LY3214996 + Abemaciclib for Glioblastoma

Not currently recruiting at 2 trial locations

Overseen By Phase 0 Navigator

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Nader Sanai

Must not be taking: Coumarin anticoagulants

Disqualifiers: Pregnancy, Active infection, Liver disease, 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: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of two drugs, LY3214996 (Temuterkib) and Abemaciclib, can help treat glioblastoma, an aggressive brain cancer. Participants will take these drugs before undergoing surgery to remove their tumor. The trial aims to assess how well these drugs work together in shrinking the tumor and to evaluate their safety. Individuals who have already undergone standard glioblastoma treatments, such as surgery and radiation, and whose cancer has returned might be suitable for this trial. As an Early Phase 1 trial, this research focuses on understanding how these new treatments work in people, offering participants the opportunity to be among the first to receive potentially groundbreaking therapy.

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

The trial protocol does not specify if you need to stop taking your current medications. However, there is a required washout period of at least 21 days after your last chemotherapy dose and 14 days after radiotherapy before starting the trial. You cannot use coumarin-derived anticoagulants, but heparin, LMWH, or fondaparinux are allowed. It's best to discuss your specific medications with the trial team.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does mention a washout period (time without taking certain medications) of at least 21 days for chemotherapy and 14 days for radiotherapy before starting the trial. It's best to discuss your specific medications with the trial team.

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

Research has shown that the combination of LY3214996 and Abemaciclib was safe in earlier studies. LY3214996, when combined with Abemaciclib, reached significant levels in brain tumor tissues in many patients, indicating potential effectiveness. Importantly, these studies suggest that the side effects were manageable and not too severe for participants.

Abemaciclib is already used for other health conditions, providing some confidence about its safety. However, since LY3214996 is still under investigation, it is crucial to assess its effects in people with glioblastoma. These studies are in the early stages, so safety information is still being gathered. So far, participants have tolerated it well. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about LY3214996 combined with Abemaciclib for glioblastoma because it targets the cancer in a novel way. Unlike standard treatments that often rely on chemotherapy and radiation, this combination works by inhibiting specific proteins involved in cell division, potentially slowing tumor growth more effectively. LY3214996 targets the ERK pathway, while Abemaciclib inhibits CDK4 and CDK6 proteins, making this approach a promising new direction for attacking glioblastoma at the molecular level.

What evidence suggests that LY3214996 and Abemaciclib could be effective for glioblastoma?

Research has shown that when Abemaciclib and LY3214996, the treatments under study in this trial, are used together, they reach significant levels in glioblastoma tissue. Specifically, Abemaciclib achieves these levels in 80% of patients, while LY3214996 does so in 30%. These levels are associated with slowing cancer cell growth. Abemaciclib ranks among the top drugs for cancer treatment and is being tested with LY3214996 in this trial. The combination aims to halt tumor cell multiplication by targeting specific pathways essential for their growth. Early results suggest this combination could effectively treat recurrent glioblastoma. ^{1 2 5 6 7}

Who Is on the Research Team?

Nader Sanai, MD

Principal Investigator

Deputy Director of the Ivy Brain Tumor Center

Are You a Good Fit for This Trial?

This trial is for adults over 18 with recurrent glioblastoma who've had prior treatment including surgery, temozolomide, and radiotherapy. They must have measurable disease, specific genetic features in their tumor tissue, and be able to swallow pills. Pregnant or breastfeeding individuals can't join; neither can those with certain heart conditions, severe infections or liver diseases, a history of blood clots in the eye causing vision loss, or those on coumarin anticoagulants.

Inclusion Criteria

Prior resection of histologically diagnosed WHO Grade IV glioma defined as glioma participants who have progressed on or following standard (Stupp regimen) therapy, which included maximal surgical resection, temozolomide, and fractionated radiotherapy.

Recurrence must be confirmed by diagnostic biopsy with local pathology review or contrast-enhanced MRI.

Participants must have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 perpendicular measurements of at least 1 cm, as per RANO criteria.

Exclusion Criteria

Pregnancy or lactation.

The patient has a personal history of any of the following conditions: syncope of cardiovascular etiology, ventricular arrhythmia of pathological origin (including, but not limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.

Current use of coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 0 Treatment

Participants receive LY3214996 plus Abemaciclib prior to surgical resection

5.5 days

Daily visits for drug administration

Surgical Resection

Participants undergo craniotomy for tumor resection

1 day

1 visit (in-person)

Phase 2 Treatment

Dose expansion cohort to achieve a total of 25 participants in Phase 2

Variable, based on dose expansion

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 60 months

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Abemaciclib
• LY3214996

Trial Overview The trial tests LY3214996 plus Abemaciclib given before surgical removal of brain tumors in patients with recurrent glioblastoma. Initially up to 10 participants will receive this combination therapy; if successful based on PK results from Phase 0 and enrollment into Phase 2 reaches at least five participants, around 40 more may join for further evaluation.

How Is the Trial Designed?

Group I: Arm 1 Experimental Treatment 2 Interventions

400 mg of LY3214996 QD for 6 doses and 100 mg of Abemaciclib BID for 11 doses over 5.5 days prior to surgical resection. On Day 6, participants will receive Abemaciclib + LY3214996 dose 7 to 9 hours prior to craniotomy for tumor resection.

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

Who Is Running the Clinical Trial?

Nader Sanai

Lead Sponsor

Trials

11

Recruited

440+

Barrow Neurological Institute

Collaborator

Trials

27

Recruited

7,100+

Ivy Brain Tumor Center

Collaborator

Trials

12

Recruited

910+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

In a phase II trial involving 56 patients with recurrent glioblastoma (GBM) enriched for EGFR gene amplification, dacomitinib showed effective penetration into tumors, but only 14.3% of patients experienced a clinical benefit lasting at least 6 months.

The presence of specific EGFR mutations (EGFRvIII or EGFR ECD missense mutations) did not predict clinical benefit from dacomitinib, suggesting that alternative biomarkers, such as RNA signatures in circulating extracellular vesicles, may be more promising for identifying patients who could respond to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring Predictors of Response to Dacomitinib in EGFR-Amplified Recurrent Glioblastoma. Chi, AS., Cahill, DP., Reardon, DA., et al.[2021]

Abemaciclib, a CDK4 and CDK6 inhibitor, shows significantly better brain penetration compared to palbociclib, making it a promising candidate for treating primary brain tumors like glioblastoma.

In preclinical models, abemaciclib not only increased survival in rats with brain tumors but also demonstrated additive effects when combined with the standard treatment temozolomide, suggesting its potential as an effective therapy for brain cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft. Raub, TJ., Wishart, GN., Kulanthaivel, P., et al.[2019]

In a phase 1/2 study involving patients with recurrent glioblastoma, the combination of sorafenib and temsirolimus showed limited efficacy, with only 17.1% of VEGF inhibitor-naive patients achieving progression-free survival at 6 months, while only 9.8% of those who had previously received VEGF inhibitors met this threshold.

The treatment was associated with significant toxicity, as 75.5% of VEGF inhibitor-naive patients and 73.9% of prior VEGF patients experienced at least one grade ≥3 adverse event, suggesting that the high toxicity may have contributed to the lack of effectiveness observed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572. Schiff, D., Jaeckle, KA., Anderson, SK., et al.[2022]

In a phase 2 study involving 39 patients with recurrent grade III malignant glioma, the combination of imatinib mesylate and hydroxyurea showed a 24% progression-free survival rate at 6 months, indicating some efficacy in this challenging condition.

The treatment was well tolerated, with serious side effects occurring in less than 4% of cases, primarily hematologic, suggesting a favorable safety profile for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas. Desjardins, A., Quinn, JA., Vredenburgh, JJ., et al.[2018]

Proneural glioblastoma (GBM) shows increased sensitivity to CDK4/6 inhibition with palbociclib, which significantly reduced cell proliferation in vitro and prolonged survival in mice with proneural GBM xenografts.

Palbociclib treatment not only inhibited proneural GSCs but also induced a transition to a mesenchymal state, highlighting the need for combination therapies, such as with ALDH1A3 inhibitors, to effectively target this subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDK4/6 inhibition is more active against the glioblastoma proneural subtype. Li, M., Xiao, A., Floyd, D., et al.[2018]

In a phase II trial involving 65 patients with recurrent glioblastoma, the pan-PI3K inhibitor buparlisib showed minimal efficacy as a single agent, with only 8% of patients achieving 6-month progression-free survival.

Despite demonstrating significant brain penetration and some reduction in PI3K pathway activity in tumor tissue, the incomplete blockade of the pathway likely contributed to the lack of clinical effectiveness, suggesting that more effective PI3K inhibitors may be needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. Wen, PY., Touat, M., Alexander, BM., et al.[2020]

In a phase 1b study involving 50 patients with advanced non-small cell lung cancer (NSCLC), the combination of abemaciclib and pembrolizumab showed significant toxicity, with 80% of patients in cohort A and 76% in cohort B experiencing severe treatment-emergent adverse events.

Despite some antitumor activity, including a disease control rate of 56% in cohort A and 64% in cohort B, the overall risk-benefit profile of this combination therapy does not support further investigation in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib in Combination With Pembrolizumab for Stage IV KRAS-Mutant or Squamous NSCLC: A Phase 1b Study. Pujol, JL., Vansteenkiste, J., Paz-Ares Rodríguez, L., et al.[2022]

Selective CDK inhibitors (CDKis) like abemaciclib and dinaciclib show significant antitumoral effects on glioblastoma multiforme (GBM) in both 2D and 3D models, affecting cell viability, morphology, and inducing senescence.

Combining dinaciclib with abemaciclib produced synergistic effects, but combining dinaciclib with the standard chemotherapy temozolomide (TMZ) was counterproductive, highlighting the importance of drug selection and timing in treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclin-dependent kinase inhibitors exert distinct effects on patient-derived 2D and 3D glioblastoma cell culture models. Riess, C., Koczan, D., Schneider, B., et al.[2021]

Abemaciclib has demonstrated promising clinical activity in patients with relapsed mesothelioma that is deficient in the p16ink4A protein, suggesting it may be an effective treatment option for this specific cancer type.

The findings indicate a potential new therapeutic avenue for mesothelioma patients, particularly those whose tumors lack the p16ink4A protein, which is often associated with tumor suppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CDK4/6 Inhibition Shows Clinical Activity in p16ink4A-Deficient Mesothelioma. [2022]

Dasatinib, a multitargeted tyrosine kinase inhibitor, was evaluated in a phase II trial for adults with recurrent glioblastoma, but the study found it ineffective, with no radiographic responses and a median overall survival of only 7.9 months.

Although intrapatient dose escalation was feasible and tolerated by some participants, the clinical benefit was insufficient, leading to the trial's closure without proceeding to further stages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 trial of dasatinib in target-selected patients with recurrent glioblastoma (RTOG 0627). Lassman, AB., Pugh, SL., Gilbert, MR., et al.[2019]

In a study of 31 patients with recurrent glioblastoma treated with apatinib and temozolomide, the combination showed an objective response rate of 26.3% and a disease control rate of 84.2%, indicating it can be an effective treatment option.

The treatment resulted in a median progression-free survival of 4.9 months and overall survival of 8.2 months, with manageable side effects such as hypertension and decreased appetite, suggesting it is a viable salvage therapy for this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apatinib Plus Temozolomide: An Effective Salvage Treatment for Recurrent Glioblastoma. Ge, J., Li, C., Xue, F., et al.[2022]

The phase I/II trial established that the maximum tolerated dose of afatinib is 40 mg/day when combined with temozolomide, with common side effects including diarrhea and rash, affecting 71-82% of participants.

In terms of efficacy, afatinib alone showed limited activity in recurrent glioblastoma, with a 6-month progression-free survival rate of only 3%, while the combination with temozolomide had a slightly better rate of 10%, indicating that temozolomide alone (23%) was more effective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/randomized phase II study of afatinib, an irreversible ErbB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma. Reardon, DA., Nabors, LB., Mason, WP., et al.[2022]

Glioblastomas, particularly the IDH-wildtype type, are challenging to treat, with standard care involving surgery, radiotherapy, and temozolomide chemotherapy since 2005, but no pharmacological treatments have significantly improved overall survival.

Targeting specific genetic vulnerabilities in rare glioblastoma subsets and focusing on the tumor microenvironment may offer new avenues for treatment, highlighting the need for improved clinical trial designs to test these strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular targeted therapy of glioblastoma. Le Rhun, E., Preusser, M., Roth, P., et al.[2019]

In a phase II trial involving 49 patients with recurrent glioblastoma and EGFR amplification, dacomitinib showed limited efficacy, with a 6-month progression-free survival rate of only 10.6%.

The treatment was associated with significant adverse effects, as 40.8% of patients experienced grade 3-4 drug-related side effects, primarily diarrhea and rash, highlighting the need for careful patient selection based on molecular characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of dacomitinib, a pan-human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification. Sepúlveda-Sánchez, JM., Vaz, MÁ., Balañá, C., et al.[2022]

Citations

1. academic.oup.com academic.oup.com/neuro-oncology/article/26/Supplement_8/viii110/7890035

CTNI-58. A PHASE 0/2 TRIAL OF ABEMACICLIB PLUS ... Abemaciclib and LY3214996 achieved pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue in 80% and 30% of the patients, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04391595

NCT04391595 | LY3214996 Plus Abemaciclib in Recurrent ... This trial is an open-label, multicenter, Phase 0/2 trial that will enroll up to 50 participants with recurrent glioblastoma which are schedule for resection.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.2005

A Phase 0 'trigger' trial of CDK4/6 plus ERK1/2 inhibitors in ... Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of the RB ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9367381/

Drug Repurposing, a Fast-Track Approach to Develop ... According to Li et al., abemaciclib is considered the most optimal candidate of its class and is currently being investigated as monotherapy as well as in ...

5. researchgate.net researchgate.net/publication/385734266_CTNI-58_A_PHASE_02_TRIAL_OF_ABEMACICLIB_PLUS_LY3214996_IN_RECURRENT_GLIOBLASTOMA

CTNI-58. A PHASE 0/2 TRIAL OF ABEMACICLIB PLUS ... CONCLUSION Abemaciclib and LY3214996 achieved pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue in 80% and 30% of the patients, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9463526/

Simultaneous determination of LY3214996, abemaciclib, and ... The LC-MS/MS method was validated to measure LY3214996, abemaciclib, M2 and M20 in human plasma, brain tumor, and CSF.

7. delta.larvol.com delta.larvol.com/Products/?ProductId=e64cfd4d-8116-4b85-9480-b4653d7ef1e0

temuterkib (LY3214996) / Eli Lilly ... LY3214996 ± Abemaciclib had a manageable safety ... Delicious. November 07, 2024. A phase 0/2 trial of abemaciclib plus LY3214996 in recurrent glioblastoma.