Targeted Drug Therapy for Pancreatic Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Charles D. Lopez

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase < 1

Recruiting

Sponsor: OHSU Knight Cancer Institute

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: Uncontrolled infection, Cardiac disease, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial is testing four experimental drugs to see if they can help treat pancreatic cancer. The drugs work by blocking important processes that cancer cells need to grow and survive. The trial focuses on patients with pancreatic cancer who do not respond well to standard treatments. Gemcitabine was the first agent investigated for its potential to improve symptoms and overall well-being in pancreatic cancer patients.

Will I have to stop taking my current medications?

The trial requires a 10-day period without taking any previous cancer treatments before starting the study drugs. Additionally, you cannot take certain medications that affect liver enzymes (CYP3A) or those that prolong the QT interval (a heart rhythm measure).

What evidence supports the effectiveness of the drug combination including Cobimetinib, Cotellic, LY3214996, Temuterkib, Olaparib, Lynparza, and Onvansertib for pancreatic cancer?

There is some evidence that the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib showed a positive tumor response in a patient with a specific type of advanced pancreatic cancer. However, overall, targeted therapies have not shown significant benefits for most pancreatic cancer patients, and the effectiveness of the specific drug combination in the trial is not directly supported by the available research. ^{1 2 3 4 5}

Is targeted drug therapy for pancreatic cancer generally safe in humans?

Cobimetinib, one of the drugs mentioned, was used in combination with another drug in a case report for pancreatic cancer, showing a tumor response, but specific safety data for this combination in humans is not detailed in the provided research. ^{2 5 6 7 8}

How is the drug combination of Cobimetinib, LY3214996, Olaparib, and Onvansertib unique for treating pancreatic cancer?

This drug combination is unique because it targets specific pathways and molecules involved in the growth and spread of pancreatic cancer cells, unlike traditional chemotherapy that attacks all rapidly dividing cells. Cobimetinib, for example, is a MEK inhibitor that has shown promise in targeting specific mutations in pancreatic cancer, offering a more tailored approach to treatment. ^{5 9 10 11 12}

Eligibility Criteria

Adults (18+) with pancreatic cancer, either resectable or metastatic adenocarcinoma, who can consent to treatment and biopsies. They may be new to treatment or have had prior therapy with a specific washout period. Good organ function is required, and they must not be pregnant or breastfeeding. Contraception use is necessary for participants of childbearing potential.

Inclusion Criteria

Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (> 1500 per mm^3) (within 4 weeks prior to initiating window treatment)

My cancer can potentially be cured with surgery.

Platelet count >= 100 x 10^9/L (> 100,000 per mm^3) (within 4 weeks prior to initiating window treatment)

Exclusion Criteria

I have a condition that affects my ability to swallow or absorb pills.

I am not pregnant or breastfeeding.

I am not taking strong or moderate drugs that affect liver enzymes.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive assigned study agent (cobimetinib, olaparib, onvansertib, azenosertib, AZD5305, or tremelimumab) for 10 days, followed by biopsy or surgery

10 days

1 visit (in-person) for treatment, 1 visit (in-person) for biopsy/surgery

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Cobimetinib (MEK/ERK Inhibitor)
• LY3214996 (MEK/ERK Inhibitor)
• Olaparib (PARP Inhibitor)
• Onvansertib (Other)

Trial Overview The trial tests the effectiveness of cobimetinib, olaparib, LY3214996 (temuterkib), and onvansertib in treating pancreatic cancer by comparing tissue samples before and after treatment. It's an early phase I trial designed to inform future trials based on biomarkers.

Participant Groups

Group I: Arm Tremelimumab Experimental Treatment 1 Intervention

Patients receive tremelimumab IV over 60 minutes one-time. Within 12-24 hours of cycle completion, patients undergo biopsy or surgery as clinically appropriate per institutional standards for management of patient's disease.

Group II: Arm Onvansertib Experimental Treatment 1 Intervention

Patients receive onvansertib PO QD on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery as clinically appropriate per institutional standards for management of patient's disease. (Arm Closed as of 8/12/2024)

Group III: Arm Olaparib Experimental Treatment 1 Intervention

Patients receive olaparib PO BID on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery as clinically appropriate per institutional standards for management of patient's disease. (Arm Closed as of 8/12/2024)

Group IV: Arm Cobimetinib Experimental Treatment 1 Intervention

Patients receive cobimetinib PO QD on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery as clinically appropriate per institutional standards for management of patient's disease. (Arm Closed as of 8/12/2024)

Group V: Arm Azenosertib Experimental Treatment 1 Intervention

Patients receive azenosertib PO QD on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery as clinically appropriate per institutional standards for management of patient's disease.

Group VI: Arm AZD5305 Experimental Treatment 1 Intervention

Patients receive AZD5305 PO QD on days 1-10 in the absence of disease progression or unacceptable toxicity. Within 12-24 hours, patients undergo biopsy or surgery as clinically appropriate per institutional standards for management of patient's disease.

Cobimetinib is already approved in European Union, United States, Canada, Switzerland, Japan for the following indications:

🇪🇺 Approved in European Union as Cotellic for:

• Melanoma

🇺🇸 Approved in United States as Cotellic for:

• Melanoma

🇨🇦 Approved in Canada as Cotellic for:

• Melanoma

🇨🇭 Approved in Switzerland as Cotellic for:

• Melanoma

🇯🇵 Approved in Japan as Cotellic for:

• Melanoma

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

OHSU Knight Cancer Institute Portland, OR

Who Is Running the Clinical Trial?

OHSU Knight Cancer Institute Lead Sponsor

American Association for Cancer Research Collaborator

Cardiff Oncology Industry Sponsor

Oregon Health and Science University Collaborator

Genentech, Inc. Industry Sponsor

References

1. England pubmed.ncbi.nlm.nih.gov

New directions in the management of advanced pancreatic cancer: a review. [2022] Complete surgical resection is the only potentially curative option for pancreatic cancer. However, most patients have advanced/metastatic disease at the time of diagnosis, or will relapse after surgery. Systemic chemotherapy is only palliative. Gemcitabine-based therapy is an acceptable standard for unresectable locally advanced/metastatic pancreatic cancer, but average median survival is only 6 months. The addition of other chemotherapies (including other antimetabolites, platinum, and topoisomerase I inhibitors) or targeted therapies (farnesyl transferase inhibitors, metalloproteinase inhibitors, cetuximab and bevacizumab) to gemcitabine has failed to improve outcome. The combination of gemcitabine and erlotinib, a small-molecule tyrosine kinase inhibitor of the human epidermal growth factor receptor, was recently approved by the US/European authorities for use in advanced disease. In a phase III trial, the combination demonstrated a significant improvement in overall survival compared with gemcitabine monotherapy. Positive efficacy results have also been observed in a phase III trial, favoring the addition of capecitabine to gemcitabine compared with gemcitabine alone. This review focuses on the recent developments in systemic treatment, and discusses how novel agents might be incorporated into future treatment strategies for pancreatic cancer.

2. England pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. [2022] Cediranib and olaparib combination did not result in clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma without known BRCA mutation.

3. England pubmed.ncbi.nlm.nih.gov

Small molecule inhibitors in pancreatic cancer. [2023] Pancreatic cancer (PC), with a 5 year survival of &lt;7%, is one of the most fatal of all human cancers. The highly aggressive and metastatic character of this disease poses a challenge that current therapies are failing, despite significant efforts, to meet. This review examines the current status of the 35 small molecule inhibitors targeting pancreatic cancer in clinical trials and the &gt;50 currently under investigation. These compounds inhibit biological targets spanning protein kinases, STAT3, BET, HDACs and Bcl-2 family proteins. Unsurprisingly, protein kinase inhibitors are overrepresented. Some trials show promise; a phase I combination trial of vorinostat 11 and capecitabine 17 gave a median overall survival (MoS) of 13 months and a phase II study of pazopanib 15 showed a MoS of 25 months. The current standard of care for metastatic pancreatic ductal adenocarcinoma, fluorouracil/folic acid (5-FU, Adrucil&#174;), and gemcitabine (GEMZAR&#174;) afforded a MoS of 23 and 23.6 months (EPAC-3 study), respectively. In patients who can tolerate the FOLFIRINOX regime, this is becoming the standard of treatment with a MoS of 11.1 months. Clinical study progress has been slow with limited improvement in patient survival relative to gemcitabine 1 monotherapy. A major cause of low PC survival is the late stage of diagnosis, occurring in patients who consider typical early stage warning signs of aches and pains normal. The selection of patients with specific disease phenotypes, the use of improved efficient drug combinations, the identification of biomarkers to specific cancer subtypes and more effective designs of investigation have improved outcomes. To move beyond the current dire condition and paucity of PC treatment options, determination of the best regimes and new treatment options is a challenge that must be met. The reasons for poor PC prognosis have remained largely unchanged for 20 years. This is arguably a consequence of significant changes in the drug discovery landscape, and the increasing pressure on academia to deliver short term 'media' friendly short-term news 'bites'. PC research sits at a pivotal point. Perhaps the greatest challenge is enacting a culture change that recognises that major breakthroughs are a result of blue sky, truly innovative and curiosity driven research.

4. England pubmed.ncbi.nlm.nih.gov

Translational advances in pancreatic ductal adenocarcinoma therapy. [2023] Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is most frequently detected at advanced stages, limiting treatment options to systemic chemotherapy with modest clinical responses. Here, we review recent advances in targeted therapy and immunotherapy for treating subtypes of PDAC with diverse molecular alterations. We focus on the current preclinical and clinical evidence supporting the potential of these approaches and the promise of combinatorial regimens to improve the lives of patients with PDAC.

5. France pubmed.ncbi.nlm.nih.gov

Molecular Targeting of a BRAF Mutation in Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review. [2021] Current standard-of-care treatment for advanced pancreatic ductal adenocarcinoma is mainly based on conventional cytotoxic chemotherapy. Until recently, no randomized clinical trials had shown any clinically meaningful outcome benefit from targeted therapy in this indication. This is in contrast to many other tumor types. The majority of pancreatic tumors are driven by KRAS mutations, which are generally not amenable to targeted therapy. Driving mutations in the BRAF oncogene have proven to be an interesting molecular target in the management of advanced melanoma and colorectal adenocarcinoma and can be found in 3% of patients with advanced pancreatic ductal adenocarcinoma. Here, we report objective tumor response to treatment with the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib in a patient with poorly differentiated, V600E mutant, advanced pancreatic ductal adenocarcinoma.

6. Greece pubmed.ncbi.nlm.nih.gov

Phase II trial of erlotinib plus capecitabine as first-line treatment for metastatic pancreatic cancer (XELTA study). [2015] To evaluate the efficacy and safety of erlotinib plus capecitabine for metastatic pancreatic cancer.

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

Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium. [2022] Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease.

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

Dose finding and early efficacy study of gemcitabine plus capecitabine in combination with bevacizumab plus erlotinib in advanced pancreatic cancer. [2022] This study evaluated safety and efficacy of chemotherapy (gemcitabine plus capecitabine) plus bevacizumab/erlotinib in advanced pancreatic cancer because dual epidermal growth factor receptor/vascular endothelial growth factor blockade has a rational biologic basis in this malignancy.

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

A Phase Ib Study of the FGFR/VEGFR Inhibitor Dovitinib With Gemcitabine and Capecitabine in Advanced Solid Tumor and Pancreatic Cancer Patients. [2022] Preclinical studies demonstrated antitumor activity of dovitinib in pancreatic cancer models. This phase Ib study aimed to determine the maximum tolerated dose (MTD) of dovitinib in combination with gemcitabine and capecitabine and to characterize the safety and pharmacokinetic profile in patients with advanced pancreatic and biliary tract cancers and solid malignancies.

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

Future strategies for targeted therapies and tailored patient management in pancreatic cancer. [2018] Pancreatic cancer represents the fourth leading cause of cancer-related mortality in the United States. The vast majority of patients are diagnosed at advanced stages of the disease, at which time gemcitabine-based chemotherapy is typically offered as the standard of care. However, as investigators have arrived at a greater understanding of pancreatic tumor biology, newer therapeutic agents that "target" specific pathways or molecules governing the growth, spread, and maintenance of tumor cells have gained considerable interest. Erlotinib, an orally bioavailable small molecule inhibitor of the epidermal growth factor receptor, is the first of these targeted compounds to be approved for use in combination with gemcitabine for patients with advanced pancreatic cancer. Other targeted agents, including monoclonal antibodies and small molecule inhibitors aimed at a variety of targets, also have been extensively evaluated, with limited success to date. A newer strategy worth pursuing involves tailoring an individual patient's therapy according to the molecular characteristics of both host and tumor, as has shown promise in other solid tumor types.

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

Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-directed intergroup trial S0205. [2022] Patients with advanced pancreas cancer present with disease that is poorly responsive to conventional therapies. Preclinical and early clinical evidence has supported targeting the epidermal growth factor receptor (EGFR) signaling pathway in patients with pancreas cancer. This trial was conducted to evaluate the contribution of an EGFR-targeted agent to standard gemcitabine therapy. Cetuximab is a monoclonal antibody against the ligand-binding domain of the receptor.

12. Germany pubmed.ncbi.nlm.nih.gov

Targeted therapy of the epidermal growth factor receptor in the treatment of pancreatic cancer. [2019] The epidermal growth factor receptor (EGFR)-mediated pathway is one of the most promising targets for the development of new strategies in anticancer treatments. The so-called "small molecule" tyrosine kinase inhibitor erlotinib has gained marketing authorization in the United States for advanced adenocarcinoma of the lung and for pancreatic cancer, whereas the antibody cetuximab is registered for metastatic colorectal cancer and cancers of the head and neck. Ongoing studies are evaluating the impact of EGFR-targeting therapy in the treatment of locally advanced and metastatic pancreatic cancer.