Ribociclib + Everolimus + Dexamethasone for Acute Lymphoblastic Leukemia

Recruiting at 11 trial locations

Overseen By Andrew Place, MD, PhD

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CYP3A4/5 inducers/inhibitors, Anticoagulants

Disqualifiers: Down syndrome, CNS 3 leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 3 weeks per cycle

45 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires stopping certain medications before starting the study drugs. Specifically, you must stop taking strong inducers or inhibitors of CYP3A4/5, medications with a narrow therapeutic window metabolized through CYP3A4/5, and certain herbal preparations at least 7 days before starting the study. Additionally, you must stop systemic corticosteroids 14 days before the study, but some uses like inhaled sprays are allowed.

What data supports the effectiveness of the drug combination Ribociclib, Everolimus, and Dexamethasone for treating Acute Lymphoblastic Leukemia?

Research shows that dexamethasone, a part of this drug combination, has been effective in treating acute lymphoblastic leukemia (ALL) when used with other drugs. Additionally, studies suggest that combining dexamethasone with other inhibitors can enhance its effectiveness in targeting leukemia cells. ^{1 2 3 4 5}

What safety information is available for the combination of Ribociclib, Everolimus, and Dexamethasone in treating acute lymphoblastic leukemia?

Dexamethasone, used in treating acute lymphoblastic leukemia, can cause adverse reactions, especially in adolescents, and may lead to long-term issues like bone problems and heart issues. Everolimus has been tested with other drugs in children with relapsed leukemia, showing it can be combined safely, but specific safety data for the combination with Ribociclib is not detailed in the available research. ^{4 6 7 8 9}

How is the drug combination of Ribociclib, Everolimus, and Dexamethasone unique for treating acute lymphoblastic leukemia?

This drug combination is unique because it combines Ribociclib, a CDK4/6 inhibitor, with Everolimus, an mTOR inhibitor, and Dexamethasone, a steroid, which may offer a novel approach by targeting different pathways in cancer cells compared to traditional chemotherapy regimens like hyper-CVAD. ^{1 7 10 11 12}

What is the purpose of this trial?

This research study is evaluating a drug called ribociclib (LEE011) given in combination with everolimus and other standard of care chemotherapy drugs as a possible treatment for relapsed or refractory ALL. The names of the drugs involved in this study are: * ribociclib * everolimus * dexamethasone

Research Team

Andrew Place, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for individuals aged between 1 and 30 years with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) or CML in lymphoid blast crisis. They must have at least 1% lymphoblasts in their bone marrow, adequate organ function, no severe heart conditions, not be pregnant or breastfeeding, and agree to use contraception. Excluded are those with certain recent treatments, uncontrolled infections, HIV/Hepatitis A/B/C infection.

Inclusion Criteria

I haven't taken systemic corticosteroids in the last 14 days, but I may have used them topically, inhaled, as eye drops, or locally.

I received radiation for chloroma without needing a waiting period.

I do not have symptoms of graft-versus-host disease.

Exclusion Criteria

I have not taken long-acting medications like Neulasta in the last 14 days.

Inability to determine the QTcF interval on screening EKG (using Fridericia's correction)

I have had cancer before, but it wasn't acute lymphoblastic leukemia (ALL).

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ribociclib, everolimus, and dexamethasone in combination. Ribociclib and everolimus are administered daily for 21 consecutive days, while dexamethasone is administered intravenously on days 1-5 and again on days 11-15.

3 weeks per cycle

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including pharmacokinetic analysis and toxicity assessments.

3 years

Treatment Details

Interventions

• Dexamethasone
• Everolimus
• Ribociclib

Trial Overview The study tests the effectiveness of ribociclib combined with everolimus and dexamethasone as a treatment for ALL that has returned after treatment or hasn't responded to previous therapies. It aims to see if this drug combination can help patients whose leukemia has been difficult to treat.

Participant Groups

Group I: Ribociclib (RIBO) + Dexamethasone (DEX) Experimental Treatment 2 Interventions

* Ribociclib administered daily for 21 consecutive days * Dexamethasone administered intravenously on days 1-5 and again on days 11-15

Group II: RIBO + Everolimus (EVE) + DEX Experimental Treatment 3 Interventions

* Ribociclib administered daily for 21 consecutive days * Dexamethasone administered intravenously on days 1-5 and again on days 11-15 * Everolimus administered daily for 21 consecutive days

Group III: RIBO + EVE+ DEX (dose expansion) Experimental Treatment 3 Interventions

* Ribociclib administered daily for 21 consecutive days. Dosing at RDE * Dexamethasone administered intravenously on days 1-5 and again on days 11-15 * Everolimus administered daily for 21 consecutive days. Dosing at RDE

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

Approved in European Union as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases
• Immune system disorders

Approved in United States as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders
• Neoplastic diseases
• Nervous system disorders

Approved in Canada as Dexamethasone for:

• Inflammation
• Allergic reactions
• Respiratory diseases
• Skin conditions
• Eye diseases

Approved in Japan as Dexamethasone for:

• Inflammatory conditions
• Allergic states
• Respiratory diseases
• Blood disorders

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Findings from Research

In a pilot study involving 34 patients with refractory acute lymphoblastic leukemia (ALL), high-dose dexamethasone combined with standard drugs achieved a complete remission (CR) rate of 47%, with a median duration of remission lasting 10 months.

For patients with late recurrences of ALL, the CR rate was notably higher at 70%, while those with primary resistant forms had a CR rate of 37.5%, indicating that high-dose dexamethasone is a promising treatment option for difficult cases of ALL.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Superhigh doses of dexamethasone in treatment of refractory forms of acute lymphoblast leukemia of adults]. Parovichnikova, EN., Savchenko, VG., Isaev, VG., et al.[2013]

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]

A 5-year-old boy with high-risk B-acute lymphoblastic leukemia (B-ALL) achieved minimal residual disease-negative remission after receiving a novel treatment regimen combining chemotherapy and immunotherapy, which included rituximab, inotuzumab ozogamicin, and blinatumomab.

The treatment was well tolerated, leading to a successful transplant without significant infections or toxicities, marking the first reported use of this condensed sequential therapy in a pediatric leukemia patient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mini-hyper CVD + CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab) for refractory pediatric B-acute lymphoblastic leukemia. McCall, D., Jabbour, E., Roth, M., et al.[2022]

Adolescents with Acute Lymphoblastic Leukaemia (ALL) experience more severe adverse drug reactions (ADRs) from oral dexamethasone compared to younger children, with higher incidences of issues like hyperglycemia, infections, and thrombosis, based on a review of 11 studies.

The increased severity of ADRs in adolescents may be linked to age-related differences in how dexamethasone is processed in the body and the effects of puberty, highlighting the need for healthcare professionals to closely monitor this age group during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reactions of oral dexamethasone in children and adolescents with childhood acute lymphoblastic leukemia: a systematic review. Hu, L., Kim Emily, AN., Juh Allen, YE.[2022]

The hyper-CVAD regimen shows a high complete remission rate of 90.4% after the first cycle in adults with acute lymphoblastic leukemia (ALL), indicating its efficacy as a treatment option.

The study found a low induction mortality rate of 1.9%, but highlighted the need for antiviral prophylaxis in patients with hepatitis B to prevent reactivation, as 11% experienced hepatitis flare due to HBV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical outcomes of patients with acute lymphoblastic leukemia receiving the hyper-CVAD regimen and assessment of the risk of hepatitis flares due to hepatitis B virus reactivation after chemotherapy. Law, MF., Chan, HN., Kong, SY., et al.[2022]

References

1. Italy pubmed.ncbi.nlm.nih.gov

Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM. [2023]

2. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Superhigh doses of dexamethasone in treatment of refractory forms of acute lymphoblast leukemia of adults]. [2013]

3. 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]

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

Mini-hyper CVD + CRIB (condensed rituximab, inotuzumab ozogamicin, and blinatumomab) for refractory pediatric B-acute lymphoblastic leukemia. [2022]

5. India pubmed.ncbi.nlm.nih.gov

Evaluate the Response Rate of Acute Lymphocytic Leukemia Patients to Hyper Cyclophosphamide, Vincristine, Adriamycin, and Dexamethasone Regimen and Remission Rate to Stay Until the End of the Arbitrary Treatment. [2022]

6. Australia pubmed.ncbi.nlm.nih.gov

Adverse drug reactions of oral dexamethasone in children and adolescents with childhood acute lymphoblastic leukemia: a systematic review. [2022]

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

Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia. [2021]

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

Dexamethasone-associated toxicity during induction chemotherapy for childhood acute lymphoblastic leukemia is augmented by concurrent use of daunomycin. [2015]

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

Balancing cure and long-term risks in acute lymphoblastic leukemia. [2022]

10. Poland pubmed.ncbi.nlm.nih.gov

Clinical outcomes of patients with acute lymphoblastic leukemia receiving the hyper-CVAD regimen and assessment of the risk of hepatitis flares due to hepatitis B virus reactivation after chemotherapy. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. [2017]

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

Yin and yang of glucocorticoid receptors in apoptosis. [2021]