Bortezomib + Clofarabine for Cancer

No longer recruiting at 1 trial location

Overseen By Alice P Chen, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Antiretrovirals, Investigational agents

Disqualifiers: Neuropathy, Brain metastases, Allergies, others

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

Compensation: Varies

Number of Visits: 3

Duration: 21 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial seeks to improve cancer treatment by testing the safety and effectiveness of two drugs, bortezomib (a proteasome inhibitor) and clofarabine (a chemotherapy agent), when used together. These drugs are already used separately for certain blood cell cancers, but researchers aim to assess their combined effect. The trial targets adults whose advanced cancer has worsened after standard treatments or for whom no effective options exist. Participants will receive both drugs in 21-day cycles, with close monitoring to ensure safety and evaluate the treatment's impact on their cancer. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to contribute to groundbreaking cancer research.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you must have completed any chemotherapy, radiation, or biologic therapy at least 3 weeks before starting the study, and HIV-positive patients on antiretroviral therapy are not eligible.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

In past studies, researchers have used bortezomib and clofarabine separately to treat certain blood cancers. Research has shown that both drugs are generally well-tolerated on their own. However, specific safety information about using them together is not yet available. This study is in its early stages and primarily focuses on testing the safety of the combination and determining the best dose. As a result, safety information is still being collected.

When used alone, bortezomib may cause fatigue, nausea, or low blood cell counts in some individuals. Clofarabine can also lead to similar side effects, such as fever and infections. It is important to note that these effects may not occur in everyone and can vary from person to person. This study aims to understand the safety of using these two drugs together. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of Bortezomib and Clofarabine for cancer treatment because it offers a unique approach compared to standard therapies. Most existing cancer treatments work by targeting rapidly dividing cells. However, Bortezomib, a proteasome inhibitor, disrupts cancer cell proliferation by preventing protein breakdown, while Clofarabine, a nucleoside analog, interferes with DNA synthesis. This dual mechanism could potentially enhance the effectiveness against cancer cells and lead to better outcomes with possibly fewer side effects. Additionally, the subcutaneous administration of Bortezomib may offer convenience and improved patient compliance compared to traditional intravenous methods.

What evidence suggests that the combination of bortezomib and clofarabine might be an effective treatment for cancer?

Research has shown that bortezomib and clofarabine are each effective in treating certain blood cancers individually. Studies indicate that bortezomib, when combined with other chemotherapy drugs, can improve outcomes in cancers like multiple myeloma and mantle cell lymphoma. Additionally, lab studies suggest that using bortezomib and clofarabine together is more effective than using either drug alone in various cancer cell types. Early results also suggest that this combination may work against colon cancer. Although more research in humans is needed, these findings offer hope that this drug pair, which participants in this trial will receive, could help treat different types of cancer. ^{1 2 6 7 8}

Who Is on the Research Team?

Alice P Chen, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults over 18 with advanced cancer that's worsened after standard treatment or lacks effective therapy can join. They need normal organ/marrow function, a life expectancy over 3 months, and must use contraception. Excluded are pregnant/breastfeeding women, those with certain heart conditions, uncontrolled illnesses, severe neuropathy, active brain metastases/CNS disease, or allergies to similar drugs.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

Life expectancy of greater than 3 months

Agreement to use adequate contraception for women of child-bearing potential and men

Exclusion Criteria

I am not pregnant, breastfeeding, or HIV-positive on antiretroviral therapy.

I am eligible regardless of my gender, race, or ethnicity.

I do not have active brain tumors or cancer in my spinal fluid.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive bortezomib and clofarabine in 21-day cycles. Bortezomib is injected subcutaneously on days 1 and 4, and clofarabine is injected intravenously on days 1-5.

21 days per cycle

Week 1: daily visits; Weeks 2-3: 1-2 visits

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up for 30 days after the last dose of study drugs.

4 weeks

1-2 visits (in-person)

Dose Escalation

Dose escalation follows a 3+3 design to determine the maximum tolerated dose (MTD) of the drug combination.

Varies

What Are the Treatments Tested in This Trial?

Interventions

• Bortezomib plus Clofarabine

Trial Overview

The trial tests the safety and effectiveness of combining Bortezomib and Clofarabine in treating solid tumors and lymphoma. Participants receive these drugs in cycles: Bortezomib by injection on days 1 & 4; Clofarabine intravenously on days 1-5. The study includes initial dose-safety testing followed by an expansion cohort for further evaluation.

How Is the Trial Designed?

Group I: 1 Experimental Treatment 1 Intervention

Starting doses are clofarabine at 1 mg/m2 IV on days 1 through 5 of a 21-day cycle, and bortezomib at 0.8 mg/m2 subcutaneously on days 1 and 4 of a 21-day cycle.

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Clofarabine is the only drug approved in the last decade for treating pediatric acute leukemia, showing significant efficacy in both pediatric and adult patients with poor prognosis leukemias.

The drug works by directly inhibiting DNA synthesis and ribonucleotide reductase, leading to cancer cell death, and is being explored for oral use and in combination therapies for various leukemia subtypes and solid tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of anti-cancer action and pharmacology of clofarabine. Zhenchuk, A., Lotfi, K., Juliusson, G., et al.[2018]

Clofarabine demonstrated significant efficacy in treating relapsed/refractory acute lymphoblastic leukemia in children, with 42% achieving complete remission after the first cycle and 85% after the second cycle among those who received two cycles.

The treatment was generally well-tolerated, with common adverse effects including myelosuppression and infections, but no chemotherapy-related deaths were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Therapeutic effect of clofarabine in children with relapsed or refractory acute lymphoblastic leukemia]. Suo, P., Zhang, LP., Wu, J., et al.[2018]

Clofarabine, a purine nucleoside analog, has shown efficacy in treating pediatric patients with relapsed or refractory acute lymphoblastic leukemia, achieving complete remission rates of 12% and partial remission rates of 10% in a study of 61 patients.

The treatment is associated with significant adverse events, primarily hematologic issues like anemia and leukopenia, as well as gastrointestinal symptoms and infections, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine: in pediatric patients with acute lymphoblastic leukemia. Curran, MP., Perry, CM.[2018]

In a study of 49 patients with newly diagnosed multiple myeloma, the combination therapy of bortezomib, bendamustine, and prednisone showed a high response rate, with 82% of patients responding after at least one treatment cycle.

The treatment was well tolerated and demonstrated promising progression-free survival (PFS) and overall survival (OS) rates, particularly in patients with normal or mild renal dysfunction, indicating its efficacy across varying levels of renal function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with newly diagnosed/untreated multiple myeloma. Pönisch, W., Holzvogt, B., Plötze, M., et al.[2021]

In a study of 57 patients with relapsed, refractory multiple myeloma, combining bortezomib with common chemotherapeutic agents resulted in a significantly higher early objective response rate (76%) compared to bortezomib alone (37.5%), indicating enhanced efficacy of the combination treatment.

Despite the increased effectiveness of the combination therapy, the rate of serious side effects, such as peripheral neuropathy, was similar between the two groups, suggesting that the combination treatment is relatively safe while providing better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib in combination with conventional chemotherapeutic agents for multiple myeloma compared with bortezomib alone. Min, CK., Lee, MJ., Eom, KS., et al.[2015]

Bortezomib, a proteasome inhibitor, shows clinical efficacy in treating relapsed and refractory mantle cell lymphoma (MCL), achieving an objective response in up to 45% of patients, although complete remission rates are low and responses are often short-lived.

Combining bortezomib with cytarabine may enhance treatment effectiveness, with in vitro data suggesting that administering cytarabine first, followed by bortezomib, could be the most effective sequence for improving outcomes in MCL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma. Weigert, O., Pastore, A., Rieken, M., et al.[2019]

In a study of 60 pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL), clofarabine treatment resulted in a remission rate of 45% and an overall response rate of 46.7%, indicating its efficacy in this challenging patient population.

Despite the observed remission, the study highlighted concerns regarding long-term survival outcomes, as 14 of the 24 deaths were attributed to treatment-emergent adverse events, suggesting a need for careful monitoring of safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness and Safety of Clofarabine Monotherapy or Combination Treatment in Relapsed/Refractory Childhood Acute Lymphoblastic Leukemia: A Pragmatic, Non-interventional Study in Korea. Choi, JY., Hong, CR., Hong, KT., et al.[2022]

Bortezomib effectively induces apoptosis (cell death) in chronic lymphocytic leukemia (CLL) cells, showing faster action compared to other treatments like glucocorticoids and fludarabine, based on experiments with over 100 patient samples.

In a Phase II clinical trial involving 5 patients, bortezomib demonstrated increased apoptosis in CLL cells, particularly in patients who were resistant to fludarabine, confirming its potential as a therapeutic option for challenging cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of the proteasome inhibitor, bortezomib, on apoptosis in isolated lymphocytes obtained from patients with chronic lymphocytic leukemia. Pahler, JC., Ruiz, S., Niemer, I., et al.[2017]

Bortezomib, a proteasome inhibitor, has shown strong efficacy in treating relapsed multiple myeloma and is well tolerated, even when combined with other treatments like dexamethasone and immunomodulators.

Tipifarnib, a farnesyltransferase inhibitor, has demonstrated good efficacy in clinical trials for high-risk acute leukemias and myelodysplastic syndromes, highlighting its potential as a targeted treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of targeted therapy for hematologic malignancies: update on bortezomib and tipifarnib. Armand, JP., Burnett, AK., Drach, J., et al.[2016]

Clofarabine has shown a 61% overall response rate in treating 18 patients with active poor-risk Acute Myeloid Leukemia (AML), with 50% achieving a complete response, indicating its efficacy as a treatment option.

The treatment was well tolerated, with an acceptable safety profile, including manageable grade 4 neutropenia and an induction mortality rate of 17%, suggesting clofarabine could be a viable alternative for patients unsuitable for standard therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine in the treatment of poor risk acute myeloid leukaemia. Krawczyk, J., Ansar, N., Swords, R., et al.[2018]

Bortezomib, a proteasome inhibitor, shows potential effectiveness in treating acute myeloid leukemia (AML) when combined with cytarabine and anthracyclines, particularly by targeting NF-kappaB in AML stem cells.

The study found that only P-glycoprotein contributed to resistance against bortezomib, and the interactions between bortezomib and other drugs were concentration-dependent, suggesting that the effectiveness of these combinations can vary based on drug levels, regardless of p53 status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bortezomib activity and in vitro interactions with anthracyclines and cytarabine in acute myeloid leukemia cells are independent of multidrug resistance mechanisms and p53 status. Minderman, H., Zhou, Y., O'Loughlin, KL., et al.[2015]

Bortezomib alone significantly increased apoptosis in JEG-3 choriocarcinoma cells, indicating its potential as an effective treatment for this type of cancer.

When combined with 5-fluorouracil (5-FU), bortezomib not only enhanced apoptosis rates but also showed a synergistic effect in inhibiting cell proliferation, suggesting that this combination could be a more powerful therapeutic strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of bortezomib alone or in combination with 5-fluorouracil on proliferation and apoptosis of choriocarcinoma cells. Wang, HF., Tong, Y., Liu, L., et al.[2020]

Bortezomib-based combinations have shown enhanced response rates in treating relapsed or refractory multiple myeloma, including high complete response rates, even in challenging patient populations such as the elderly and those with adverse prognostic factors.

The toxicities associated with bortezomib combinations are manageable and similar to those of bortezomib alone, suggesting that these combinations could significantly improve treatment outcomes and survival rates for multiple myeloma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beyond single-agent bortezomib: combination regimens in relapsed multiple myeloma. Richardson, PG., Mitsiades, C., Ghobrial, I., et al.[2015]

In a study involving 35 patients with relapsed or refractory multiple myeloma, the combination of bortezomib and melphalan demonstrated a response rate of 68%, indicating significant efficacy in treating this condition.

The maximum-tolerated dose was established at bortezomib 1.0 mg/m² and melphalan 0.10 mg/kg, with manageable toxicity primarily related to myelosuppression, suggesting that this combination therapy is both effective and relatively safe for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II trial assessing bortezomib and melphalan combination therapy for the treatment of patients with relapsed or refractory multiple myeloma. Berenson, JR., Yang, HH., Sadler, K., et al.[2015]

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