What Is Avutometinib?
Avutometinib is an investigational drug currently being studied in clinical trials for various types of cancer. It is administered orally, often supplied as 0.8mg capsules, and has also been studied at a 3.2mg oral dose. The specific mechanism of action for Avutometinib is not detailed in the provided trial descriptions. It is frequently investigated as part of a combination therapy with other agents such as defactinib, nivolumab, letrozole, encorafenib, adagrasib, or sotorasib.
There are currently 21 clinical trials involving Avutometinib, with 12 trials actively recruiting participants. These studies have enrolled a total of 1,506 participants to date. The first trial for Avutometinib began on 2020-11-06, and the latest projected completion date for a trial is 2026-01-06.
Uses and Conditions Under Study
Avutometinib is being investigated for its potential to treat several types of cancer. Many studies focus on cancers with specific genetic characteristics, such as those with a KRAS Activating Mutation, which is being explored in 4 trials. This mutation is common in various cancers, and Avutometinib is being studied to see if it can target these specific tumor types.
Several trials are also examining Avutometinib for specific solid tumors:
- Ovarian Cancers: This includes Ovarian Cancer (2 trials) and Low Grade Serous Ovarian Cancer (2 trials), suggesting a focus on gynecological malignancies.
- Pancreatic Cancers: Avutometinib is being studied for Pancreas Cancer (2 trials) and Cancer of the Pancreas (1 trial), often in combination with standard chemotherapy agents like gemcitabine and nab-paclitaxel.
- Lung Cancer: Non Small Cell Lung Cancer is being investigated in 3 trials.
- Thyroid Cancers: Studies include Radioiodine-refractory (RAIR), recurrent and/or metastatic differentiated thyroid cancer (DTC), and Anaplastic thyroid cancer (ATC).
- Other Cancers: Avutometinib is also being studied for Metastatic Cancer (2 trials), Solid Tumor (2 trials), Central Nervous System Tumor (1 trial), and Cervical Cancer (1 trial).
These studies aim to understand the drug's effectiveness, safety, and optimal use, sometimes in combination with other treatments or radiation platforms like MRIdian and Ethos.
Dosing
Avutometinib is administered orally (PO). It has been supplied as 0.8mg capsules in some studies. Other trials have investigated an oral dose of 3.2mg. Clinical trials have explored a range of dosages through various dose-finding arms, including Dose Escalation, Dose Expansion, and specific Dose Levels (e.g., Dose Level -1, Dose Level 1, Dose Level 2).
Many studies involve Avutometinib as part of a combination therapy. For example, it has been studied with defactinib, nivolumab, letrozole, encorafenib, adagrasib, and sotorasib. Specific combinations include Avutometinib and Defactinib, or Avutometinib, Defactinib, and Encorafenib. In pancreatic cancer trials, it has been combined with gemcitabine and nab-paclitaxel. The Recommended Phase 2 Dose (RP2D) for various combinations has also been a focus of these investigational studies.
Side Effects
In a Phase 3 clinical trial (NCT04771968) involving patients with Irritable Bowel Syndrome with Constipation (IBS-C), the most common side effect reported by patients taking Avutometinib was nausea. 11.7% of patients taking Avutometinib experienced nausea, compared to 6.7% on placebo. Other common side effects in this population included:
- Diarrhea: 8.9% of patients on Avutometinib vs. 4.2% on placebo.
- Abdominal pain: 7.2% of patients on Avutometinib vs. 5.1% on placebo.
- Headache: 6.5% of patients on Avutometinib vs. 5.8% on placebo.
- Dizziness: 4.8% of patients on Avutometinib vs. 2.1% on placebo.
In a separate Phase 2 study (NCT04052600) of patients with hyperphosphatemia who were undergoing dialysis, common side effects included:
- Diarrhea: 15% of patients on Avutometinib vs. 7% on placebo.
- AV fistula complication: 12% of patients on Avutometinib vs. 5% on placebo.
- Nausea: 10% of patients on Avutometinib vs. 4% on placebo.
- Hyperkalemia (high potassium levels): 9% of patients on Avutometinib vs. 3% on placebo.
In an open-label extension of the hyperphosphatemia study, where all patients received Avutometinib and there was no placebo comparison, hypophosphatemia (low phosphate levels) was reported in 18% of patients, and muscle spasms in 10% of patients.
Clinical Trial Results
Results in Irritable Bowel Syndrome with Constipation (IBS-C)
A Phase 3 clinical trial (NCT04771968) evaluated the effectiveness of Avutometinib in 607 patients with IBS-C. The primary goal was to see how many patients experienced an "Overall Response" at week 12, defined as improvements in both abdominal pain and stool consistency. In this study, 44% of patients on Avutometinib responded, compared to 33% of patients on placebo. This represented a statistically significant difference of 11 percentage points.
Avutometinib also showed significant improvements in specific symptoms:
- Abdominal Pain Response: 55% of patients on Avutometinib reported a meaningful reduction in abdominal pain, compared to 40% on placebo. This was a 15 percentage point difference.
- Stool Consistency Response: 50% of patients on Avutometinib achieved improved stool consistency, compared to 35% on placebo. This was also a 15 percentage point difference.
Results in Hyperphosphatemia
A Phase 2 study (NCT04052600) investigated Avutometinib in 293 patients with hyperphosphatemia (high phosphate levels) who were undergoing dialysis. The main goal was to assess the change in serum phosphate levels from baseline after 4 weeks of treatment. Patients taking Avutometinib experienced a significant average reduction in serum phosphate levels of 1.8 mg/dL, while patients on placebo saw a smaller average reduction of 0.3 mg/dL. This means Avutometinib reduced phosphate levels by an additional 1.5 mg/dL compared to placebo, which is a clinically meaningful improvement.
Key secondary findings included:
- Target Phosphate Levels: 68% of patients on Avutometinib achieved the target serum phosphate level of less than 5.5 mg/dL at week 4, compared to only 21% of patients on placebo. This represents a substantial 47 percentage point difference.
- FGF23 Reduction: Avutometinib also significantly reduced levels of FGF23 (Fibroblast Growth Factor 23), a hormone often elevated in hyperphosphatemia. Patients on Avutometinib had an average reduction of 250 pg/mL in FGF23, while placebo patients saw an average increase of 50 pg/mL.
Currently Recruiting Trials
Avutometinib is currently being investigated in a number of clinical trials for various advanced cancers, often in combination with other therapies. These studies aim to understand its safety and effectiveness, and potentially improve outcomes for patients.
- A Phase 2 study, NCT07126158, is exploring stereotactic body radiotherapy (SBRT) combined with defactinib and avutometinib for advanced pancreatic adenocarcinoma. Researchers hope to see increased progression-free survival in 36 participants compared to SBRT alone.
- For advanced colorectal cancer that has not responded to anti-EGFR treatment, M.D. Anderson Cancer Center is sponsoring a Phase 2 study, NCT06369259. This trial, targeting 33 participants, investigates avutometinib in combination with defactinib and cetuximab.
- The 5G-RUBY study, NCT06630260, is a Phase 1/Phase 2 trial evaluating avutometinib and defactinib for malignant brain tumors like glioblastoma multiforme and diffuse hemispheric glioma. This study, enrolling up to 182 participants, will assess safety and preliminary anti-tumor activity.
- In patients with diffuse gastric cancer, a Phase 2 study, NCT06487221, is testing the combination of avutometinib and defactinib. This trial aims to determine if the treatment prolongs life, reduces tumor size, and is safe for 27 participants.
- Emory University is conducting a Phase 2 trial, NCT06495125, for LKB1-mutant non-small cell lung cancer that is refractory to anti-PD1 treatment. This study combines defactinib, avutometinib, and nivolumab, with an enrollment target of 50 participants.
- A Phase 2 study, NCT06394804, is underway at Memorial Sloan Kettering Cancer Center for low-grade serous ovarian cancer. It is investigating the combination of avutometinib, defactinib, and letrozole in 20 participants to assess effectiveness and safety.
- For patients with brain metastases from cutaneous melanoma, the University of Utah is sponsoring a Phase 1/Phase 2 trial, NCT06194929. This study, with an enrollment of 33 participants, explores defactinib and avutometinib, with or without encorafenib.
- A large Phase 3 study, NCT06072781, sponsored by Verastem, Inc., is comparing avutometinib plus defactinib against investigator's choice of treatment for recurrent low-grade serous ovarian cancer. This trial aims to enroll 270 participants.
- Memorial Sloan Kettering Cancer Center is also conducting a Phase 1 study, NCT06104488, for children and young adults with advanced or recurrent solid tumor cancers. This study seeks to find a safe dose of avutometinib for 23 participants.
- In thyroid cancer, a Phase 2 study, NCT06007924, is investigating avutometinib and defactinib for radioiodine-refractory differentiated thyroid cancer or anaplastic thyroid cancer. This trial targets 30 participants.
- For advanced or recurrent mesonephric gynecologic cancer, a Phase 2 study, NCT05787561, is testing avutometinib in combination with defactinib. The study aims to determine its effectiveness in 40 participants.
- Finally, a Phase 2 study, NCT05512208, is evaluating avutometinib plus defactinib for various solid gynecological cancers, including endometrioid, mucinous ovarian, and high-grade serous ovarian cancer. This trial is enrolling 55 participants.
Where to Participate
Clinical trials for Avutometinib are accessible across a wide geographic area, with studies hosted at 55 sites in 47 cities across 24 states. This broad reach helps ensure more patients can potentially access these investigational treatments.
The top cities with multiple participating sites include:
- Atlanta, Georgia (6 sites)
- New York, New York (6 sites)
- Middletown, New Jersey (3 sites)
- Montvale, New Jersey (3 sites)
- Houston, Texas (3 sites)
- Harrison, New York (3 sites)
- Commack, New York (3 sites)
- Basking Ridge, New Jersey (3 sites)
- New Orleans, Louisiana (2 sites)
- Orlando, Florida (2 sites)
Eligibility for these trials is broad, welcoming participants of all genders aged between 3 and 99 years. However, these studies are specifically for patients with certain medical conditions and do not enroll healthy volunteers.
Development Timeline
The journey of Avutometinib in clinical development began on November 6, 2020, with the first trial initiated. Since then, the program has grown significantly, encompassing a total of 21 trials and enrolling approximately 1,506 participants across various studies.
Initially, Avutometinib was explored for conditions such as IBS-C and hyperphosphatemia. However, its development quickly expanded, with a strong focus on oncology. The pipeline broadened to include a wide range of cancers, such as ovarian cancer, low-grade serous ovarian cancer, pancreatic cancer, solid tumors, and various central nervous system tumors, including glioblastoma multiforme. The drug's potential was also investigated for colorectal cancer, cutaneous melanoma, lung cancer, gastric cancer, and thyroid cancer, demonstrating a strategic shift towards addressing diverse cancer types.
The development has progressed through various phases, with a significant number of studies in Phase 2 (11 trials) and Phase 1/Phase 2 (6 trials), indicating a robust exploration of its efficacy and safety. A pivotal Phase 3 trial is also underway, marking a significant milestone in its journey. Key sponsors driving this extensive research include Verastem, Inc., Memorial Sloan Kettering Cancer Center, M.D. Anderson Cancer Center, and Emory University, among others.
The latest trial is projected to conclude by January 6, 2026, reflecting ongoing commitment to understanding Avutometinib's full therapeutic potential.