Bortezomib + Clofarabine for Cancer

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

75 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination Bortezomib plus Clofarabine for cancer?

Research shows that Bortezomib, when combined with other chemotherapy drugs, can improve outcomes in certain cancers like multiple myeloma and mantle cell lymphoma. These studies suggest that combining Bortezomib with other drugs may enhance its effectiveness, which could be promising for its use with Clofarabine. ^{1 2 3 4 5}

Is the combination of Bortezomib and Clofarabine safe for humans?

There is no specific safety data available for the combination of Bortezomib and Clofarabine, but Clofarabine alone or in combination with other drugs has been used in treating certain types of leukemia with an acceptable safety profile. Common side effects of Clofarabine include blood-related issues like anemia (low red blood cells) and infections, as well as gastrointestinal problems like nausea and vomiting. ^{6 7 8 9 10}

How is the drug Bortezomib + Clofarabine unique for cancer treatment?

Bortezomib is a proteasome inhibitor that has shown effectiveness in treating various blood cancers by targeting specific cellular processes, and it is often used in combination with other drugs to enhance its efficacy. Clofarabine is a chemotherapy drug that works by interfering with the growth of cancer cells. The combination of Bortezomib and Clofarabine may offer a novel approach by combining their unique mechanisms to potentially improve treatment outcomes for certain cancers. ^{1 11 12 13 14}

What is the purpose of this trial?

Background: - Researchers want to develop better ways to treat cancer. In this study, they will give people with cancer two drugs. These drugs have been used on their own to treat some blood cell cancers. Objectives: - To test the safety and efficacy of the drug combination of bortezomib and clofarabine. Eligibility: - Adults age 18 and over with advanced cancer that has progressed after receiving standard treatment or that has no effective therapy. Design: * Participants will be screened with medical history, physical exam, and scans to measure their tumors. They will also have heart, blood, and urine tests. All of these may be done by their regular doctors. * Participants will get the study drugs in 21-day cyles. They will stay at the clinic for week 1 of every cycle, then have 2 weeks off. \<TAB\>- Bortezomib will be injected under the skin on days 1 and 4. \<TAB\>- Clofarabine will be injected in a vein for days 1-5. * During cycle 1 only, participants will go to the clinic or their doctor to have a physical exam and blood tests at the start of the second and third week. * Participants will have clinical evaluations throughout the study, including before receiving treatment and then before the start of each cycle. * Participants may stay in the study as long as they are tolerating the drugs and their tumor is not getting worse. * Participants will have follow-up for 30 days after the last dose of study drugs. * The first part of this study tests the safety of different doses of clofarabine and bortezomib. * The second part of this study involves a separate group of participants who will undergo mandatory research biopsies to learn more about the effects of clofarabine and bortezomib on cancer cells.

Research Team

Alice P Chen, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

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.

Receiving any other investigational agents

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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-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]

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 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]

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]

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]

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]

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 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]

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]

References

1. Singapore pubmed.ncbi.nlm.nih.gov

The effects of bortezomib alone or in combination with 5-fluorouracil on proliferation and apoptosis of choriocarcinoma cells. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Bortezomib in combination with conventional chemotherapeutic agents for multiple myeloma compared with bortezomib alone. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Beyond single-agent bortezomib: combination regimens in relapsed multiple myeloma. [2015]

4. England pubmed.ncbi.nlm.nih.gov

Sequence-dependent synergy of the proteasome inhibitor bortezomib and cytarabine in mantle cell lymphoma. [2019]

5. United States 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. [2015]

6. Korea (South) 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. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Clofarabine in the treatment of poor risk acute myeloid leukaemia. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Mechanisms of anti-cancer action and pharmacology of clofarabine. [2018]

9. China pubmed.ncbi.nlm.nih.gov

[Therapeutic effect of clofarabine in children with relapsed or refractory acute lymphoblastic leukemia]. [2018]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Clofarabine: in pediatric patients with acute lymphoblastic leukemia. [2018]

11. Germany 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. [2015]

12. United States pubmed.ncbi.nlm.nih.gov

Effects of the proteasome inhibitor, bortezomib, on apoptosis in isolated lymphocytes obtained from patients with chronic lymphocytic leukemia. [2017]

13. England pubmed.ncbi.nlm.nih.gov

The emerging role of targeted therapy for hematologic malignancies: update on bortezomib and tipifarnib. [2016]

14. Germany pubmed.ncbi.nlm.nih.gov

Bendamustine and prednisone in combination with bortezomib (BPV) in the treatment of patients with newly diagnosed/untreated multiple myeloma. [2021]