Abemaciclib + Temozolomide for Brain Cancer
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: CYP3A inhibitors/inducers
Disqualifiers: Pregnancy, Severe renal impairment, others
No Placebo Group
Breakthrough Therapy
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?Background:
Diffuse midline gliomas are the most aggressive brain tumors of childhood and young adults. Most people with these tumors survive less than 2 years. Researchers want to see if an anticancer drug (abemaciclib) can help.
Objective:
To see if researchers can measure how much abemaciclib is in a person's brain tumor and brain fluid after they take the drug for a few days.
Eligibility:
People aged 18 to 39 with recurrent high-grade glioma or diffuse midline glioma.
Design:
Participants will be screened with:
Medical history
Physical exam
Blood and urine tests
Tests of heart function
Imaging scans of the brain, with a contrast agent
Screening tests will be repeated during the study. Participants will also have chest X-rays.
Participants will take abemaciclib by mouth twice a day for 4 and a half days.
Participants will undergo surgery. They will have either a tumor biopsy (a needle will be inserted to remove a small piece of tissue) or a surgical resection (part or all of the tumor will be removed). A small tube (catheter) will be placed in their brain for 48 hours to collect fluid samples. They will have a neurological exam every few hours while the tube is in place. Two days later, the tube will be removed without surgery. Participants will stay in the hospital for about 4 days for treatment.
Based on the results of abemaciclib levels in the brain, participants may keep taking abemaciclib and another drug (temozolomide) by mouth until their cancer gets worse or they have bad side effects. While taking these two drugs, participants will come back to the clinic for follow-up routinely. They will be followed by the study for life.
Do I need to stop my current medications to join the trial?
The trial does not specify if you need to stop all current medications, but you cannot take medications that are strong or moderate CYP3A inhibitors or inducers. It's important to discuss your current medications with the study team to ensure there are no interactions.
What data supports the effectiveness of the drug Abemaciclib for brain cancer?
Abemaciclib has shown effectiveness in treating certain types of breast cancer and lung cancer by inhibiting specific proteins (CDK4/6) that help cancer cells grow. While this data is not directly about brain cancer, it suggests that Abemaciclib might have potential in treating other cancers by targeting similar pathways.
12345Is Abemaciclib safe for use in humans?
Abemaciclib, also known as Verzenio, has been approved for treating certain types of breast cancer and is generally considered safe when used as directed. Common side effects include diarrhea, infections, and low white blood cell counts, but these are usually manageable.
46789What makes the drug combination of Abemaciclib and Temozolomide unique for treating brain cancer?
The combination of Abemaciclib and Temozolomide is unique because Abemaciclib is a targeted therapy that inhibits specific proteins involved in cancer cell growth, while Temozolomide is an oral chemotherapy that works by damaging the DNA of cancer cells. This combination may offer a novel approach by potentially enhancing the effectiveness of treatment for brain cancer compared to using Temozolomide alone.
1011121314Eligibility Criteria
This trial is for young adults aged 18 to 39 with recurrent high-grade glioma or diffuse midline glioma. They must have recovered from previous treatments, have good organ function, and not be pregnant. Participants should be able to swallow pills and avoid grapefruit during the study.Inclusion Criteria
My high-grade brain tumor was confirmed by tests during surgery.
I can swallow pills.
Women considered to be of childbearing potential must have a negative pregnancy test within 7 days of the first dose of abemaciclib
+14 more
Exclusion Criteria
I do not have any active infections.
I have a history of fainting due to heart issues, irregular heartbeats, or sudden cardiac arrest.
I have severe nausea and vomiting that could interfere with taking medication.
+8 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Multiple visits for medical history, physical exam, and imaging scans
Pre-operative Treatment
Participants take abemaciclib by mouth twice a day for 4.5 days before surgery
4.5 days
Inpatient stay for drug administration
Surgery and Microdialysis
Participants undergo surgery for tumor biopsy or resection, followed by microdialysis catheter placement for 48 hours
4 days
Inpatient stay for surgery and monitoring
Maintenance Therapy
Participants may continue abemaciclib and temozolomide therapy based on PK and PD findings
28-day cycles
Clinic visits every 28 days for drug administration and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment, with ongoing contact for survival
10 years post-enrollment
Follow-up every 6 months
Participant Groups
The trial tests if abemaciclib levels can be measured in brain tumors and fluid after intake. It involves taking abemaciclib orally, surgery for tumor biopsy or resection, and cerebral fluid collection via a catheter. If effective, participants may continue treatment with abemaciclib plus temozolomide.
1Treatment groups
Experimental Treatment
Group I: 1/Abemaciclib and microdialysis monitoringExperimental Treatment4 Interventions
Abemaciclib orally BID for 4.5 days followed by resection or biopsy and microdialysis catheter placement with continuous monitoring for 48 hours post-operative and genomic sampling of tissue/blood; followed by abemaciclib+temozolomide maintenance therapy
Abemaciclib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Verzenio for:
- Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
- HR+, HER2- node-positive early breast cancer
🇪🇺 Approved in European Union as Verzenio for:
- HR+, HER2- advanced or metastatic breast cancer
- HR+, HER2- node-positive early breast cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
First-Line Abemaciclib Effective in ER+ Breast Cancer. [2019]Interim data from the MONARCH3 study indicate that abemaciclib is an effective first-line therapy for advanced ER-positive, HER2-negative breast cancer. Adding the investigational CDK4/6 inhibitor to letrozole significantly improved patients' progression-free survival, compared with those given a placebo alongside endocrine therapy.
Abemaciclib in Combination With Pembrolizumab for Stage IV KRAS-Mutant or Squamous NSCLC: A Phase 1b Study. [2022]Abemaciclib is an oral, selective small-molecule CDK 4 and 6 inhibitor. In preclinical models, abemaciclib synergized with programmed cell death protein-1 blockade to enhance antitumor efficacy. Here, we report the safety and anticancer activity of abemaciclib plus pembrolizumab in two cohorts with NSCLC.
CDK4/6 Inhibition Shows Clinical Activity in p16ink4A-Deficient Mesothelioma. [2022]Abemaciclib shows promising clinical activity in patients with relapsed, p16ink4A-deficient mesothelioma.
Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. [2023]Abemaciclib [Verzenio® (USA) or Verzenios® (EU)] is a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor approved in combination with adjuvant endocrine therapy for patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), node-positive, early breast cancer with a high risk of recurrence. In a phase III trial, abemaciclib plus endocrine therapy reduced the risk of recurrence of breast cancer compared with endocrine therapy alone, including in patients who had previously received neoadjuvant chemotherapy, in patients with high- and low-scoring Ki-67 tumours, and in both premenopausal and postmenopausal patients. The tolerability profile of abemaciclib plus endocrine therapy was acceptable and manageable, with diarrhoea, infections and neutropenia being the most common adverse events. Thus, abemaciclib in combination with standard endocrine therapy is a valuable additional treatment option for patients with HR+, HER2-, node-positive early breast cancer with a high risk of recurrence.
A Gene Panel Associated With Abemaciclib Utility in ESR1-Mutated Breast Cancer After Prior Cyclin-Dependent Kinase 4/6-Inhibitor Progression. [2023]Label="PURPOSE">For patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), first-line treatment is endocrine therapy (ET) plus cyclin-dependent kinase 4/6 inhibition (CDK4/6i). After disease progression, which often comes with ESR1 resistance mutations (ESR1-MUT), which therapies to use next and for which patients are open questions. An active area of exploration is treatment with further CDK4/6i, particularly abemaciclib, which has distinct pharmacokinetic and pharmacodynamic properties compared with the other approved CDK4/6 inhibitors, palbociclib and ribociclib. We investigated a gene panel to prognosticate abemaciclib susceptibility in patients with ESR1-MUT MBC after palbociclib progression.
Phase I study of vemurafenib in children with recurrent or progressive BRAFV600E mutant brain tumors: Pacific Pediatric Neuro-Oncology Consortium study (PNOC-002). [2021]Background: BRAFV600E mutation is present in a subset of pediatric brain tumors. Vemurafenib is an oral, selective ATP-competitive inhibitor of BRAFV600E kinase. The goal of this multi-center study conducted through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) was to determine the recommended phase 2 dose (RP2D) and dose limiting toxicities (DLTs) in children < 18 years with recurrent or progressive BRAFV600E mutant brain tumors. Results: Nineteen eligible patients were enrolled. Eleven patients had received three or more prior therapies. Data reported are from the start of treatment for the first patient (April 30 2014) through August 31 2019. The RP2D was defined as 550 mg/m2 twice daily after DLT criteria adjustment for rash. Related grade ≥ 3 adverse events included secondary keratoacanthoma (n = 1); rash (n =16); and fever (n = 5). Subjects received a median of 23 cycles (range 3-63). Four patients remain on treatment. Centrally reviewed best radiographic responses included 1 complete response, 5 partial responses, and 13 stable disease. The steady-state area under the curve (AUC0-∞median) was 604 mg*h/L (range 329-1052). Methods: Vemurafenib was given starting at 550 mg/m2, twice daily which corresponds to the adult RP2D. Adverse events were graded using the NIH Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Central imaging review was performed. Pharmacokinetic sampling was performed. Conclusions: Vemurafenib has promising anti-tumor activity in recurrent BRAF V600E-positive brain tumors with manageable toxicity. A phase 2 study is ongoing (NCT01748149).
A randomized phase I/II study of ABT-888 in combination with temozolomide in recurrent temozolomide resistant glioblastoma: an NRG oncology RTOG group study. [2019]This study tested the hypothesis that ABT-888 (velparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, can modulate temozolomide (TMZ) resistance in recurrent TMZ refractory glioblastoma patients. The combination regimen (TMZ/ABT-888) was tested using two randomized schedules (5 vs. 21 days), with 6-month progression free survival (PFS6) as the primary endpoint. The maximum tolerated dose (MTD) for TMZ using the 21 day of 28 TMZ schedule, in concert with 40 mg BID ABT-888 was determined in a phase I portion of this study, and previously reported to be 75 mg/m(2) (arm1). The MTD for ABT-888 (40 mg BID) and the 5 of 28 day TMZ (150-200 mg/m(2)) schedule was known from prior trials (arm2). Two cohorts were studied: bevacizumab (BEV) naïve (n = 151), and BEV refractory (n = 74). Overall ten patients were ineligible. The incidence rate of grade 3/4 myelosuppression over all was 20.0 %. For the BEV refractory cohort, the PFS 6 was 4.4 %; for the BEV naïve cohort, PFS6 was 17 %. Overall survival was similar for both arms in both the BEV naïve [median survival time (MST) 10.3 M; 95 % CI 8.4-12] and BEV refractory cohort (MST 4.7 M; 95 %CI 3.5-5.6). The median PFS was essentially the same for both arms and both cohorts at ~2.0 M (95 % CI 1.9-2.1).
Abemaciclib: First Global Approval. [2019]Abemaciclib (Verzenio™) is an orally administered inhibitor of cyclin-dependent kinases 4 and 6 that is being developed by Eli Lilly and Company. Abemaciclib has been approved in the USA for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, in combination with fulvestrant in women with disease progression following endocrine therapy, and as monotherapy in adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. In addition, abemaciclib is in various stages of development internationally for a variety of cancers. This article summarizes the milestones in the development of abemaciclib leading to its first approval for the treatment of patients with HR-positive, HER2-negative advanced or metastatic breast cancer.
Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma. [2018]A single-institution Phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) and define the safety profile of temozolomide and capecitabine when used in combination to treat brain metastases from breast cancer.
Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. [2022]Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM.
Nuclear factor I A promotes temozolomide resistance in glioblastoma via activation of nuclear factor κB pathway. [2019]To investigate the underlying mechanism by which glioblastoma (GBM) cells gain temozolomide (TMZ) resistance and to clarify novel therapeutic targets and new prognostic biomarkers for GBM.
Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor. [2021]Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, pamiparib demonstrated improved penetration across the blood brain barrier (BBB) in mice. Oral administration of pamiparib at a dose as low as 3 mg/kg is sufficient to abrogate PARylation in brain tumor tissues. In SCLC-derived, TMZ-resistant H209 intracranial xenograft model, combination of pamiparib with TMZ overcomes its resistance and shows significant tumor inhibitory effects and prolonged life span. Our data suggests that combination of pamiparib with TMZ has unique potential for treatment of brain tumors. Currently, the combination therapy of pamiparib with TMZ is evaluated in clinical trial [NCT03150862].
Temodar offers promise for treating astrocytomas. [2018]Temodar is an exciting new drug that shows promise in the treatment of brain tumors as well as in other types of cancers. Research currently is being conducted with Temodar to determine its efficacy in treating various solid tumors, glioblastoma multiform, and even metastatic melanoma. Temodar provides adult patients with anaplastic astrocytoma with another option of therapy that is convenient, produces minimal side effects, and, above all, instills hope.
Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. [2018]Continuous research into new strategies and chemotherapy agents for the treatment of malignant high-grade gliomas have led to the synthesis of a new chemotherapy drug, temozolomide (TMZ), with a lower toxicity profile compared to conventional chemotherapy agents, such as nitrosoureas. Temozolomide is an oral alkylating chemotherapy agent licensed for the treatment of recurrent high-grade gliomas, anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM). Because of its favorable pharmacokinetic and pharmacodynamic properties and improved tolerability, TMZ is now under investigation for concomitant use with radiotherapy in patients with newly-diagnosed GBM. We present a phase II clinical trial investigating the efficacy and safety of radio-chemotherapy combined treatment using TMZ, followed by six cycles of adjuvant chemotherapy with TMZ, in patients with newly-diagnosed GBM who have undergone debulking surgery or biopsy only.