SGLT2 Inhibitors for Pediatric Brain Cancer

Recruiting in Saint Louis (>99 mi)

+1 other location

Overseen By Andrew Cluster, M.D.

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Washington University School of Medicine

Must not be taking: SGLT2i, Thiazolidinedione, Insulin, others

Disqualifiers: Type 1 diabetes, Stroke, Pregnancy, others

Stay on Your Current Meds You can continue your current medications while participating

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 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 12 weeks

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing whether dapagliflozin, a drug that helps lower blood sugar, is safe for brain tumor patients who are receiving chemotherapy. The goal is to see if the medication can be used without causing significant side effects. Dapagliflozin works by helping the kidneys remove sugar from the blood, which is then passed out in urine.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be on high doses of dexamethasone or insulin. If you're on dexamethasone, you need to be on a stable or decreasing dose before starting the trial.

What data supports the effectiveness of the drug Dapagliflozin for pediatric brain cancer?

Research suggests that SGLT2 inhibitors like Dapagliflozin may help slow down cancer growth by reducing glucose uptake in cancer cells, as seen in studies with breast cancer. While this is promising, more research is needed to confirm its effectiveness specifically for pediatric brain cancer. ^{1 2 3 4 5}

Is dapagliflozin generally safe for humans?

Dapagliflozin, used for type 2 diabetes, is generally well tolerated with a low risk of low blood sugar, but it can cause genital infections, especially in women. It is not recommended for people with moderate or severe kidney problems. ^{1 6 7 8 9}

How do SGLT2 inhibitors differ from other drugs for pediatric brain cancer?

SGLT2 inhibitors, originally used for diabetes, are unique in treating pediatric brain cancer because they target cancer cell growth by affecting glucose uptake and energy pathways in the cells, which is different from traditional chemotherapy that directly targets cell division. ^{1 2 5 10 11}

Research Team

Andrew Cluster, M.D.

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

This trial is for children and young adults aged 6-21 with recurrent primary brain tumors, who have tried other treatments like radiation or chemotherapy. They must have a life expectancy over 12 weeks, stable vital signs, and normal organ function. Participants need to agree to use contraception if they can have children.

Inclusion Criteria

I can understand and am willing to sign the consent form.

Measurable disease using pediatric Response Assessment in Neuro-Oncology Criteria (RANO) criteria

Leukocytes ≥ 3,000/mcL

Exclusion Criteria

My HbA1c level is above 8.5%, and I am not using insulin.

I am not taking more than 4 mg/day of dexamethasone.

Currently receiving any other investigational agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive dapagliflozin in addition to standard of care chemotherapy for 12 weeks

12 weeks

Weekly visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Long-term follow-up

Participants are monitored for long-term safety and tumor response

Up to 39 months

Treatment Details

Interventions

• Dapagliflozin

Trial Overview The study tests the safety of Dapagliflozin (a diabetes drug) in pediatric brain tumor patients undergoing chemotherapy. It's an early-phase trial where everyone gets the same treatment to see how well they tolerate it.

Participant Groups

Group I: Solid Tumor Cancer: Dapagliflozin + Standard of Care Chemotherapy (Ages 6-10) Experimental Treatment 3 Interventions

* Dapagliflozin will be initiated by mouth once daily at the same time as standard of care chemotherapy (topotecan + cyclophosphamide). * Dapagliflozin 5 mg by mouth once daily on days 1-84 (duration of study) * All patients will stop taking dapagliflozin after 12 weeks of treatment. * Each cycle is 21 days.

Group II: Solid Tumor Cancer: Dapagliflozin + Standard of Care Chemotherapy (Ages 11-21) Experimental Treatment 3 Interventions

* Dapagliflozin will be initiated by mouth once daily at the same time as standard of care chemotherapy (topotecan + cyclophosphamide). * Dapagliflozin will be initiated at 5 mg by mouth once daily, days 1-4 (2 weeks) * Dapagliflozin will be escalated to 10 mg by mouth once daily for the remaining 10 weeks (after consultation with study endocrinologist) * All patients will stop taking dapagliflozin after 12 weeks of treatment. * Each cycle is 21 days.

Group III: Brain Cancer: Dapagliflozin + Standard of Care Chemotherapy (Ages 6-10) Experimental Treatment 2 Interventions

* Dapagliflozin will be initiated by mouth once daily at the same time as standard of care chemotherapy (carmustine). * Dapagliflozin 5 mg by mouth once daily on days 1-84 (duration of study) * All patients will stop taking dapagliflozin after 12 weeks of treatment.

Group IV: Brain Cancer: Dapagliflozin + Standard of Care Chemotherapy (Ages 11-21) Experimental Treatment 2 Interventions

* Dapagliflozin will be initiated by mouth once daily at the same time as standard of care chemotherapy (carmustine). * Dapagliflozin will be initiated at 5 mg by mouth once daily, days 1-4 (2 weeks) * Dapagliflozin will be escalated to 10 mg by mouth once daily for the remaining 10 weeks (after consultation with study endocrinologist) * All patients will stop taking dapagliflozin after 12 weeks of treatment.

Who Is Running the Clinical Trial?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

Children's Discovery Institute

Collaborator

Trials

4

Recruited

430+

Children's Discovery Institute

Collaborator

Trials

6

Recruited

540+

Findings from Research

Dapagliflozin effectively lowers blood sugar levels and glycated hemoglobin (HbA1c) in patients with type 2 diabetes, with a low risk of hypoglycemia and additional benefits like weight loss and reduced blood pressure.

While it is generally safe, dapagliflozin can increase the risk of genital infections, particularly in women, and its efficacy may be reduced in patients with kidney issues; ongoing trials are investigating its potential cardiovascular and renal protective effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Dapagliflozin (forxiga®) : SGLT 2 cotransporter inhibitor as glucose-lowering agent in type 2 diabetes]. Scheen, AJ.[2021]

SGLT2 inhibitors, Canagliflozin and Dapagliflozin, have shown significant anti-proliferative effects on breast cancer cells in both laboratory tests and animal models, indicating their potential as a treatment option for breast cancer.

The mechanism of action involves inducing cell cycle arrest in the G1/G0 phase and promoting apoptosis through AMPK activation, suggesting a novel therapeutic strategy for targeting breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway. Zhou, J., Zhu, J., Yu, SJ., et al.[2021]

SGLT2 inhibitors, including canagliflozin and ipragliflozin, significantly inhibit the growth of various cancer cell lines in a dose-dependent manner, with IC50 values indicating effective concentrations for treatment.

These inhibitors not only reduce cell proliferation and migration but also induce apoptosis in cancer cells, while showing potential for synergistic effects when combined with certain chemotherapeutic drugs like doxorubicin, although they may have antagonistic effects with others like cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring the Role of Sodium-Glucose Cotransporter as a New Target for Cancer Therapy. Bardaweel, S., Issa, A.[2022]

In a study involving lean breast tumor-bearing mice, the SGLT2 inhibitor dapagliflozin was found to enhance the effectiveness of the chemotherapy drug paclitaxel, leading to reduced tumor glucose uptake and improved survival rates.

The effectiveness of dapagliflozin in combination with paclitaxel was linked to its ability to lower circulating insulin levels, particularly in tumors with specific genetic mutations that affect insulin signaling pathways, suggesting a potential precision medicine approach for certain breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A precision medicine approach to metabolic therapy for breast cancer in mice. Akingbesote, ND., Norman, A., Zhu, W., et al.[2023]

Ipragliflozin, an SGLT2 inhibitor, significantly suppresses the growth of human breast cancer MCF-7 cells in a dose-dependent manner, indicating its potential as an anti-cancer agent.

The anti-cancer effects of ipragliflozin are linked to its mechanism of action, which involves inhibiting SGLT2, leading to membrane hyperpolarization and instability of mitochondrial membranes in breast cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation. Komatsu, S., Nomiyama, T., Numata, T., et al.[2020]

Dapagliflozin is an effective SGLT2 inhibitor for managing type 2 diabetes, showing consistent reductions in blood glucose levels and body weight over long-term follow-up periods of 1-4 years across various clinical trials.

It has a low risk of causing hypoglycemia and is generally well tolerated, although it can lead to genital infections, particularly in women, and is not recommended for patients with moderate to severe renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin: a review of its use in patients with type 2 diabetes. Plosker, GL.[2022]

Dapagliflozin is an effective treatment for type 2 diabetes, showing noninferiority to metformin and glimepiride in clinical trials involving 9 studies, indicating it can be a reliable option for patients.

While generally safe, dapagliflozin is associated with an increased risk of urinary infections and other side effects, suggesting it may be best used as an add-on therapy for patients not adequately controlled on other diabetes medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dapagliflozin for the Treatment of Type 2 Diabetes Mellitus. Aylsworth, A., Dean, Z., VanNorman, C., et al.[2019]

Dapagliflozin has been shown to be effective for up to 4 years in improving glycemic control, reducing blood pressure, and aiding weight loss in patients with type 2 diabetes, whether used alone or with other diabetes medications.

The long-term safety profile of dapagliflozin is favorable, with no significant increase in adverse events over time, and it is safe for use in patients with cardiovascular disease, mild renal impairment, and elderly patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durability of response to dapagliflozin: a review of long-term efficacy and safety. Jabbour, S.[2022]

Dapagliflozin (DAPA) is an effective SGLT2 inhibitor for treating type 2 diabetes, showing favorable pharmacokinetics and pharmacodynamics that help lower blood sugar levels while having beneficial effects on other metabolic risk factors.

While DAPA is generally safe, it carries an increased risk of genital and urinary infections, and concerns about bladder cancer and cardiovascular safety remain, prompting the FDA to seek further data on these issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 diabetes. Maranghi, M., Carnovale, A., Durante, C., et al.[2021]

Canagliflozin, an SGLT2 inhibitor, has been shown to significantly inhibit the growth of prostate and lung cancer cells at clinically achievable concentrations, especially when combined with radiation and chemotherapy, indicating potential anti-cancer properties.

The mechanism of action involves reducing glucose uptake and mitochondrial respiration, leading to decreased ATP production and increased activation of AMPK, which are critical for its anti-proliferative effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration. Villani, LA., Smith, BK., Marcinko, K., et al.[2018]

Canagliflozin, a SGLT2 inhibitor, was found to significantly inhibit the proliferation of glioblastoma (GBM) cells in vitro, particularly at a concentration of 40 μM, by affecting glucose uptake and activating AMPK signaling pathways.

In a mouse model of GBM, canagliflozin administration also led to a significant reduction in tumor growth, suggesting its potential as a therapeutic option for treating glioblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Canagliflozin Inhibits Glioblastoma Growth and Proliferation by Activating AMPK. Shoda, K., Tsuji, S., Nakamura, S., et al.[2023]

References

1. Belgium pubmed.ncbi.nlm.nih.gov

[Dapagliflozin (forxiga®) : SGLT 2 cotransporter inhibitor as glucose-lowering agent in type 2 diabetes]. [2021]

2. France pubmed.ncbi.nlm.nih.gov

Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway. [2021]

3. Switzerland pubmed.ncbi.nlm.nih.gov

Exploring the Role of Sodium-Glucose Cotransporter as a New Target for Cancer Therapy. [2022]

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

A precision medicine approach to metabolic therapy for breast cancer in mice. [2023]

5. Japan pubmed.ncbi.nlm.nih.gov

SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation. [2020]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Dapagliflozin: a review of its use in patients with type 2 diabetes. [2022]

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

Dapagliflozin for the Treatment of Type 2 Diabetes Mellitus. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Durability of response to dapagliflozin: a review of long-term efficacy and safety. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 diabetes. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration. [2018]

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

Canagliflozin Inhibits Glioblastoma Growth and Proliferation by Activating AMPK. [2023]