Targeted Drug Therapy for Pancreatic Cancer

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: OHSU Knight Cancer Institute

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: Uncontrolled infection, Cardiac disease, others

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

Compensation: Varies

Number of Visits: 1

Duration: 10 days

90 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how six different drugs—cobimetinib (Cotellic), olaparib (Lynparza), onvansertib, azenosertib, AZD5305, and tremelimumab—affect pancreatic cancer. Researchers aim to determine if these drugs can outperform standard treatments by examining tissue samples before and after treatment. Each drug is tested in separate groups to identify the most effective one. People with resectable, borderline resectable, locally advanced, or metastatic pancreatic cancer might be suitable candidates, especially if their condition allows for tissue biopsy. As an Early Phase 1 trial, this research focuses on understanding how these treatments work in people, offering participants the opportunity to receive potentially groundbreaking therapies.

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).

Is there any evidence suggesting that this trial's treatments are likely to be safe?

In previous studies, olaparib has shown serious side effects, including bone marrow issues such as Myelodysplastic Syndrome (a bone marrow disorder) or Acute Myeloid Leukemia (a type of blood cancer). About 40% of patients experienced severe side effects.

Cobimetinib, another drug under study, has been tested with other treatments and is generally considered safe. In some trials, patients tolerated it well, but like all medications, it can have side effects.

Onvansertib has shown positive results in treating pancreatic cancer. It passed important safety checks in combination studies, indicating it is safe enough for further research.

For azenosertib, safety data from trials with over 1,500 people suggest it is well-tolerated, even over long periods. This data is promising for its safety in humans.

AZD5305, a new cancer drug, has shown a promising safety profile in early studies. It is more tolerable than older drugs in its class, causing fewer or less severe side effects.

Lastly, tremelimumab was tolerated in studies with pancreatic cancer patients. Some patients experienced mild to moderate side effects, but its single-dose form helps activate the body's immune response against tumors.

These drugs are in early testing phases, meaning they are still being evaluated for safety. This phase aims to ensure they are safe before larger trials, a standard process in drug development. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for pancreatic cancer because they represent a diverse array of innovative approaches. Unlike traditional chemotherapy, which targets rapidly dividing cells, cobimetinib modifies specific signaling pathways to potentially halt cancer growth more precisely. Onvansertib is unique due to its role as a PLK1 inhibitor, which may disrupt cell division in cancer cells. Olaparib, a PARP inhibitor, targets DNA repair processes, potentially leading to cancer cell death. Azenosertib and AZD5305 also focus on novel pathways to impede cancer progression, offering hope for more targeted and effective interventions. Tremelimumab stands out as an immune checkpoint inhibitor, aiming to boost the body's immune response against cancer cells. These treatments, with their unique mechanisms, could offer new hope where traditional approaches have limited success.

What evidence suggests that this trial's treatments could be effective for pancreatic cancer?

Research has shown promising results for several treatments studied in this trial for pancreatic cancer. Participants may receive Olaparib, which has proven effective for patients with a specific genetic change (BRCA), helping them live longer without cancer progression compared to those on a placebo. Another option is Cobimetinib, which, when combined with other drugs, has helped stop tumor growth, allowing patients to exceed expected survival times. Onvansertib has shown promise in shrinking tumors and improving patient response. Azenosertib, when combined with gemcitabine, has shown potential by targeting stress in cancer cells. AZD5305, a new drug in this trial, has demonstrated better tumor-shrinking results compared to older treatments in early studies. Lastly, tremelimumab has been part of studies showing some survival benefits, though its effectiveness is still under exploration. These treatments offer hope, but further research is needed to confirm their benefits. ^{1 2 4 6 7}

Who Is on the Research Team?

Charles D. Lopez

Principal Investigator

OHSU Knight Cancer Institute

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Cobimetinib
• LY3214996
• Olaparib
• Onvansertib

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.

How Is the Trial Designed?

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

Who Is Running the Clinical Trial?

OHSU Knight Cancer Institute

Lead Sponsor

Trials

239

Recruited

2,089,000+

American Association for Cancer Research

Collaborator

Trials

9

Recruited

830+

Cardiff Oncology

Industry Sponsor

Trials

12

Recruited

650+

Oregon Health and Science University

Collaborator

Trials

1,024

Recruited

7,420,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

Complete surgical resection is the only potentially curative option for pancreatic cancer, but most patients are diagnosed with advanced disease, leading to a median survival of only 6 months with standard gemcitabine-based therapy.

Recent phase III trials have shown that combining gemcitabine with erlotinib or capecitabine significantly improves overall survival compared to gemcitabine alone, indicating potential new strategies for treating advanced pancreatic cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New directions in the management of advanced pancreatic cancer: a review. Rocha-Lima, CM.[2022]

The combination of cediranib and olaparib did not show clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who do not have a known BRCA mutation, as no objective responses were observed in the study of 19 patients.

Despite some patients experiencing stable disease for a median of 3.1 months, the overall survival was only 3.4 months, indicating limited efficacy of this treatment combination in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. Kim, JW., Cardin, DB., Vaishampayan, UN., et al.[2022]

Pancreatic cancer has a very low 5-year survival rate of less than 7%, and current therapies have not significantly improved patient outcomes, with median overall survival (MoS) for standard treatments like gemcitabine and fluorouracil being around 23 months.

Some clinical trials of new small molecule inhibitors show promise, such as a phase I trial with vorinostat and capecitabine achieving a MoS of 13 months, and a phase II trial of pazopanib showing a MoS of 25 months, indicating potential for improved treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Small molecule inhibitors in pancreatic cancer. Sun, J., Russell, CC., Scarlett, CJ., et al.[2023]

Recent advances in targeted therapy and immunotherapy show promise for treating pancreatic ductal adenocarcinoma (PDAC), which is often diagnosed at advanced stages and has limited treatment options.

Combining these new therapies may enhance treatment effectiveness and improve patient outcomes, as supported by current preclinical and clinical evidence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Translational advances in pancreatic ductal adenocarcinoma therapy. Hosein, AN., Dougan, SK., Aguirre, AJ., et al.[2023]

A patient with advanced pancreatic ductal adenocarcinoma harboring a V600E BRAF mutation showed an objective tumor response to a combination treatment of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib.

This case highlights the potential for targeted therapy in a small subset of pancreatic cancer patients, suggesting that BRAF mutations, although rare, may offer a new avenue for treatment beyond conventional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular Targeting of a BRAF Mutation in Pancreatic Ductal Adenocarcinoma: Case Report and Literature Review. Seghers, AK., Cuyle, PJ., Van Cutsem, E.[2021]

Dovitinib, when combined with gemcitabine and capecitabine, was found to be safe at a recommended dose of 300 mg daily, with manageable side effects such as fatigue and neutropenia in a study involving 29 patients with advanced pancreatic and biliary tract cancers.

The combination treatment showed promising efficacy, with partial responses observed in 5 patients, indicating potential benefits for those suffering from advanced pancreatic cancer.

NCBI (Pubmed)

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. Ma, WW., Xie, H., Fetterly, G., et al.[2022]

Erlotinib, a targeted therapy that inhibits the epidermal growth factor receptor, has been approved for use alongside gemcitabine in treating advanced pancreatic cancer, marking a significant step in personalized cancer treatment.

Despite the exploration of various targeted agents, most have shown limited success, highlighting the need for therapies tailored to the specific molecular characteristics of both the patient and the tumor.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future strategies for targeted therapies and tailored patient management in pancreatic cancer. Ko, AH.[2018]

In a study involving 745 patients with advanced pancreatic cancer, adding the EGFR-targeted drug cetuximab to standard gemcitabine therapy did not significantly improve overall survival compared to gemcitabine alone, with median survival times of 6.3 months versus 5.9 months, respectively.

Despite 90% of patients showing positive EGFR expression, there was no observed treatment benefit from cetuximab, suggesting that targeting EGFR may not be effective and highlighting the need to explore alternative therapeutic targets for pancreatic cancer.

NCBI (Pubmed)

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. Philip, PA., Benedetti, J., Corless, CL., et al.[2022]

Erlotinib, a small molecule tyrosine kinase inhibitor, is approved for treating advanced lung adenocarcinoma and pancreatic cancer, highlighting its efficacy in targeting the EGFR pathway.

Cetuximab, an antibody targeting EGFR, is registered for metastatic colorectal cancer and head and neck cancers, indicating the broad potential of EGFR-targeting therapies in various cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapy of the epidermal growth factor receptor in the treatment of pancreatic cancer. Heeger, S.[2019]

In a phase II trial involving 32 patients with untreated metastatic pancreatic cancer, the combination of erlotinib and capecitabine showed an overall response rate of 6% and a median overall survival of 4.3 months, indicating limited efficacy.

The treatment demonstrated a favorable safety profile, with major non-hematological toxicities being manageable (skin rash, asthenia, and diarrhea), and no grade 4 toxicities or treatment-related deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of erlotinib plus capecitabine as first-line treatment for metastatic pancreatic cancer (XELTA study). López, R., Méndez, CM., Fernández, MJ., et al.[2015]

In a phase II trial involving 17 patients with advanced pancreatic cancer, the combination of sorafenib and gemcitabine showed no objective responses, with only 18% of patients achieving stable disease.

The treatment resulted in a median overall survival of 4.0 months and was associated with significant toxicities, including thrombosis in 18% of patients, indicating that this combination is not effective for this type of cancer.

NCBI (Pubmed)

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. Kindler, HL., Wroblewski, K., Wallace, JA., et al.[2022]

The combination of gemcitabine, capecitabine, bevacizumab, and erlotinib showed promising efficacy in treating advanced pancreatic cancer, with 10 partial responses observed among 20 patients and median overall survival of 12.5 months.

The maximum-tolerated dose of capecitabine was determined to be 1,660 mg/m², with a recommended dose of 1,440 mg/m² for further studies, while the treatment was generally well-tolerated with manageable side effects like diarrhea and skin rash.

NCBI (Pubmed)

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. Starling, N., Watkins, D., Cunningham, D., et al.[2022]

Citations

1. genomemedicine.biomedcentral.com genomemedicine.biomedcentral.com/articles/10.1186/s13073-024-01370-z

The PARP1 selective inhibitor saruparib (AZD5305) elicits ... Results. AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%) ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39187844/

The PARP1 selective inhibitor saruparib (AZD5305) elicits ... Results: AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%) ...

3. cancernetwork.com cancernetwork.com/view/azd5305-yields-promising-clinical-and-safety-findings-across-several-solid-malignancies

AZD5305 Yields Promising Clinical and Safety Findings ... Treatment with the next-generation, highly selective PARP inhibitor AZD5305 resulted in a promising safety profile and compelling clinical activity vs first- ...

4. aacrjournals.org aacrjournals.org/cancerres/article/82/12_Supplement/CT007/701955/Abstract-CT007-PETRA-First-in-class-first-in-human

Abstract CT007: PETRA: First in class, first in human trial of the ... Results: At data cutoff (Nov 17, 2021), 46 pts received AZD5305 10-90 mg QD (43.5% had prior PARPi; median 3.5 prior lines of therapy).

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04644068

NCT04644068 | Study of AZD5305 as Monotherapy and in ... This research is designed to determine if experimental treatment with PARP inhibitor, AZD5305, alone, or in combination with anti-cancer agents is safe, ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9623235/

Preclinical Characterization of AZD5305, A Next- ... In summary, these data show that AZD5305 delivers robust and durable efficacy in the BRCA1/2m models, but not in the BRCA WT/HRR-proficient preclinical models ...

7. aacrjournals.org aacrjournals.org/cancerdiscovery/article/12/7/1602/705195/AZD5305-More-Tolerable-than-Earlier-PARP

AZD5305 More Tolerable than Earlier PARP Agents AZD5305 (AstraZeneca), a first-in-class selective PARP1 inhibitor, show improved safety and tolerability compared with first-generation PARP1/2 inhibitors, as ...