AB598 + Chemotherapy for Advanced Cancers

(ARC-25 Trial)

Recruiting at 24 trial locations

Overseen By Medical Director

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Arcus Biosciences, Inc.

Must not be taking: Live vaccines, Immunosuppressants

Disqualifiers: Autoimmune diseases, Recent surgery, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 12-24 weeks

87 Participants Needed

Trial Summary

What is the purpose of this trial?

The primary purpose of this study is to assess the safety and tolerability of AB598 in participants with advanced malignancies.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take systemic immunosuppressive medication within 2 weeks before starting the study treatment. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination AB598 + Chemotherapy for Advanced Cancers?

Research shows that pemetrexed combined with carboplatin has been effective in treating advanced non-small cell lung cancer, with a response rate of about 28.6%. Additionally, 5-fluorouracil, when used with leucovorin and other agents, has shown effectiveness in treating gastrointestinal cancers, suggesting potential benefits of these components in the combination therapy. ^{1 2 3 4 5}

Is the combination of AB598 and chemotherapy safe for humans?

The combination of pemetrexed and carboplatin has been studied in elderly patients with advanced non-small cell lung cancer and was found to have a balanced safety profile, though it can cause side effects like neutropenia (low white blood cell count), anemia (low red blood cell count), and thrombocytopenia (low platelet count). In some cases, serious side effects like infections and interstitial lung disease occurred, but the treatment was generally tolerated. ^{4 5 6 7 8}

What makes the drug AB598 + Chemotherapy unique for advanced cancers?

The combination of AB598 with chemotherapy drugs like carboplatin, fluorouracil, leucovorin, oxaliplatin, pemetrexed, and zimberelimab is unique because it integrates multiple agents with different mechanisms of action, potentially enhancing effectiveness against advanced cancers. This approach leverages the novel multitargeted antifolate action of pemetrexed and the immune-modulating effects of zimberelimab, which may offer benefits over standard chemotherapy regimens. ^{2 3 9 10 11}

Research Team

Medical Director

Principal Investigator

Arcus Biosciences

Eligibility Criteria

This trial is for adults with certain advanced cancers, including stomach, lung, and breast cancer. Participants must have a specific performance status score and at least one measurable lesion. They should not have received prior treatment for their advanced cancer or progressed within 6 months after platinum-based chemotherapy.

Inclusion Criteria

My cancer did not worsen within 6 months after receiving platinum-based chemotherapy.

My lung cancer is not mixed with small-cell type.

Must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) guidance

Exclusion Criteria

I have not had major surgery or serious injury in the last 28 days.

I haven't taken immunosuppressive drugs in the last 2 weeks and don't expect to need them during the study.

I haven't had an autoimmune disease in the last 3 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AB598 IV infusion every 2-3 weeks, with some cohorts receiving combination therapy with zimberelimab and FOLFOX

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• AB598
• Carboplatin
• Fluorouracil
• Leucovorin
• Oxaliplatin
• Pemetrexed
• Zimberelimab

Trial Overview The study tests the safety of AB598 alone and combined with zimberelimab plus standard chemo drugs like Pemetrexed and Oxaliplatin in patients with advanced malignancies. It aims to find out how well these treatments are tolerated by participants.

Participant Groups

Group I: Pharmacodynamic Cohort 3 Experimental Treatment 1 Intervention

Participants will receive AB598 IV infusion once every 3 weeks

Group II: Pharmacodynamic Cohort 2 Experimental Treatment 1 Intervention

Participants will receive AB598 IV infusion once every 3 weeks

Group III: Pharmacodynamic Cohort 1 Experimental Treatment 1 Intervention

Participants will receive AB598 IV infusion once every 3 weeks

Group IV: Dose Expansion Gastric/GEJ Cancer (phase 1b) Experimental Treatment 5 Interventions

Participants will receive AB598 IV infusion every 2 weeks in combination with zimberelimab and FOLFOX (oxaliplatin, leucovorin, fluorouracil)

Group V: Dose Escalation Cohort 4 Experimental Treatment 1 Intervention

Participants will receive AB598 IV infusion once every 3 weeks

Group VI: Dose Escalation Cohort 3 Experimental Treatment 1 Intervention

Participants will receive AB598 IV infusion once every 3 weeks

Group VII: Dose Escalation Cohort 2 Experimental Treatment 1 Intervention

Participants will receive AB598 IV infusion once every 3 weeks

Group VIII: Dose Escalation Cohort 1 Experimental Treatment 1 Intervention

Participants will receive AB598 intravenous (IV) infusion once every 3 weeks

Who Is Running the Clinical Trial?

Arcus Biosciences, Inc.

Lead Sponsor

Trials

44

Recruited

7,500+

Findings from Research

Pemetrexed shows promising efficacy in treating gastrointestinal tumors, with a 15-17% response rate in metastatic colorectal cancer and a 6% response rate in advanced pancreatic cancer, comparable to standard treatments like gemcitabine.

The drug has a generally mild side effect profile, especially when combined with folate supplementation and dexamethasone, indicating potential for further studies to explore its role in combination therapies for colorectal, pancreatic, and gastric cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed in patients with gastrointestinal carcinoma. de Gramont, A., Kindler, HL.[2019]

The PELF regimen (cisplatin, epirubicin, and leucovorin) demonstrated a significantly higher overall response rate (43%) compared to the FAM regimen (15%) in treating advanced gastric carcinoma, indicating its greater efficacy in inducing tumor responses.

Although the PELF combination was more effective, it also had higher toxicity compared to FAM, making it less suitable for routine clinical use despite its potential for further investigation in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluorouracil, doxorubicin, and mitomycin combination versus PELF chemotherapy in advanced gastric cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research. Cocconi, G., Bella, M., Zironi, S., et al.[2017]

In a study of 200 patients with untreated advanced gastric carcinoma, the PELF treatment regimen showed a significantly higher complete response rate (13%) compared to the FAMTX regimen (2%), indicating greater efficacy in treating this type of cancer.

The objective response rates were also better for PELF (39%) versus FAMTX (22%), suggesting that PELF is a more effective treatment option, although the survival rate differences were not statistically significant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. Cocconi, G., Carlini, P., Gamboni, A., et al.[2022]

In a study involving 361 patients with advanced nonsquamous non-small-cell lung cancer, the combination of pemetrexed and carboplatin (Pem+Cb) did not show a significant advantage in progression-free survival without grade 4 toxicity compared to paclitaxel, carboplatin, and bevacizumab (Pac+Cb+Bev).

While both treatment regimens were generally well tolerated, Pem+Cb was associated with higher rates of grade 3/4 anemia and thrombocytopenia, whereas Pac+Cb+Bev had more cases of grade 3/4 neutropenia and alopecia, indicating differing toxicity profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. Zinner, RG., Obasaju, CK., Spigel, DR., et al.[2022]

In a phase II study involving 62 elderly patients (average age 76.4 years) with advanced non-small cell lung cancer (NSCLC), the combination of pemetrexed and carboplatin achieved an objective tumor response rate of 28.6%, indicating its potential efficacy in this population.

The treatment was generally well-tolerated, although neutropenia was the most common severe side effect, affecting over half of the patients, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed and carboplatin, an active option in first-line treatment of elderly patients with advanced non-small cell lung cancer (NSCLC): a phase II trial. Gervais, R., Robinet, G., Clément-Duchêne, C., et al.[2015]

In a meta-analysis of 486 patients with advanced non-squamous non-small cell lung cancer, the pemetrexed plus carboplatin regimen at 5 mg/min•mL (PCb5) showed a significantly lower incidence of treatment-emergent adverse events (TEAEs) compared to the 6 mg/min•mL (PCb6) regimen, including less thrombocytopenia, anemia, and fatigue.

Despite the differences in safety profiles, both PCb5 and PCb6 regimens demonstrated similar efficacy outcomes in terms of overall survival and progression-free survival, indicating that PCb5 may be a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies. Okamoto, I., Schuette, WH., Stinchcombe, TE., et al.[2018]

The combination of carboplatin and pemetrexed was found to be safe and well tolerated in a study of 20 patients with platinum-sensitive recurrent ovarian cancer, with no serious adverse events related to the therapy.

The treatment showed promising efficacy, with a complete response rate of 63.2% and a partial response rate of 21.1%, indicating that this combination could be a viable option for improving outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase-I trial of pemetrexed plus carboplatin in recurrent ovarian cancer. Sehouli, J., Camara, O., Mahner, S., et al.[2015]

In a phase II trial involving 34 elderly patients (median age 77) with non-squamous non-small cell lung cancer, the combination of carboplatin and pemetrexed followed by pemetrexed maintenance therapy resulted in a 1-year overall survival rate of 58% and a median overall survival of 20.5 months.

The treatment was generally well tolerated, although there were notable grade ≥3 adverse events, including neutropenia (55.9%) and infections (23.5%), indicating that while effective, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of pemetrexed plus carboplatin followed by maintenance pemetrexed as first-line chemotherapy for elderly patients with advanced non-squamous non-small cell lung cancer. Tamiya, M., Tamiya, A., Kaneda, H., et al.[2022]

Oral fluoropyrimidines, such as capecitabine and UFT/LV, offer a more convenient and less toxic alternative to traditional intravenous 5-fluorouracil (5-FU) for treating advanced colorectal cancer (CRC).

Oxaliplatin, with a different mechanism of action than 5-FU, significantly improves response rates and time to disease progression when used in combination with 5-FU and leucovorin in first-line treatment, and is effective even in patients whose cancer has progressed after 5-FU treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel chemotherapy agents for colorectal cancer: oral fluoropyrimidines, oxaliplatin, and raltitrexed. Royce, ME., Hoff, PM., Padzur, R.[2019]

In a phase II trial involving 42 chemotherapy-naïve patients with advanced pancreatic cancer, LY231514 (pemetrexed) was found to be well-tolerated, with common side effects including neutropenia in 40% of patients, but rare infectious complications.

The treatment showed minimal antitumor activity, with an objective response rate of only 5.7%, although 40% of patients experienced stable disease for at least 6 months, and the median survival was 6.5 months, suggesting potential for further investigation in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of the multitargeted antifolate LY231514 (ALIMTA, MTA, pemetrexed disodium) in patients with advanced pancreatic cancer. Miller, KD., Picus, J., Blanke, C., et al.[2020]

Pemetrexed is a multitargeted antifolate that effectively inhibits key enzymes involved in cancer cell growth and is active against various solid tumors, including non-small-cell lung cancer and ovarian cancer.

A recent randomized trial found that administering pemetrexed followed by gemcitabine on specific days every 21 days resulted in the best efficacy and lowest toxicity, highlighting an optimized treatment sequence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical studies of pemetrexed and gemcitabine combinations. Adjei, AA.[2022]

References

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

Pemetrexed in patients with gastrointestinal carcinoma. [2019]

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

Fluorouracil, doxorubicin, and mitomycin combination versus PELF chemotherapy in advanced gastric cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research. [2017]

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

Cisplatin, epirubicin, leucovorin and 5-fluorouracil (PELF) is more active than 5-fluorouracil, doxorubicin and methotrexate (FAMTX) in advanced gastric carcinoma. [2022]

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

PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. [2022]

5. Ireland pubmed.ncbi.nlm.nih.gov

Pemetrexed and carboplatin, an active option in first-line treatment of elderly patients with advanced non-small cell lung cancer (NSCLC): a phase II trial. [2015]

6. England pubmed.ncbi.nlm.nih.gov

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies. [2018]

7. Germany pubmed.ncbi.nlm.nih.gov

A phase-I trial of pemetrexed plus carboplatin in recurrent ovarian cancer. [2015]

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

A phase II study of pemetrexed plus carboplatin followed by maintenance pemetrexed as first-line chemotherapy for elderly patients with advanced non-squamous non-small cell lung cancer. [2022]

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

Novel chemotherapy agents for colorectal cancer: oral fluoropyrimidines, oxaliplatin, and raltitrexed. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Phase II study of the multitargeted antifolate LY231514 (ALIMTA, MTA, pemetrexed disodium) in patients with advanced pancreatic cancer. [2020]

11. England pubmed.ncbi.nlm.nih.gov

Clinical studies of pemetrexed and gemcitabine combinations. [2022]