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

Disqualifiers: Pregnancy, Breastfeeding, CNS leukemia, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well the drug palbociclib works alone or with other drugs (sorafenib, decitabine, or dexamethasone) in treating leukemia that has returned or does not respond to standard treatments. The trial aims to find the best dose and identify any side effects. It may suit individuals with acute myeloid leukemia or acute lymphoblastic leukemia who have not succeeded with other treatments and have not received leukemia therapy in the past two weeks. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this potentially groundbreaking therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining palbociclib with dexamethasone is generally safe, and one study found that patients tolerated this combination well.

For palbociclib with sorafenib, studies indicate it is safe for those with relapsed or resistant acute myeloid leukemia, suggesting potential safety for leukemia treatments.

Regarding palbociclib and decitabine, research shows that the FDA has approved palbociclib for certain breast cancers, indicating its safety. Decitabine is also well-tolerated, especially in older patients.

This trial aims to determine the best dose and monitor side effects, ensuring close attention to safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for refractory leukemia, which often include chemotherapy and targeted therapies like imatinib or dasatinib, the investigational treatments in this trial bring something new to the table. Palbociclib, a CDK4/6 inhibitor, is combined with other drugs such as sorafenib, decitabine, and dexamethasone in different arms of the study. Researchers are excited about these combinations because palbociclib targets cancer cell division in a unique way, potentially halting the growth of leukemia cells more effectively. Each combination also adds a different mechanism: sorafenib targets cancer cell signaling, decitabine modifies DNA to affect gene expression, and dexamethasone is a steroid that can mitigate inflammation. These innovative approaches offer hope for improved outcomes in patients who have not responded to existing therapies.

What evidence suggests that this trial's treatments could be effective for leukemia?

This trial will evaluate the effectiveness of different palbociclib combination therapies for refractory leukemia. Studies have shown that palbociclib, when combined with dexamethasone, may effectively slow leukemia cell growth. Research supports the potential of this combination to combat leukemia. Another arm of this trial will test sorafenib with palbociclib, which has slowed tumor growth and extended survival times in some patients. Additionally, decitabine, effective for acute myeloid leukemia (AML), may improve survival and response rates when used with palbociclib; this combination is also being tested in this trial. These findings suggest that palbociclib with any of these drugs could help treat leukemia that has returned or is resistant to other treatments. ^{3 6 7 8 9}

Who Is on the Research Team?

Tapan M Kadia

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

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.

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

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

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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]

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 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, 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]

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]

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]

Citations

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Palbociclib Combination Therapy for Refractory Leukemia Decitabine is an effective hypomethylating agent for treating acute myeloid leukemia (AML), significantly improving overall survival and response rates compared ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12235782/

One step further in targeting acute leukemia by combining ... This review focuses on antibody-based targeted treatments, which so far, have been shown to improve the treatment outcomes.

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A phase I study of the combination of palbociclib and ... Preclinical studies suggest that the combination of the CDK4/6 inhibitor palbociclib and dexamethasone may be effective in targeting leukemic cell growth.

4. onclive.com onclive.com/view/real-world-outcomes-support-use-of-first-line-palbociclib-plus-et-in-hr-her2-advanced-breast-cancer

Real-World Outcomes Support Use of First-Line Palbociclib ... Findings supporting the approval showed that patients who received palbociclib plus letrozole (n = 444) experienced an ORR of 55.3% (95% CI, ...

5. jmcp.org jmcp.org/doi/10.18553/jmcp.2020.26.7.826

Real-World Clinical and Economic Outcomes Associated ... For the 292 patients treated with palbociclib and fulvestrant, the 12-month progression-free rate was 79.8% overall, and the 12-month survival ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT03132454

NCT03132454 | Palbociclib and Sorafenib, Decitabine, or ... To assess the safety and tolerability of one cycle of single-agent palbociclib in patients with R/R leukemias. OUTLINE: This is a dose-escalation study of ...

7. go.drugbank.com go.drugbank.com/drugs/DB09073

Palbociclib: Uses, Interactions, Mechanism of Action It was originally FDA approved on March 2015 for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer and its indications were ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0006497119401572

Phase I Study of Palbociclib Alone and in Combination ... We designed an investigator-initiated phase I clinical trial to study the safety and feasibility of the oral CDK4/6 inhibitor palbociclib (palbo) alone (during ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11294977/

Newer combination treatments for breast cancer coexisting ... The present study describes a rare case of AML coexisting with metastatic BC (mBC), focusing on the treatment options with the use of venetoclax combined with ...