Venetoclax for Relapsed Hairy Cell Leukemia
Recruiting in Palo Alto (17 mi)
+11 other locations
Overseen byRobert J Kreitman
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Investigational agents
Disqualifiers: Pregnancy, Malabsorption, Allergic reactions, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?This phase II trial tests how well venetoclax works in treating patients with hairy cell leukemia that has come back after a period of improvement (relapsed). Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival.
Do I need to stop my current medications to join the trial?
The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on other investigational agents, and live vaccines should not be given within 4 weeks before, during, or 30 days after the study treatment.
What data supports the effectiveness of the drug Venetoclax for treating relapsed Hairy Cell Leukemia?
Venetoclax has shown effectiveness in treating other blood-related conditions, such as relapsed/refractory multiple myeloma and light-chain amyloidosis, with a high response rate in patients with specific genetic markers. This suggests potential effectiveness in similar blood cancers like Hairy Cell Leukemia.
12345Is Venetoclax generally safe for humans?
In a study involving patients with a specific type of blood disorder, Venetoclax was generally well-tolerated, with serious side effects occurring in 19% of patients, including 7% due to infections. This suggests that while Venetoclax can cause some serious side effects, it is generally considered safe for use in humans.
12678How is the drug Venetoclax unique for treating relapsed hairy cell leukemia?
Venetoclax is unique because it is an oral drug that selectively inhibits the BCL-2 protein, which helps cancer cells survive. This mechanism is different from traditional chemotherapy, offering a targeted approach that has shown effectiveness in other blood cancers like chronic lymphocytic leukemia.
910111213Eligibility Criteria
This trial is for adults over 18 with relapsed hairy cell leukemia after prior treatment, who can't have BRAF therapy and haven't tried Venetoclax. They need functioning kidneys, acceptable liver tests, and a decent performance status. People with treated hepatitis C or controlled HIV are eligible; those with chronic hepatitis B must be on suppressive therapy.Inclusion Criteria
Total bilirubin ≤ 3 x institutional upper limit of normal (ULN) unless consistent with Gilbert's (ratio between total and direct bilirubin > 5)
I can take care of myself but may not be able to do heavy physical work.
My hepatitis B virus load is undetectable with treatment.
+13 more
Exclusion Criteria
I have previously been treated with venetoclax.
I do not have conditions that affect how my body absorbs nutrients.
Patients who are receiving any other investigational agents
+4 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive venetoclax orally once daily on days 1-28 of each cycle, repeating every 28 days for up to 19 cycles
Up to 19 months
Monthly visits for each cycle
Follow-up
Participants are monitored for safety and effectiveness after treatment completion
4 weeks
1 visit (in-person) at 30 days post-treatment
Participant Groups
The study is testing Venetoclax's effectiveness in patients whose hairy cell leukemia has returned. It involves taking the drug and undergoing various assessments like blood tests, bone marrow procedures, CT scans, and MRIs to see how well it works against cancer cells.
1Treatment groups
Experimental Treatment
Group I: Treatment (venetoclax)Experimental Treatment6 Interventions
Patients receive venetoclax PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for up to 19 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI and blood sample collection throughout the study. Patients may undergo bone marrow biopsy and/or aspiration on study.
Venetoclax is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Venclexta for:
- Chronic lymphocytic leukemia (CLL)
- Small lymphocytic lymphoma (SLL)
- Acute myeloid leukemia (AML)
🇪🇺 Approved in European Union as Venclyxto for:
- Chronic lymphocytic leukemia (CLL)
- Small lymphocytic lymphoma (SLL)
- Acute myeloid leukemia (AML)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UM Sylvester Comprehensive Cancer Center at AventuraAventura, FL
UM Sylvester Comprehensive Cancer Center at Coral GablesCoral Gables, FL
UM Sylvester Comprehensive Cancer Center at Coral SpringsCoral Springs, FL
UM Sylvester Comprehensive Cancer Center at Deerfield BeachDeerfield Beach, FL
More Trial Locations
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Venetoclax induces deep hematologic remissions in t(11;14) relapsed/refractory AL amyloidosis. [2021]Venetoclax is efficacious in relapsed/refractory t(11;14) multiple myeloma, thus warranting investigation in light-chain amyloidosis (AL). This retrospective cohort includes 43 patients with previously treated AL, from 14 centers in the US and Europe. Thirty-one patients harbored t(11;14), 11 did not, and one t(11;14) status was unknown. Patients received a venetoclax-containing regimen for at least one 21- or 28-day cycle; the median prior treatments was three. The hematologic response rate for all patients was 68%; 63% achieved VGPR/CR. t(11;14) patients had higher hematologic response (81% vs. 40%) and higher VGPR/CR rate (78% vs. 30%, odds ratio: 0.12, 95% CI 0.02-0.62) than non-t(11;14) patients. For the unsegregated cohort, median progression-free survival (PFS) was 31.0 months and median OS was not reached (NR). For t(11;14), median PFS was NR and for non-t(11;14) median PFS was 6.7 months (HR: 0.14, 95% CI 0.04-0.53). Multivariate analysis incorporating age, sex, prior lines of therapy, and disease stage suggested a risk reduction for progression or death in t(11;14) patients. Median OS was NR for either subgroup. The organ response rate was 38%; most responders harbored t(11;14). Grade 3 or higher adverse events occurred in 19% with 7% due to infections. These promising results require confirmation in a randomized clinical trial.
Recurrent cervical cancer in a patient who was compound heterozygous for UGT1A1*6 and UGT1A1*28 presenting with serious adverse events during irinotecan hydrochloride/nedaplatin therapy. [2018]There have been no case reports of the risk of serious adverse events associated with the administration of irinotecan hydrochloride (CPT-11) in patients with gynecologic cancer who are compound heterozygous for UGT1A1*6 and UGT1A1*28. A 71-year-old patient presented with recurrent stage IIIb cervical cancer. Combined chemotherapy was initiated with CPT-11 (60 mg/m² on days 1 and 8) plus nedaplatin (NDP; 80 mg/m² on day 1), with each cycle lasting for 28 days. The patient was a compound heterozygote for UGT1A1*6 and UGT1A1*28. Hematotoxic adverse events observed during the chemotherapy were grade 4 neutropenia, grade 3 anemia, and grade 4 thrombocytopenia, and the non-hematotoxic adverse events were grade 3 diarrhea and grade 3 fatigue. The findings in this patient indicate that CPT-11 should be administered with great care, even at a dose of 60 mg/m², in patients receiving combined therapy with CPT-11 and NDP who are compound heterozygous for UGT1A1*6 and UGT1A1*28.
Genotype-Guided Dosing Study of FOLFIRI plus Bevacizumab in Patients with Metastatic Colorectal Cancer. [2022]Purpose:UGT1A1*28 confers a higher risk of toxicity in patients treated with irinotecan. Patients with *1/*1 and *1/*28 genotypes might tolerate higher than standard doses of irinotecan. We aimed to identify the MTD of irinotecan in patients with metastatic colorectal cancer (mCRC) with *1/*1 and *1/*28 genotypes treated with FOLFIRI plus bevacizumab, and to determine whether bevacizumab alters irinotecan pharmacokinetics.Experimental Design: Previously untreated patients with mCRC (25 *1/*1; 23 *1/*28) were given FOLFIRI plus bevacizumab every 2 weeks. The irinotecan dose was escalated using a 3 + 3 design in each genotype group as follows: 260, 310, and 370 mg/m2 The MTD was the highest dose at which <4/10 patients had a dose-limiting toxicity (DLT). Pharmacokinetics of irinotecan and SN-38 were measured on days 1 to 3 (without bevacizumab) and 15 to 17 (with bevacizumab).Results: For *1/*1 patients, 2 DLTs were observed among 10 patients at 310 mg/m2, while 370 mg/m2 was not tolerated (2 DLTs in 4 patients). For *1/*28 patients, 2 DLTs were observed among 10 patients at 260 mg/m2, while 310 mg/m2 was not tolerated (4 DLTs in 10 patients). Neutropenia and diarrhea were the most common DLTs. Changes in the AUCs of irinotecan and SN-38 associated with bevacizumab treatment were marginal.Conclusions: The MTD of irinotecan in FOLFIRI plus bevacizumab is 310 mg/m2 for UGT1A1 *1/*1 patients and 260 mg/m2 for *1/*28 patients. Bevacizumab does not alter the pharmacokinetics of irinotecan. The antitumor efficacy of these genotype-guided doses should be tested in future studies of patients with mCRC treated with FOLFIRI plus bevacizumab. Clin Cancer Res; 23(4); 918-24. ©2016 AACR.
Studies of the efficacy and pharmacology of irinotecan against human colon tumor xenograft models. [2018]Irinotecan, administered i.v. on days 1-5 and 8-12 [(dx5)2 i.v.] has demonstrated significant activity against advanced human tumor xenografts. To explore the feasibility of prolonged oral administration of irinotecan, we compared the efficacy of oral and i.v. irinotecan on the (dx5)2 schedule. We also evaluated oral therapy for 12 consecutive weeks [(dx5)12] at 25 and 50 mg/kg and two consecutive 5-day courses repeated every 21 days for up to four cycles ([(dx5)2]4) at 50 and 75 mg/kg/dose in a series of human colon carcinoma xenograft lines. In addition, we evaluated the effect of a sensitive (HC1) and resistant (ELC2) human colon adenocarcinoma xenograft on irinotecan and SN-38 lactone disposition after administration of irinotecan 10 mg/kg i.v. and 10 and 25 mg/kg p.o. Irinotecan i.v. at 40 mg/kg and oral at 50 and 75 mg/kg on the (dx5)2 schedule had similar activity against the panel of adult colon adenocarcinoma xenografts. Irinotecan given p.o. also demonstrated significant activity against a topotecan-resistant derivative, VRC5/TOPO. Oral administration of 75 mg/kg [(dx5)2]4 and 50 mg/kg (dx5)12 achieved complete response in five of seven xenograft lines evaluated. After i.v. administration, mice bearing HC1 xenografts had 43% greater SN-38 lactone systemic exposure compared to those with ELC2 xenografts and non-tumor-bearing mice. After oral (10 mg/kg) administration, there was a 5-fold higher molar formation of SN-38 lactone compared to i.v. (10 mg/kg) administration in tumor and non-tumor-bearing mice. SN-38 systemic exposure associated with the lowest oral dose (25 mg/kg) achieving complete response for HC1 was 942.6 ng/ml x h. These results emphasize the importance of pharmacokinetic studies as part of tumor response studies in xenograft models.
Chemo-sensitivity in a panel of B-cell precursor acute lymphoblastic leukemia cell lines, YCUB series, derived from children. [2013]Sensitivity to 10 anticancer drugs was evaluated in 6 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cell lines. Authenticity of newly established cell lines was confirmed by genomic fingerprinting. The line YCUB-5R established at relapse was more resistant to 4-hydroperoxy-cyclophosphamide, cytarabine, L-asparaginase, topotecan, fludarabine, and etoposide than YCUB-5 from the same patient at diagnosis. Of the drugs tested, etoposide and SN-38 (irinotecan) showed highest efficacy in the panel, with 50% growth inhibition at 0.22-1.8 microg/ml and 0.57-3.6 ng/ml, respectively. This cell line panel offers an in vitro model for the development of new therapies for childhood BCP-ALL.
First-line liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) in pancreatic ductal adenocarcinoma: A phase I/II study. [2021]This open-label, phase I/II study evaluated safety and efficacy for first-line liposomal irinotecan + oxaliplatin + 5-fluorouracil + leucovorin (NALIRIFOX).
Intermittent, repetitive administrations of irinotecan (CPT-11) reduces its side-effects. [2019]To reduce the side-effects of irinotecan (CPT-11) while maintaining its anti-cancer effects against recurrent ovarian carcinomas, we devised a novel administration schedule for CPT-11 single chemotherapy. It consisted of an initial dose of 70 mg/m2, followed by increasing the dose to 100 mg/m2 every 10 days (three times per month) for 9 cycles. Nineteen patients with refractory or recurrent ovarian carcinomas were treated. In comparison with a late phase II study of single CPT-11 chemotherapy in Japan (100 mg/m2 every 7 days; four times per month), the number of patients who suffered from leukocytopenia and diarrhea higher than grade 3 was significantly lower with our new method (36.8 versus 57.1%; P
Irinotecan hydrochloride for the treatment of recurrent and refractory non-Hodgkin lymphoma: a single institution experience. [2019]Irinotecan hydrochloride (CPT-11) has a broad range of antitumor activity and has demonstrated little cross-resistance with doxorubicin or vincristine. In the current study, the authors investigated the efficacy and adverse effects of irinotecan in the treatment of recurrent and refractory non-Hodgkin lymphoma, for which current therapies appear to be unsatisfactory.
Venetoclax: First Global Approval. [2018]Venetoclax (Venclexta™) is an oral selective inhibitor of the prosurvival protein BCL-2 and therefore restores the apoptotic ability of malignant cells. The drug arose from research by Abbott Laboratories (now AbbVie) during a collaboration with Genentech and is being co-developed by AbbVie and Genentech/Roche primarily for the treatment of haematological malignancies. Venetoclax is approved in the USA for use as monotherapy in patients with chronic lymphocytic leukaemia (CLL) with the 17p deletion (as detected by an approved FDA test) who have received at least one prior therapy, and is awaiting approval for similar indications in the EU and Canada. Venetoclax is also in phase I-III development as combination therapy for CLL, phase I/II development as monotherapy and/or combination therapy for non-Hodgkin lymphomas (including diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma) and acute myeloid leukaemia, and phase I development for multiple myeloma, systemic lupus erythematosus and breast cancer. This article summarizes the milestones in the development of venetoclax leading to this first approval for CLL.
Single-Center Retrospective Clinical Evaluation of Venetoclax Combined with HMAs and Half-Dose CAG for Unfit or Refractory/Relapsed AML. [2023]The prognosis of patients with unfit or relapsed/refractory (R/R) AML remains poor. Venetoclax (VEN) has been shown to exhibit anti-leukemia stem cell activity; however, few studies have been published on the efficacy and safety of VEN combined with both hypomethylating agents (HMAs) and low-dose chemotherapy for patients with unfit or R/R AML.
Venetoclax: A Review in Relapsed/Refractory Chronic Lymphocytic Leukemia. [2020]Venetoclax (Venclyxto®; Venclexta®) is a first-in-class, oral, selective B cell lymphoma-2 (BCL-2) inhibitor. The drug is approved in numerous countries, including those of the EU and in the USA, for the treatment of adults with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL); the specific indication(s) for venetoclax may vary between individual countries. Venetoclax monotherapy or combination therapy with rituximab was an effective treatment, provided durable responses, and had a manageable safety profile in pivotal clinical trials in adults with RR CLL, including in patients with adverse prognostic factors. In combination with 6 cycles of rituximab, venetoclax (fixed 24 months' treatment) was more effective than bendamustine plus rituximab (6 cycles) in prolonging progression-free survival (PFS) and inducing undetectable minimal residual disease (uMRD) in peripheral blood (PB) and bone marrow (BM), with these benefits sustained during 36 months' follow-up. Hence, with its novel mechanism of action and convenient oral once-daily regimen, venetoclax monotherapy or fixed 24-month combination therapy with rituximab represents an important option for treating RR CLL, including in patients with del(17p) or TP53 mutation and those failing a B cell receptor (BCR) inhibitor and/or chemotherapy.
Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . [2018]Venetoclax (Venclexta™) is a potent, selective, orally available, small-molecule B-cell lymphoma 2 inhibitor that achieves response rates of about 80% and has an acceptable safety profile for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). .
Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. [2021]Venetoclax (Venclexta®; Venclyxto®) is a first-in-class, oral, selective inhibitor of B cell lymphoma 2 (BCL2). In several countries, including the USA and those of the EU, venetoclax is indicated in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Approval was based on the results of the phase III CLL14 trial in patients with previously untreated CLL and co-existing conditions. In this study, fixed-duration (12 months) targeted treatment with venetoclax + obinutuzumab resulted in significantly longer progression-free survival (PFS; primary endpoint) relative to fixed-duration chemoimmunotherapy with chlorambucil + obinutuzumab. Venetoclax + obinutuzumab was also associated with significantly higher rates of undetectable minimal residual disease (MRD), complete response and overall response than chlorambucil + obinutuzumab. Improvements in clinical outcomes with venetoclax + obinutuzumab were maintained during long-term follow-up, when all patients had been off treatment for ≥ 2 years. No significant between-group difference was observed in overall survival (OS). Venetoclax had an acceptable tolerability profile. Notable adverse events such as grade 3 or 4 neutropenia can be managed with supportive therapy and venetoclax dose modifications. In conclusion, fixed-duration venetoclax + obinutuzumab represents an important chemotherapy-free first-line treatment option for patients with CLL, particularly those who are not fit enough to receive intensive chemoimmunotherapy.