Palbociclib Combination Therapy for Refractory Leukemia

Overseen By Tapan Kadia

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

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

Compensation: Varies

Number of Visits: Unknown

Duration: 8 cycles (each cycle is 28 days)

32 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase I trial studies the side effects and best dose of palbociclib when given alone and in combination with sorafenib, decitabine, or dexamethasone in treating patients with leukemia that has come back (recurrent) or that does not respond to previous treatment (refractory). Palbociclib, sorafenib, and decitabine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving palbociclib alone and in combination with sorafenib, decitabine, or dexamethasone may work better in treating patients with recurrent or refractory leukemia.

Will I have to stop taking my current medications?

The trial requires that you stop leukemia therapy for 14 days before starting palbociclib, but you may use hydroxyurea until 24 hours before starting the trial if your disease is rapidly growing. The protocol does not specify other medication restrictions, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination therapy for refractory leukemia?

Research shows that decitabine, a key component of the combination therapy, has been effective in treating acute myeloid leukemia (AML), especially when combined with other chemotherapy drugs, improving response rates and survival in patients with refractory or relapsed AML. ^{1 2 3 4 5}

Is Palbociclib Combination Therapy for Refractory Leukemia safe for humans?

Decitabine, a component of the therapy, is generally well tolerated in older patients with acute myeloid leukemia, with common side effects including fever, low platelet count, and anemia. It has a relatively modest nonhematologic toxicity, making it a promising option for those not suited for intensive therapy. ^{6 7 8 9 10}

What makes the Palbociclib Combination Therapy for Refractory Leukemia unique?

This treatment is unique because it combines multiple drugs, including Palbociclib, which is typically used for breast cancer, with Decitabine, Dexamethasone, and Sorafenib, to target leukemia cells in a novel way. The combination aims to enhance the effectiveness of each drug, potentially offering a new option for patients with refractory leukemia who have not responded to standard treatments. ^{7 9 11 12 13}

Research Team

Tapan M Kadia

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL), who have no standard treatment options left. They should not have received leukemia therapy in the last 14 days, must be physically stable with certain organ function levels maintained, and women of childbearing age need a negative pregnancy test and agree to use contraception.

Inclusion Criteria

I understand the study's requirements and have signed the consent form.

My leukemia has returned or didn't respond to treatment, and no standard treatments are expected to work.

Known cardiac ejection fraction of > or = 45% within the past 3 months

Exclusion Criteria

I do not have active, uncontrolled leukemia in my brain or spinal cord.

I am using contraception or agree to start using it during the study.

I do not have any severe illnesses that could interfere with the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive palbociclib alone or in combination with sorafenib, decitabine, or dexamethasone for up to 8 cycles

8 cycles (each cycle is 28 days)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• Decitabine
• Dexamethasone
• Palbociclib
• Sorafenib

Trial Overview The study is testing palbociclib alone and combined with sorafenib, decitabine, or dexamethasone to see which works best for stopping tumor growth in recurrent or resistant leukemia. It's looking at side effects and the best doses for these drugs.

Participant Groups

Group I: Arm III (palbociclib, dexamethasone) Experimental Treatment 2 Interventions

Patients receive palbociclib as in Arm I. Patients also receive dexamethasone PO QD or IV over 15-30 minutes on days 1-4 and 15-18 beginning on cycle 2. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm II (palbociclib, decitabine) Experimental Treatment 2 Interventions

Patients receive palbociclib as in Arm I. Beginning cycle 2, patients receive palbociclib PO QC on days 1-7 and decitabine IV QD over 1 hour on days 8-17 of cycle 2 and days 8-12 of cycles 3-8. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

Group III: Arm I (palbociclib, sorafenib) Experimental Treatment 2 Interventions

Patients receive palbociclib PO QD on days 1-28. Patients also receive sorafenib PO QD on days 1-28 beginning on cycle 2. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

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+

Findings from Research

In a study of 21 patients with refractory or recurrent acute myeloid leukemia (R/R AML), the triple therapy of decitabine, idarubicin, and cytarabine (D-IA) resulted in a 47.6% complete remission rate after one treatment cycle, indicating significant efficacy.

The treatment was generally well tolerated, with no treatment-related mortalities reported, although common side effects included hematological toxicity and infections, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Management of Decitabine prior to Full-Dose Idarubicin and Cytarabine in the Treatment of Refractory/Recurrent Acute Myeloid Leukemia. Zhao, H., Xu, L., Yang, Y., et al.[2018]

Decitabine is an effective hypomethylating agent for treating acute myeloid leukemia (AML), significantly improving overall survival and response rates compared to standard care, based on results from the phase 3 DACO-016 trial with adult patients who are not eligible for standard chemotherapy.

The treatment is generally well tolerated and remains effective even in patients with adverse-risk karyotypes or TP53 mutations, making it a valuable option for those unfit for more intensive therapies, with potential for future combination treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. Santini, V., Lübbert, M., Wierzbowska, A., et al.[2022]

Decitabine, administered at a dose of 20 mg/m² for 5 consecutive days, has been approved for older patients (≥65 years) with acute myeloid leukaemia (AML) who cannot undergo standard treatment, showing clinically meaningful improvements in overall survival after extended follow-up.

In a pivotal phase III trial, decitabine demonstrated significantly higher complete remission rates compared to standard treatment options like cytarabine, with a safety profile similar to cytarabine, including common side effects like fever and low blood cell counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine: a review of its use in older patients with acute myeloid leukaemia. Curran, MP.[2021]

Low-dose decitabine has been shown to improve the overall response rate in elderly patients with acute myeloid leukemia (AML) compared to standard treatment options, although the median overall survival remains less than one year.

The combination of low-dose decitabine with venetoclax significantly enhances both the overall response rate and median overall survival in elderly AML patients, indicating a promising treatment strategy for this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The history of oral decitabine/cedazuridine and its potential role in acute myeloid leukemia. Briski, R., Garcia-Manero, G., Kantarjian, H., et al.[2023]

In a study of 8 geriatric patients with acute myeloid leukemia, treatment with decitabine, with or without low-dose cytarabine, resulted in a 50% overall response rate, with 25% achieving complete remission and 25% achieving partial remission.

The treatment showed a median overall survival time of 9.5 months, with some patients surviving over a year, although it was associated with significant side effects, including severe myelosuppression in 87.5% of patients and pneumonia in 50%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. Zhou, HW., Zhou, MH., Wang, ZH., et al.[2019]

In a study of 12 patients with relapsed or refractory acute myeloid leukemia (AML), a combination of decitabine and gemtuzumab ozogamicin resulted in a 42% complete response rate, with five patients achieving complete remission and undergoing stem cell transplantation.

The treatment was well tolerated, with only mild nonhematologic toxicity observed, suggesting that this regimen could be a promising option for further investigation in larger controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine combined with fractionated gemtuzumab ozogamicin therapy in patients with relapsed or refractory acute myeloid leukemia. Chowdhury, S., Seropian, S., Marks, PW.[2019]

Decitabine is a DNA methyltransferase inhibitor with a long history of antileukemic efficacy, particularly effective in treating acute myeloid leukemia in older patients or those unable to undergo intensive therapy.

The current dosing regimen of decitabine (20 mg/m² for 5 days) has been refined to minimize nonhematologic toxicity, making it a promising option for patients who may not tolerate more aggressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine for acute myeloid leukemia. Marks, PW.[2018]

The addition of carboplatin to high-dose cytarabine and anthracycline drugs showed improved efficacy in treating high-risk acute myeloid leukemia (AML), with a complete response rate of 53% in the lower toxicity regimen (R-2).

The R-2 regimen was well tolerated and resulted in a significantly lower death rate from complications, but despite these improvements, no patients remained disease-free at 3 years, highlighting the need for new post-remission strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new combination of carboplatin, high-dose cytarabine and cross-over mitoxantrone or idarubicin for refractory and relapsed acute myeloid leukemia. Bassan, R., Lerede, T., Buelli, M., et al.[2013]

The combination of decitabine and idarubicin showed a synergistic effect in inducing cell death in various myeloid leukemia cell lines and primary AML cells, suggesting a more effective treatment strategy than decitabine alone.

This combination therapy not only inhibited tumor growth more effectively in mouse models but also triggered apoptosis and downregulated the Wnt/β-catenin pathway, which is linked to leukemia progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target. Li, K., Hu, C., Mei, C., et al.[2021]

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]

References

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Successful Management of Decitabine prior to Full-Dose Idarubicin and Cytarabine in the Treatment of Refractory/Recurrent Acute Myeloid Leukemia. [2018]

2. Greece pubmed.ncbi.nlm.nih.gov

Clinical efficacy of decitabine‑containing induction chemotherapy in de novo non‑elderly acute myeloid leukemia. [2021]

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The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Decitabine: a review of its use in older patients with acute myeloid leukaemia. [2021]

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

The history of oral decitabine/cedazuridine and its potential role in acute myeloid leukemia. [2023]

8. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with or without Cytarabine-based Low Dose Regimen for Senile patients with Acute Myeloid Leukemia]. [2019]

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

Decitabine combined with fractionated gemtuzumab ozogamicin therapy in patients with relapsed or refractory acute myeloid leukemia. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Decitabine for acute myeloid leukemia. [2018]

11. Italy pubmed.ncbi.nlm.nih.gov

A new combination of carboplatin, high-dose cytarabine and cross-over mitoxantrone or idarubicin for refractory and relapsed acute myeloid leukemia. [2013]

12. England pubmed.ncbi.nlm.nih.gov

Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target. [2021]

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

New chemotherapeutic agents in acute myeloid leukemia. [2013]