Ribociclib + Everolimus + Dexamethasone for Acute Lymphoblastic Leukemia

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of drugs—ribociclib (a cancer treatment drug), everolimus (an immunosuppressant), and dexamethasone (a corticosteroid)—to determine their effectiveness in treating acute lymphoblastic leukemia (ALL) that has returned or resisted treatment. The goal is to assess whether this combination outperforms current treatments. Individuals diagnosed with relapsed or hard-to-treat ALL, or a similar condition called CML in lymphoid blast crisis, might be suitable candidates, particularly if previous treatments have failed. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

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

Research shows that ribociclib is generally well-tolerated when used with other medications. Previous studies found that it does not significantly alter safety when combined with drugs like exemestane or anastrozole, suggesting ribociclib might also be safe with dexamethasone and everolimus.

Ribociclib enhances the effectiveness of certain cancer treatments and has been used safely with other treatments, which is encouraging. Dexamethasone, another drug in the trial, is often used for leukemia and other conditions but can cause side effects, such as bone health issues, especially in younger patients.

Everolimus, also included in the trial, has a known safety profile from its use in other treatments. When combined with ribociclib and dexamethasone, it may work well, but monitoring for side effects is crucial.

This trial is in its early stages, focusing primarily on safety. Limited data exist on how well this combination is tolerated specifically for acute lymphoblastic leukemia. However, the existing safety profiles of these drugs provide a promising start. Participants will be closely monitored to ensure their safety throughout the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for acute lymphoblastic leukemia because they combine innovative drugs that target cancer cells in unique ways. Unlike standard chemotherapy, Ribociclib is a CDK4/6 inhibitor that disrupts cancer cell division, while Everolimus is an mTOR inhibitor that blocks pathways cancer cells use to grow and survive. Pairing these with Dexamethasone, a steroid that reduces inflammation and kills leukemia cells, offers a multi-pronged attack on the disease. This combination could potentially enhance treatment effectiveness while minimizing damage to healthy cells.

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

This trial will evaluate different combinations of treatments for acute lymphoblastic leukemia (ALL). Some participants will receive Ribociclib and Dexamethasone, while others will receive a combination of Ribociclib, Everolimus, and Dexamethasone. Studies have shown that Ribociclib, a drug that blocks certain proteins, can enhance the effectiveness of chemotherapy drugs like Dexamethasone by affecting genes that control cell growth. Research suggests that using Ribociclib with Everolimus might stop leukemia cells from growing and could improve the effectiveness of other treatments for ALL. Everolimus may help by preventing cancer cells from multiplying. Previous findings indicate that these drugs, when used together, can be safe and might work well in treating ALL that has returned or is not responding to treatment. Overall, early research is promising for these drug combinations in fighting ALL. ^{1 3 6 7 8}

Who Is on the Research Team?

Andrew Place, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03740334

NCT03740334 | Ribociclib in Combination With Everolimus ... This research study is evaluating a drug called ribociclib (LEE011) given in combination with everolimus and other standard of care chemotherapy drugs as a ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29408328/

Ribociclib, a Cdk4/Cdk6 kinase inhibitor, enhances ... Immunoblot analysis showed a significant increase in glucocorticoid receptor (GR) along with some of its target genes, after combined treatment ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9335101/

Rational drug combinations with CDK4/6 inhibitors in acute ... We provide novel evidence that combining CDKi and conventional chemotherapy can be safe and effective. These results led to the rational design of a clinical ...

4. kisqali-hcp.com kisqali-hcp.com/metastatic-breast-cancer/efficacy/efficacy-across-trials

Efficacy Across Trials | mBC Learn more about the efficacy of KISQALI® (ribociclib) for mBC and review data from 3 phase III trials. See full Prescribing and Safety Information.

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2024/209092s018,209935s027MultidisciplineR.pdf

Summary Review - accessdata.fda.gov Based upon data from the most recent USPI, severe renal impairment increased ribociclib exposure (GMR) by 2.7 for Cmax and 2.1 for AUCinf.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2017/209092orig1s000multidiscipliner.pdf

209092Orig1s000 - accessdata.fda.gov demonstrated no alteration in safety signal with ribociclib in combination with exemestane or anastrozole, and also ... both combination therapy ...

7. go.drugbank.com go.drugbank.com/drugs/DB01234

Dexamethasone: Uses, Interactions, Mechanism of Action Dexamethasone and ciprofloxacin otic suspension is indicated for bacterial infections with inflammation in acute otitis media and acute otitis externa.

8. drugs.com drugs.com/drug-interactions/dexamethasone-with-kisqali-810-0-3790-18417.html

Drug Interactions between dexamethasone and Kisqali DexAMETHasone may reduce the blood levels of ribociclib. In some cases, this may make the medication less effective in treating your cancer.