Non-hodgkin Lymphoma Clinical Trial
Official title:
A Phase I Trial of Venetoclax in Combination With BEAM Conditioning Regimen for Autologous Stem Cell Transplantation in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma
Verified date | December 2023 |
Source | Case Comprehensive Cancer Center |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
The purpose of this study is to determine the correct dose and safety of adding a new cancer drug, Venetoclax, to a standard combination of chemotherapy drugs used prior to Autologous stem cell transplant (ASCT) in participants with Non-Hodgkin Lymphoma (NHL). In this study, Venetoclax will be added to BEAM (BCNU or carmustine, etoposide, cytarabine or ara-c, and melphalan). All NHL participants are admitted for conditioning chemotherapy which is given prior to the infusion of stem cells. Venetoclax is a new anti-cancer drug that works by targeting a protein (known as the Bcl-2 protein). By inhibiting or "blocking" this protein, a downstream cascade occurs which results in cancer cells to die. Adding Venetoclax to the standard BEAM conditioning chemotherapy with autologous stem cell transplant is believed to increase the chance of remission. Venetoclax is Food and Drug Administration (FDA) approved for participants with chronic lymphocytic leukemia (CLL). However, Venetoclax is investigational for this study because it is not yet approved for use in participants with NHL or in combination with BEAM chemotherapy.
Status | Active, not recruiting |
Enrollment | 25 |
Est. completion date | June 1, 2024 |
Est. primary completion date | June 1, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | 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 CHOP, R-CHOP, CHOEP, R-EPOCH, R-HyperCVAD, BR, 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. - ECOG Performance status = 2 at time of consent [See Appendix I]. - Patients must have normal organ and marrow function as defined below: - Hemoglobin = 8.0 g/dl - Absolute neutrophil count = 1,000/mcL - Platelet count = 75,000/mcL - Total bilirubin = 1.5X the upper limit of normal (ULN) unless a known history of impaired bilirubin conjugation such as Gilbert's. - AST (SGOT) = 2.5 X institutional ULN - ALT (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. - Cardiac ejection fraction >45% or clearance by PI or Cardiology - 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: - HBsAg negative, 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 HBV 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 PCR testing monthly x 3 months beginning from the start of treatment - Female patients who are not surgically sterile or postmenopausal (for at least 1year) 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 3months prior to study drug administration - 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: The presence of any of the following will exclude a patient from study enrollment: - 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 NCI 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. - 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-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. Lists including medications or substances known or with the potential to interact with the specific CYP3A4 isoenzymes and P-gp are provided in Appendix II. - 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: - Moderate/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. |
Country | Name | City | State |
---|---|---|---|
United States | Cleveland Clinic Taussig Cancer institute, Case Comprehensive Cancer Center | Cleveland | Ohio |
United States | University Hospitals Cleveland Medical Center, Case Comprehensive Cancer Center | Cleveland | Ohio |
Lead Sponsor | Collaborator |
---|---|
Case Comprehensive Cancer Center |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Safety of intervention as defined by hematopoietic non-engraftment (failure of either ANC engraftment or platelet engraftment). | Safety of intervention will be measured by the effect on hematologic engraftment (engraftment Dose Limiting Toxicity DLT). This includes failure of absolute neutrophil count (ANC) engraftment OR platelet engraftment. • Failure of ANC engraftment which is defined as failure to engraft by day 15. OR • Failure of platelet engraftment which is defined as failure to engraft by day 30. |
Up to 30 days after Autologous Stem Cell Transplant (ASCT) | |
Secondary | Time to neutrophil engraftment | Compare time to neutrophil engraftment of patients who receive V-BEAM followed by ASCT, compared to historical controls and among cohorts. | 24 months after hospital discharge | |
Secondary | Time to platelet engraftment | Compare time to platelet engraftment of patients who receive V-BEAM followed by ASCT, compared to historical controls and among cohort. | 24 months after hospital discharge | |
Secondary | Progression-free survival (PFS) | Determine the Progression Free Survival (PFS) of V+BEAM followed by ASCT relative to historical controls of BEAM alone followed by ASCT. PFS is defined as the time from entry onto study until lymphoma progression or death from any cause. PFS reflects tumor growth and, therefore, occurs prior to the endpoint of overall survival. |
24 months after hospital discharge | |
Secondary | Overall Survival (OS) | Determine the Overall Survival (OS) of V+BEAM followed by ASCT relative to historical controls of BEAM alone followed by ASCT. | 24 months after hospital discharge |
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