RAD001 + PKC412 for Acute Myeloid Leukemia

Recruiting at 2 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Richard Stone, MD

Must not be taking: Systemic steroids, Immunosuppressants

Disqualifiers: Pregnancy, Uncontrolled infection, HIV, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

29 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on chronic treatment with systemic steroids or another immunosuppressive agent.

What data supports the effectiveness of the drug PKC412 for treating acute myeloid leukemia?

PKC412, also known as midostaurin, has shown effectiveness in treating acute myeloid leukemia (AML) with FLT3 mutations, as it can inhibit the growth of leukemic cells and improve overall survival when combined with standard chemotherapy. It has been approved for use in AML patients with these specific mutations. ^{1 2 3 4 5}

Is the combination of RAD001 and PKC412 safe for humans?

PKC412, also known as Midostaurin, has been studied for its effects on acute myeloid leukemia (AML) cells, particularly those with specific mutations. It can cause cell death in certain leukemia cells, but its safety profile in humans, especially in combination with other drugs like RAD001, is not fully detailed in the available studies. Further clinical trials are needed to better understand its safety in humans. ^{1 3 4 6 7}

How does the drug combination of RAD001 and PKC412 differ from other treatments for acute myeloid leukemia?

The combination of RAD001 and PKC412 is unique because it targets the FLT3 mutation, which is common in acute myeloid leukemia (AML) and associated with poor prognosis. PKC412 (Midostaurin) is a kinase inhibitor that has shown effectiveness in treating FLT3-mutated AML, and combining it with RAD001 may enhance its therapeutic effects, potentially overcoming resistance seen with PKC412 alone. ^{1 2 3 5 7}

What is the purpose of this trial?

The purpose of this research study is to determine the safety of the combination of RAD001 and PKC412 as a cancer treatment, and to establish the highest dose of RAD001 that can be given in conjunction with PKC412. These drugs have been used in other research trials for individuals with solid and hematology malignancies. Past research on PKC412 shows that it blocks the abnormal functioning of an enzyme called FLT3. FLT3 is found in your cells in either a normal (wild type) or genetically changed form and plays a role in the survival and growth of AML cells. RAD001 is an inhibitor of a central growth pathway that involves the protein MTOR. The MTOR pathway is overactive in cancer cells, causing the cells to grow abnormally. By inhibiting the abnormal growth activity of the MTOR pathway, RAD001 slows down and possibly stops the growth of cancer cells.

Research Team

Richard Stone, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

This trial is for adults with relapsed or refractory AML, MDS, or CMML who can't have standard therapy. They should be in relatively stable health (ECOG ≤2), not pregnant, using double barrier contraception if of childbearing potential, and without recent transplants or other cancers within 5 years.

Inclusion Criteria

I can take care of myself but cannot do heavy physical work.

INR < 1.3 (or < 3 on anticoagulants)

I don't expect to need treatment to reduce my blood cell count within a month, except for hydroxyurea.

Exclusion Criteria

I have been diagnosed with acute promyelocytic leukemia.

I had a bone marrow or stem cell transplant less than 2 months ago.

I do not have severe health or mental conditions that could stop me from completing the study.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive RAD001 and PKC412 in a dose-escalation study to determine the maximum tolerated dose

28 days per cycle

Multiple visits for evaluations and procedures

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• PKC412
• RAD001

Trial Overview The study tests RAD001 combined with PKC412 to find the safest high dose against certain blood cancers. RAD001 targets a protein pathway that's overactive in cancer cells while PKC412 blocks an enzyme linked to AML cell growth.

Participant Groups

Group I: Only one arm on this study. Experimental Treatment 2 Interventions

Who Is Running the Clinical Trial?

Richard Stone, MD

Lead Sponsor

Trials

2

Recruited

50+

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

Beth Israel Deaconess Medical Center

Collaborator

Trials

872

Recruited

12,930,000+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

Brigham and Women's Hospital

Collaborator

Trials

1,694

Recruited

14,790,000+

Findings from Research

Midostaurin (PKC412) combined with standard chemotherapy (daunorubicin) shows a synergistic effect in inhibiting intracellular signaling in FLT3-mutated acute myeloid leukemia (AML) cells, which may enhance treatment efficacy.

In contrast, cytarabine appears to antagonize the effects of PKC412, leading to increased FLT3 receptor expression and potentially complicating treatment outcomes, highlighting the need for further research into optimal combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multiplexed single-cell mass cytometry reveals distinct inhibitory effects on intracellular phosphoproteins by midostaurin in combination with chemotherapy in AML cells. Rörby, E., Adolfsson, J., Hultin, E., et al.[2021]

References

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

A highly sensitive method for the detection of PKC412 (CGP41251) and its metabolites by high-performance liquid chromatography. [2016]

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

Clinical resistance to the kinase inhibitor PKC412 in acute myeloid leukemia by mutation of Asn-676 in the FLT3 tyrosine kinase domain. [2021]

3. Greece pubmed.ncbi.nlm.nih.gov

Synergistic effect of all‑trans retinoic acid in combination with protein kinase C 412 in FMS-like tyrosine kinase 3-mutated acute myeloid leukemia cells. [2016]

4. Germany pubmed.ncbi.nlm.nih.gov

The FLT3 inhibitor PKC412 in combination with cytostatic drugs in vitro in acute myeloid leukemia. [2016]

5. England pubmed.ncbi.nlm.nih.gov

Multiplexed single-cell mass cytometry reveals distinct inhibitory effects on intracellular phosphoproteins by midostaurin in combination with chemotherapy in AML cells. [2021]

6. England pubmed.ncbi.nlm.nih.gov

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations. [2017]

7. Germany pubmed.ncbi.nlm.nih.gov

Mechanisms of resistance against PKC412 in resistant FLT3-ITD positive human acute myeloid leukemia cells. [2016]