Veliparib + Temozolomide for Leukemia

No longer recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: Investigational agents

Disqualifiers: CNS leukemia, Uncontrolled infection, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per course

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how combining veliparib and temozolomide can treat acute leukemia by determining the optimal dosage and understanding potential side effects. Veliparib blocks specific enzymes to stop cancer cells from growing, while temozolomide, a chemotherapy drug, kills these cells or prevents them from dividing. This study suits individuals with certain types of leukemia, such as those who have not responded to prior treatments or those with specific genetic markers. Participants should not have previously received temozolomide and must be able to swallow pills. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking all biologic agents, including certain cancer medications like imatinib, at least 1 week before starting the study. If you're using hydroxyurea, corticosteroids, or leukopheresis for controlling blast counts, you must stop at least 24 hours before starting the trial treatment.

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

Research has shown that the combination of veliparib and temozolomide is generally safe for people. In earlier studies, common side effects included nausea, vomiting, and tiredness, affecting about 36-40% of participants. Despite these side effects, this combination has shown promise in treating advanced acute myeloid leukemia, a type of blood cancer. Although the treatment remains in the early testing stages, its good tolerance in past studies is a positive sign for its safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using Veliparib and Temozolomide together for leukemia because this combo offers a fresh angle on treatment. Unlike other therapies that target leukemia cells directly, Veliparib works by interfering with a protein involved in DNA repair, making cancer cells more vulnerable to damage. Temozolomide, on the other hand, adds to this effect by damaging the DNA of leukemia cells, which can lead to their destruction. This dual approach could potentially enhance treatment effectiveness and offer hope for patients who haven't responded to existing options.

What evidence suggests that veliparib and temozolomide might be an effective treatment for leukemia?

Research has shown that the combination of veliparib and temozolomide is active in treating patients with acute myeloid leukemia (AML) who have high-risk features. This suggests the drug combo might effectively attack leukemia cells. In this trial, participants will receive both veliparib and temozolomide. Veliparib blocks certain enzymes that cancer cells need to grow, while temozolomide prevents cancer cells from dividing. Although earlier studies did not find a significant survival benefit for brain cancer patients, this combination might still hold promise for treating leukemia. Therefore, it is being tested further in clinical trials. ^{1 2 3 6 7}

Who Is on the Research Team?

Ivana Gojo

Principal Investigator

Johns Hopkins University/Sidney Kimmel Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with various types of acute leukemia, including those who have relapsed or are not responding to other treatments. It's also open to older patients who can't undergo intensive chemotherapy and those with certain genetic mutations. Participants must be able to swallow pills, have no severe infections or illnesses that could interfere with the study, and agree to use contraception.

Inclusion Criteria

My leukemia has returned or didn't respond to treatment, and I've tried at least 2 TKIs without success.

My CML is in an advanced stage and I've not responded to at least 2 TKIs or have a specific resistance mutation.

I had a stem cell transplant over 60 days ago, have no graft vs. host disease, and stopped all immunosuppressive therapy over 2 weeks ago.

Exclusion Criteria

I do not have any ongoing infections that are not being treated.

I do not have any severe illnesses that would stop me from following the study's requirements.

I am HIV positive with a CD4 count over 250, not on zidovudine or stavudine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive veliparib and temozolomide in a dose-escalation study to determine the maximum-tolerated dose and observe pharmacokinetics and pharmacodynamics.

28 days per course

Multiple visits for dose administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion

30 days

Extension

Patients achieving complete remission receive 5 more courses of treatment in the absence of disease progression or unacceptable toxicity.

5 courses of 28 days each

What Are the Treatments Tested in This Trial?

Interventions

• Temozolomide
• Veliparib

Trial Overview The trial is testing the combination of two drugs: Veliparib and Temozolomide. The goal is to find the safest dose that effectively treats acute leukemia by blocking enzymes cancer cells need for growth while stopping their division. This phase I trial will also look at how these drugs affect biomarkers in lab tests.

How Is the Trial Designed?

Group I: Treatment (temozolomide and veliparib) Experimental Treatment 4 Interventions

Patients receive veliparib PO QD on day 1 and twice daily on days 4-12 and temozolomide PO QD on days 3-9 of course 1. Beginning at least 30 days after the start of treatment, patients receive veliparib PO BID on days 1-8 and temozolomide PO QD on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients achieving complete remission receive 5 more courses in the absence of disease progression or unacceptable toxicity.

Temozolomide is already approved in European Union, United States for the following indications:

Approved in European Union as Temodal for:

• Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment
• Children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy

Approved in United States as Temodar for:

• Newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment
• Newly diagnosed or refractory anaplastic astrocytoma

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

In a study of 114 patients with stage IV non-small cell lung cancer (NSCLC) and metastatic bone disease (MBD), only 37.7% received zoledronic acid (ZA) alongside their first chemotherapy treatment.

Patients who received ZA with chemotherapy (ZCt) had significantly better overall survival, with a median of 34 weeks compared to 19 weeks for those who received chemotherapy alone, suggesting that ZA may enhance treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Under usage of zoledronic acid in non-small cell lung cancer patients with metastatic bone disease--a short communication. Calderone, R., Nimako, K., Leary, A., et al.[2018]

In a phase I trial involving 29 children with recurrent brain tumors, the combination of veliparib and temozolomide was found to be well tolerated, with established recommended phase II doses of 25 mg/m² for veliparib and 135 mg/m² for temozolomide.

While no objective responses were observed, 4 patients maintained stable disease for over 6 months, indicating potential efficacy in this challenging population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: a pediatric brain tumor consortium report. Su, JM., Thompson, P., Adesina, A., et al.[2021]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

Temozolomide (TMZ) is the only anticancer drug proven to improve survival in glioblastoma when used with radiotherapy, showing high concentrations in brain tumors and cerebrospinal fluid, which enhances its effectiveness.

Molecular markers like MGMT promoter methylation can predict better responses to TMZ treatment, but side effects such as myelosuppression and nausea are common, necessitating precautions like prophylaxis against Pneumocystis carinii pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. Shinoura, N., Yamada, R., Tabei, Y., et al.[2018]

Gleevec (imatinib mesylate) has been approved for treating malignant gastrointestinal stromal tumors, showing efficacy at doses of 400 or 600 mg daily, indicating its role in managing aggressive cancer types.

Zometa (zoledronic acid) is approved for patients with multiple myeloma and bone metastases, demonstrating its effectiveness as a supportive care drug when used alongside standard cancer treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration drug approval summaries: imatinib mesylate, mesna tablets, and zoledronic acid. Cohen, MH., Dagher, R., Griebel, DJ., et al.[2019]

In a study of 137 chemo-naïve patients with metastatic castration-resistant prostate cancer, Enzalutamide (EZ) showed a significantly higher PSA response rate compared to Abiraterone (AA) in the first line of treatment (95.9% vs 67%).

Both AA and EZ had comparable toxicity rates and progression-free survival (PFS) outcomes, indicating that both treatments are effective and well-tolerated options for managing mCRPC without chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing lines of therapy in castration-resistant prostate cancer: real-life snapshot from a multicenter cohort. Ferriero, M., Mastroianni, R., De Nunzio, C., et al.[2021]

Temozolomide (TMZ) is an effective oral anticancer drug for treating newly diagnosed glioblastoma and shows comparable efficacy to dacarbazine for metastatic melanoma, making it a promising option for various cancers.

Resistance to TMZ is a common challenge that limits its effectiveness, prompting ongoing research into combination therapies with DNA repair inhibitors and other treatments to enhance its efficacy and overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent approaches to improve the antitumor efficacy of temozolomide. Tentori, L., Graziani, G.[2019]

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5290001/

A phase 1 study of the PARP inhibitor veliparib in combination ... In summary, veliparib/temozolomide is a well-tolerated oral regimen with clinical activity in patients whose AML exhibits multiple poor-risk features. These ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11528341/

Efficacy of Adding Veliparib to Temozolomide for Patients With ... This randomized clinical trial did not demonstrate a significant overall survival benefit for patients with MGMT-hypermethylated GBM treated ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT01026493

Veliparib and Temozolomide in Treating Patients With ... Giving veliparib together with temozolomide may kill more tumor cells. PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of ...

4. cancertherapyadvisor.com cancertherapyadvisor.com/news/glioblastoma-veliparib-temozolomide-does-not-improve-survival/

Adding Veliparib to Temozolomide Does Not Improve ... These results, from a phase 3 trial, showed that veliparib plus temozolomide did not improve overall survival (OS) or progression-free survival ...

5. curetoday.com curetoday.com/view/veliparib-and-temozolomide-combo-does-not-significantly-extend-survival-for-patients-with-glioma

Veliparib and Temozolomide Combo Does Not ... Veliparib plus temozolomide did not significantly extend overall survival in patients with newly diagnosed, MGMT-hypermethylated glioblastoma.

6. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2018.77.7672

Randomized, Double-Blind, Phase II Study of ... No significant difference in 4-month PFS was noted between TMZ/veliparib (36%) and TMZ/placebo (27%; P = .19); median OS was also not improved ...

7. aacrjournals.org aacrjournals.org/clincancerres/article-abstract/23/3/697/80349

A Phase 1 Study of the PARP Inhibitor Veliparib in ... Three of 4 patients with MGMT promoter methylation achieved CR. Conclusions: Veliparib plus temozolomide is well tolerated, with activity in advanced AML.