SGLT2 Inhibitors for Pediatric Brain Cancer
Recruiting in Palo Alto (17 mi)
+1 other location
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
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
No Placebo Group
Breakthrough Therapy
Approved in 3 Jurisdictions
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.
12345Is 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.
16789How 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.
1251011Eligibility 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
+13 more
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
+8 more
Trial 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
Participant Groups
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.
4Treatment groups
Experimental Treatment
Group I: Solid Tumor Cancer: Dapagliflozin + Standard of Care Chemotherapy (Ages 6-10)Experimental Treatment3 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 Treatment3 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 Treatment2 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 Treatment2 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Washington University School of Medicine/St. Louis Children's HospitalSaint Louis, MO
Washington University School of MedicineSaint Louis, MO
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Who Is Running the Clinical Trial?
Washington University School of MedicineLead Sponsor
Children's Discovery InstituteCollaborator
Children's Discovery InstituteCollaborator
References
[Dapagliflozin (forxiga®) : SGLT 2 cotransporter inhibitor as glucose-lowering agent in type 2 diabetes]. [2021]Dapagliflozin, a specific inhibitor of sodium-glu¬cose cotransporters type 2 (SGLT2, inhibits glucose reabsorp¬tion in renal tubules and thus promotes glucosuria. This effect results in a reduction in fasting and postprandial glycaemia and a decrease of glycated haemoglobin (HbA1c), with a minor risk of hypoglycaemia, a weight reduction and a reduction in arterial blood pressure. The efficacy of empagliflozin on HbA1c reduction increases according to the level of hyper¬glycaemia but decreases in patients with renal insufficiency. Mycotic genital infections occur more frequently, especially in women, while a negligible increase in mild urinary tract infections may be observed. Dapagliflozin (Forxiga®), 10 mg once daily, is indicated for the treatment of T2DM and reim¬bursed in Belgium with conditions as add-on to a background glucose-lowering therapy (either metformin or sulfonylurea/ repaglinide or metformin plus sulfonylurea/repaglinide or basal insulin plus at least one of these oral glucose-lowering agents). Preliminary results suggest some cardiovascular and renal protection. These results should be confirmed in an ongoing large prospective controlled trial (DECLARE) in type 2 diabetic patients at high cardiovascular risk.
Sodium-glucose co-transporter-2 (SGLT-2) inhibition reduces glucose uptake to induce breast cancer cell growth arrest through AMPK/mTOR pathway. [2021]The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate the potential ability of SGLT2 inhibitors to attenuate cancer growth of SGLT2-expressing cancer cells, but there is little known about the effects of SGLT2 inhibitors on breast cancer. The goal in this research was to assess the anticancer activity of SGLT2 inhibitors in breast cancerin vitro and in vivo.
Exploring the Role of Sodium-Glucose Cotransporter as a New Target for Cancer Therapy. [2022]To evaluate the effects of SGLT2 inhibitors on the proliferation, tumorigenesis, migration, colony formation, apoptosis, selected gene expression pattern, and combination with known chemotherapeutic drugs in different human cancer cell lines.
A precision medicine approach to metabolic therapy for breast cancer in mice. [2023]Increasing evidence highlights approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic drugs. To our knowledge, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach for this devastating disease. Here, we treat lean breast tumor-bearing mice with the SGLT2 inhibitor dapagliflozin as monotherapy and in combination with paclitaxel chemotherapy. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival. Further, the ability of dapagliflozin to enhance the efficacy of chemotherapy correlates with its effect to reduce circulating insulin in some but not all breast tumors. Our data suggest a genetic signature for breast tumors more likely to respond to dapagliflozin in combination with paclitaxel. In the current study, tumors driven by mutations upstream of canonical insulin signaling pathways responded to this combined treatment, whereas tumors driven by mutations downstream of canonical insulin signaling did not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach.
SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation. [2020]Cancer is currently one of the major causes of death in patients with type 2 diabetes mellitus. We previously reported the beneficial effects of the glucagon-like peptide-1 receptor agonist exendin-4 against prostate and breast cancer. In the present study, we examined the anti-cancer effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin using a breast cancer model. In human breast cancer MCF-7 cells, SGLT2 expression was detected using both RT-PCR and immunohistochemistry. Ipragliflozin at 1-50 μM significantly and dose-dependently suppressed the growth of MCF-7 cells. BrdU assay also revealed that ipragliflozin attenuated the proliferation of MCF-7 cells in a dose-dependent manner. Because the effect of ipragliflozin against breast cancer cells was completely canceled by knocking down SGLT2, ipragliflozin could act via inhibiting SGLT2. We next measured membrane potential and whole-cell current using the patch clamp technique. When we treated MCF-7 cells with ipragliflozin or glucose-free medium, membrane hyperpolarization was observed. In addition, glucose-free medium and knockdown of SGLT2 by siRNA suppressed the glucose-induced whole-cell current of MCF-7 cells, suggesting that ipragliflozin inhibits sodium and glucose cotransport through SGLT2. Furthermore, JC-1 green fluorescence was significantly increased by ipragliflozin, suggesting the change of mitochondrial membrane potential. These findings suggest that the SGLT2 inhibitor ipragliflozin attenuates breast cancer cell proliferation via membrane hyperpolarization and mitochondrial membrane instability.
Dapagliflozin: a review of its use in patients with type 2 diabetes. [2022]Dapagliflozin (Forxiga(®), Farxiga(®)) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the management of patients with type 2 diabetes. Dapagliflozin reduces renal glucose reabsorption by inhibiting the transporter protein SGLT2 in the renal proximal tubule, thereby increasing urinary glucose excretion and reducing blood glucose levels. Its mechanism of action is independent of insulin secretion or action; therefore, dapagliflozin provides complementary therapy when used in combination with other antihyperglycaemic drugs. This article updates an earlier review of dapagliflozin and focuses on longer-term efficacy and tolerability data (e.g. from extensions of earlier clinical trials), as well as data from studies in special patient populations (e.g. history of cardiovascular disease). Numerous well-designed clinical trials with dapagliflozin, primarily as add-on therapy for 24 weeks (but also as monotherapy or initial combination therapy), have consistently demonstrated reductions in glycosylated haemoglobin, fasting plasma glucose levels and bodyweight. Extensions of these trials show the effects are maintained over longer-term follow-up periods of ≈1-4 years and dapagliflozin is generally well tolerated. Dapagliflozin has a low risk of hypoglycaemia, although the incidence varies depending on background therapy, and genital mycotic infections (particularly in women) are the most common adverse events. Dapagliflozin is not recommended in patients with moderate or severe renal impairment. In view of its unique mechanism of action and now well-established efficacy and tolerability profile, dapagliflozin is a useful treatment option in the management of type 2 diabetes, although its effects on diabetic complications remain to be evaluated.
Dapagliflozin for the Treatment of Type 2 Diabetes Mellitus. [2019]To review the pharmacology, pharmacokinetics, clinical trials, and adverse effects of dapagliflozin, a sodium glucose co-transporter 2 (SGLT-2) inhibitor.
Durability of response to dapagliflozin: a review of long-term efficacy and safety. [2022]Due to the chronic nature of type 2 diabetes (T2D), it is essential for an anti-diabetic drug to have durable efficacy and a good long-term safety profile. Dapagliflozin is a member of a unique class of anti-diabetic drugs that inhibit the sodium-glucose cotransporter 2 (SGLT-2) in the renal tubules and have an insulin-independent mechanism of action. In short-term studies (≤ 24 weeks), dapagliflozin reduced glycated hemoglobin (A1c), weight, and systolic blood pressure, and had a good safety profile.
Pharmacokinetics, pharmacodynamics and clinical efficacy of dapagliflozin for the treatment of type 2 diabetes. [2021]Dapagliflozin (DAPA) (Farxiga or Forxiga) is a sodium glucose cotransporter 2 (SGLT2) inhibitor approved for type 2 diabetes mellitus(T2DM) treatment.
The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration. [2018]The sodium-glucose transporter 2 (SGLT2) inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 inhibitors may inhibit the growth of some cancer cells but the mechanism(s) remain unclear.
Canagliflozin Inhibits Glioblastoma Growth and Proliferation by Activating AMPK. [2023]Sodium-glucose transporter 2 (SGLT2) inhibitors are antidiabetic drugs affecting SGLT2. Recent studies have shown various cancers expressing SGLT2, and SGLT2 inhibitors attenuating tumor proliferation. We evaluated the antitumor activities of canagliflozin, a SGLT2 inhibitor, on glioblastoma (GBM). Three GBM cell lines, U251MG (human), U87MG (human), and GL261 (murine), were used. We assessed the expression of SGLT2 of GBM through immunoblotting, specimen-use, cell viability assays, and glucose uptake assay with canagliflozin. Then, we assessed phosphorylation of AMP-activated protein kinase (AMPK), p70 S6 kinase, and S6 ribosomal protein by immunoblotting. Concentrations of 5, 10, 20, and 40 μM canagliflozin were used in these tests. We also evaluated cell viability and immunoblotting using U251MG with siRNA knockdown of SGLT2. Furthermore, we divided the mice into vehicle group and canagliflozin group. The canagliflozin group was administrated with 100 mg/kg of canagliflozin orally for 10 days starting from the third days post-GBM transplant. The brains were removed and the tumor volume was evaluated using sections. SGLT2 was expressed in GBM cell and GBM allograft mouse. Canagliflozin administration at 40 μM significantly inhibited cell proliferation and glucose uptake into the cell. Additionally, canagliflozin at 40 μM significantly increased the phosphorylation of AMPK and suppressed that of p70 S6 kinase and S6 ribosomal protein. Similar results of cell viability assays and immunoblotting were obtained using siRNA SGLT2. Furthermore, although less effective than in vitro, the canagliflozin group significantly suppressed tumor growth in GBM-transplanted mice. This suggests that canagliflozin can be used as a potential treatment for GBM.