Avutometinib + Defactinib + Chemotherapy for Pancreatic Cancer

(RAMP205 Trial)

Recruiting at 11 trial locations

Overseen By Verastem Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Verastem, Inc.

Must not be taking: MEK inhibitors, FAK inhibitors

Disqualifiers: Heart disease, Severe lung disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment combining two experimental drugs with two existing treatments for patients with newly diagnosed pancreatic cancer. The goal is to see if this combination can safely and effectively stop cancer growth and kill cancer cells. The study focuses on patients who have not yet received any treatment. One of the existing treatments used in the trial has been important in pancreatic cancer treatment but offers only modest improvements in symptoms and survival.

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, but it excludes those who have had prior treatment for pancreatic cancer or certain other conditions. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Avutometinib, Defactinib, and Chemotherapy for pancreatic cancer?

Research shows that combining nab-paclitaxel with gemcitabine improves survival rates in patients with advanced pancreatic cancer compared to using gemcitabine alone. ^{1 2 3 4 5}

Is the combination of Avutometinib, Defactinib, and chemotherapy safe for humans?

The combination of nab-paclitaxel and gemcitabine, which are part of the chemotherapy regimen, has been shown to have an acceptable safety profile in patients with advanced pancreatic cancer. However, specific safety data for the combination with Avutometinib and Defactinib is not provided in the available research. ^{2 6 7 8 9}

What makes the drug combination Avutometinib + Defactinib + Chemotherapy unique for pancreatic cancer?

This drug combination is unique because it includes Avutometinib and Defactinib, which are targeted therapies that may work differently from standard chemotherapy by inhibiting specific pathways in cancer cells, potentially offering a new approach to treating pancreatic cancer compared to traditional treatments like gemcitabine alone. ^{4 5 10 11 12}

Research Team

MD Verastem

Principal Investigator

Verastem, Inc.

Eligibility Criteria

This trial is for adults with untreated metastatic pancreatic ductal adenocarcinoma (PDAC), who are in good physical condition (ECOG ≤ 1) and have measurable disease. They must have proper organ and heart function, and agree to use effective contraception. Excluded are those with neuroendocrine tumors, prior PDAC treatments, RAS/MAPK or FAK inhibitor history, other recent malignancies unless cured, major surgery within the last month, severe heart/lung diseases, eye disorders, lung conditions like fibrosis or edema, or a recent SARS-CoV-2 infection.

Inclusion Criteria

My organs are working well.

My cancer is a type of pancreatic cancer that has spread.

I am fully active or can carry out light work.

Exclusion Criteria

I have received treatment for advanced pancreatic cancer.

I have a pancreatic neuroendocrine tumor.

I have an eye condition.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive gemcitabine, nab-paclitaxel, avutometinib (VS-6766), and defactinib to determine the recommended phase 2 dose (RP2D) and assess efficacy

6 months

Follow-up

Participants are monitored for safety, efficacy, and overall survival after treatment

24 months

Long-term follow-up

Participants are monitored for overall survival and disease progression

Up to 5 years

Treatment Details

Interventions

• Avutometinib (VS-6766)
• Defactinib
• Gemcitabine
• Nab-paclitaxel

Trial Overview The study tests the safety and effectiveness of avutometinib (VS-6766) combined with defactinib alongside standard chemotherapy drugs gemcitabine and nab-paclitaxel in patients who haven't been treated before for their pancreatic cancer. The goal is to see if this combination works better than current treatments.

Participant Groups

Group I: Gemcitabine + nab-paclitaxel + avutometinib (VS-6766) + defactinib RP2D Experimental Treatment 1 Intervention

To determine the efficacy of the RP2D identified in Part A in untreated metastatic PDAC patients

Group II: Gemcitabine + nab-paclitaxel + avutometinib (VS-6766) + defactinib Experimental Treatment 1 Intervention

To determine the recommended phase 2 dose (RP2D) for gemcitabine Gemcitabine + nab-paclitaxel + avutometinib (VS-6766) + defactinib in patients with untreated metastatic PDAC.

Avutometinib (VS-6766) is already approved in United States for the following indications:

Approved in United States as Avutometinib for:

• Recurrent low-grade serous ovarian cancer (Breakthrough Therapy Designation)

Who Is Running the Clinical Trial?

Verastem, Inc.

Lead Sponsor

Trials

42

Recruited

2,800+

Findings from Research

In a study of patients with resected pancreatic ductal adenocarcinoma (PDAC), adjuvant chemotherapy with nab-paclitaxel plus gemcitabine (AG) significantly improved median disease-free survival (15.8 months) and overall survival (28.3 months) compared to gemcitabine alone (12.2 months and 20.6 months, respectively).

While AG showed better survival outcomes, it also led to a higher incidence of sensory neuropathy (53.3% in AG vs. 23.3% in GEM), indicating a trade-off between efficacy and side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant nab-paclitaxel plus gemcitabine vs gemcitabine alone for resected pancreatic ductal adenocarcinoma: A single center experience in China. Yin, ZZ., Zhao, ZM., Tang, WB., et al.[2020]

A study of 5465 patients with advanced pancreatic cancer in Ontario showed that the introduction of new chemotherapy regimens, GEMNAB and FOLFIRINOX, significantly improved overall survival rates over time, with median survival increasing from 5.6 months to 7.6 months between 2008 and 2018.

FOLFIRINOX was found to provide better overall survival compared to GEMNAB, particularly in younger and healthier patients, while GEMNAB still showed improved survival compared to the older standard treatment, gemcitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer. Raphael, MJ., Raskin, W., Habbous, S., et al.[2023]

In a subanalysis of the MPACT trial involving 63 Canadian patients with metastatic pancreatic cancer, nab-paclitaxel plus gemcitabine (nab-P + Gem) showed a median overall survival of 11.9 months compared to 7.1 months for gemcitabine alone, indicating that nab-P + Gem is an effective treatment option.

The safety profile of nab-P + Gem was manageable, with common grade ≥3 adverse events including neutropenia (22%), fatigue (34%), and neuropathy (25%), suggesting that while there are risks, the benefits in terms of efficacy are significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

nab-Paclitaxel Plus Gemcitabine Versus Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma: Canadian Subgroup Analysis of the Phase 3 MPACT Trial. Tehfe, M., Dowden, S., Kennecke, H., et al.[2023]

Recent studies indicate that gemcitabine, either alone or in combination with 5-fluorouracil and radiation, plays a significant role in the treatment of resected and locally advanced pancreatic cancer, although survival rates remain low.

Combination therapies involving gemcitabine with other agents like oxaliplatin or capecitabine have shown improved response rates in clinical trials, but they have not significantly enhanced overall survival according to phase III trial results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic cancer: are we moving forward yet? Highlights from the Gastrointestinal Cancers Symposium. Orlando, FL, USA. January 20th, 2007. Saif, MW.[2018]

Chemotherapy for unresectable and metastatic pancreatic cancer, particularly with 5-fluorouracil, has shown minimal benefits, with no improvement in overall survival rates.

Gemcitabine is a promising new treatment that has demonstrated clinical benefits in about 25% of pancreatic cancer cases, making it a more effective option compared to traditional therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy of adenocarcinoma of the pancreas. Schnall, SF., Macdonald, JS.[2022]

In a meta-analysis of 16 studies involving 3813 patients with metastatic pancreatic cancer, both GEM-NAB and FOLFIRINOX showed similar overall survival rates, despite FOLFIRINOX having a numerically longer median overall survival.

GEM-NAB was associated with lower rates of nausea and severe neutropenia compared to FOLFIRINOX, while FOLFIRINOX had lower rates of neurotoxicity and anemia, indicating that the choice between these treatments may depend on the patient's tolerance to side effects rather than a clear efficacy advantage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Effectiveness of Gemcitabine plus Nab-Paclitaxel and FOLFIRINOX in the First-Line Setting of Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis. Pusceddu, S., Ghidini, M., Torchio, M., et al.[2020]

Itacitinib, a selective JAK1 inhibitor, combined with nab-paclitaxel and gemcitabine, showed an acceptable safety profile and clinical activity in patients with advanced solid tumors, including pancreatic cancer, with a 24% overall response rate across various doses.

The study indicated that while itacitinib was tolerated at lower doses, treatment-related toxicities such as neutropenia and fatigue were common, leading to dose adjustments; however, the study was terminated early due to negative results from a related phase III trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors. Beatty, GL., Shahda, S., Beck, T., et al.[2022]

The combination of nab-paclitaxel and gemcitabine remains the standard first-line treatment for pancreatic cancer, but ongoing research is exploring the addition of other therapeutic agents to improve patient outcomes.

A review of seven studies suggests that combining nab-paclitaxel and gemcitabine with agents like ibrutinib and necuparanib may enhance treatment efficacy, although further research is needed to determine the safest and most effective combinations for patients with untreated metastatic pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Review on the Efficacy and Safety of Nab-Paclitaxel with Gemcitabine in Combination with Other Therapeutic Agents as New Treatment Strategies in Pancreatic Cancer. Chapa-González, C., López, K., Lomelí, KM., et al.[2022]

In a study of 27 patients with unresectable pancreatic cancer, nab paclitaxel plus gemcitabine was found to be effective and well-tolerated in elderly patients aged 75 and older, showing similar disease control rates and overall survival compared to younger patients.

Despite a lower relative dose intensity of the drugs in the elderly group, the safety profile was comparable, with neutropenia being the most common severe adverse event, indicating that this treatment regimen can be safely administered to older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of nab paclitaxel plus gemcitabine in elderly patients over 75 years with unresectable pancreatic cancer compared with younger patients. Ishimoto, U., Kinoshita, A., Hirose, Y., et al.[2022]

Fewer than 20% of pancreatic cancer patients have tumors confined to the pancreas, highlighting the need for effective treatment strategies for advanced disease, as about 40% present with locally advanced cancer.

Gemcitabine is established as the first-line treatment for pancreatic cancer, showing significant clinical benefits, and is being explored in combination with various other agents like 5-fluorouracil and irinotecan to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions in the treatment of pancreatic cancer. Haller, DG.[2022]

Gemcitabine remains the standard treatment for advanced pancreatic cancer, but combination therapies with other chemotherapeutic agents have shown improved response rates without significantly extending survival, based on recent phase III trials.

Research is ongoing into novel therapies that target specific molecular pathways in pancreatic cancer cells, suggesting that future treatments may combine traditional chemotherapy with these new targeted approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A review of systemic therapy for advanced pancreatic cancer. El-Rayes, BF., Philip, PA.[2007]

In a comparison of two chemotherapy regimens for metastatic pancreatic cancer, FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GN), both treatments showed equivalent overall survival of 11.1 months and similar progression-free survival rates, indicating comparable efficacy.

However, the safety profiles differed: GN was associated with more frequent grade 3/4 anemia, while FFX led to higher rates of grade 3/4 vomiting and diarrhea, suggesting that while both treatments are effective, their side effects vary significantly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Equivalent Efficacy but Different Safety Profiles of Gemcitabine Plus Nab-Paclitaxel and FOLFIRINOX in Metastatic Pancreatic Cancer. Rapposelli, IG., Casadei-Gardini, A., Vivaldi, C., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Adjuvant nab-paclitaxel plus gemcitabine vs gemcitabine alone for resected pancreatic ductal adenocarcinoma: A single center experience in China. [2020]

2. United States pubmed.ncbi.nlm.nih.gov

The Association of Drug-Funding Reimbursement With Survival Outcomes and Use of New Systemic Therapies Among Patients With Advanced Pancreatic Cancer. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

nab-Paclitaxel Plus Gemcitabine Versus Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma: Canadian Subgroup Analysis of the Phase 3 MPACT Trial. [2023]

4. Italy pubmed.ncbi.nlm.nih.gov

Pancreatic cancer: are we moving forward yet? Highlights from the Gastrointestinal Cancers Symposium. Orlando, FL, USA. January 20th, 2007. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Chemotherapy of adenocarcinoma of the pancreas. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative Effectiveness of Gemcitabine plus Nab-Paclitaxel and FOLFIRINOX in the First-Line Setting of Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis. [2020]

7. England pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of the JAK1 Inhibitor, Itacitinib, plus nab-Paclitaxel and Gemcitabine in Advanced Solid Tumors. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

A Review on the Efficacy and Safety of Nab-Paclitaxel with Gemcitabine in Combination with Other Therapeutic Agents as New Treatment Strategies in Pancreatic Cancer. [2022]

9. Germany pubmed.ncbi.nlm.nih.gov

The efficacy and safety of nab paclitaxel plus gemcitabine in elderly patients over 75 years with unresectable pancreatic cancer compared with younger patients. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Future directions in the treatment of pancreatic cancer. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

A review of systemic therapy for advanced pancreatic cancer. [2007]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Equivalent Efficacy but Different Safety Profiles of Gemcitabine Plus Nab-Paclitaxel and FOLFIRINOX in Metastatic Pancreatic Cancer. [2022]