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Galunisertib

This article provides an overview of clinical trials using galunisertib (also known as LY2157299), a small molecule inhibitor that targets the TGF-β signaling pathway. Galunisertib has been investigated across multiple cancer types, including hepatocellular carcinoma, pancreatic cancer, glioblastoma, colorectal cancer, and others. Clinical trials have evaluated galunisertib both as a monotherapy and in combination with other treatments such as chemotherapy, immunotherapy, and radiation therapy. These studies aim to assess the safety, tolerability, effectiveness, and pharmacokinetic properties of galunisertib in patients with various advanced cancers.

Table of Contents

What is Galunisertib?

Galunisertib, also known by its research code LY2157299, is an investigational anti-cancer medication that is being studied for the treatment of various types of cancer. It belongs to a class of drugs called TGF-β receptor I kinase inhibitors, which means it targets a specific pathway in the body that can contribute to cancer growth[1]. This medication is not yet approved for regular use outside of clinical trials, which are research studies that test how well new medical approaches work in people. Researchers are studying galunisertib to learn if it can help treat different types of cancer, either alone or in combination with other treatments[2].

How Galunisertib Works

Galunisertib works by blocking a protein called Transforming Growth Factor-beta (TGF-β), specifically by inhibiting the TGF-β receptor I kinase. The TGF-β pathway plays an important role in many cellular processes, including cell growth, immune system function, and tissue repair[3]. In normal cells, TGF-β helps control cell growth and division. However, in cancer, this pathway can become dysregulated and actually help cancer cells grow, spread, and evade the immune system. By blocking this pathway, galunisertib may help[4]:
  • Slow or stop cancer cell growth
  • Reduce the ability of cancer to spread (metastasize) to other parts of the body
  • Help the immune system recognize and attack cancer cells
  • Potentially overcome resistance to other cancer treatments

Conditions Treated with Galunisertib

Based on clinical trials, galunisertib is being investigated for the treatment of several types of cancer, including[5][6]:
  • Hepatocellular Carcinoma (HCC) – A type of liver cancer
  • Pancreatic Cancer – Especially advanced or metastatic pancreatic cancer
  • Glioblastoma – An aggressive type of brain tumor
  • Colorectal Cancer – Particularly advanced cases with specific genetic features
  • Non-Small Cell Lung Cancer (NSCLC) – Especially recurrent or refractory cases
  • Myelodysplastic Syndromes (MDS) – A group of disorders where the bone marrow doesn’t produce enough healthy blood cells
  • Triple-Negative Breast Cancer – A type of breast cancer that tests negative for estrogen receptors, progesterone receptors, and excess HER2 protein
  • Ovarian Carcinosarcoma – A rare type of cancer that contains features of both carcinomas and sarcomas

How Galunisertib is Administered

Galunisertib is typically administered as an oral medication in tablet form. Based on clinical trials, the common dosing schedule is[7]:
  • Taken twice daily (morning and evening)
  • Usually following a pattern of 14 days on the medication, followed by 14 days off (a 28-day cycle)
  • Common dosages range from 80 mg to 150 mg twice daily, depending on the specific trial and condition being treated
The medication may be taken with or without food, though some studies have evaluated the effect of food on how the drug is absorbed by the body[8].

Current Clinical Research

Galunisertib is being evaluated in various phases of clinical trials. These trials are designed to assess[9]:
  • Safety and side effects – Understanding how the drug affects the body and what side effects it may cause
  • Effective dosage – Determining the right amount of the drug to give patients
  • How the drug works in the body – Studying how the drug is absorbed, distributed, metabolized, and eliminated
  • Effectiveness – Measuring how well the drug works against different types of cancer
Many of these studies are examining galunisertib both as a single agent (monotherapy) and in combination with other cancer treatments[1].

Combination Therapies

Research shows that galunisertib may work better when combined with other cancer treatments. Some of the combinations being studied include[10][11]:
  • Galunisertib + Sorafenib – For liver cancer (HCC)
  • Galunisertib + Gemcitabine – For pancreatic cancer
  • Galunisertib + Nivolumab or Durvalumab – These are immunotherapy drugs (anti-PD-1/PD-L1 antibodies) being tested in combination with galunisertib for various cancers
  • Galunisertib + Lomustine – For recurrent glioblastoma (brain tumor)
  • Galunisertib + Capecitabine – For colorectal cancer, especially those with TGF-β activation
  • Galunisertib + Paclitaxel – For triple-negative breast cancer
  • Galunisertib + Enzalutamide – For prostate cancer
  • Galunisertib + Radiation therapy – Being tested in several cancer types
These combinations are designed to target cancer through multiple pathways simultaneously, potentially making the treatment more effective than either drug alone[12].

Potential Side Effects

As with any medication, galunisertib may cause side effects. Based on clinical trials, some potential side effects may include[13]:
  • Fatigue
  • Nausea
  • Diarrhea
  • Decreased appetite
  • Vomiting
  • Abdominal pain
  • Changes in liver function tests
  • Anemia (low red blood cell count)
It’s important to note that the side effects can vary depending on the dosage, the specific combination of treatments, and individual patient factors. In clinical trials, researchers carefully monitor patients for side effects and adjust treatment as needed[4].

Effectiveness of Galunisertib

The effectiveness of galunisertib is still being evaluated in clinical trials. Some studies have shown promising results in certain cancer types, including[14]:
  • Improved survival in some patients with hepatocellular carcinoma
  • Signs of activity in pancreatic cancer when combined with gemcitabine
  • Potential benefit in glioblastoma patients
  • Possible effects on specific biomarkers that indicate the drug is working as intended
However, it’s important to understand that results can vary significantly between individuals, and more research is needed to fully understand which patients are most likely to benefit from this treatment[15].

Monitoring During Treatment

During treatment with galunisertib in clinical trials, patients are typically monitored with[12]:
  • Regular blood tests – To check blood cell counts, liver function, and other important values
  • Imaging scans – Such as CT scans or MRIs to assess how the cancer is responding to treatment
  • Electrocardiograms (ECGs) – To monitor heart activity, as some studies evaluate the effect of galunisertib on the electrical activity of the heart
  • Regular check-ups – To assess overall health and any side effects
Some trials also collect blood samples to measure levels of the drug in the bloodstream and to look for biomarkers that might indicate how well the treatment is working[16].

Important Considerations for Patients

If you’re considering participating in a clinical trial involving galunisertib, here are some important points to consider[10]:
  • Clinical trial participation – Because galunisertib is an investigational drug, it’s only available through participation in clinical trials
  • Eligibility criteria – Each trial has specific requirements for who can participate, including factors like cancer type, stage, previous treatments, and overall health
  • Treatment schedule – Understanding the time commitment required for taking the medication and attending follow-up appointments
  • Potential benefits and risks – Discussing with your healthcare team what potential benefits you might experience and what risks you should be aware of
  • Alternative treatments – Understanding what other treatment options are available for your specific condition
  • Insurance coverage – While the study medication is typically provided at no cost in clinical trials, other aspects of care may or may not be covered by insurance
It’s essential to have thorough discussions with your healthcare team about these considerations before deciding whether to participate in a clinical trial[1].
Category Details
Drug Name Galunisertib (LY2157299)
Mechanism of Action TGF-β receptor I kinase inhibitor
Administration Oral tablets, typically 150mg twice daily for 14 days followed by 14 days off (28-day cycle)
Cancer Types Studied Hepatocellular carcinoma, pancreatic cancer, glioblastoma, colorectal cancer, non-small cell lung cancer, myelodysplastic syndromes, triple-negative breast cancer, ovarian carcinosarcoma, prostate cancer, nasopharyngeal carcinoma
Combination Therapies Chemotherapy (gemcitabine, capecitabine, paclitaxel, carboplatin, lomustine), immunotherapy (nivolumab, durvalumab), targeted therapies (sorafenib, enzalutamide, ramucirumab), radiation therapy
Key Outcomes Measured Safety, tolerability, overall survival, progression-free survival, objective response rate, pharmacokinetics, biomarker changes, quality of life
Trial Phases Phase 1, Phase 1b, Phase 2, Phase 2/3, and combination Phase 1b/2 studies
Common Study Designs Dose-escalation studies, randomized controlled trials, umbrella trials, combination therapy trials
Safety Monitoring Evaluation of dose-limiting toxicities, adverse events, laboratory parameters, cardiac monitoring (QT interval)
Biomarker Assessments TGF-β levels, alpha-fetoprotein (AFP) for liver cancer, immune cell subsets, cytokine levels, tumor molecular profiling

FAQ

  • What is galunisertib and how does it work? Galunisertib (also known as LY2157299) is a small molecule inhibitor that targets the TGF-β receptor I kinase, which is part of the transforming growth factor-beta (TGF-β) signaling pathway. TGF-β plays multiple roles in cancer development, including promoting tumor growth, suppressing the immune system, and enabling cancer spread. By blocking this receptor, galunisertib aims to interrupt these cancer-promoting signals and potentially slow cancer growth or make tumors more responsive to other treatments.
  • In which types of cancer has galunisertib been studied? Based on the clinical trials data, galunisertib has been studied in multiple cancer types, including hepatocellular carcinoma (liver cancer), pancreatic cancer, glioblastoma (brain cancer), colorectal cancer with peritoneal metastases, non-small cell lung cancer, myelodysplastic syndromes, triple-negative breast cancer, ovarian carcinosarcoma, prostate cancer, and nasopharyngeal carcinoma. The drug has been investigated in both early and advanced stages of these cancers.
  • How is galunisertib administered to patients? Galunisertib is administered orally as tablets. The typical dosing schedule in most trials is 150 mg taken twice daily for 14 days, followed by 14 days with no treatment (a 28-day cycle). Some trials tested different doses ranging from 40 mg to 300 mg daily. This intermittent dosing schedule (14 days on, 14 days off) appears to be designed to manage potential side effects while maintaining therapeutic effectiveness.
  • What other treatments has galunisertib been combined with in clinical trials? Galunisertib has been studied in combination with various other cancer treatments, including: chemotherapy agents (gemcitabine, capecitabine, paclitaxel, carboplatin, lomustine); immunotherapy drugs (nivolumab, durvalumab – both PD-1/PD-L1 inhibitors); targeted therapies (sorafenib, enzalutamide, ramucirumab); and radiation therapy (including stereotactic body radiotherapy and conventional radiotherapy). These combination approaches aim to enhance treatment effectiveness by targeting cancer through multiple mechanisms simultaneously.
  • What are the main outcomes being measured in galunisertib clinical trials? The main outcomes measured in galunisertib clinical trials include: safety and tolerability (monitoring adverse events and determining the maximum tolerated dose); efficacy measurements such as overall survival, progression-free survival, time to tumor progression, and objective response rate; pharmacokinetic properties (how the drug is absorbed, distributed, and eliminated from the body); biomarker changes (like TGF-β levels and immune markers); quality of life assessments; and specific disease-related symptoms. In early phase trials, safety is the primary focus, while later phase trials emphasize effectiveness against cancer.

Ongoing Clinical Trials on Galunisertib

  • Study of Galunisertib and Capecitabine for Patients with Advanced Chemotherapy-Resistant Colorectal Cancer with Peritoneal Metastases

    Recruiting

    1 1 1
    Investigated diseases:
    Investigated drugs:
    The Netherlands

Glossary

  • TGF-β (Transforming Growth Factor-Beta): A protein that controls cell growth, cell division, and other functions in cells. In cancer, TGF-β can promote tumor growth, suppress the immune system, and help cancer spread to other parts of the body. Galunisertib works by blocking the TGF-β signaling pathway.
  • Galunisertib: A small molecule inhibitor (also known as LY2157299) that blocks the kinase domain of the TGF-β receptor I, preventing TGF-β signaling. It is being studied as a potential treatment for various types of cancer.
  • Pharmacokinetics (PK): The study of how a drug moves through the body, including how it's absorbed, distributed in tissues, broken down, and eliminated. PK measurements include maximum concentration (Cmax), time to maximum concentration (Tmax), and area under the curve (AUC).
  • Overall Survival (OS): The length of time from either the date of diagnosis or the start of treatment that patients are still alive. This is a key measure of effectiveness for cancer treatments in clinical trials.
  • Progression-Free Survival (PFS): The length of time during and after treatment that a patient lives with cancer without the disease getting worse. PFS is measured from the start of treatment until the cancer progresses or the patient dies from any cause.
  • Objective Response Rate (ORR): The percentage of patients whose cancer shrinks or disappears after treatment. It combines the complete response (CR) and partial response (PR) rates.
  • Dose-Limiting Toxicity (DLT): Side effects of a drug that are severe enough to prevent an increase in dose or that require a dose to be reduced. Identifying DLTs helps determine the maximum tolerated dose.
  • Maximum Tolerated Dose (MTD): The highest dose of a drug that can be given without causing unacceptable side effects. This is typically determined in Phase 1 clinical trials.
  • Recommended Phase 2 Dose (RP2D): The dose determined in Phase 1 trials to be appropriate for further testing in Phase 2 trials. This dose balances potential effectiveness with acceptable side effects.
  • BID: Twice daily dosing (from Latin 'bis in die'). In galunisertib trials, the drug was typically given as oral tablets twice daily.
  • RECIST: Response Evaluation Criteria in Solid Tumors – a standard way to measure how well a cancer patient responds to treatment based on changes in tumor size observed in imaging tests.
  • Complete Response (CR): The disappearance of all target tumors. No new tumors can be detected, and tumor markers (if applicable) must return to normal ranges.
  • Partial Response (PR): A decrease of at least 30% in the sum of diameters of target tumors, compared to the baseline measurements.
  • Stable Disease (SD): Neither enough tumor shrinkage to qualify as partial response nor enough increase to qualify as progressive disease.
  • Progressive Disease (PD): At least a 20% increase in the sum of diameters of target tumors or the appearance of new tumors.
  • Hepatocellular Carcinoma (HCC): The most common type of primary liver cancer that begins in the liver cells. Several galunisertib trials focused on this cancer type.
  • Glioblastoma (GB): An aggressive type of cancer that begins in the brain or spinal cord. It's one of the cancer types studied in galunisertib clinical trials.
  • Myelodysplastic Syndromes (MDS): A group of disorders caused by poorly formed or dysfunctional blood cells. Galunisertib was studied in patients with very low, low, and intermediate risk MDS.
  • Best Supportive Care (BSC): Treatment given to improve quality of life by preventing or treating symptoms of the disease or side effects caused by other treatments as early as possible.
  • Peritoneal Metastases (PM): Cancer that has spread to the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). Galunisertib was studied in colorectal cancer with peritoneal metastases.

References

  1. https://clinicaltrials.gov/study/NCT02423343
  2. https://clinicaltrials.gov/study/NCT01722825
  3. https://clinicaltrials.gov/study/NCT02304419
  4. https://clinicaltrials.gov/study/NCT01682187
  5. https://clinicaltrials.gov/study/NCT02178358
  6. https://clinicaltrials.gov/study/NCT02734160
  7. https://clinicaltrials.gov/study/NCT01582269
  8. https://clinicaltrials.eu/trial/study-of-galunisertib-and-capecitabine-for-patients-with-advanced-chemotherapy-resistant-colorectal-cancer-with-peritoneal-metastases/
  9. https://clinicaltrials.gov/study/NCT02008318
  10. https://clinicaltrials.gov/study/NCT02672475
  11. https://clinicaltrials.gov/study/NCT01246986
  12. https://clinicaltrials.gov/study/NCT01373164
  13. https://clinicaltrials.gov/study/NCT01220271
  14. https://clinicaltrials.gov/study/NCT02752919
  15. https://clinicaltrials.gov/study/NCT01965808
  16. https://clinicaltrials.gov/study/NCT03470350
  17. https://clinicaltrials.gov/study/NCT02240433
  18. https://clinicaltrials.gov/study/NCT02452008
  19. https://clinicaltrials.gov/study/NCT02906397
  20. https://clinicaltrials.gov/study/NCT02688712
  21. https://clinicaltrials.gov/study/NCT04605562
  22. https://clinicaltrials.gov/study/NCT01746004