Avapritinib + Decitabine for Systemic Mastocytosis

Recruiting at 6 trial locations

Overseen By Caroline Wagstaff

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: H. Lee Moffitt Cancer Center and Research Institute

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: AML, Seizure disorder, Pregnancy, 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

Compensation: Varies

Number of Visits: Unknown

34 Participants Needed

Trial Summary

What is the purpose of this trial?

Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) is a challenging disease to treat. Targeted KIT inhibitors have been approved for this indication based on their ability to control the mastocytosis portion of the disease, but patients frequently experience progression of the concomitant myeloid malignancy (i.e. the AHN). Using a combination approach to treat both aspects of the disease has the potential to provide enhanced disease control; however, overlapping toxicity is a concern. In this study, investigators aim to study the safety and tolerability of combined avapritinib and decitabine for the treatment of SM-AHN.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications, but it does exclude participants taking strong or moderate CYP3A inhibitors or inducers. It's important to discuss your current medications with the trial team to ensure there are no interactions.

What data supports the effectiveness of the drug Avapritinib + Decitabine for Systemic Mastocytosis?

Research shows that Decitabine, one of the drugs in the combination, has been effective in treating certain types of leukemia by improving survival rates and response rates. This suggests potential benefits in other conditions, although specific data for Systemic Mastocytosis is not available. ^{1 2 3 4 5}

Is the combination of Avapritinib and Decitabine safe for humans?

Decitabine has been studied in various forms of leukemia and is generally well tolerated, with common side effects including low blood cell counts and infections. There is no specific safety data available for the combination of Avapritinib and Decitabine, but Decitabine alone has been used safely in humans. ^{1 2 3 6 7}

How is the drug Avapritinib + Decitabine unique for treating systemic mastocytosis?

The combination of Avapritinib and Decitabine is unique because it targets systemic mastocytosis, a condition with limited standard treatments, by potentially combining the effects of Avapritinib, which inhibits specific enzymes involved in cell growth, with Decitabine, which alters DNA methylation to affect cell behavior. This dual approach may offer a novel way to manage the disease compared to existing therapies. ^{1 4 5 6 8}

Research Team

Andrew Kuykendall, MD

Principal Investigator

Moffitt Cancer Center

Eligibility Criteria

This trial is for patients with a condition called SM-AHN, which includes systemic mastocytosis and an associated blood cancer. Participants should have this specific diagnosis to be eligible.

Inclusion Criteria

My condition meets the 2022 WHO criteria for SM-AHN.

I am HIV positive, on treatment, and my viral load is undetectable.

My heart is healthy enough for this trial, according to a recent assessment.

Exclusion Criteria

Participants with uncontrolled intercurrent illness

Women who are breast feeding

Patients who are receiving any other investigational agents or are participating in another interventional study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants will take a combination of Avapritinib and Decitabine in escalating doses to determine safety and tolerability

Up to 6 months

Monthly visits for dose adjustments

Dose Expansion

Participants receive the determined dose of Avapritinib and Decitabine based on platelet count, with adjustments as needed

At least 6 cycles

Monthly visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 24 months

Treatment Details

Interventions

• Avapritinib
• Decitabine

Trial Overview The study tests the combination of two drugs, Avapritinib and Decitabine, to see if they can better control both systemic mastocytosis and the related blood cancer compared to current treatments.

Participant Groups

Group I: Dose Expansion Experimental Treatment 3 Interventions

Participants with baseline platelet count (cycle 1, day 1) ≥ 75 x 10\^9/L will begin the combination of Avapritinib at the dose determined by the dose-finding portion of the study and decitabine or Decitabine/Cedazuridine will be initiated during the first cycle. Participants with a baseline platelet count between 25 x 10\^9/L and 74 x 10\^9/L will receive decitabine or Decitabine/Cedazuridine (choice of investigator) as a single-agent for at least the first two cycles. Starting with cycle 3 and continuing with each subsequent cycle, patients will be eligible to receive Avapritinib in combination with decitabine or Decitabine/Cedazuridine if the platelet count on day 1 of the cycle is ≥ 75 x 10\^9. If the platelet count is \< 75 x 10\^9/L on day 1 of the cycle, patient will receive single-agent Decitabine or Decitabine/Cedazuridine. In the absence of clear disease progression, patients will be treated for at least 6 cycles before being judged to have not responded.

Group II: Dose Escalation Experimental Treatment 3 Interventions

Participants will be enrolled in cohorts of size 1-3. Participants will take a combination of Avapritinib and Decitabine. Decitabine will be administered in one of the following forms: I) Decitabine: starting IV dose of 20 mg/m2 on days 1-5 of a 28-day treatment cycle. II) Decitabine/Cedazuridine: starting dose of 35mg/100 mg oral tablet on days 1-5 of a 28-day treatment cycle. The starting dose of Avapritinib for the first cohort of patients will begin at dose level 1 with dose modifications to be made according to a Bayesian design. Avapritnib Dose levels Level -1: 50mg Level 1: 100mg Level 2: 150mg Level 3: 200mg

Avapritinib is already approved in United States, European Union for the following indications:

Approved in United States as Ayvakit for:

• Unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations
• Advanced systemic mastocytosis
• Indolent systemic mastocytosis

Approved in European Union as Ayvakit for:

• Unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations
• Advanced systemic mastocytosis
• Indolent systemic mastocytosis

Who Is Running the Clinical Trial?

H. Lee Moffitt Cancer Center and Research Institute

Lead Sponsor

Trials

576

Recruited

145,000+

Blueprint Medicines Corporation

Industry Sponsor

Trials

31

Recruited

6,000+

Findings from Research

The optimal biologic dose (OBD) of decitabine for treating acute myeloid leukemia (AML) was determined to be 20 mg/m²/day, which showed limited nonhematologic toxicity and promising clinical activity, with a response rate of 44% among 25 patients.

Combining decitabine with valproic acid (VA) resulted in dose-limiting encephalopathy at lower doses of VA, indicating safety concerns, while the clinical responses were similar whether patients received decitabine alone or in combination with VA.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. Blum, W., Klisovic, RB., Hackanson, B., et al.[2019]

In a study of 8 patients with relapse-refractory acute myeloid leukemia (AML) with AML1-ETO+, the combination of decitabine and a modified CAG regimen resulted in a high overall remission rate of 87.5%, with 7 out of 8 patients achieving complete remission.

The treatment was associated with manageable side effects, primarily myelosuppression, and no serious complications like lung infections were reported, indicating a favorable safety profile for this therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with Modified CAG Regimen for Relapse/Refractory Acute Myeloid Leukemia with AML1-ETO]. Liu, Q., Fei, XM.[2018]

Decitabine has been approved for treating older patients (65 years and older) with newly diagnosed acute myeloid leukemia (AML) who cannot undergo standard chemotherapy, showing a median overall survival of 7.7 months compared to 5.0 months for those receiving low-dose cytarabine or supportive care.

The treatment demonstrated improved response rates and progression-free survival, with a manageable safety profile, making it a valuable option for older patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use. Nieto, M., Demolis, P., Béhanzin, E., et al.[2018]

In a study involving 13 patients with relapsed/refractory acute lymphoblastic leukemia (ALL), the combination of decitabine and vorinostat with chemotherapy showed a clinical response rate of 46.2%, indicating potential efficacy in this challenging patient population.

The treatment was generally tolerable, although some patients experienced significant nonhematological toxicities, such as infections and neutropenia, and notable changes in DNA methylation patterns were observed, suggesting that these methylation profiles could help predict treatment responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute lymphoblastic leukemia. Burke, MJ., Lamba, JK., Pounds, S., et al.[2021]

In a study of 84 patients with myeloid neoplasms, the combination of decitabine (DEC) and all-trans retinoic acid (ATRA) showed a significantly higher overall response rate (75%) compared to DEC alone (42.86%), indicating enhanced efficacy in treating these conditions.

The DEC/ATRA regimen demonstrated a similar efficacy to DEC combined with G-CSF priming, while also resulting in lower rates of severe bone marrow suppression and infections compared to the DEC/priming group, suggesting a safer profile for the DEC/ATRA combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The Effects of Decitabine Combined with All-Trans Retinoic Acid on the Number of Immune Cells in Myeloid Neoplasms]. Wei, W., Liu, Y., Shang, LM., et al.[2022]

In a study of 19 children with high-risk, refractory, or relapsed acute myeloid leukemia (AML), treatment with decitabine combined with low dose chemotherapy resulted in a high response rate, with 15 achieving complete remission and only 1 not responding.

The treatment was found to be safe, with no treatment-related deaths, and led to a promising three-year overall survival rate of 79%, indicating it is an effective option for these challenging cases of pediatric AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy of decitabine combined with low dose chemotherapy on children with acute myeloid leukemia]. Fan, LY., Gao, L., Hu, DX., et al.[2023]

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]

In a study of 44 elderly patients with acute myeloid leukemia (AML), the combination of decitabine with half-course pre-excitation therapy resulted in a higher remission rate (72.73%) compared to the control group (50.00%), indicating enhanced efficacy of the combined treatment.

The combined therapy group also showed a longer median survival time (17.82 months) compared to the control group (12.43 months), while experiencing fewer severe adverse reactions related to blood system and bone marrow suppression, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Half-Course Pre-excitation for the Treatment of Elderly Patients with Acute Myeloid Leukemia]. Qiu, HC., Kong, R., Wu, PF., et al.[2020]

References

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

Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. [2019]

2. China pubmed.ncbi.nlm.nih.gov

[Clinical Efficacy of Decitabine Combined with Modified CAG Regimen for Relapse/Refractory Acute Myeloid Leukemia with AML1-ETO]. [2018]

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

The European Medicines Agency Review of Decitabine (Dacogen) for the Treatment of Adult Patients With Acute Myeloid Leukemia: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use. [2018]

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

A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute lymphoblastic leukemia. [2021]

5. China pubmed.ncbi.nlm.nih.gov

[The Effects of Decitabine Combined with All-Trans Retinoic Acid on the Number of Immune Cells in Myeloid Neoplasms]. [2022]

6. China pubmed.ncbi.nlm.nih.gov

[Efficacy of decitabine combined with low dose chemotherapy on children with acute myeloid leukemia]. [2023]

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

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia. [2022]

8. China pubmed.ncbi.nlm.nih.gov

[Efficacy and Safety of Decitabine Combined with Half-Course Pre-excitation for the Treatment of Elderly Patients with Acute Myeloid Leukemia]. [2020]