoclax and decitabine in adult patients with R/R HR-MDS who have previously failed HMA therapy. This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2. In the phase I dose escalation portion, patients will receive navitoclax in combination with standard dosing of venetoclax and decitabine. The maximally tolerated dose (MTD) will be the recommended phase II dose (RP2D). Previously, navitoclax in combination with venetoclax and chemotherapy in ALL found the MTD to 50mg of nativoclax po.
In the phase II dose expansion portion, patients will receive navitoclax at the RP2D in combination with standard dose venetoclax and decitabine. Patients will continue on treatment with navitoclax, venetoclax and decitabine until relapse, dose-limiting toxicity, availability of alternate therapy or withdrawal of consent.
Intervention: Biospecimen Collection (Procedure)
Treatment (navitoclax, decitabine, venetoclax)
This is a single-center trial of navitoclax, venetoclax and decitabine in adult patients with R/R HR-MDS who have previously failed HMA therapy. This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2. In the phase I dose escalation portion, patients will receive navitoclax in combination with standard dosing of venetoclax and decitabine. The maximally tolerated dose (MTD) will be the recommended phase II dose (RP2D). Previously, navitoclax in combination with venetoclax and chemotherapy in ALL found the MTD to 50mg of nativoclax po.
In the phase II dose expansion portion, patients will receive navitoclax at the RP2D in combination with standard dose venetoclax and decitabine. Patients will continue on treatment with navitoclax, venetoclax and decitabine until relapse, dose-limiting toxicity, availability of alternate therapy or withdrawal of consent.
Intervention: Navitoclax (Biological)
Treatment (navitoclax, decitabine, venetoclax)
This is a single-center trial of navitoclax, venetoclax and decitabine in adult patients with R/R HR-MDS who have previously failed HMA therapy. This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2. In the phase I dose escalation portion, patients will receive navitoclax in combination with standard dosing of venetoclax and decitabine. The maximally tolerated dose (MTD) will be the recommended phase II dose (RP2D). Previously, navitoclax in combination with venetoclax and chemotherapy in ALL found the MTD to 50mg of nativoclax po.
In the phase II dose expansion portion, patients will receive navitoclax at the RP2D in combination with standard dose venetoclax and decitabine. Patients will continue on treatment with navitoclax, venetoclax and decitabine until relapse, dose-limiting toxicity, availability of alternate therapy or withdrawal of consent.
Intervention: Venetoclax (Drug)
Treatment (navitoclax, decitabine, venetoclax)
This is a single-center trial of navitoclax, venetoclax and decitabine in adult patients with R/R HR-MDS who have previously failed HMA therapy. This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2. In the phase I dose escalation portion, patients will receive navitoclax in combination with standard dosing of venetoclax and decitabine. The maximally tolerated dose (MTD) will be the recommended phase II dose (RP2D). Previously, navitoclax in combination with venetoclax and chemotherapy in ALL found the MTD to 50mg of nativoclax po.
In the phase II dose expansion portion, patients will receive navitoclax at the RP2D in combination with standard dose venetoclax and decitabine. Patients will continue on treatment with navitoclax, venetoclax and decitabine until relapse, dose-limiting toxicity, availability of alternate therapy or withdrawal of consent.
Intervention: Decitabine (Drug)
Treatment (navitoclax, decitabine, venetoclax)
This is a single-center trial of navitoclax, venetoclax and decitabine in adult patients with R/R HR-MDS who have previously failed HMA therapy. This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2. In the phase I dose escalation portion, patients will receive navitoclax in combination with standard dosing of venetoclax and decitabine. The maximally tolerated dose (MTD) will be the recommended phase II dose (RP2D). Previously, navitoclax in combination with venetoclax and chemotherapy in ALL found the MTD to 50mg of nativoclax po.
In the phase II dose expansion portion, patients will receive navitoclax at the RP2D in combination with standard dose venetoclax and decitabine. Patients will continue on treatment with navitoclax, venetoclax and decitabine until relapse, dose-limiting toxicity, availability of alternate therapy or withdrawal of consent.
Intervention: Laboratory Biomarker Analysis (Other)
Treatment (navitoclax, decitabine, venetoclax)
This is a single-center trial of navitoclax, venetoclax and decitabine in adult patients with R/R HR-MDS who have previously failed HMA therapy. This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2. In the phase I dose escalation portion, patients will receive navitoclax in combination with standard dosing of venetoclax and decitabine. The maximally tolerated dose (MTD) will be the recommended phase II dose (RP2D). Previously, navitoclax in combination with venetoclax and chemotherapy in ALL found the MTD to 50mg of nativoclax po.
In the phase II dose expansion portion, patients will receive navitoclax at the RP2D in combination with standard dose venetoclax and decitabine. Patients will continue on treatment with navitoclax, venetoclax and decitabine until relapse, dose-limiting toxicity, availability of alternate therapy or withdrawal of consent.
Intervention: Quality-of-Life Assessment (Other)
Outcomes
Primary Outcomes
Maximally Tolerated Dose (MTD) of Navitoclax in Combination with Venetoclax and Decitabine (Phase I)
Time Frame: Within 30 days of the first dose of study treatment
The Bayesian optimal interval (BOIN) design will be employed to find the MTD. The BOIN design is implemented in a simple way. It is more flexible and possesses superior operating characteristics that are comparable to those of the more complex model based designs.
Complete Response (CR) Rate (Phase II)
Time Frame: Up to cycle 4, an average of 4 months
A 90% confidence interval will be computed for the CR rate by cycle 4.
Secondary Outcomes
- Number of Dose-Limiting Toxicities (Phase I)(Within 30 days of the first dose of study treatment)
- Marrow Complete Response Rate (mCR) (Phase II)(Up to 2 years from enrollment of the last patient)
- Hematologic Improvement (HI) rate (Phase II)(Up to 2 years from enrollment of the last patient)
- Leukemia Free Survival (LFS) (Phase II)(Up to 2 years from enrollment of the last patient)
- Overall survival (OS) (Phase II)(Up to 2 years from enrollment of the last patient)
- Change in quality of life (QOL) (Phase II)(Up to 2 years from enrollment of the last patient)
- Change in quality of life (QOL) measured by PROMIS-Fatigue (20) (Phase II)(Up to 2 years from enrollment of the last patient)
- Hematologic Improvement (HI) rate (Phase II)(Up to 2 years from enrollment of the last patient)