Triple Therapy for Chronic Lymphocytic Leukemia
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: M.D. Anderson Cancer Center
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This phase II trial studies how well atezolizumab, obinutuzumab, and venetoclax work in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma or Richter syndrome that has come back (recurrent) or does not respond to treatment (refractory). Immunotherapy with monoclonal antibodies, such as atezolizumab and obinutuzumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as venetoclax, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving atezolizumab, obinutuzumab, and venetoclax may work better in treating patients with chronic lymphocytic leukemia, small lymphocytic lymphoma, or Richter syndrome.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications. However, if you are on high-dose steroids or immune suppression medications, these need to be stopped at least 3 days before starting the study drugs. Also, you cannot take strong CYP3A inhibitors or inducers within 7 days of starting venetoclax.
What data supports the effectiveness of the drug combination including Venetoclax for treating Chronic Lymphocytic Leukemia?
Venetoclax, when used in combination with obinutuzumab, has shown to significantly improve progression-free survival and response rates in patients with previously untreated chronic lymphocytic leukemia, according to the CLL14 trial. Additionally, Venetoclax combined with rituximab has been effective in prolonging progression-free survival in relapsed or refractory cases, demonstrating its potential as a key component in CLL treatment.
12345Is there safety data available for the drugs used in the triple therapy for chronic lymphocytic leukemia?
Venetoclax (Venclexta) has been approved for chronic lymphocytic leukemia, indicating it has undergone safety evaluations for this condition. However, no specific safety data for the combination of Atezolizumab, Obinutuzumab, and Venetoclax in chronic lymphocytic leukemia is provided in the available research articles.
678910What makes the drug combination of Atezolizumab, Obinutuzumab, and Venetoclax unique for treating chronic lymphocytic leukemia?
This drug combination is unique because it combines Atezolizumab, an immune checkpoint inhibitor, with Obinutuzumab and Venetoclax, which target specific proteins on cancer cells, offering a novel approach that may enhance the immune system's ability to fight chronic lymphocytic leukemia.
12345Eligibility Criteria
Adults over 18 with chronic lymphocytic leukemia, small lymphocytic lymphoma, or Richter syndrome that's untreated or resistant to treatment. They must be in good physical condition (ECOG ≤2), have normal liver and kidney function, not be pregnant or breastfeeding, agree to use effective contraception, and have no major health issues like uncontrolled hypertension or recent strokes.Inclusion Criteria
I am 18 years old or older.
I have been diagnosed with CLL, SLL, or RT and have not received any treatment.
I can take care of myself and am up and about more than half of my waking hours.
My kidney and liver are working well.
I am not pregnant and agree to use birth control.
Exclusion Criteria
I have taken specific medications before.
I haven't had major surgery or therapy in the last 4 weeks.
I have not received any live vaccines recently.
I have severe ongoing health or mental health issues.
I still have side effects from previous cancer treatments.
I have serious heart-related conditions.
My blood pressure is not controlled by medication.
My CLL has spread to my brain or its coverings.
I have received an organ transplant from another person.
I do not have any untreated or uncontrolled infections.
I have a history of lung conditions.
I have hepatitis B, C, or HIV.
I have taken strong CYP3A inhibitors or inducers.
I am currently taking high-dose steroids or medications that suppress my immune system.
I have a serious liver condition.
Participant Groups
The trial is testing a combination of atezolizumab (an immune system booster) with obinutuzumab and venetoclax (chemotherapy drugs). It aims to see if this mix can better stop the growth of cancer cells in patients with certain blood cancers compared to current treatments.
2Treatment groups
Experimental Treatment
Group I: Cohort II (obinutuzumab, atezolizumab, venetoclax)Experimental Treatment4 Interventions
Patients receive obinutuzumab intravenously IV over 4-6 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-9 and atezolizumab IV over 30-60 minutes on days 3-4 of cycle 1 and on days 1-2 of cycles 2-9. Treatment repeats every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 2, patients receive venetoclax PO on days 1-28. Treatment repeats every 28 days for 25 cycles in the absence of disease progression or unacceptable toxicity.
Group II: Cohort I (obinutuzumab, atezolizumab, venetoclax)Experimental Treatment4 Interventions
Patients receive obinutuzumab IV over 4-6 hours on days 1, 2, 8, and 15 of cycle 1 and on day 1 of cycles 2-9 and atezolizumab IV over 30-60 minutes on days 3-4 of cycle 1 and on days 1-2 of cycles 2-9. Treatment repeats every 28 days for 9 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 3, patients also receive venetoclax PO on days 1-28. Treatment repeats every 28 days for 14 cycles in the absence of disease progression or unacceptable toxicity.
Atezolizumab is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Tecentriq for:
- Melanoma
- Hepatocellular carcinoma
- Small cell lung cancer
- Non-small cell lung cancer
- Urothelial carcinoma
🇪🇺 Approved in European Union as Tecentriq for:
- Melanoma
- Hepatocellular carcinoma
- Small cell lung cancer
- Non-small cell lung cancer
- Urothelial carcinoma
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
M D Anderson Cancer CenterHouston, TX
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Who is running the clinical trial?
M.D. Anderson Cancer CenterLead Sponsor
National Cancer Institute (NCI)Collaborator
References
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.
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.
Chronic lymphocytic leukemia at ASH 2017. [2020]At ASH (American Society of Hematology) 2017 three out of a plethora of trials showed remarkable and promising results. The combinations of venetoclax with rituximab and ibrutinib with venetoclax convinced with striking efficacy together with a manageable safety profile in relapsed/refractory setting as well as in first line therapy of high-risk disease. These two combinations are potential new standard treatment options in chronic lymphocytic leukemia.
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.
Pharmaceutical Approval Update. [2020]Venetoclax (Venclexta) for chronic lymphocytic leukemia; riboflavin 5'-phosphate solutions (Photrexa Viscous and Photrexa) for progressive keratoconus; and pimavanserin (Nuplazid) for Parkinson's disease psychosis.
Circumvention of methotrexate resistance in childhood leukemia subtypes by rationally designed antifolates. [2021]Cellular methotrexate (MTX) resistance may cause treatment failure in childhood common/preB-acute lymphoblastic leukemia (c/preB-ALL), T-lineage ALL (T-ALL), and acute myeloid leukemia (AML). The ex vivo potency of several antifolates (MTX, trimetrexate [TMQ], GW1843U89, multitargeted antifolate [MTA], Raltitrexed, and ZD9331) was studied via in situ inhibition of thymidylate synthase (TS). After short-term exposure, relapsed c/preB-ALL (rALL, n = 21), T-ALL (n = 22), and AML (n = 22) were 3-fold, 10-fold, and 6-fold less sensitive to MTX (P
A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer. [2020]Trimetrexate (TMTX) biochemically modulates 5-fluorouracil (5-FU) and leucovorin (LCV). Two phase II trials demonstrated promising activity for TMTX/5-FU/LCV in patients with untreated advanced colorectal cancer (ACC). This trial was designed to demonstrate the safety and efficacy of TMTX/5-FU/LCV as first-line treatment in ACC.
Cross resistance of pleiotropically drug resistant P338 leukemia cells to the lipophilic antifolates trimetrexate and BW 301U. [2019]Several antifolate compounds were examined for their cytotoxic activity in a pleiotropically resistant P388 cell line (P388R). The sensitivity of P388R cells to methotrexate (MTX) and the lipophilic antifols, metoprine and methotrexate gamma-mono t-butyl ester (MTX-gamma-t-butyl ester) were comparable with that activity observed in the parental cell line (P388S). P388R cells were, however, resistant to 2 other lipophilic antifols, trimetrexate (TMQ) and BW 301U. The degree of resistance to TMQ and BW 301U was 22-fold and 15-fold, respectively and could be partially overcome by the calcium channel blocker, verapamil (VER) or the detergent Tween 80. Transport studies showed that net accumulation of trimetrexate was markedly reduced in P388R cells resulting in a steady-state level which was 25% of the sensitive line. This impaired uptake was reversed by 5 micrograms/ml VER which increased the steady-state to a level comparable to P388S. P388R also exhibited a 50% reduction in the unindirectional influx rate, however, this defect could not be reversed by VER. The resistance of P388R cells to TMQ and BW 301U and their potentiation by VER extends pleiotropic resistance to yet another class of drugs which have important clinical implications.
Adverse effects with intravenous methotrexate in children with acute lymphoblastic leukemia/lymphoma: a retrospective study. [2021]Methotrexate (MTX) forms the backbone of maintenance cycles in childhood acute lymphoblastic leukemia (ALL) chemotherapy, including interim maintenance. There is sufficient published data describing toxicities of high dose MTX (HD-MTX), but toxicities with escalating doses of MTX (Capizzi regimen) is not well documented. Capizzi regimen is thought to be relatively safe; we contend that even low escalating doses of MTX have significant toxicities. Our study intends to characterise such events with Capizzi MTX in comparison to that seen with HD-MTX. The retrospective study was conducted at a tertiary care centre of North India. We looked for the presence of six main toxicities: febrile neutropenia, thrombocytopenia, mucositis, hepatic toxicity, renal toxicity and skin toxicity from the clinical records of children with newly diagnosed acute lymphoblastic leukemia and lymphoma (intermediate and high risk disease), treated at our centre from November 2013 to July 2018. Intermediate risk ALL (IR-ALL) received Capizzi MTX, whereas high risk ALL (HR-ALL/T-NHL), received HD-MTX. Both these regimens do not use L-asparaginase. A total of 237 cycles of Capizzi escalating MTX and 151 cycles of HD-MTX (B cell: 3 gm/m2 and T cell ALL/T-NHL: 5 gm/m2) during interim maintenance were studied in 93 children. Fifty-four (54) children were of IR (all B cell ALL) and 39 of HR-ALL (21 B-ALL, 18 T-ALL/T-NHL). The combined incidence of toxicities, were similar between the two groups: 68/237 cycles (28.7%) of Capizzi MTX and 45/151 cycles (29.8%) of HD-MTX (P = 0.815). However, mucositis was more commonly witnessed in the later group at 22/151 cycle (14.6%) versus 13/237 cycles (5.5%) in Capizzi MTX (P = 0.002). Nephrotoxicity and skin toxicity was seen only in the HD-MTX group. There was no difference in the severity of toxicity, graded using NCI CTCAE v 5.0, between the two groups. There was no mortality directly attributable to methotrexate toxicity (Grade V toxicity). Serum MTX levels were available in 69/151 (45.7%) cycles of HD-MTX and showed no association with toxicity in this group. Also, there was no difference in the incidence of combined toxicities between groups with (19/69 cycles) or without (26/82 cycles) available serum MTX levels in the HR group (P = 0.577). Male gender, lower baseline ANC and lower BMI had significant association with toxicity. Methotrexate related toxicity is common with both Capizzi and HD-MTX schedule in childhood ALL with a correlation of lower BMI, baseline ANC and male gender. However, it is possible to administer Capizzi as well as HD-MTX in lower middle income countries, with manageable toxicity. Further studies will be required to substantiate our findings and determine the predictors of such events.