SGLT2 Inhibitors for Pediatric Brain Cancer

Recruiting at 2 trial locations

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if dapagliflozin, a medication typically used for diabetes management, is safe and tolerable for children and young adults with recurring brain tumors or hard-to-treat solid tumors. The researchers hope that dapagliflozin, when combined with standard chemotherapy, can aid in treating these cancers by affecting specific metabolic processes. Children and young adults aged 6 to 21, who have recurring brain tumors or solid tumors without available cures and have already tried other treatments, might be suitable candidates. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants an opportunity to contribute to groundbreaking research.

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.

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

Research shows that dapagliflozin, a drug commonly used for diabetes, is being tested for safety in children with brain and solid tumors. Studies suggest that dapagliflozin might have manageable side effects when combined with standard chemotherapy, allowing most patients to undergo treatment without major issues.

Dapagliflozin is already approved for diabetes, providing some confidence in its safety. However, ongoing studies are assessing its safety for young patients with cancer. While safety data for cancer use is still being collected, existing evidence from its use in diabetes suggests it is generally well-tolerated. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for brain cancer?

Researchers are excited about using dapagliflozin for pediatric brain and solid tumor cancers because it works differently from traditional chemotherapy. While standard treatments like carmustine and topotecan target cancer cells directly, dapagliflozin is originally a diabetes medication that reduces glucose levels, potentially starving cancer cells that rely on glucose for growth. This unique mechanism offers a novel approach, complementing existing therapies, and could enhance treatment effectiveness and safety for young patients.

What evidence suggests that dapagliflozin could be an effective treatment for pediatric brain and solid tumor cancers?

Research has shown that dapagliflozin, a type of medication, might slow cancer growth by reducing the sugar intake of cancer cells. Studies on various cancers have observed this effect. Dapagliflozin affects sugar pathways, crucial for energy production in many tumors. Early studies suggest that this could make tumors less aggressive when combined with standard chemotherapy. In this trial, participants with pediatric brain and solid tumors will receive dapagliflozin alongside standard chemotherapy. Although direct evidence for its use in children's brain and solid tumors is limited, these findings offer hope for dapagliflozin's potential effectiveness in these cases. ^{2 3 4 5 6}

Who Is on the Research Team?

Andrew Cluster, M.D.

Principal Investigator

Washington University School of Medicine

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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, 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]

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]

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 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]

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]

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]

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]

Citations

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clinicaltrials.gov

clinicaltrials.gov/study/NCT05521984

NCT05521984 | Targeting Pediatric Brain Tumors and ...

This is a pilot phase Ib study of the feasibility and safety of dapagliflozin (in addition to standard of care treatment) for the treatment of pediatric ...

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withpower.com

withpower.com/trial/phase-1-pediatric-brain-tumors-10-2022-2cc67?condition=&query=Carmustine&overallStatus=Recruiting&hasNoPlacebo=false

SGLT2 Inhibitors 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 ...

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cancer.gov

cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-09210

Dapagliflozin in Combination with Standard Chemotherapy ...

To explore the effects of dapagliflozin on metabolic and tumor response in pediatric patients with recurrent brain tumors and relapsed/refractory solid tumors.

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC10376602/

SGLT2 Inhibitors as Potential Anticancer Agents - PMC

The researchers hypothesize that four weeks of treatment with dapagliflozin will be safe and efficacious in these patients [65]. The results ...

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mdpi.com

mdpi.com/2072-6694/17/3/466?type=check_update&version=2

Exploring the Role of SGLT2 Inhibitors in Cancer

Conversely, Sung et al. found that dapagliflozin and empagliflozin reduced the risk of cancer compared with DPP-4 inhibitors, whereas canagliflozin did not ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11815934/

Exploring the Role of SGLT2 Inhibitors in Cancer

SGLT2 inhibitors, first introduced in the clinical practice for diabetes, have been suggested to be effective against different types of cancer.