Talazoparib + Chemotherapy for Acute Myeloid Leukemia

(PARPAML Trial)

Recruiting at 9 trial locations

Overseen by Jennifer L Kamens, MD

Age: < 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Stanford University

Must not be taking: Chemotherapy, Radiation, Immunotherapy, Biologics

Disqualifiers: Down syndrome, APL, JMML, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing the safety of using talazoparib with standard chemotherapy in cancer patients. Talazoparib works by stopping cancer cells from repairing themselves, which could make chemotherapy more effective. The study aims to find the safest dose combination and see if this approach helps patients. Talazoparib is FDA approved for certain types of breast cancer that have spread and were previously treated with chemotherapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does require that you are not receiving any other cancer therapies. You should discuss your current medications with the trial team to see if they are compatible with the study.

What data supports the effectiveness of the drug combination Talazoparib + Chemotherapy for Acute Myeloid Leukemia?

Research shows that topotecan, one of the drugs in the combination, has been effective in treating acute myeloid leukemia (AML) when used with other chemotherapy drugs, achieving complete remission in some patients. However, the effectiveness of the specific combination of Talazoparib with these drugs for AML is not directly supported by the provided studies. ^{1 2 3 4 5}

What safety data exists for topotecan in combination with other drugs?

Topotecan, when used in combination with other chemotherapy drugs, has been studied for safety in various cancers. The main safety concern is myelosuppression (a decrease in bone marrow activity), particularly neutropenia (low levels of a type of white blood cell), which limits the dose that can be safely given. ^{2 6 7 8 9}

What makes the drug combination of Talazoparib, Gemcitabine, and Topotecan unique for treating acute myeloid leukemia?

This drug combination is unique because it includes Talazoparib, a PARP inhibitor that may enhance the effects of chemotherapy by preventing cancer cells from repairing their DNA, combined with Gemcitabine and Topotecan, which have shown antitumor activity in various cancers. This approach explores a novel mechanism of action compared to traditional treatments for acute myeloid leukemia. ^{1 2 3 4 5}

Research Team

Jennifer L Kamens, MD

Principal Investigator

Stanford Universiy

Eligibility Criteria

This trial is for children and young adults up to 21 years old with relapsed or refractory Acute Myeloid Leukemia (AML) or similar conditions. They should have had a stem cell transplant at least 60 days ago, be recovered from previous treatments, and not have uncontrolled infections or other cancer therapies ongoing. Pregnant individuals or those with certain leukemia subtypes are excluded.

Inclusion Criteria

My leukemia has the same genetic features as when first diagnosed.

It's been over 24 hours since my last mild cancer treatment.

It's been over 2 weeks since my last intense cancer treatment, and I feel mostly recovered.

Exclusion Criteria

I am currently undergoing or planning to start any cancer treatment soon.

Pregnant subjects or those unwilling to use an effective method of birth control.

People with Down syndrome cannot participate in the study.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Talazoparib is administered orally on Days 1 to 5 concurrently with topotecan and a single dose of gemcitabine on Day 1 of a 28-day cycle for 1 or 2 cycles. Subjects on dose level 5 receive an additional 5-day treatment course of talazoparib on days 15-19.

4-8 weeks

Multiple visits (in-person)

Dose Expansion

Preliminary estimates of efficacy are obtained through a dose expansion cohort receiving the maximum tolerated dose from the dose escalation phase.

28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Gemcitabine (Anti-metabolite)
• Talazoparib (PARP Inhibitor)
• Topotecan (Topoisomerase I inhibitor)

Trial Overview The study tests the safety and effectiveness of Talazoparib combined with chemotherapy drugs Gemcitabine and Topotecan in pediatric AML patients. It's a Phase 1 trial that will first find the highest dose patients can tolerate without severe side effects before assessing how well it works.

Participant Groups

Group I: Talazoparib with topotecan and gemcitabine Experimental Treatment 3 Interventions

Talazoparib will be administered orally on Days 1 to 5 concurrently with topotecan and a single dose of gemcitabine on Day 1 of 28 day cycle for 1 or 2 cycles. Subjects on dose level 5 will receive an additional 5 day treatment course of talazoparib on days 15-19.

Gemcitabine is already approved in Canada, Japan for the following indications:

Approved in Canada as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Approved in Japan as Gemzar for:

• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Non-small cell lung cancer

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Jennifer Lauren Kamens

Lead Sponsor

Trials

1

Recruited

30+

Norman J. Lacayo

Lead Sponsor

Trials

1

Recruited

30+

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

Findings from Research

In a clinical trial involving 21 patients with relapsed acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), the combination of topotecan and cytarabine showed promising efficacy, achieving complete remission in 33% of patients and partial remission in 38%.

The treatment was generally safe for older patients (60 years and older), with no treatment-related deaths, although hematologic toxicity led to dose adjustments in some cases, and fever was a common side effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II clinical study of topotecan and cytarabine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia. Weihrauch, MR., Staib, P., Seiberlich, B., et al.[2019]

Topotecan, a drug that targets topoisomerase I, has shown significant antitumor activity when combined with various chemotherapy agents like cisplatin and doxorubicin in both adult and pediatric patients with solid tumors.

The main side effect of these combination therapies is myelosuppression, particularly neutropenia, which limits the dosage; however, many early studies have reported major responses, indicating the potential effectiveness of these regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topotecan in combination chemotherapy. Rowinsky, EK., Kaufmann, SH.[2017]

Irinotecan can be safely administered in combination with cytarabine (Ara-C) to patients with acute myeloid leukemia (AML) who are refractory to or have relapsed after previous treatments, showing promising results in terms of safety and efficacy.

The treatment led to rapid cytoreduction in all courses, with two patients achieving complete remission, indicating that this combination therapy warrants further investigation for its effectiveness in AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential administration of irinotecan and cytarabine in the treatment of relapsed and refractory acute myeloid leukemia. Minderman, H., O'Loughlin, KL., Smith, PF., et al.[2018]

Current frontline treatments for acute myeloid leukemia (AML) using ara-C and topoisomerase II agents achieve complete response rates of 70%, but long-term survival remains low at 25%.

Newer agents like nucleoside analogs and hypomethylating agents show promise, with combination therapies yielding higher complete response rates, particularly when used alongside traditional treatments like ara-C.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New chemotherapeutic agents in acute myeloid leukemia. Kantarjian, HM., Estey, EH., Keating, MA.[2013]

In a study involving 12 patients with relapsed or secondary acute myeloid leukemia, the combination of topotecan and cytarabine showed low extra-hematologic toxicity, indicating a relatively safe profile.

Despite the low toxicity, the treatment response was very poor, suggesting that this combination is not an effective option for these patients, and that incorporating additional agents may be necessary to improve outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The association of topotecan and cytarabine in the treatment of secondary or relapsed acute myeloid leukemia. Pagano, L., Mele, L., Voso, MT., et al.[2013]

In a study of 23 patients with relapsed ovarian and primary peritoneal cancer, weekly administration of topotecan showed a promising overall response rate of 47.8%, with complete responses in 17.4% of patients, indicating its effectiveness even in those with platinum-resistant disease.

The treatment was generally well-tolerated, with manageable side effects such as grade II and III thrombocytopenia in a small number of patients and fatigue in 39.1%, suggesting that topotecan could be a viable option for patients who have already undergone platinum-based chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of weekly topotecan in patients with recurrent or persistent epithelial ovarian cancer. Levy, T., Inbar, M., Menczer, J., et al.[2013]

A retrospective study of 30 patients with recurrent ovarian cancer showed that long-term treatment with topotecan is feasible, with patients receiving an average of 14.4 cycles and a median time to treatment progression of 28 months.

Topotecan demonstrated a response rate of 53%, with manageable non-hematologic toxicity, suggesting it may provide a survival benefit for patients who continue treatment beyond six cycles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term topotecan therapy in recurrent or persistent ovarian cancer. Cormio, G., Loizzi, V., Gissi, F., et al.[2020]

In a study of 63 patients with relapsed or persistent epithelial ovarian cancer and primary peritoneal carcinoma, weekly topotecan treatment resulted in an overall response rate of 23.8%, with a median survival of 22.3 months, indicating its efficacy as a treatment option.

Topotecan was generally well tolerated, with manageable hematologic toxicities such as grade 3 anemia and thrombocytopenia occurring in 4.8% of patients, and the most common nonhematologic side effects being fatigue and nausea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and toxicity of weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer. Safra, T., Menczer, J., Bernstein, R., et al.[2013]

The recommended dose for the combination of topotecan (TPT) and temozolomide (TMZ) in children with relapsed or refractory solid tumors is TMZ 150 mg/m²/day and TPT 0.75 mg/m²/day, with manageable dose-limiting toxicities primarily involving blood cell counts.

In a study of 16 patients, 25% showed confirmed responses to the treatment, indicating potential effectiveness, particularly in cases of metastatic neuroblastoma and high-grade glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours. Rubie, H., Geoerger, B., Frappaz, D., et al.[2023]

References

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

Phase I/II clinical study of topotecan and cytarabine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia. [2019]

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

Topotecan in combination chemotherapy. [2017]

3. Germany pubmed.ncbi.nlm.nih.gov

Sequential administration of irinotecan and cytarabine in the treatment of relapsed and refractory acute myeloid leukemia. [2018]

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

New chemotherapeutic agents in acute myeloid leukemia. [2013]

5. Italy pubmed.ncbi.nlm.nih.gov

The association of topotecan and cytarabine in the treatment of secondary or relapsed acute myeloid leukemia. [2013]

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

Phase II study of weekly topotecan in patients with recurrent or persistent epithelial ovarian cancer. [2013]

7. Singapore pubmed.ncbi.nlm.nih.gov

Long-term topotecan therapy in recurrent or persistent ovarian cancer. [2020]

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

Efficacy and toxicity of weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer. [2013]

9. England pubmed.ncbi.nlm.nih.gov

Phase I study of topotecan in combination with temozolomide (TOTEM) in relapsed or refractory paediatric solid tumours. [2023]