Low Dose Decitabine + Venetoclax for Blood Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Mendel Goldfinger, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Montefiore Medical Center

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

Myeloid malignancies which include AML (acute myeloid leukemia) and MDS (myelodysplatic syndrome) are cancers of the bone marrow which lead to bone marrow failure. The bone marrow is the place or factory in the body where components of blood such as red cells, platelets and white cells are made. In bone marrow failure, the ability of the bone marrow to make these cells is decreased. The decreased bone marrow function is the result from abnormalities that develop in the malignant cells which prevent the normal maturation process by which bone marrow cells develop into red blood cells, white blood cells and platelets. The malignant cells in the bone marrow are not good at maturing to make the components of the blood that you need, they occupy space in the bone marrow and prevent the function of remaining normal bone marrow cells. DNA is a chemical substance within cells that stores information needed for cell growth and cell behavior. One approach to treating the malignant cells is to give chemotherapy which damages DNA within these cells and causes their death. Unfortunately, such therapy has side-effects, since even normal cells can be affected by the treatment. Decitabine is FDA approved for treatment of MDS and AML. Venetoclax is approved for AML in combination with Azacitidine for patients with AML or are over age 75 or unfit for chemotherapy. In this study, Decitabine and venetoclax will be administered using a low dose weekly schedule in an attempt to improve efficacy by decreasing the side effects often seen when these drugs are given at standard dosing.

Do I have to stop taking my current medications for the trial?

The trial requires that you stop any disease-directed therapy, except for hydroxyurea, for 14 days before starting the study. The protocol does not specify other medications, so it's best to discuss your current medications with the trial team.

What data supports the idea that Low Dose Decitabine + Venetoclax for Blood Cancer is an effective drug?

The available research shows that Low Dose Decitabine combined with Venetoclax is effective for treating blood cancer, specifically acute myeloid leukemia (AML), in older patients who cannot undergo intensive chemotherapy. In one study, 67% of patients achieved complete remission, meaning their cancer symptoms disappeared. Another study found that this combination is now a standard treatment for elderly patients with AML, showing promising results even in high-risk groups. This suggests that the drug combination is effective and well-tolerated, offering a viable option for patients who have limited treatment choices. ^{1 2 3 4 5}

What safety data exists for Low Dose Decitabine + Venetoclax treatment for blood cancer?

The provided research does not contain safety data for Low Dose Decitabine + Venetoclax treatment for blood cancer. The studies focus on different drugs, primarily irinotecan and raltitrexed, and their effects on colorectal cancer, not on Decitabine or Venetoclax. ^{6 7 8 9 10}

Is the drug combination of Decitabine and Venetoclax promising for treating blood cancer?

Yes, the combination of Decitabine and Venetoclax is promising for treating blood cancer. It has shown effectiveness in treating certain types of leukemia, especially in patients who are older or cannot handle intense chemotherapy. This drug combination has been successful in achieving remission in some cases and is considered a new standard of care for specific blood cancers. ^{2 3 5 11 12}

Research Team

Mendel Goldfinger, MD

Principal Investigator

Montefiore Medical Center

Eligibility Criteria

Adults diagnosed with Myelodysplastic Syndrome (MDS), Acute Myeloid Leukemia (AML), or MDS/MPN who may benefit from hypomethylating agents. Participants must be over 18, have an ECOG status of ≥3, and adequate liver function. Pregnant or breastfeeding individuals, those with certain heart conditions, uncontrolled illnesses, active infections not well-managed by medication, or known allergies to the drugs are excluded.

Inclusion Criteria

My condition has previously responded well to HMA therapy.

I need help with my daily activities due to my health condition.

Patients must have adequate end organ function defined as: AST (aspartate aminotransferase) and ALT (alanine transaminase) < 4× the upper limit of normal (ULN), Bilirubin ≤ 2× the ULN (upper limit of normal). If elevated bilirubin is due to impaired conjugation (e.g Gilbert's disease or concomitant medication) or disease related hemolysis, then direct bilirubin ≤ 1.5× the ULN, Renal function with a creatinine clearance ≥30 mL/min or on dialysis is allowed, Subjects must have the ability to understand and the willingness to sign a written informed consent document and complete study related procedures

Exclusion Criteria

I have been treated with azacitidine, decitabine, or venetoclax before.

I have been diagnosed with acute promyelocytic leukemia.

I haven't taken any cancer treatment except hydroxyurea in the last 14 days.

Treatment Details

Interventions

• Decitabine (Anti-metabolites)
• Venetoclax (B-cell lymphoma 2 (BCL-2) inhibitor)

Trial Overview The trial is testing a combination of two drugs: Venetoclax and Decitabine at low doses on a weekly schedule for treating bone marrow cancers like AML and MDS. The goal is to see if this regimen can reduce side effects while effectively targeting malignant cells in the bone marrow.

Participant Groups

Group I: Decitabine/Venetoclax (Single Arm) Experimental Treatment 2 Interventions

Administration: Decitabine is reconstituted with 5 ml sterile water to facilitate subcutaneous administration. Decitaboine is given by subcutaneous injection. Venetoclax is taken as a tablet prepared by patients pharmacy. Venetoclax is given at a dose of 400 mg po once per week concurrently with the Decitabine dose (+/- 1 day allowed ).

Decitabine is already approved in European Union, United States, Canada, Japan for the following indications:

🇪🇺 Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

🇺🇸 Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

🇨🇦 Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

🇯🇵 Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Montefiore Medical Center Bronx, NY

Who Is Running the Clinical Trial?

Montefiore Medical Center

Lead Sponsor

Trials

468

Patients Recruited

599,000+

References

1. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021] Venetoclax plus azacitidine is indicated in the USA for the treatment of newly diagnosed acute myeloid leukaemia in older patients (≥75 years) or those ineligible for induction chemotherapy due to co-morbidities.

2. England pubmed.ncbi.nlm.nih.gov

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial. [2021] Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukaemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine that has shown promising results in patients with high-risk AML in phase 2 trials. We hypothesised that venetoclax with 10-day decitabine could have improved activity in patients with newly diagnosed AML and those with relapsed or refractory AML, particularly in high-risk subgroups.

3. New Zealand pubmed.ncbi.nlm.nih.gov

Efficacy of Venetoclax Combined with Decitabine-Based Treatment for Heavily Pre-Treated Relapsed or Refractory AML Patients in a Real-World Setting. [2022] We report the efficacy and safety of venetoclax plus decitabine-based treatment in heavily pre-treated relapsed or refractory acute myeloid leukaemia (RR-AML) in a real-world setting.

4. United States pubmed.ncbi.nlm.nih.gov

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. [2021] Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (&gt;30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).

5. United States pubmed.ncbi.nlm.nih.gov

A Metabolically Optimized, Noncytotoxic Low-Dose Weekly Decitabine/Venetoclax in MDS and AML. [2023] Venetoclax (VEN) added to the hypomethylating agents (HMA) decitabine or azacitidine is the new standard of care for elderly patients with acute myeloid leukemia (AML) and is being evaluated in myelodysplastic syndrome (MDS). Current dosing of HMA/VEN relies on leukemia suppression through cytotoxicity which also impacts normal hematopoiesis. A regimen using once-weekly low-dose decitabine (LDDec) has demonstrated activity in myeloid malignancies. To overcome the severe myelosuppression often seen with HMA/VEN, we evaluated a once-weekly dosing regimen of VEN and LDDec in elderly and/or frail patients who were felt less likely to tolerate severe myelosuppression.

6. Switzerland pubmed.ncbi.nlm.nih.gov

Multicenter phase I study of irinotecan plus raltitrexed in patients with 5-fluorouracil-refractory advanced colorectal cancer. [2018] Irinotecan and raltitrexed are active against advanced colorectal cancer, act through different mechanisms, and have non-overlapping toxicity profiles. In vitro studies have shown a schedule-dependent synergism between both drugs. The aim of this multicenter study was to determine the maximum tolerated dose (MTD) of this combination. Patients with 5-fluorouracil-refractory, advanced colorectal cancer were eligible. Dose escalation consisted of irinotecan (250-350 mg/m(2) as a 60-min infusion) in combination with a fixed dose of raltitrexed (3 mg/m(2) as a 15-min infusion, 1 h after irinotecan). Courses were repeated every 21 days. Three to 6 patients were to be included at each dose level. Dose limiting (NCI-CTC grade 3-4) toxicities (DLT) were assessed during the first 2 cycles. Thirteen patients were recruited (4, 3 and 6 in levels I, II and III, respectively). Main toxicity was diarrhea and asthenia, whereas myelotoxicity was mild. At level III, 2/6 patients experienced DLT (grade 4 diarrhea and neutropenia). The MTD was not reached, but further dose escalation was not attempted. Among 12 patients with measurable disease, 2 partial responses were observed for an overall response rate of 17%. The combination of single-agent full doses of irinotecan (350 mg/m(2)) and raltitrexed (3 mg/m(2)) in a 3-weekly schedule is feasible, with mild toxicity and a promising clinical activity. Diarrhea is the DLT, but it is not more common or severe than that described with irinotecan alone.

7. United States pubmed.ncbi.nlm.nih.gov

Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks. [2017] Exatecan mesylate (DX-8951f) is a topoisomerase I inhibitor that has increased solubility and antitumor activity compared with other topoisomerase I inhibitors. The purpose of this study was to establish a safe dose of DX-8951f given as a weekly 24-h infusion 3 of every 4 weeks. DX-8951f was administered as a 24-h continuous infusion in escalating doses. Twenty-seven patients were treated with 81 courses of the drug. Dose-limiting toxicities included neutropenia, thrombocytopenia, and inability to administer all three doses in the first cycle. In minimally pretreated patients, a dose of 0.8 mg/m(2) was tolerable. In patients who were heavily pretreated, a slightly lower dose, 0.53 mg/m(2), was tolerated without any severe toxicities. Nonhematological toxicities were mild and consisted of mild diarrhea, asthenia, mild nausea, and constipation. Pharmacokinetic parameters could be well described with a one-compartment model in most patients, although the application of the one-compartment model probably resulted in an underestimated elimination half-life. In conclusion, the recommended Phase II dose for DX-8951f administered as a weekly 24-h infusion on a 3-of-4 week schedule is 0.8 mg/m(2) in minimally pretreated patients and 0.53 mg/m(2) in patients who are heavily pretreated.

8. England pubmed.ncbi.nlm.nih.gov

Exposure-response analysis of Raltitrexed assessing liver toxicity. [2022] Label="AIM">Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5-fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to replace this drug for colorectal cancer patients, mainly due to its toxicity at the recommended dose of 3 mg/m2 every 3 weeks. However, every 2 weeks administration at 2 mg/m2 demonstrated a favourable toxicity profile.

9. Greece pubmed.ncbi.nlm.nih.gov

Phase II trial of irinotecan and raltitrexed in chemotherapy-naive advanced colorectal cancer. [2018] Irinotecan and raltitrexed are active agents in advanced colorectal cancer (ACC) and preclinical data suggest a remarkable synergistic activity. Phase I studies demonstrated that single-agent full dose of both drugs can be administered with moderate toxicity. The aim of this phase II trial was to assess the activity and tolerability of the combination in untreated ACC.

10. United States pubmed.ncbi.nlm.nih.gov

Schedule-dependent synergism between raltitrexed and irinotecan in human colon cancer cells in vitro. [2022] The quinazoline folate analogue raltitrexed (ZD1694; Tomudex) and the camptothecin derivative irinotecan are two new agents showing clinical activity against colorectal cancer. To identify the optimal conditions to achieve synergistic cytotoxicity before the clinical development of their combination, we explored the interactions between ZD1694 and the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), in vitro. Cytotoxicity was evaluated with a clonogenic assay using the human colon cancer cell line HCT-8. Different schedules of administration and different dose ratios of the two agents were compared and evaluated for synergism, additivity, or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay (T. C. Chou and P. Talalay, Adv. Enzyme Regul., 22: 27-55, 1984). Sequential short-term (1 and 4-h) exposures to SN-38 followed by ZD1694 resulted in synergistic cytotoxicity at broad dose-effect ranges. At a high level of cell kill, the synergism was greater when either equiactive doses of the two agents or higher relative doses of ZD1694 were used. A 24-h interval between exposure to SN-38 and ZD1694 significantly enhanced the magnitude of the synergy (P = 0.001). The opposite sequence or simultaneous exposures produced significantly less potentiation or nearly additive interactions (P = 0.0006 and P

11. England pubmed.ncbi.nlm.nih.gov

Venetoclax in association with decitabine as effective bridge to transplant in a case of relapsed early T-cell lymphoblastic leukemia. [2020] A case of an early-relapsed high-risk T-ALL with high BCL-2 expression on leukemic blasts was successfully treated with decitabine and venetoclax, achieving a CR. We suggest decitabine and venetoclax should be synergistic in BCL2-positive ALL.

12. United States pubmed.ncbi.nlm.nih.gov

Venetoclax combination therapy in acute myeloid leukemia and myelodysplastic syndromes. [2023] Venetoclax is a BCL-2 inhibitor that was approved in combination therapy with hypomethylating agents or low dose cytarabine for newly diagnosed acute myeloid leukemia (AML). The purpose of this review is to outline the most recent venetoclax-based combination therapies in newly diagnosed or relapsed myelodysplastic syndrome (MDS) and AML patients.