Defactinib Clinical Trials

What Is Defactinib?

Defactinib is an investigational drug currently being studied in clinical trials for various types of cancer. It is administered orally, often in capsule form. While the specific mechanism of action is not detailed in the provided information, Defactinib is being explored as a potential treatment, sometimes in combination with other therapies. For example, one study aims to evaluate if Defactinib can safely combine with decitabine/cedazuridine to improve outcomes in people with high-risk myelodysplastic syndrome (MDS), certain forms of Acute Myeloid Leukaemia (AML), and Chronic Myelomonocytic Leukaemia (CMML).

Another clinical trial is investigating Defactinib in combination with Pembrolizumab to determine the highest tolerable dose. Overall, Defactinib has been part of 33 clinical trials involving a total of 8,551 participants, with the first trial starting in 2013 and the latest projected to conclude in 2026. These studies are exploring its use across a range of advanced cancers, often as part of a combination treatment strategy.

Uses and Conditions Under Study

Defactinib is being investigated in clinical trials for a variety of cancers, often focusing on advanced or difficult-to-treat forms. Across 33 total trials, Defactinib has been studied for its potential role in several conditions:

• Ovarian Cancers: Defactinib is being studied in 6 trials for ovarian cancers, including Ovarian Cancer and Low Grade Serous Ovarian Cancer. These studies aim to understand how Defactinib might impact the progression of these gynecological malignancies.
• Pancreatic Cancers: A significant focus is on pancreatic cancers, with Defactinib being evaluated in 8 trials for Pancreas Cancer, Pancreatic Cancer, and Cancer of the Pancreas. This highlights its potential in addressing one of the most challenging cancer types.
• Lung Cancer: For Non Small Cell Lung Cancer, Defactinib is under investigation in 3 trials. Researchers are exploring its efficacy, particularly in advanced stages.
• Mesothelioma: Defactinib is being studied in 2 trials for Malignant Pleural Mesothelioma, a rare and aggressive cancer affecting the lining of the lungs.
• Lymphoma: In 2 trials, Defactinib is being explored for Advanced Lymphoma, a type of blood cancer.
• Cancers with KRAS Activating Mutation: Defactinib is also being specifically investigated in 3 trials for cancers characterized by a KRAS Activating Mutation. This indicates a targeted approach for tumors with this specific genetic alteration.
• Advanced Solid Neoplasms: Beyond specific cancer types, Defactinib is being studied in 2 trials for Advanced Malignant Solid Neoplasm, suggesting its potential broad applicability in various advanced-stage solid tumors.

These studies are sponsored by a range of organizations, including industry partners like Verastem, Inc., and academic institutions such as Memorial Sloan Kettering Cancer Center and Washington University School of Medicine.

Dosing

Defactinib is administered orally and has been studied in various forms and dosages across its clinical trials. It has been supplied as 0.8 mg capsules, and a 3.2 mg oral dose has also been investigated. As an investigational drug, the exact dosing regimen can vary significantly depending on the specific clinical trial and the condition being studied.

Many studies involve Defactinib as part of a combination therapy. Examples of investigational dosing forms and combinations include:

• Dose Escalation and Dose Expansion studies to determine optimal and safe dosages.
• Combination with other agents such as avutometinib (VS-6766), pembrolizumab, decitabine/cedazuridine, nivolumab, encorafenib, letrozole, gemcitabine, nab-paclitaxel, and sotorasib.
• Specific arms of studies, such as "Experimental Arm: SBRT + Defactinib + Avutometinib" or "Arm I (Defactinib)."
• Studies targeting specific genetic mutations, for example, in combination with sotorasib for KRAS G12C inhibitor-naive or exposed patients.

These varied approaches reflect the ongoing research to understand the most effective ways to use Defactinib, either alone or in combination, for different types of cancer.

Side Effects

Specific frequencies of individual side effects for Defactinib are not available in the provided clinical trial data. However, general observations regarding drug-related toxicities were reported.

In a study ( NCT03727880 ) investigating Defactinib combined with pembrolizumab for pancreatic cancer, 6 participants in the combination arm experienced study drug-related toxicities, compared to 3 participants who received pembrolizumab alone.

Another study ( NCT04720417 ) evaluating Defactinib with VS-6766 for metastatic uveal melanoma reported a total of 43 adverse events across all participants in the treatment arm.

Clinical Trial Results

Pancreatic Ductal Adenocarcinoma

A study ( NCT03727880 ) evaluated Defactinib in combination with pembrolizumab as a neoadjuvant and adjuvant treatment for resectable pancreatic ductal adenocarcinoma. Patients received either pembrolizumab with Defactinib or pembrolizumab alone.

• The mean disease-free survival (DFS) was 16.59 months for patients treated with pembrolizumab and Defactinib, compared to 15.99 months for those receiving pembrolizumab alone.
• The mean overall survival (OS) was 25.01 months for the combination arm, while patients on pembrolizumab alone had a mean OS of 27.39 months.
• No participants in either treatment arm achieved a pathologic complete response (pCR).

Cancers with NF2 Genetic Changes

In a study ( NCT04439331 ) testing Defactinib as a targeted treatment for cancers with NF2 genetic changes, the following results were observed:

• The 6-month progression-free survival (PFS) rate was 22.8% of participants.
• The objective response rate (ORR) was 3.2% of participants.
• The median progression-free survival was 1.9 months.

Metastatic Uveal Melanoma

A trial ( NCT04720417 ) investigated Defactinib in combination with VS-6766 for the treatment of patients with metastatic uveal melanoma.

• No participants achieved a best overall response.
• The disease control rate was observed in 6 participants.
• The median progression-free survival (PFS) was 3.04 months.

Dose Escalation in Japanese Subjects

A Phase I dose escalation study ( NCT01943292 ) assessed the safety and tolerability of Defactinib in Japanese subjects with non-hematologic malignancies. The study aimed to define the maximum tolerated dose (MTD) and establish the recommended Phase 2 dose (RP2D). Based on the provided data, the MTD and RP2D were not achieved or reported as "NA mg".

Currently Recruiting Trials

Defactinib is currently being investigated in a number of clinical trials for various cancers, often in combination with other therapies. These studies aim to evaluate the safety and effectiveness of new treatment approaches for patients.

One notable study, NCT06072781, is a Phase 3 trial sponsored by Verastem, Inc., enrolling up to 270 participants with recurrent low-grade serous ovarian cancer. It compares the combination of avutometinib and defactinib against an investigator's choice of treatment to assess safety and efficacy.

Several Phase 2 trials are also actively recruiting. For patients with advanced pancreatic adenocarcinoma, NCT07126158 is studying stereotactic body radiotherapy (SBRT) combined with defactinib and avutometinib, enrolling 36 participants. In the realm of colorectal cancer, NCT06369259 is a Phase 2 study for 33 participants with unresectable, anti-EGFR-refractory advanced colorectal cancer, exploring defactinib with avutometinib and cetuximab.

Brain tumors are also a focus, with NCT06630260, a Phase 1/2 study, evaluating avutometinib and defactinib in 182 patients with malignant brain tumors, including glioblastoma multiforme. Another trial, NCT06194929, is a Phase 1/2 study for 33 participants with brain metastases from cutaneous melanoma, investigating defactinib and avutometinib, with or without encorafenib.

Other Phase 2 trials include NCT06487221 for 27 participants with diffuse gastric cancer, NCT06495125 for 50 patients with LKB1-mutant advanced non-small cell lung cancer that is refractory to anti-PD1 treatment, and NCT06394804 for 20 individuals with low-grade serous ovarian cancer, all combining defactinib with avutometinib and other agents. Thyroid cancer is addressed in NCT06007924, recruiting 30 participants with certain types of thyroid cancer. Mesonephric gynecologic cancer is the focus of NCT05787561, enrolling 40 participants, and NCT05512208 is a broader Phase 2 study for 55 participants with various solid gynecological cancers.

Finally, NCT05636514 is a Phase 1 study for 12 participants with high-risk myelodysplastic syndromes, chronic myelomonocytic leukemia, or acute myeloid leukemia, investigating defactinib in combination with decitabine/cedazuridine.

Where to Participate

Clinical trials for Defactinib are currently recruiting across a wide geographic area, offering opportunities for participation in many regions. These studies are active at 54 sites across 47 cities in 24 states, primarily within the United States.

Some of the top locations with multiple recruiting sites include:

• Atlanta, Georgia
• New York, New York
• Middletown, New Jersey
• Montvale, New Jersey
• Houston, Texas
• Harrison, New York
• Commack, New York

To be eligible for participation in these trials, individuals must generally be between 16 and 99 years of age. All genders are welcome to participate, and while children are eligible for some studies, healthy volunteers are not being recruited for these specific Defactinib trials.

Development Timeline

The journey of Defactinib in clinical development began on January 29, 2013, with the first trial initiated. Since then, a robust research program has unfolded, with the latest trial projected to conclude by January 6, 2026. In total, 33 clinical trials have been conducted or are ongoing, involving a significant number of participants, with a cumulative enrollment of 8,551 individuals.

Early development phases included one Early Phase 1 study and eight Phase 1 studies, focusing on initial safety and dosage. The program quickly expanded into later stages, with 18 Phase 2 trials and five Phase 1/Phase 2 studies, exploring effectiveness in specific conditions. A pivotal moment in its development is the ongoing Phase 3 trial, indicating progression to advanced stages of clinical investigation.

Initially, Defactinib was explored for conditions such as IBS-C and hyperphosphatemia. However, the development pipeline rapidly expanded to focus predominantly on oncology. Key sponsors like Verastem, Inc., leading with 11 trials, along with institutions such as Memorial Sloan Kettering Cancer Center and Washington University School of Medicine, have driven this expansion. The drug's investigation now spans a broad spectrum of cancers, including pancreatic cancer, non-small cell lung cancer, various ovarian cancers, colorectal cancer, glioblastoma, melanoma, thyroid cancer, and several hematologic malignancies like myelodysplastic syndromes and acute myeloid leukemia, reflecting a comprehensive effort to address diverse unmet medical needs.