Venetoclax + Chemotherapy for Leukemia
Recruiting in Palo Alto (17 mi)
+4 other locations
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: Dana-Farber Cancer Institute
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This research study is studying a medication called Venetoclax and a chemotherapy regimen as a possible treatment for Acute Lymphoblastic Leukemia.
The drugs involved in this study are:
* Venetoclax
* Standard Chemotherapy (which includes cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, 6-mercaptopurine, etoposide, and cytarabine
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop all current medications, but you cannot use warfarin or certain drugs that affect liver enzymes (like fluconazole or rifampin) within 3 days of starting venetoclax. It's best to discuss your specific medications with the study team.
What data supports the effectiveness of the drug Venetoclax in combination with chemotherapy for leukemia?
Venetoclax, when combined with low-intensity chemotherapy, has shown to improve survival and remission rates in patients with acute myeloid leukemia (AML), achieving complete remission in 73.1% of patients. It is also effective in chronic lymphocytic leukemia (CLL), with response rates of about 80% in relapsed or refractory cases.
12345Is the combination of Venetoclax and chemotherapy safe for humans?
Carboplatin, a chemotherapy drug often used in combination with other treatments, has been shown to have a better safety profile than cisplatin, with less kidney and nerve damage and less nausea. The main side effect is myelosuppression (a decrease in bone marrow activity), which affects blood cell counts but is generally manageable.
678910How does the drug Venetoclax combined with chemotherapy differ from other leukemia treatments?
Venetoclax, when combined with chemotherapy, offers a unique approach by specifically targeting and inhibiting a protein called BCL-2, which helps cancer cells survive. This mechanism is different from traditional chemotherapy drugs like cisplatin and carboplatin, which work by damaging the DNA of cancer cells to stop their growth.
79111213Eligibility Criteria
This trial is for adults with untreated or relapsed/refractory acute lymphoblastic leukemia. Older patients (≥60 years) and those aged ≥18 with prior treatments can join if they have a certain level of bone marrow involvement, are in good physical condition, and have proper organ function. Participants must not be pregnant, agree to use contraception, and cannot have severe medical conditions that could affect the study.Inclusion Criteria
I am 60 or older with acute lymphoblastic leukemia that has not been treated and affects over 20% of my bone marrow.
I am 18 or older with acute lymphoblastic leukemia that has not improved after treatment, can move around, and have more than 5% cancer cells in my bone marrow.
Exclusion Criteria
My leukemia is Ph-positive ALL, Burkitt's, or lymphoblastic lymphoma.
I have symptoms or untreated issues with my brain or spinal cord.
I cannot take medications by mouth due to a digestive condition.
I do not have any infections that are currently uncontrolled.
I am currently taking warfarin.
I have hepatitis B, hepatitis C, or HIV.
I have not had major surgery or radiation therapy in the last 4 weeks.
I do not have severe heart disease or recent major heart events.
I have been treated with venetoclax before.
I haven't taken strong CYP3A affecting drugs within 3 days before starting venetoclax.
My heart's pumping ability is below 40%.
Participant Groups
The trial is testing Venetoclax combined with standard chemotherapy drugs like cyclophosphamide and doxorubicin as a treatment for acute lymphoblastic leukemia. It aims to see how well this combination works in older patients or those who've had previous treatments without success.
1Treatment groups
Experimental Treatment
Group I: Venetoclax + ChemotherapyExperimental Treatment2 Interventions
* Venetoclax is administered orally once daily for 21 days in each cycle
* Standard Chemotherapy will be administered every 28 days
Standard Chemotherapy is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:
🇪🇺 Approved in European Union as Standard Chemotherapy for:
- Non-small cell lung cancer (NSCLC)
- Small cell lung cancer
🇺🇸 Approved in United States as Standard Chemotherapy for:
- Non-small cell lung cancer (NSCLC)
- Small cell lung cancer
🇨🇦 Approved in Canada as Standard Chemotherapy for:
- Non-small cell lung cancer (NSCLC)
- Small cell lung cancer
🇯🇵 Approved in Japan as Standard Chemotherapy for:
- Non-small cell lung cancer (NSCLC)
- Small cell lung cancer
🇨🇳 Approved in China as Standard Chemotherapy for:
- Non-small cell lung cancer (NSCLC)
- Small cell lung cancer
🇨🇭 Approved in Switzerland as Standard Chemotherapy for:
- Non-small cell lung cancer (NSCLC)
- Small cell lung cancer
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
MD Anderson Cancer CenterHouston, TX
Dana Farber Cancer InstituteBoston, MA
Intermountain LDS HospitalSalt Lake City, UT
Massachusetts General HospitalBoston, MA
More Trial Locations
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Who is running the clinical trial?
Dana-Farber Cancer InstituteLead Sponsor
AbbVieIndustry Sponsor
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). .
Outpatient initiation of venetoclax in patients with acute myeloid leukemia. [2023]Venetoclax is a treatment option in patients with acute myeloid leukemia (AML) in both the front-line and relapsed/refractory settings. Initiation of therapy has been previously restricted to the inpatient setting at some institutions due to a risk of tumor lysis syndrome (TLS) and limitations in medication access efficiency given the high cost of therapy.
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.
BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell? [2021]Venetoclax is an oral drug with an excellent side-effect profile that has the potential to revolutionize acute myeloid leukemia (AML) therapy in two areas. Venetoclax-based combination therapies could be a bridge to hematopoietic cell transplant with curative intent for patients with refractory/relapsed AML, and venetoclax-based therapy could provide meaningful survival prolongation for older patients with AML who are not candidates for more aggressive therapies. Cancer Discov; 6(10); 1082-3. ©2016 AACR.See related article by Konopleva and colleagues, p. 1106.
Safety and efficacy of venetoclax for acute myeloid leukaemia in real-world clinical practice. [2023]Venetoclax combined with low-intensity chemotherapy has led to longer survival and higher remission rates in patients with untreated acute myeloid leukaemia who are ineligible for intensive chemotherapy. We reviewed 41 newly diagnosed and relapse/refractory acute myeloid leukaemia patients who received venetoclax at our institute. Complete remission or complete remission with incomplete recovery was achieved in 73.1% of patients. A total of 95.1% of patients discontinued venetoclax, mainly because of severe cytopenia, disease progression and haematopoietic stem cell transplantation. The median number of courses of venetoclax was 2. In all, 92.6% of the patients experienced grade ≥ 3 neutropenia. The median overall survival was 287 days. Venetoclax dose reduction resulted in better continuity of treatment with fewer complications. In conclusion, venetoclax and low-intensity chemotherapy led to high remission rates, but survival was restrained because of the large number of venetoclax discontinuations. Dose reduction of venetoclax may mitigate cytopenia while maintaining efficacy.
Phase I study of intraperitoneal carboplatin as adjuvant therapy in early ovarian cancer. [2019]Early stage poor-risk ovarian cancer patients are at considerable risk for recurrent disease. Adjuvant radio- or chemotherapy has been found to improve disease-free and overall survival. Carboplatin, a second generation platinum, is documented comparable in efficacy to cisplatin in patients with advanced ovarian cancer. The toxicity profile is different from that of cisplatin. Dose-limiting toxicity is myelosuppression. The incidence and grade of renal and neurological toxicity is much lower compared with cisplatin, as is nausea and vomiting. Carboplatin given intraperitoneally (ip) is shown to have a favorable theoretical therapeutic advantage compared with iv administration since the peak peritoneal cavity/peak plasma concentration ratio is 18. Patients with early stage ovarian cancer seem suitable for carboplatin ip treatment. The study was designed to find the maximal tolerated dose (MTD). Three new patients were given two courses at each dose level. The MTD found was confirmed with further patients. Carboplatin was given in 2 liters of glucose via a subcutaneous implantable port without removal of fluid from the cavity. The starting dose was 300 mg/m2. Dose-limiting toxicity was thrombocytopenia and leukopenia. Leukocyte and platelet counts were reconstituted within 28 days in all cases. One case of severe but transient nephrotoxicity was observed. MTD was determined to 500 mg/m2.
A phase II study of carboplatin in advanced squamous cell carcinoma of the cervix (a Gynecologic Oncology Group Study). [2019]The Gynecologic Oncology Group conducted a Phase II trial of carboplatin in patients with measurable advanced squamous cell carcinoma of cervix. No prior therapy with cytotoxic drugs was permitted in patients entered into this study. Patients entered were GOG performance status 2 or better. Carboplatin 400 mg/m2 (340 mg/m2 in patients who had had prior pelvic radiotherapy with subsequent escalation to 400 mg/m2 if bone marrow tolerance was good) was administered as a 15-minute IV infusion. Treatments were repeated every four weeks until disease progressed or until toxicity prohibited further therapy. Thirty-nine evaluable patients were treated. Two complete and nine partial responses were observed (response rate 28.2%). No neurotoxicity and only mild reversible nephrotoxicity was seen. Gastrointestinal toxicity was severe in three patients (7.7%). Dose limiting toxicity was myelosuppression. Carboplatin is active against squamous cell carcinoma of cervix and appears to be less nephrotoxic, neurotoxic, and nauseogenic than cisplatin. Randomized studies of this drug against cisplatin are indicated to determine the role of carboplatin in the therapy of squamous cell carcinoma of cervix.
A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: a Southwest Oncology Group study. [2019]Forty-one eligible patients with metastatic or recurrent carcinoma of the uterine cervix received 149 courses of carboplatin. The drug was administered at a starting dosage of 400 mg/m2 IV every 28 days. The overall response rate was 15% (two complete responses, four partial responses; 95% confidence interval 6-29%) and response durations were 2.0, 2.0, 2.5 +, 2.5+, 5.25 +, and 6.75 months. The major toxic effects included nausea and vomiting in 48% of courses, anemia in 47%, leukopenia in 38%, and thrombocytopenia in 22%. The activity of carboplatin against advanced cervical cancer is modest and similar to the activity of cisplatin alone. However, the toxicity profile of carboplatin is substantially better than that of cisplatin and warrants exploration of this agent against cervix cancer in more aggressive regimens or in combination with other agents.
A phase I study of carboplatin in children with acute leukemia in bone marrow relapse. A report from the Childrens Cancer Group. [2019]Carboplatin is an analogue of cisplatin with less nonhematologic toxicity and a similar spectrum of antineoplastic activity as the parent compound. Although cisplatin has not been found to be an active agent in leukemia, carboplatin induced complete remissions in adults with acute myelogenous leukemia (AML). Therefore, a pediatric Phase I study in acute leukemia was performed.
Infusion carboplatin treatment of relapsed and refractory acute leukemia: evidence of efficacy with minimal extramedullary toxicity at intermediate doses. [2017]Carboplatin (CBDCA) is a second-generation platinum analog with prominent myelotoxicity and modest extramedullary toxicity. We performed a phase I study of CBDCA in adult patients with relapsed acute leukemia. Therapy was administered as a five-day continuous infusion. The initial dose of 875 mg/m2 over five days was escalated in 15% increments to a final dose of 2,100 mg/m2 over five days. Twenty-eight patients received 35 induction courses of CBDCA, including two patients who achieved a complete remission (CR) following the first course, and received a second induction course at the time of relapse. Therapy was well tolerated. No grade 3 or 4 extramedullary toxicity was seen. Myelosuppression was regularly observed, with prolonged myelosuppression at 2,100 mg/m2 over five days being the indication to cease dose escalation. Eight of 28 patients (28.5%) responded to CBDCA therapy (six CR, two partial remission [PR]) or ten of 30 initial induction courses (33.3%). Continuous-infusion CBDCA has an advantage over other therapy for acute leukemia because of its highly selective myelotoxicity and minimal gastrointestinal and renal toxicity. A standard phase II study should be undertaken to establish a more accurate response rate.
Progression-free survival and overall survival of patients with clear cell carcinoma of the ovary treated with paclitaxel-carboplatin or irinotecan-cisplatin: retrospective analysis. [2018]Irinotecan hydrochloride, a topoisomerase I inhibitor, has been preliminarily recognized as an effective agent against clear cell carcinoma of the ovary (CCC), but there are few clinical data. Our aim was to compare progression-free survival (PFS) between patients treated with irinotecan hydrochloride and cisplatin (CPT-P) and those with treated with paclitaxel and carboplatin (TC).
Comparison of cisplatin and carboplatin cytotoxicity in human ovarian cancer cell lines using the MTT assay. [2019]In this study, we compared the cytotoxicity of cisplatin and carboplatin against a panel of human ovarian cancer cell lines using the MTT assay, a rapid colorimetric test that can be used to evaluate the number of residual viable tumor cells following chemotherapy. The established human ovarian cancer cell line OVCAR-3 and the recently isolated and characterized A721, A90, A286, A1, and A121A cell lines were evaluated for chemosensitivity. Each cell line was treated separately with cisplatin and carboplatin at concentrations ranging from 500 to 0.16 micrograms/ml. Various chemotherapeutic exposure periods (1, 4, 24, and 48 hr) were tested to determine maximal efficacy. All cell lines were more susceptible to cisplatin than carboplatin at all drug concentrations and all exposure periods tested (P = 0.005). The overall median 50% inhibitory concentration (ID50) for cisplatin was 107 micrograms/ml compared with 490 micrograms/ml for carboplatin P = 0.005). For both cisplatin and carboplatin a 24-hr exposure was significantly more cytotoxic than a 1-hr exposure (P = 0.003 and P = 0.006, respectively). These in vitro results suggest that cisplatin is significantly more cytotoxic than carboplatin against human ovarian cancer cell lines and that cisplatin should not be replaced by carboplatin in the treatment of advanced epithelial ovarian cancer until randomized trials using maximum dosing of the cisplatin-containing regimen are performed.
Cytotoxicity of cisplatin and carboplatin used alone and in combination with the other anticancer drugs in the mouse embryo C3H10T1/2 cell line. [2018]Cytotoxicity of cisplatin and carboplatin was compared using each drug alone and in combination with either 5-fluorouracil (5-FU) or methotrexate (MTX) and with 5-FU, vincristine (VCR) and bleomycin (BLM) together in the mouse embryo fibroblast line C3H10T1/2. The survival curves, drawn on the basis of the colony-forming ability of cells, indicated that carboplatin was about 25 times less effective in cell killing compared to cisplatin. Dose-response curves obtained with different concentrations of cisplatin combined with 5-FU or MTX showed a dose modification factor (DMF) of 1.8. A DMF of 5.7 was obtained when cisplatin was combined with 5-FU + VCR + BLM. A combination of carboplatin with 5-FU and MTX resulted in DMFs of 3.4 and 2.4, respectively, while a DMF of 4.8 was obtained by combining the platinum analogue with 5-FU + VCR + BLM. Initial shoulders in the cell survival curves resulting from treatments with cisplatin, carboplatin and 5-FU used as single agents disappeared after combined drug treatments. While the data generally indicated a higher cytotoxic effectiveness of combined drug treatments, there was no great difference between the DMFs for cisplatin and carboplatin when used in different combination protocols. These results may reflect the functional similarity of the two platinum compounds and suggest that the replacement of one with the other may not significantly alter the cytotoxic effectiveness in combined treatments.