Palbociclib + Chemotherapy for Acute Lymphoblastic Leukemia

Overseen By Tanja A Gruber

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Tanja Andrea Gruber

Must not be taking: Proteasome inhibitors, CDK4/6 inhibitors

Disqualifiers: Isolated CNS/testicular disease, uncontrolled infection, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 months

22 Participants Needed

Trial Summary

What is the purpose of this trial?

With this research study has following goals * To confirm the highest tolerable dose of palbociclib in combination with chemotherapy is safe and well-tolerated. * To learn more about side effects of palbociclib in combination with chemotherapy; * To learn more about the biological effects of palbociclib on the cells in your body

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, it mentions that participants must have recovered from the effects of previous cancer treatments and meet certain time requirements since their last treatments. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Palbociclib for treating acute lymphoblastic leukemia?

A phase I study suggests that combining Palbociclib with dexamethasone may help target the growth of leukemia cells in patients with relapsed or hard-to-treat B-cell acute lymphoblastic leukemia. ^{1 2 3 4 5}

Is Palbociclib safe for humans?

A phase I study explored the safety of Palbociclib combined with dexamethasone for treating relapsed or refractory B-cell acute lymphoblastic leukemia, indicating it has been tested in humans for safety. ^{1 6 7 8 9}

How is the drug palbociclib unique in treating acute lymphoblastic leukemia?

Palbociclib is unique because it is a CDK4/6 inhibitor, which means it targets specific proteins that help cancer cells grow, and it is being studied in combination with chemotherapy to improve outcomes for patients with relapsed or refractory acute lymphoblastic leukemia, a condition where standard treatments often fail. ^{1 2 5 10 11}

Research Team

Tanja A Gruber, MD

Principal Investigator

Stanford Universiy

Eligibility Criteria

This trial is for children and young adults under 25 with acute lymphoblastic leukemia that's come back or didn't respond to treatment. They should be off certain medications, have no severe infections, and not be pregnant. Participants need functioning major organs and a minimum performance score indicating they can do daily activities.

Inclusion Criteria

At least 2 weeks must have elapsed since local XRT (small port); ≥ 3 months must have elapsed if prior cranial or craniospinal XRT was received, if ≥ 50% of the pelvis was irradiated, or if TBI was received; ≥ 6 weeks must have elapsed if other substantial bone marrow irradiation was given

Participants must be < 25 years of age

Subjects must have had histologic, morphologic or flow cytometric verification of the malignancy at relapse

Exclusion Criteria

Extramedullary disease status: subjects with isolated CNS disease or isolated testicular disease are not eligible

Subject with concurrent severe and/or uncontrolled medical conditions that, in the opinion of the investigator, may impair participation in the study or the evaluation of safety and/or efficacy

Subjects that have an active, uncontrolled infection are not eligible

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive palbociclib in combination with chemotherapy, including dexamethasone, bortezomib, and doxorubicin, over 30-day cycles for up to 3 cycles

3 months

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of dose-limiting toxicities and overall response rate

24 months

Treatment Details

Interventions

• Palbociclib

Trial Overview The study tests the highest dose of palbociclib (a cancer drug) that's safe when given with chemotherapy in young patients with leukemia. It aims to understand the side effects and how this drug affects cancer cells in the body.

Participant Groups

Group I: Cohort 2-(Ph+ / Ph like ALL subtypes): Experimental Treatment 4 Interventions

Dose escalation phase- 12 subjects in Cohort 2, Palbociclib dose escalation will begin at 75 mg/m2/day, on Days 1 to 5; 11 to 15; and 21 to 30, and escalate or de escalate. All subjects will receive palbociclib with dexamethasone, bortezomib, and doxorubicin. dexamethasone of each 30 day cycle for up to 3 cycles for responders which include complete remission, complete remission morphologic, and partial response as defined in section 10.2.1. Bortezomib will be given on Days 7, 10, 17 and 20. Doxorubicin will be given on Days 7 and 17. Subjects with Ph+ / Ph-like mutation will receive a tyrosine kinase inhibitor (TKI or KI, either dasatinib or ruxolitinib).3 on 3 dose escalation with 2 dose levels.

Group II: Cohort 1 -(without Ph+ / Ph like mutation) Experimental Treatment 4 Interventions

Dose expansion phase-10 subjects in Cohort 1, 100 mg/m2/daily palbociclib on Days 1 to 5; 11 to 15; and 21 to 30, in combination with chemotherapy. All subjects will receive palbociclib with dexamethasone, bortezomib, and doxorubicin. dexamethasone of each 30 day cycle for up to 3 cycles for responders which include complete remission, complete remission morphologic, and partial response as defined in section 10.2.1. Bortezomib will be given on Days 7, 10, 17 and 20. Doxorubicin will be given on Days 7 and 17.

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

Approved in United States as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in European Union as Ibrance for:

• HR-positive, HER2-negative locally advanced or metastatic breast cancer

Approved in Canada as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in Japan as Ibrance for:

• HR-positive, HER2-negative advanced or recurrent breast cancer

Who Is Running the Clinical Trial?

Tanja Andrea Gruber

Lead Sponsor

Trials

2

Recruited

110+

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Findings from Research

In a phase I study involving 7 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), the combination of the CDK4/6 inhibitor palbociclib and dexamethasone showed potential efficacy, with one patient achieving a complete response.

The treatment was well-tolerated with no dose-limiting toxicities reported, and biological markers indicated on-target effects, including reductions in specific cell populations and proteins associated with leukemic growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of the combination of palbociclib and dexamethasone for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia. Wilde, L., Porazzi, P., Trotta, R., et al.[2023]

Recent studies indicate that risk-tailored treatment approaches can improve overall survival rates in high-risk groups of acute lymphoblastic leukemia, particularly for patients with Philadelphia chromosome-positive leukemia.

Incorporating imatinib mesylate into treatment regimens for these patients may enhance outcomes, and monitoring minimal residual disease during therapy could help predict responses and guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progress and challenges in the therapy of adult acute lymphoblastic leukemia. Kebriaei, P., Larson, RA.[2019]

Recent advancements in treatments for acute lymphoblastic leukemia (ALL), including inotuzumab ozogamicin, blinatumomab, and CAR T-cell therapy, have significantly improved patient outcomes for both younger and older adults.

The review emphasizes the need for optimal combinations and sequences of these new therapies, as well as their integration into standard treatment regimens, to enhance the effectiveness of ALL management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms. Short, NJ., Kantarjian, H., Jabbour, E.[2022]

Recent advancements in immunotherapy for B-precursor acute lymphoblastic leukemia, including monoclonal antibodies and CAR T-cell therapies, have led to high rates of remission in patients, even those who are chemo-resistant or have relapsed after transplantation.

These therapies target specific antigens (CD22, CD20, CD19) and may redefine treatment standards, emphasizing the goal of achieving molecular remission as a primary objective in managing the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy approaches to treat adult acute lymphoblastic leukemia. Maino, E., Bonifacio, M., Scattolin, AM., et al.[2017]

In Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), adding BCR-ABL tyrosine kinase inhibitors like imatinib is essential for treatment, but outcomes are still poor, highlighting the need for new therapies.

Resistance to imatinib has led to the development of second-generation inhibitors, such as dasatinib and nilotinib, which are designed to target mutant forms of the Bcr-Abl protein, offering hope for improved treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Acute lymphoblastic leukemia with Philadelphia chromosome: treatment with kinase inhibitors]. Thomas, X.[2022]

Recent immunotherapy agents like blinatumomab, inotuzumab, and CAR T-cells have significantly improved treatment outcomes for adult patients with relapsed acute lymphoblastic leukemia (ALL), addressing the limitations of conventional chemotherapy.

While these therapies show impressive efficacy, they also come with potential toxicities and high costs, highlighting the need for careful consideration in their use and optimal sequencing in treatment plans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The ABCs of Immunotherapy for Adult Patients With B-Cell Acute Lymphoblastic Leukemia. Horvat, TZ., Seddon, AN., Ogunniyi, A., et al.[2019]

The FDA has approved three innovative therapies for relapsed/refractory B-cell acute lymphoblastic leukemia, including inotuzumab ozogamicin and blinatumomab, which have significantly changed treatment options for this disease.

Understanding the unique toxicities and adverse effects of these therapies is crucial for safe administration, and the article provides recommendations for preventing and managing these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse effects of new monoclonal antibody treatments in acute lymphoblastic leukemia. Conde-Royo, D., Juárez-Salcedo, LM., Dalia, S.[2020]

Brexucabtagene autoleucel is the first FDA-approved CAR T-cell therapy targeting CD19 for adults with relapsed and refractory B-cell acute lymphoblastic leukemia, marking a significant advancement in treatment options.

The approval was based on the outcomes of the Zuma-3 trial, which demonstrated the efficacy of this therapy in improving patient outcomes in a challenging-to-treat population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval of brexucabtagene autoleucel for adults with relapsed and refractory acute lymphocytic leukemia. Frey, NV.[2022]

Out of 236 Individual Case Safety Reports (ICSRs) analyzed, only 18 (7.6%) were classified as off-label cases, indicating a low incidence of off-label use of antineoplastic drugs in pediatric patients, primarily related to therapeutic indications.

Among the off-label cases, 29 adverse drug reactions (ADRs) were reported, with common reactions including diarrhea and neutropenia, suggesting that while off-label use is limited, it can still lead to significant safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of Anticancer Agents Used in Children: A Focus on Their Off-Label Use Through Data From the Spontaneous Reporting System. Mascolo, A., Scavone, C., Bertini, M., et al.[2022]

Recent advancements in targeted therapies for acute lymphoblastic leukaemia (ALL), such as tyrosine kinase inhibitors and monoclonal antibodies, have significantly improved long-term survival rates, with over 50% survival in precursor B-ALL patients.

New FDA-approved therapies like blinatumomab and tisagenlecleucel have contributed to survival rates of 50-70% in Philadelphia chromosome-positive ALL and 80% in mature B-ALL, highlighting the efficacy of these innovative treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapy paves the way for the cure of acute lymphoblastic leukaemia. Rafei, H., Kantarjian, HM., Jabbour, EJ.[2020]

Imatinib has significantly improved treatment outcomes for adults with newly diagnosed Philadelphia chromosome acute lymphoblastic leukemia, leading to higher rates of complete response and molecular remission.

Resistance to imatinib due to ABL mutations is a growing concern, prompting the development of new, more potent kinase inhibitors to enhance anti-leukemic activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Thomas, X., Dombret, H.[2019]

References

1. England pubmed.ncbi.nlm.nih.gov

A phase I study of the combination of palbociclib and dexamethasone for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia. [2023]

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

Progress and challenges in the therapy of adult acute lymphoblastic leukemia. [2019]

3. England pubmed.ncbi.nlm.nih.gov

Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms. [2022]

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

Immunotherapy approaches to treat adult acute lymphoblastic leukemia. [2017]

5. France pubmed.ncbi.nlm.nih.gov

[Acute lymphoblastic leukemia with Philadelphia chromosome: treatment with kinase inhibitors]. [2022]

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

The ABCs of Immunotherapy for Adult Patients With B-Cell Acute Lymphoblastic Leukemia. [2019]

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

Management of adverse effects of new monoclonal antibody treatments in acute lymphoblastic leukemia. [2020]

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

Approval of brexucabtagene autoleucel for adults with relapsed and refractory acute lymphocytic leukemia. [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Safety of Anticancer Agents Used in Children: A Focus on Their Off-Label Use Through Data From the Spontaneous Reporting System. [2022]

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

Targeted therapy paves the way for the cure of acute lymphoblastic leukaemia. [2020]

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

Treatment of Philadelphia chromosome-positive adult acute lymphoblastic leukemia. [2019]