Combination Therapy for Pancreatic Cancer

(ARC-8 Trial)

Not currently recruiting at 29 trial locations

Overseen By Medical Director

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Arcus Biosciences, Inc.

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Cardiovascular disease, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial investigates a new combination of treatments to determine their safety and effectiveness for individuals with advanced pancreatic cancer. The trial tests a mix of drugs, including AB680 (a CD73 inhibitor), zimberelimab, nab-paclitaxel, and gemcitabine, to identify optimal dosages and observe their effects. It is open to those with confirmed metastatic pancreatic adenocarcinoma who have not received prior treatment for their advanced condition. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking immunosuppressive medications, like high doses of corticosteroids, at least 2 weeks before starting the study. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

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

Research has shown that AB680, a drug tested for advanced pancreatic cancer, is generally safe. In a study with 19 patients, only one experienced a serious side effect, indicating that most handled it well, even when combined with treatments like nab-paclitaxel, gemcitabine, and zimberelimab.

Zimberelimab, another drug in the trial, also has a manageable safety profile. Studies indicate it does not cause unexpected side effects when used with other treatments.

Nab-paclitaxel and gemcitabine are standard chemotherapy drugs for pancreatic cancer. They have been used in many patients and are known to extend survival. Their safety is well-documented, though they can cause side effects like low blood counts and tiredness, common with chemotherapy.

Overall, evidence suggests these treatments are well-tolerated by most patients. However, individual experiences may vary. ^{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 combine innovative agents with standard chemotherapy. AB680 is a standout due to its action as a CD73 inhibitor, which may enhance the immune response against cancer by blocking a pathway that tumors use to evade the immune system. When used alongside zimberelimab, a PD-1 inhibitor, this combination targets different aspects of tumor immune evasion. Additionally, combining these with the standard nab-paclitaxel and gemcitabine offers a multifaceted approach to attacking cancer cells from multiple angles, potentially leading to more effective outcomes compared to current standard treatments alone.

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

Research has shown that AB680, a drug that blocks a specific protein, can significantly enhance chemotherapy effects for pancreatic cancer. In this trial, some participants will receive AB680 with the chemotherapy drugs nab-paclitaxel and gemcitabine, which early studies showed resulted in a 41% overall response rate. Other participants will receive AB680 combined with zimberelimab, a treatment that helps the immune system fight cancer. This combination has shown encouraging results with other treatments, helping patients live longer with various cancers. The combination of nab-paclitaxel and gemcitabine has proven effective in extending patient survival and slowing pancreatic cancer progression, showing a 31% reduction in the risk of worsening or death. Together, these treatments offer strong potential to combat advanced pancreatic cancer. ^{3 6 7 8 9}

Who Is on the Research Team?

Medical Director

Principal Investigator

Arcus Biosciences, Inc.

Are You a Good Fit for This Trial?

This trial is for adults with advanced pancreatic cancer who haven't had treatment for metastatic disease. They must be able to consent, not pregnant, and have adequate organ function. Prior therapy is okay if it was over 6 months ago. Participants can't join if they've recently used certain steroids, had live vaccines, or have active infections or autoimmune diseases.

Inclusion Criteria

I have at least one tumor that can be measured and it's not in an area treated with radiation.

I have not received any treatment for my metastatic disease.

I had treatment for pancreatic cancer that ended over 6 months ago.

Exclusion Criteria

I do not have any health conditions that would make taking new medications dangerous.

I do not have an active autoimmune disease or a history that required strong immune system medications, except for vitiligo or childhood asthma.

Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of AB680 in combination with Zimberelimab, nab-paclitaxel, and gemcitabine to determine the recommended phase 2 dose

Approximately 12 weeks

Multiple visits for dose escalation and monitoring

Dose Expansion

Participants receive AB680 at the recommended phase 2 dose in combination with Zimberelimab, nab-paclitaxel, and gemcitabine

Approximately 24 weeks

Regular visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Periodic visits for follow-up assessments

What Are the Treatments Tested in This Trial?

Interventions

• AB680
• Gemcitabine
• Nab-paclitaxel
• Zimberelimab

Trial Overview The study tests AB680 combined with Zimberelimab, Nab-paclitaxel, and Gemcitabine in patients with advanced pancreatic cancer. It's a Phase 1 trial focusing on safety and how the body processes the drugs (pharmacokinetics), as well as their effects on the body (pharmacodynamics) and early signs of effectiveness.

How Is the Trial Designed?

Group I: Dose Expansion (AB680+zimberelimab+NP/Gem):Cohort A1 (front-line/1L) Experimental Treatment 4 Interventions

Participants with advanced pancreatic cancer, naïve to any prior treatment will receive AB680 (at the RP2D identified during dose escalation) combined with zimberelimab and the standard nab-paclitaxel (NP) and gemcitabine (Gem) (NP/Gem) chemotherapy regimen

Group II: Dose Expansion (AB680+zimberelimab+ NP/Gem): Cohort A (front-line/1L) Experimental Treatment 4 Interventions

Participants with advanced pancreatic cancer, naïve to any prior treatment will receive AB680 (at the RP2D identified during dose escalation) combined with zimberelimab and the standard nab-paclitaxel (NP) and gemcitabine (Gem) (NP/Gem) chemotherapy regimen

Group III: Dose Expansion (AB680 + zimberelimab + NP/Gem): Cohort C (front-line/1L) Experimental Treatment 4 Interventions

Participants with advanced pancreatic cancer naïve to any prior treatment will receive AB680 combined with zimberelimab and NP-Gem chemotherapy regimen.

Group IV: Dose Expansion (AB680 + zimberelimab + NP/Gem): Cohort B (second-line/2L) Experimental Treatment 4 Interventions

Participants with advance pancreatic cancer who have received 1 prior line of treatment will receive AB680 (at the RP2D identified during dose escalation) combined with zimberelimab and NP-Gem chemotherapy regimen.

Group V: Dose Expansion (AB680 + NP/Gem): Cohort D (front-line/1L) Experimental Treatment 3 Interventions

Participants with advanced pancreatic cancer naïve to any prior treatment will receive AB680 combined with NP-Gem chemotherapy regimen.

Group VI: Dose Expansion (AB680 + NP/Gem): Cohort A2 (front-line/1L) Experimental Treatment 3 Interventions

Participants with advanced pancreatic cancer who are naïve to any prior treatment will receive AB680 (at the RP2D identified during dose escalation) and the standard NP/Gem chemotherapy regimen.

Group VII: Dose Escalation Experimental Treatment 4 Interventions

Dose escalation is a 3+3 design, including a Dose Limiting Toxicity (DLT) evaluation period. The dose expansion dose level will be determined in this part with escalating doses of AB680 in combination with zimberelimab at the recommended phase 2 dose (RP2D) and the standard nab-paclitaxel and gemcitabine chemotherapy regimen in participants with advanced pancreatic cancer.

Who Is Running the Clinical Trial?

Arcus Biosciences, Inc.

Lead Sponsor

Trials

44

Recruited

7,500+

Published Research Related to This Trial

In a retrospective study of 29 patients with advanced pancreatic carcinoma and elevated bilirubin levels, treatment with nanoparticle albumin-bound paclitaxel and gemcitabine (nab-P/G) was found to be safe, showing no unexpected toxicities.

The median overall survival for patients treated with nab-P/G was 11.7 months, with no significant differences in survival based on bilirubin levels, indicating that nab-P/G is a feasible treatment option for this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of Nab-paclitaxel plus gemcitabine in patients with advanced pancreatic cancer suffering from cholestatic hyperbilirubinaemia-A retrospective analysis. Pelzer, U., Wislocka, L., Jühling, A., et al.[2022]

In a phase 3 trial involving 861 patients with metastatic pancreatic cancer, the combination of nab-paclitaxel and gemcitabine significantly improved overall survival (8.5 months) compared to gemcitabine alone (6.7 months), with a hazard ratio for death of 0.72, indicating a 28% reduction in the risk of death.

The combination therapy also resulted in better progression-free survival (5.5 months vs. 3.7 months) and a higher overall response rate (23% vs. 7%), although it was associated with increased rates of adverse events like neutropenia and neuropathy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. Von Hoff, DD., Ervin, T., Arena, FP., et al.[2022]

In a small study of 6 women with heavily pretreated HER2-negative metastatic breast cancer, the combination of nab-paclitaxel (nab-P) and bevacizumab (B), with or without gemcitabine (G), showed promising safety and preliminary efficacy, with only one patient experiencing significant toxicity.

Out of the 6 patients, 2 achieved partial responses and 4 had stable disease, indicating that this combination therapy may be effective, warranting further investigation in a formal phase II trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Paclitaxel albumin-bound particles (abraxane) in combination with bevacizumab with or without gemcitabine: early experience at the University of Miami/Braman Family Breast Cancer Institute. Lobo, C., Lopes, G., Silva, O., et al.[2022]

The combination of nab-paclitaxel, gemcitabine, and capecitabine was found to be well tolerated in a phase I study with 15 patients, establishing a maximum-tolerated dose (MTD) but showing only modest antitumor activity in metastatic pancreatic cancer.

Despite the regimen being generally safe, with a low incidence of severe hematologic toxicities, only 14.3% of patients had a partial response, indicating that optimizing dose intensity may be crucial for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of nab-paclitaxel, gemcitabine, and capecitabine for metastatic pancreatic cancer. Ko, AH., Truong, TG., Kantoff, E., et al.[2022]

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 recent phase III MPACT trial demonstrated that nab-paclitaxel, when added to gemcitabine, significantly improved survival rates in patients with metastatic pancreatic cancer, indicating its efficacy in a previously challenging area.

The success of nab-paclitaxel highlights the importance of innovative drug delivery technologies, such as albumin nanoparticle formulations, in enhancing the effectiveness of anticancer therapies while minimizing toxicities associated with traditional formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The winning formulation: the development of paclitaxel in pancreatic cancer. Ma, WW., Hidalgo, M.[2022]

A 71-year-old woman with unresectable pancreatic cancer and peritoneal metastases was successfully treated with a combination of nab-paclitaxel and gemcitabine, leading to the conversion of her cancer to a resectable state after 8 months of chemotherapy.

The treatment was well-tolerated, and imaging studies showed no evidence of the tumor or metastases, allowing for a successful surgical resection of the affected areas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful conversion surgery for unresectable pancreatic cancer with peritoneal metastases after neoadjuvant albumin-bound paclitaxel and gemcitabine chemotherapy: case report and literature review. Kobayashi, Y., Maeda, S., Hama, N., et al.[2020]

Gemcitabine-loaded human serum albumin nanoparticles (Gem-HSA-NPs) were successfully developed and showed a favorable controlled release, with an encapsulation rate of approximately 83% and a particle size of about 150 nm.

In vivo studies demonstrated that Gem-HSA-NPs significantly inhibited tumor growth in pancreatic cancer while exhibiting lower toxicity compared to other treatment groups, indicating their potential as a safer and more effective delivery method for gemcitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An in vitro and in vivo study of gemcitabine-loaded albumin nanoparticles in a pancreatic cancer cell line. Yu, X., Di, Y., Xie, C., et al.[2022]

In a study using 10 patient-derived pancreatic cancer xenograft mouse models, the combination of S-1 and nab-paclitaxel showed significantly greater tumor growth inhibition (103.56%) compared to either treatment alone, indicating enhanced antitumor activity.

Biomarkers such as thymidylate synthase, OPRT, and DPD were identified as potential predictors of S-1 efficacy, while HER2 was linked to improved efficacy of nab-paclitaxel, suggesting that these markers could help tailor treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nab-Paclitaxel Plus S-1 Shows Increased Antitumor Activity in Patient-Derived Pancreatic Cancer Xenograft Mouse Models. Li, JA., Xu, XF., Han, X., et al.[2017]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37867243/

Tumor Microenvironment Responsive CD8+ T Cells and ... The concurrent administration of AB680 and PD-1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine ...

2. oncpracticemanagement.com oncpracticemanagement.com/issues/2021/may-2021-vol-11-no-5/cd73-inhibitor-shows-promise-as-part-of-combination-therapy-for-metastatic-pancreatic-cancer

CD73 Inhibitor Shows Promise as Part of Combination ... A small-molecule CD73 inhibitor (AB680) induced a 41% overall response rate (ORR) when combined with chemotherapy (with nab-paclitaxel and gemcitabine), ...

3. aacrjournals.org aacrjournals.org/cancerimmunolres/article/13/2_Supplement/A113/751648/Abstract-A113-The-CD73-Inhibitor-AB680-Enhances

Abstract A113: The CD73 Inhibitor, AB680 Enhances ... FFX+AB680 significantly decreased tumor mass (P < 0.01), reduced liver metastases, and eliminated lung metastases (P < 0.01) compared to ...

4. investors.arcusbio.com investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/Data-from-a-Phase-1b-Study-of-Quemliclustat-Based-Regimens-Showed-Promising-Overall-Survival-in-Treatment-Nave-Metastatic-Pancreatic-Cancer/default.aspx

Data from a Phase 1b Study of Quemliclustat-Based ... Median Overall Survival was 15.7 months for all patients treated with 100 mg quemliclustat-based regimens in the ARC-8 study, which exceeds ...

5. nature.com nature.com/articles/s41467-023-38578-3

Transcriptional control of pancreatic cancer ... 1f). Monotherapy with AB680 or anti-PD-1 Ab partially slowed tumor progression, while combination therapy significantly increased the inhibitory ...

6. arcusbio.com arcusbio.com/wp-content/uploads/2020/09/a-phase-1-study-to-evaluate-the-safety-and-tolerability-of-AB680-combination-therapy-in-participants-with-gastrointestinal.pdf

a-phase-1-study-to-evaluate-the-safety-and-tolerability-of- ... Murine B16F10 melanoma models have shown inhibition of tumor growth after treatment with. AB680. This growth inhibition was further reduced with combination ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.3_suppl.404

ARC-8: Phase I/Ib study to evaluate safety and tolerability ... AB680, the first clinical-stage small-molecule CD73 inhibitor, in combination with SOC chemotherapy + Zim has a manageable safety profile consistent with that ...

8. aacrjournals.org aacrjournals.org/cancerpreventionresearch/article/17/10/457/748694/Preventive-Treatment-with-a-CD73-Small-Molecule

Preventive Treatment with a CD73 Small Molecule Inhibitor ... Preventive treatment with a CD73 small molecule inhibitor enhances immune surveillance in K-Ras mutant pancreatic intraepithelial neoplasia.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT04104672

NCT04104672 | A Study to Evaluate the Safety and ... In this dose escalation combination study, participants with advanced pancreatic cancer will receive escalating doses of AB680 in combination with zimberelimab ...