Combination Chemotherapy for Acute Lymphoblastic Leukemia

Overseen By Maro Ohanian, DO

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Disqualifiers: Peripheral neuropathy, Hepatic GVHD, Hepatitis, Pregnancy, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

42 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how well a mix of chemotherapy drugs can treat certain blood cancers, such as acute lymphoblastic leukemia, that have returned or resisted treatment. The combination includes drugs like clofarabine and bortezomib, which aim to stop cancer cells by either killing them or preventing their spread. Suitable candidates for this trial have a type of leukemia or lymphoma that has returned or hasn't responded to past treatments. Participants should have completed their last round of chemotherapy at least 21 days ago. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications, but it does allow hydroxyurea and dexamethasone up to 24 hours before starting the trial. If you are taking a tyrosine kinase inhibitor for Philadelphia positive ALL, you do not need to stop it.

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

A previous study found clofarabine to be safe and effective for children and young adults with relapsed or hard-to-treat acute lymphoblastic leukemia (ALL), supporting its use in this trial. Cyclophosphamide, another drug in the combination, has treated ALL but can cause serious side effects like infections or bladder problems, so doctors closely monitor patients during treatment.

Research has shown that bortezomib can cause side effects like nerve damage and low blood cell counts. Its safety for children with relapsed ALL isn't fully known, but it has been used in adults. Etoposide can also lower blood cell counts, which doctors watch carefully.

Dexamethasone is commonly used to treat ALL, but it can lead to infections and mood changes. Lastly, vincristine sulfate liposome, a new version of vincristine, is approved for adults with relapsed ALL and is believed to be easier to tolerate.

All these treatments have been studied, and while they may cause side effects, doctors are aware of them and manage them carefully. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination chemotherapy treatment for acute lymphoblastic leukemia (ALL) because it integrates several potent drugs, some of which have unique mechanisms of action. Unlike standard treatments, which often focus on a limited number of drugs, this combination includes bortezomib, a proteasome inhibitor that disrupts cancer cell regulation, and clofarabine, which targets DNA replication to halt cancer growth. Additionally, vincristine sulfate liposome offers targeted delivery, potentially reducing side effects while maximizing effectiveness. This comprehensive approach aims to improve outcomes by attacking leukemia cells from multiple angles, offering hope for faster and more effective results compared to traditional therapies.

What evidence suggests that this trial's combination chemotherapy could be effective for acute lymphoblastic leukemia?

Research has shown that the combination of chemotherapy drugs used in this trial holds promise for treating certain types of leukemia and lymphoma. Participants will receive a regimen that includes bortezomib, which has led to remission in many patients, with some studies showing remission rates of up to 44%. Clofarabine, another component of the regimen, helps eliminate small amounts of remaining cancer, enhancing the treatment's effectiveness. Cyclophosphamide and etoposide, also included in the trial, have improved survival rates, with etoposide achieving up to a 43% complete remission rate in some patients. Dexamethasone plays a crucial role in reducing relapse rates, especially in children. Vincristine sulfate liposome, a new version of vincristine used in this trial, improves drug delivery and has shown positive results, particularly in patients who have undergone many previous treatments. ^{6 7 8 9 10}

Who Is on the Research Team?

Maro Ohanian

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for people over 15 with certain types of blood cancers like acute lymphoblastic leukemia or Burkitt lymphoma that have returned or are treatment-resistant. Participants need normal liver function, not be pregnant or breastfeeding, and can't have severe nerve damage or active hepatitis B/C.

Inclusion Criteria

Serum bilirubin =< 1.5 mg/dL

Serum glutamate pyruvate transaminase (SGPT) =< 3 x upper limit normal (ULN), with exception for Gilbert's syndrome

I am older than 15 years.

Exclusion Criteria

I have active liver complications from a transplant.

Pregnancy

Breast feeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive clofarabine, etoposide, cyclophosphamide, vincristine sulfate liposome, dexamethasone, bortezomib, and possibly ofatumumab or rituximab, with the option for an additional course based on disease response

Approximately 2 weeks per course

Multiple visits for IV and SC administration

Consolidation Therapy

Patients receive clofarabine, etoposide, cyclophosphamide, vincristine sulfate liposome, dexamethasone, bortezomib, and possibly ofatumumab or rituximab, repeated every 28 days for up to 5 courses

Up to 5 months

Multiple visits for IV and SC administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 8 years

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib
• Clofarabine
• Cyclophosphamide
• Dexamethasone
• Etoposide
• Vincristine Sulfate Liposome

Trial Overview

The study tests a combination chemotherapy regimen using drugs like clofarabine, etoposide, cyclophosphamide, and others to see how well they work against aggressive blood cancers when previous treatments failed.

How Is the Trial Designed?

Group I: Treatment (combination chemotherapy) Experimental Treatment 9 Interventions

See detailed description

Bortezomib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in United States as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Canada as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Approved in Japan as Velcade for:

• Multiple myeloma
• Mantle cell lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Vincristine sulfate liposome injection (Marqibo) showed an overall response rate of 35% in adult patients with relapsed or refractory acute lymphoblastic leukemia when administered at a dose of 2.25 mg/m² once weekly.

The treatment was found to be safe, with no new or unexpected toxicities reported, indicating a favorable safety profile for this formulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vincristine sulfate liposome injection: a guide to its use in refractory or relapsed acute lymphoblastic leukemia. Harrison, TS., Lyseng-Williamson, KA.[2016]

In a phase 1 trial involving 36 adults with relapsed/refractory acute lymphoblastic leukemia (ALL), the maximum tolerated dose of vincristine sulfate liposome injection (VSLI) was determined to be 2.25 mg/m², with common side effects including peripheral neuropathy and constipation.

VSLI, combined with dexamethasone, showed a complete response rate of 19% overall, and 29% for patients undergoing their first salvage attempt, indicating its potential as an effective salvage therapy for relapsed ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 multicenter study of vincristine sulfate liposomes injection and dexamethasone in adults with relapsed or refractory acute lymphoblastic leukemia. Thomas, DA., Kantarjian, HM., Stock, W., et al.[2021]

Vincristine sulfate liposome injection (VSLI) allows for higher and uncapped doses of vincristine to be delivered to patients with acute lymphoblastic leukemia (ALL), reducing the risk of neurotoxicity associated with standard dosing.

VSLI is indicated for adults with relapsed or advanced Philadelphia chromosome-negative ALL, and its unique liposomal formulation enhances drug delivery efficiency, potentially improving treatment outcomes in future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Vincristine Sulfate Liposome Injection in the Treatment of Adult Acute Lymphocytic Leukemia. Douer, D.[2018]

In a phase II trial involving 65 adults with relapsed Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL), high-dose vincristine sulfate liposome injection (VSLI) achieved a complete response (CR) or CR with incomplete hematologic recovery (CRi) in 20% of patients, demonstrating its efficacy as a treatment option for advanced ALL.

VSLI was well tolerated with a low 30-day mortality rate of 12%, and it allowed for durable responses, with some patients successfully bridging to hematopoietic cell transplantation (HCT), indicating its potential as a safe and effective therapy in challenging cases of ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. O'Brien, S., Schiller, G., Lister, J., et al.[2021]

Vincristine sulfate liposome injection (VSLI) was well tolerated in adolescent and young adult (AYA) patients with advanced acute lymphoblastic leukemia (ALL), with a 25% complete remission rate and an overall response rate of 39% after a median of 5 doses.

The safety profile of VSLI was comparable to traditional vincristine, with serious adverse events occurring in 36% of patients, primarily involving peripheral neuropathy, but no neuropathy-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-Dose Vincristine Sulfate Liposome Injection, for Advanced, Relapsed, or Refractory Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in an Adolescent and Young Adult Subgroup of a Phase 2 Clinical Trial. Schiller, GJ., Damon, LE., Coutre, SE., et al.[2019]

Liposomal vincristine (VSLI) shows promise as a treatment for relapsed or refractory acute lymphoblastic leukemia (ALL), potentially inducing complete responses in some adults, which can help them qualify for stem-cell transplantation.

VSLI may enhance drug delivery and reduce neurotoxicity compared to conventional vincristine, which is limited by cumulative toxicity, making it a safer option for patients with ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liposomal vincristine for relapsed or refractory Ph-negative acute lymphoblastic leukemia: a review of literature. Pathak, P., Hess, R., Weiss, MA.[2021]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10572992/

Bortezomib Is Effective in the Treatment of T Lymphoblastic ...

Our findings reveal that bortezomib treatment induces DNA damage and downregulates WEE1, leading to G2-M cell-cycle progression with damaged DNA.

2.

bloodresearch.or.kr

bloodresearch.or.kr/journal/view.html?uid=2699&vmd=Full

Efficacy of bortezomib combined with Hyper-CVAD in ...

ResultsOf the 20 patients with positive MRD included in this study, 60% (n = 12) exhibited MRD negative results after combination treatment, 30% ...

3.

ashpublications.org

ashpublications.org/blood/article/120/2/285/30407/Bortezomib-with-chemotherapy-is-highly-active-in

Bortezomib with chemotherapy is highly active in advanced B ...

Investigators from the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) consortium retrospective study found remission rates of 44%, 27%, and 12% ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05137860?tab=table

NCT05137860 | Efficacy of the Use of Bortezomib for ...

It has been shown that adding Bortezomib to the relapsing regimen improves the proportion of second complete remissions without increasing chemotherapy ...

5.

fda.gov

fda.gov/media/94387/download

21602 Bortezomib Statistical BPCA

In Study AALL07P1, the primary efficacy endpoint was second complete remission (CR2) rate at the end of block 1 therapy for pediatric and young adult patients ...

6.

accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2008/021602s015lbl.pdf

Velcade Label - accessdata.fda.gov

The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. 5.7 Gastrointestinal Adverse Events. VELCADE treatment can ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC12364856/

Clinical use and toxicities of bortezomib in pediatric patients

Extracted pediatric safety data was compared to reported adult safety profile from the BTZ drug insert. Results. There was heterogeneity in reporting of ...

8.

mayoclinic.org

mayoclinic.org/drugs-supplements/bortezomib-intravenous-route-subcutaneous-route/description/drg-20067371

Bortezomib (intravenous route, subcutaneous route)

Safety and efficacy have not been established in children with relapsed acute lymphoblastic leukemia (ALL). Geriatric. Appropriate studies ...

9.

ema.europa.eu

ema.europa.eu/en/documents/product-information/velcade-epar-product-information_en.pdf

Velcade, INN-bortezomib - EMA

Summary of the safety profile. Serious adverse reactions uncommonly reported during treatment with VELCADE include cardiac failure, tumour lysis syndrome, ...

10.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06034561

Bortezomib-based Regimen for Refractory or Relapsed ...

To examine the rate of febrile neutropenia, liver toxicity, neurotoxicity, and treatment-related mortality after this regimen in relapsed/refractory ALL.