Venetoclax to Augment Epigenetic Modification and Chemotherapy

Sponsor
Medical College of Wisconsin (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05317403
Collaborator
(none)
40
Enrollment
2
Arms
54
Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

The investigator is testing the addition of venetoclax to 5-azacitidine and vorinostat followed by standard chemotherapy to enhance treatment response in AML patients.

Detailed Description

The investigators are testing if the addition of venetoclax to epigenetic therapy will not only enhance the treatment response for patients with epigenetic lesions but improve the poor response we have observed in those patients without epigenetic lesions. The addition of venetoclax to 5-azacitidine and vorinostat followed by standard chemotherapy will be investigated. This regimen may be tolerable and increase LSC targeting resulting in deeper, more durable responses in children, adolescents, and young adults with relapsed or refractory AML

The study will enroll patients in two strata - a primary stratum of eligible patients without Down syndrome, and a secondary stratum of eligible patients with Down syndrome (DS-AML). Subjects will receive two 35 day cycles of therapy.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
40 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Study of Venetoclax to Augment Epigenetic Modification and Chemotherapy in Pediatric and Young Adult Patients With Relapsed and Refractory Acute Myeloid Leukemia
Anticipated Study Start Date :
Jul 1, 2022
Anticipated Primary Completion Date :
Jan 1, 2026
Anticipated Study Completion Date :
Jan 1, 2027

Arms and Interventions

ArmIntervention/Treatment
Other: AML without Down Syndrome

The subject receives 2 courses of therapy approximately 35 days each. Venetoclax: Days 1-14 Azacitidine and Vorinostat: Days 1-5 Filgrastim Days: 5 start and continue until post-nadir ANC > 500 cells/mm3 Fludarabine and Cytarabine Days 6 - 10 IT Cytarabine Day 0 or 1, optional between day 35 and 42

Drug: Venetoclax
Dose Level 0: Day 1 60 mg/m2 PO x1, Days 2-14 120 mg/m2/dose PO once daily (Max: 200 mg/day) Dose level 1: Day 1 120 mg/m2 PO x1, Days 2-14 240 mg/m2/dose PO once daily (Max: 400 mg/day) Dose level 2: Day 1 180 mg/m2 PO x1, Days 2-14 360 mg/m2/dose PO once daily (Max: 600 mg/day)

Drug: Azacitadine
75 mg/m2/dose IV once daily over 15 minutes

Drug: Vorinostat
1 year to 17.99 years old: 180 mg/m2/dose PO once daily ≥18 years old 200 mg PO BID. Doses should be separated by 12 hr (±4 hr)

Drug: Cytarabine
2000 mg/m2/dose IV once daily over 3 hours IT Cytarabine: - 1.99 years old: 30 mg - 2.99 years old: 50 mg 3 years old: 70 mg

Drug: Fludarabine
30 mg/m2/dose IV once daily over 30 minutes

Drug: Filgrastim
5 microgram/kg/dose subcutaneous (or IV over 15-30 min) once daily

Other: AML with Down Syndrome

The subject receives 2 courses of therapy approximately 35 days each. Venetoclax: Days 1-14 Azacitidine and Vorinostat: Days 1-5 Filgrastim Days: 5 start and continue until post-nadir ANC > 500 cells/mm3 Fludarabine and Cytarabine Days 6 - 10 IT Cytarabine Day 0 or 1, optional between day 35 and 42

Drug: Venetoclax
Dose Level 0: Day 1 60 mg/m2 PO x1, Days 2-14 120 mg/m2/dose PO once daily (Max: 200 mg/day) Dose level 1: Day 1 120 mg/m2 PO x1, Days 2-14 240 mg/m2/dose PO once daily (Max: 400 mg/day) Dose level 2: Day 1 180 mg/m2 PO x1, Days 2-14 360 mg/m2/dose PO once daily (Max: 600 mg/day)

Drug: Azacitadine
75 mg/m2/dose IV once daily over 15 minutes

Drug: Vorinostat
1 year to 17.99 years old: 180 mg/m2/dose PO once daily ≥18 years old 200 mg PO BID. Doses should be separated by 12 hr (±4 hr)

Drug: Cytarabine
2000 mg/m2/dose IV once daily over 3 hours IT Cytarabine: - 1.99 years old: 30 mg - 2.99 years old: 50 mg 3 years old: 70 mg

Drug: Fludarabine
30 mg/m2/dose IV once daily over 30 minutes

Drug: Filgrastim
5 microgram/kg/dose subcutaneous (or IV over 15-30 min) once daily

Outcome Measures

Primary Outcome Measures

  1. Venetoclax Dose-Limiting Toxicity [42 months]

    The primary endpoint, for dose escalation of venetoclax, is the occurrence of a dose-limiting toxicity (DLT) observed during the first course of therapy.

Secondary Outcome Measures

  1. Response Rates [42 months]

    Response rates as measured by morphologic response (CR)

  2. Response Rates [42 months]

    Response rates as measured by morphologic response (PD)

  3. Response Rates [42 months]

    Response rates as measured by morphologic response (SD)

  4. Response Rates [42 months]

    Response rates as measured by morphologic response (CRi)

  5. Response Rates [42 months]

    Response rates as measured by morphologic response (PR)

  6. MRD [42 months]

    minimal residual disease (MRD) via multiparameter flow cytometry

Eligibility Criteria

Criteria

Ages Eligible for Study:
1 Year to 25 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

Diagnosis f) Patients with AML must have measurable disease (≥M1 marrow) in the bone marrow.

  1. 1st or greater relapse, OR ii. Failed to go into remission after 1st or greater relapse, OR iii. Failed to go into remission from original diagnosis after 2 or more induction attempts Eligibility for patients with an M1 marrow; defined as >0.1% by flow cytometry or molecular testing (e.g. PCR) must have 2 serial marrows (at least 1-week apart) demonstrating stable or rising minimal residual disease (MRD) (i.e. not declining)
  1. Patients may have CNS or other sites of extramedullary disease. No cranial irradiation is allowed during the protocol therapy.

  2. Patients with treatment related AML (tAML) are eligible. A relapse of tAML is not necessary to enroll on this study thus newly diagnosed tAML are eligible.

  3. Patients with immunophenotypic AML evolving as lineage switch from ALL or acute leukemia NOS, may be eligible if they have relapsed/refractory disease

  4. Patients with Down syndrome are eligible

Performance Level Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for patients ≤ 16 years of age. (See Appendix II for Performance Scales)

Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

  1. Myelosuppressive chemotherapy
  1. Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up to 24 hours prior to the start of Venetoclax. It is recommended to use hydroxyurea in patients with significant leukocytosis (WBC > 50,000/L) to control blast count before initiation of systemic protocol therapy.

  2. Patients who relapsed while they are receiving cytotoxic therapy At least 7 days must have elapsed since the completion of the cytotoxic therapy, except Intrathecal chemotherapy.

  1. Hematopoietic stem cell transplant: Patients who have experienced relapse after a HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD), and are at least 90 days post-transplant at the time of enrollment, no longer receiving GVHD therapy.

  2. Hematopoietic growth factors: It must have been at least 7 days since the completion of therapy with GCSF or other growth factors at the time of enrollment. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).

  3. Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair. This includes flotetuzumab.

  4. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of monoclonal antibody. (i.e. Gemtuzumab = 36 days)

  5. Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g. tumor vaccines or CAR-T cells.

  6. XRT: Craniospinal XRT is prohibited during protocol therapy. No waiting period is necessary for radiation given to non-CNS chloromas; ≥ 90 days must have elapsed if prior TBI or craniospinal XRT.

  7. Infection Prevention: Patients must be able to tolerate and receive anti-fungal prophylaxis with echinocandins or amphotericin therapy for the duration of their treatment course and neutrophil recovery (post-nadir ANC is > 750/μL).

  8. Inhibitors and Inducers of CYP3A4 a. Patients taking strong CYP3A4 inhibitors should have their venetoclax dose reduced by 75%

Patients taking moderate CYP3A4 inhibitors should have their venetoclax dose reduced by 50%

  1. Inhibitors of P-glycoprotein (P-gp): Patients taking p-glycoprotein inhibitors should have their venetoclax doses reduced by 50%.

Renal and hepatic function

Patients must have adequate renal and hepatic functions as indicated by the following laboratory values:

  1. Adequate renal function defined as: Patient must have a calculated creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in the chart below:

Table 3 Age Maximum Serum Creatinine (mg/dL) Male Female

1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

≥ 16 years 1.7 1.4

The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.

  1. Adequate Liver Function Defined as: Direct bilirubin < 1.5 x upper limit of normal (ULN) for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age. The hepatic requirements are waived for patients with known or suspected liver involvement by leukemia. This must be reviewed by and approved by the study chair or vice chair.

Adequate Cardiac Function Defined as: Shortening fraction of greater than or equal to 27% OR ejection fraction of greater than or equal to 50%.

Reproductive Function A. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.

  1. Female patients with infants must agree not to breastfeed their infants while on this study.

  2. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment.

Exclusion Criteria:
  1. Patients will be excluded if they have a known allergy to any of the drugs used in the study.

  2. Patients will be excluded if they have a systemic fungal, bacterial, viral, or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours.

  3. Patients will be excluded if they have had any positive fungal culture within 30 days prior to enrollment or evidence of disseminated fungal disease.

  4. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.

  5. Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder, or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results.

  6. Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

  • Medical College of Wisconsin

Investigators

  • Study Chair: Michael Burke, MD, Medical College of Wisconsin

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Michael Burke, Associate Professor, Department of Pediatrics, Division of Hematology/Oncology/BMT, Medical College of Wisconsin
ClinicalTrials.gov Identifier:
NCT05317403
Other Study ID Numbers:
  • Venetoclax Epigenetic
First Posted:
Apr 7, 2022
Last Update Posted:
Apr 7, 2022
Last Verified:
Mar 1, 2022
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
Yes
Additional relevant MeSH terms:

Study Results

No Results Posted as of Apr 7, 2022