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Venetoclax in Combination with BEAM Chemotherapy Regimen in Treating Patients with Non-Hodgkin Lymphoma Undergoing Stem Cell Transplant

Trial Status: Active

This phase I trial studies the side effects and best dose of venetoclax when given in combination with standard chemotherapy regimen in treating patients with non-Hodgkin lymphoma undergoing stem cell transplant. Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carmustine, etoposide, cytarabine, and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known how well venetoclax works when given with standard chemotherapy in treating patients with non-Hodgkin lymphoma undergoing stem cell transplant.

Inclusion Criteria

  • Patients must have histologically confirmed non-Hodgkin lymphoma (NHL) including T-cell lymphomas, after at least one prior systemic treatment regimen such as cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine and prednisone (CHOP), rituximab (R)-CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOEP), R-etoposide, prednisone, vincristine (Oncovin), cyclophosphamide and doxorubicin hydrochloride (EPOCH), R-hyperfractionated cyclophosphamide, vincristine, adriamycin and dexamethasone (HyperCVAD), bendamustine and rituximab (BR), bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) alternating with rituximab and cytarabine, etc.
  • Patients in complete or partial remission, or in the case of patients with stable or refractory disease are undergoing autologous transplantation because it has been recommended by their treating physician as representing their best treatment option.
  • Because no dosing or adverse event data are currently available on the use of venetoclax in combination with BEAM chemotherapy in patients < 18 years of age, children are excluded from this study.
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 at time of consent.
  • Hemoglobin >= 8.0 g/dl.
  • Absolute neutrophil count >= 1,000/mcL.
  • Platelet count >= 75,000/mcL.
  • Total bilirubin =< 1.5 x the upper limit of normal (ULN) unless a known history of impaired bilirubin conjugation such as Gilbert’s.
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 X institutional ULN.
  • Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional ULN.
  • Patients must have a calculated serum creatinine clearance > 50 mL/min using Cockcroft-Gault calculation or based on 24-hour urine collection performed within 7 days prior to treatment(s) used for stem cell mobilization.
  • Cardiac ejection fraction > 45% or clearance by principal investigator (PI) or cardiology.
  • Diffusion capacity of the lung for carbon monoxide (DLCO) of > 45% predicted or clearance by PI or pulmonology.
  • Specific guidelines will be followed regarding inclusion of NHL based on hepatitis B serological testing as follows: * Hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (HBcAb) negative, HBsAb negative patients are eligible. * HBsAg negative, HBcAb negative, HBsAb positive patients are eligible. * Patients who test positive for HBsAg are ineligible. * Patients with HBsAg negative, but HBcAb positive (regardless of HBsAb status) should have a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) testing performed and protocol eligibility determined as follows: ** If HBV DNA is positive, the patient is ineligible. ** If HBV DNA is negative, the patient may be included but must undergo HBV DNA polymerase chain reaction (PCR) testing monthly x 3 months beginning from the start of treatment.
  • Female patients who are not surgically sterile or postmenopausal (for at least 1 year) must practice at least one of the following methods of birth control throughout the duration of study participation and for at least 30 days after study treatment: * Total abstinence from sexual intercourse * A vasectomized partner * Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that started at least 3 months prior to study drug administration * Double-barrier method (condom + diaphragm or cervical cup with spermicidal contraceptive sponge, jellies, or cream)
  • Male patients who are non-vasectomized must comply with at least one of the following methods of birth control throughout the duration of study participation and for at least 30 days after study treatment: * A partner who is surgically sterile or postmenopausal (for at least 1 year) or who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at least 3 months prior to study drug administration * Total abstinence from sexual intercourse * Double-barrier method (condom + diaphragm or cervical cup with spermicidal, contraceptive sponge, jellies, or cream)
  • Patients must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

  • Patients who have not recovered from adverse events due to agents administered more than 2 weeks earlier.
  • Prior treatment toxicities have not resolved to =< grade 2 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (except clinically unrelated toxicities such as alopecia or peripheral neuropathy).
  • Patients receiving any other investigational agents.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to venetoclax or other agents used in this study.
  • Patients with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients who are pregnant or breastfeeding will be excluded from this study because carmustine, etoposide, cytarabine, and melphalan are chemotherapeutic agents with the potential for teratogenic or abortifacient effects. Because there is an unknown, but potential risk for adverse events in nursing infants secondary to treatment of the mother with carmustine, etoposide, cytarabine, and melphalan, breastfeeding should be discontinued if the mother is treated with these agents. These potential risks may also apply to other agents used in this study.
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with venetoclax. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated. HIV testing prior to enrollment is not required for screening but strongly encouraged for patients with no documented prior HIV assessment.
  • Malabsorption syndrome or other condition that precludes enteral route of venetoclax administration.
  • Patients with metastatic solid tumor malignancies. Patients who have early stage solid tumors and have completed curative treatment are eligible at the discretion of the primary investigator. Patients with unresected but localized stage prostate cancer or other carcinomas in situ that are undergoing observation are also allowed. Patients with transformed lymphoma and/or underlying indolent lymphoproliferative disorder are allowed at the discretion of the investigator.
  • Major surgery, other than diagnostic surgery, within 2 weeks.
  • Medical condition requiring chronic use of high dose systemic corticosteroids (i.e., doses of prednisone higher than 10 mg/day or equivalent). Brief (< 15 days) treatment with glucocorticoids (prednisone 100 mg by mouth daily, or equivalent) is acceptable.
  • Patients with chronic use of moderate or strong CYP3A4 modulators (inhibitor or inducer) or use of a P-glycoprotein (P-gp) inhibitor, or a P-gp substrate with a narrow therapeutic index are prohibited. A washout period of 7 days is required prior to venetoclax dosing if a prohibited medication is discontinued.
  • Concomitant medications that fall into the categories below could potentially lead to adverse reactions and should be considered cautionary (except where noted). Medications and cautionary medications that fall into the categories within this section can be found at http://medicine.iupui.edu/clinpharm/ddis/main-table. If a potential study patient is taking any of the medications in the categories described below, the investigator will assess and document the use of medications known or suspected to fall in the following medication categories: * Weak CYP3A inducers such as efavirenz and oxcarbazepine. * CYP2C8 substrates such as thiazolidinediones (glitazones) and select statins (because of expected inhibition of the metabolism of CYP2C8 substrates by venetoclax). * CYP2C9 substrates such as tolbutamide (because of expected inhibition of the metabolism of CYP2C9 substrates by venetoclax). It is recommended to exclude CYP2C9 substrates with a narrow therapeutic index such as phenytoin.

Ohio

Cleveland
Case Comprehensive Cancer Center
Status: ACTIVE
Contact: Allison Marie Winter
Phone: 216-445-4782

PRIMARY OBJECTIVES:

I. Establish the safety of venetoclax (V)-carmustine, etoposide, cytarabine, melphalan (BEAM) conditioning regimen prior to autologous stem cell transplant in order to identify the recommended phase II dose (RPD2).

SECONDARY OBJECTIVES:

I. Compare time to neutrophil engraftment of patients who receive V-BEAM and autologous stem cell transplant (ASCT), compared to historical controls and among cohorts.

II. Compare time to platelet engraftment of patients who receive V-BEAM and ASCT, compared to historical controls and among cohorts.

III. Determine the progression free survival (PFS) and overall survival (OS) of V+BEAM followed by ASCT relative to historical controls of BEAM alone followed by ASCT.

OUTLINE: This is a dose escalation study of venetoclax.

Patients receive venetoclax orally (PO) on days -7 to days -6, -5, -4 -3 or -2 (depending on dose level). Patients also receive carmustine intravenously (IV) over 2 hours (or per institutional standard) on day -7, etoposide IV over 6 hours (or per institutional standard) daily on days -6 to -3, cytarabine IV over 2 hours (or per institutional standard) every 12 hours on days -6 to -4, and melphalan IV over 30 minutes or IV push (per institutional standard) on day -2. Patients then undergo ASCT on day 0.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, and 24 months.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Case Comprehensive Cancer Center

Principal Investigator
Allison Marie Winter

  • Primary ID CASE2418
  • Secondary IDs NCI-2019-00135
  • Clinicaltrials.gov ID NCT03713580