Venetoclax + Chemotherapy for Leukemia

Recruiting at 4 trial locations

Overseen By Daniel DeAngelo, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Ph-positive ALL, Hepatitis B/C, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 21 days per cycle

82 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of the medication Venetoclax with standard chemotherapy to determine its effectiveness for Acute Lymphoblastic Leukemia, a type of blood cancer. Researchers aim to discover if adding Venetoclax can improve treatment outcomes. The trial is open to individuals with Acute Lymphoblastic Leukemia who are either untreated or have relapsed after previous treatments. Those diagnosed with this type of leukemia and experiencing bone marrow involvement may be eligible to participate. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants the chance to contribute to groundbreaking advancements in leukemia treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that Venetoclax is generally well-tolerated. In one study with 158 participants, researchers closely monitored safety, and many handled the treatment without major issues. However, some side effects, such as low white blood cell counts, were noted and require monitoring.

Venetoclax is already used to treat other blood cancers, providing some confidence about its safety. Early research indicates that patients can manage the combination of Venetoclax and chemotherapy, though it may still cause side effects from both treatments. These side effects can include low blood cell counts, nausea, and tiredness.

Overall, the safety information suggests that while side effects exist, they are often manageable. Anyone considering joining a trial should discuss their health and potential risks with their doctor. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for leukemia?

Researchers are excited about the combination of Venetoclax with chemotherapy for leukemia because Venetoclax introduces a new mechanism of action. Unlike traditional treatments that focus on destroying cancer cells directly, Venetoclax targets and inhibits a protein called BCL-2, which helps cancer cells survive. This approach can potentially make cancer cells more susceptible to being eliminated by standard chemotherapy. By combining Venetoclax with chemotherapy, there's hope for more effective treatment outcomes, offering a fresh angle in the fight against leukemia.

What evidence suggests that Venetoclax combined with chemotherapy could be an effective treatment for Acute Lymphoblastic Leukemia?

Research has shown that venetoclax can effectively treat certain types of leukemia. One study found that venetoclax helped 15.5% of patients with acute myeloid leukemia, with one patient achieving complete recovery. This suggests that venetoclax may help some patients reach remission.

In this trial, participants will receive a combination of venetoclax and standard chemotherapy. Venetoclax blocks a protein that helps cancer cells survive, potentially hindering the growth of leukemia cells. Standard chemotherapy, often used with venetoclax, remains a key treatment for leukemia because it can kill rapidly dividing cancer cells. Combining venetoclax with chemotherapy might enhance the overall effectiveness in treating acute lymphoblastic leukemia. ^{2 6 7 8 9}

Who Is on the Research Team?

Marlise R Luskin, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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.

Adequate organ function: Serum total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients with Gilbert's disease, Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 x ULN, Creatinine clearance >50 mL/min, Women of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (β-hCG) pregnancy test result within 14 days prior to the first dose of study drugs and must agree to use an effective contraception method during the study and for 30 days following the last dose of study drug, Women of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy, Men who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 30 days following the last dose of study drug, Patients or their legally authorized representative must provide written informed consent

Exclusion Criteria

Patient is pregnant or breastfeeding

My leukemia is Ph-positive ALL, Burkitt's, or lymphoblastic lymphoma.

I have symptoms or untreated issues with my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Venetoclax orally once daily for 21 days in each cycle, with standard chemotherapy administered every 28 days

21 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Standard Chemotherapy
• Venetoclax

Trial Overview 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.

How Is the Trial Designed?

Group I: Venetoclax + Chemotherapy Experimental Treatment 2 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

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

AbbVie

Industry Sponsor

Trials

1,079

Recruited

535,000+

Founded

2013

Headquarters

North Chicago, USA

Known For

Immunology treatments

Top Products

Humira (adalimumab), Skyrizi (risankizumab), Rinvoq (upadacitinib)

Dr. Roopal Thakkar

AbbVie

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Robert A. Michael

AbbVie

Chief Executive Officer

Bachelor's degree in Finance from the University of Illinois

Published Research Related to This Trial

In a study of 117 patients with clear cell carcinoma of the ovary, the combination of irinotecan hydrochloride and cisplatin (CPT-P) showed a progression-free survival (PFS) rate of 55% at 5 years, suggesting it may be an effective treatment option.

While the CPT-P regimen did not show a statistically significant survival advantage over the standard paclitaxel and carboplatin (TC) treatment, it demonstrated comparable efficacy, warranting further investigation in larger clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progression-free survival and overall survival of patients with clear cell carcinoma of the ovary treated with paclitaxel-carboplatin or irinotecan-cisplatin: retrospective analysis. Takano, M., Sugiyama, T., Yaegashi, N., et al.[2018]

Cisplatin was found to be significantly more effective than carboplatin in killing cancer cells, being about 25 times more potent in the mouse embryo fibroblast line C3H10T1/2.

Combining cisplatin with other drugs like 5-fluorouracil (5-FU) or methotrexate (MTX) enhanced its cytotoxic effects, but similar enhancements were observed with carboplatin, indicating that both drugs have comparable effectiveness in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxicity of cisplatin and carboplatin used alone and in combination with the other anticancer drugs in the mouse embryo C3H10T1/2 cell line. Hussain, SS., Amer, MH., Hannan, MA.[2018]

In a Phase I study involving children with acute leukemia, carboplatin demonstrated antileukemic activity, particularly in acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML).

The study identified 216 mg/m2/day as the maximum tolerated dose for carboplatin, as higher doses led to significant nephrotoxicity and other serious side effects, including hepatotoxicity and hemorrhagic cystitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of carboplatin in children with acute leukemia in bone marrow relapse. A report from the Childrens Cancer Group. Ettinger, LJ., Krailo, MD., Gaynon, PS., et al.[2019]

Carboplatin, administered intraperitoneally, shows a favorable safety profile compared to cisplatin, with lower incidences of renal and neurological toxicity, as well as reduced nausea and vomiting, making it a suitable option for early-stage poor-risk ovarian cancer patients.

The study established the maximum tolerated dose (MTD) of intraperitoneal carboplatin at 500 mg/m2, with dose-limiting toxicities primarily being thrombocytopenia and leukopenia, which were reversible within 28 days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of intraperitoneal carboplatin as adjuvant therapy in early ovarian cancer. Malmström, H., Larsson, D., Simonsen, E.[2019]

In a study of 41 patients with advanced cervical cancer receiving carboplatin, the overall response rate was 15%, indicating modest efficacy with two complete and four partial responses.

Carboplatin had a more favorable toxicity profile compared to cisplatin, with major side effects including nausea (48%), anemia (47%), and leukopenia (38%), suggesting it may be a safer option for further exploration in treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: a Southwest Oncology Group study. Weiss, GR., Green, S., Hannigan, EV., et al.[2019]

In a phase I study involving 28 adult patients with relapsed acute leukemia, continuous infusion of carboplatin (CBDCA) was well tolerated, showing no severe extramedullary toxicity and manageable myelosuppression.

The treatment resulted in a response rate of 28.5%, with two patients achieving complete remission, suggesting that CBDCA may be a promising option for acute leukemia due to its selective myelotoxicity and minimal side effects compared to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infusion carboplatin treatment of relapsed and refractory acute leukemia: evidence of efficacy with minimal extramedullary toxicity at intermediate doses. Meyers, FJ., Welborn, J., Lewis, JP., et al.[2017]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In a study of 82 adult patients with acute myeloid leukemia (AML), 57% were able to start venetoclax treatment safely in an outpatient setting, demonstrating its feasibility outside of the hospital.

The risk of tumor lysis syndrome (TLS) was very low, with only 2.1% of patients experiencing TLS after starting venetoclax, and 98% of patients did not require hospitalization for TLS within the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outpatient initiation of venetoclax in patients with acute myeloid leukemia. Palmer, S., Patel, A., Wang, C., et al.[2023]

Venetoclax is an oral medication that selectively inhibits the BCL-2 protein, which helps cancer cells survive, thereby restoring the ability of these malignant cells to undergo programmed cell death (apoptosis).

It has been approved in the USA for treating chronic lymphocytic leukaemia (CLL) in patients with a specific genetic marker (17p deletion) who have already undergone at least one prior therapy, and it is being studied for various other blood cancers and conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: First Global Approval. Deeks, ED.[2018]

In a Phase II trial involving 39 patients with advanced squamous cell carcinoma of the cervix, carboplatin demonstrated a response rate of 28.2%, with two complete and nine partial responses observed, indicating its efficacy as a treatment option.

Carboplatin showed a favorable safety profile, with no neurotoxicity and only mild reversible nephrotoxicity, suggesting it may be less harmful than cisplatin, although myelosuppression was noted as a dose-limiting toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of carboplatin in advanced squamous cell carcinoma of the cervix (a Gynecologic Oncology Group Study). Arseneau, J., Blessing, JA., Stehman, FB., et al.[2019]

Cisplatin demonstrated significantly greater cytotoxicity against various human ovarian cancer cell lines compared to carboplatin, with a median inhibitory concentration (ID50) of 107 micrograms/ml for cisplatin versus 490 micrograms/ml for carboplatin.

A 24-hour exposure to both cisplatin and carboplatin was found to be more effective than a 1-hour exposure, indicating that longer treatment durations enhance the drugs' effectiveness against ovarian cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of cisplatin and carboplatin cytotoxicity in human ovarian cancer cell lines using the MTT assay. Fanning, J., Biddle, WC., Goldrosen, M., et al.[2019]

Venetoclax is an oral medication with a favorable side-effect profile that shows promise in treating acute myeloid leukemia (AML), particularly for patients with refractory or relapsed cases.

This drug can serve as a bridge to hematopoietic cell transplant for curative treatment and may significantly extend survival for older patients who cannot tolerate more aggressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

BCL2 Inhibition by Venetoclax: Targeting the Achilles' Heel of the Acute Myeloid Leukemia Stem Cell? Pullarkat, VA., Newman, EM.[2021]

In a study of 41 patients with untreated acute myeloid leukaemia, the combination of venetoclax and low-intensity chemotherapy achieved a high remission rate of 73.1%, indicating its efficacy for patients ineligible for intensive treatment.

Despite the high remission rates, 95.1% of patients discontinued venetoclax mainly due to severe side effects like cytopenia, highlighting the need for dose reduction to improve treatment continuity and reduce complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of venetoclax for acute myeloid leukaemia in real-world clinical practice. Fukumoto, A., Narita, K., Ikeda, D., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5026291/

The potential of venetoclax (ABT-199) in chronic lymphocytic ... In the phase I trial in R/R CLL and lymphoma patients, the ORR with ibrutinib was 60%, including 16% CRs and median PFS of 13.6 months. Results varied by ...

2. venclextahcp.com venclextahcp.com/cll/efficacy/ven-g/data.html

VENCLEXTA efficacy results: 6-year overall survival 1 In patients with CLL, Grade 3 or 4 neutropenia developed in 63% to 64% of patients and Grade 4 neutropenia developed in 31% to 33% of patients when treated with ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6499443/

Evaluating venetoclax and its potential in treatment-naïve ... Results were dramatic–venetoclax plus rituximab achieved an 84.9% progression-free survival rate at 2 years, vs the bendamustine plus rituximab arm, which ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT01889186?term=venetoclax&viewType=Table&rank=6

NCT01889186 | A Study of the Efficacy of ABT-199 in ... This was an open-label, multicenter, global study to determine the efficacy of ABT-199 ( Venetoclax ) monotherapy in participants with relapsed/refractory (R/R) ...

5. news.abbvie.com news.abbvie.com/2014-12-07-AbbVie-Presents-Results-from-Phase-2-Study-of-Investigational-Compound-Venetoclax-ABT-199-GDC-0199-in-Acute-Myelogenous-Leukemia-at-the-56th-American-Society-of-Hematology-Annual-Meeting

Study Evaluated Preliminary Efficacy of Venetoclax in 32 ... In the study, the venetoclax group showed an overall response rate (ORR) of 15.5 percent, with one patient achieving a complete response and ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT02141282

Study Details | NCT02141282 | A Phase 2 Open-Label ... This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or refractory ...

7. abbvie.com abbvie.com/content/dam/abbvie-dotcom/us/clinical-trials/venetoclax_M13-982.pdf

Venetoclax (ABT-199) M13-982 Clinical Study Report Safety was assessed in all 158 subjects; 107 subjects in the main cohort and 51 subjects in the safety expansion cohort. The data cutoff date for this final ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118474733

Safety and Efficacy of a Combination of Venetoclax (GDC ... We present preliminary efficacy and updated safety data from an ongoing phase 1b study (NCT01685892) evaluating this combination in R/R or treatment-naïve (TN) ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT01889186

NCT01889186 | A Study of the Efficacy of ABT-199 in ... The primary objective of the safety expansion cohort was to evaluate the safety of ABT-199 in approximately 50 participants with R/R CLL harboring 17p deletion ...