Avelumab + Utomilumab + Anti-OX40 + Radiation for Advanced Cancers

Overseen By Aung Naing, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Anticonvulsants

Disqualifiers: CNS tumor, Cardiovascular disease, Infection, Autoimmune disease, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatment combinations to evaluate their effectiveness and potential side effects for individuals with advanced cancers that have metastasized. It includes various combinations of immunotherapy drugs, such as avelumab, utomilumab, and an anti-OX40 antibody (PF-04518600), sometimes combined with radiation therapy. The researchers aim to determine if these treatments can enhance the immune system's ability to attack cancer. This trial may suit those whose cancer has not responded to other treatments and who have at least one measurable or monitorable cancer area. As a Phase 1/Phase 2 trial, it focuses on understanding the treatment's function in participants and assessing its initial effectiveness, offering a chance to contribute to groundbreaking cancer research.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot participate if you are currently using immunosuppressive medication or receiving other anticancer treatments. It's best to discuss your specific medications with the trial team.

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

Research shows that avelumab is generally well-tolerated when used alone, with most patients experiencing only mild side effects. Serious side effects are rare. When combined with utomilumab, avelumab maintains a manageable safety profile, meaning that while some patients may experience more serious side effects, these are uncommon.

Studies on combining avelumab with the anti-OX40 antibody PF-04518600 and radiation therapy are in the early stages. Initial results suggest that these treatments are tolerated, but more safety data is still being collected. Since this trial is in its early phases, the safety of the treatment is still under evaluation. However, these treatments are being tested because earlier studies have shown their potential.

Overall, while these combinations are promising, more research is needed to fully understand their safety. Participants can contribute to this important research. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine innovative immunotherapies with radiation to tackle advanced cancers. Unlike standard cancer treatments that mainly target tumors directly, these therapies use the body's immune system to attack cancer cells. Avelumab and utomilumab are antibodies that help the immune system recognize and destroy cancer cells. The anti-OX40 antibody, PF-04518600, boosts the immune response even further, potentially leading to more effective cancer control. This novel approach could offer new hope for patients with advanced cancers by enhancing the body's natural defenses against the disease.

What evidence suggests that this trial's treatments could be effective for advanced cancers?

This trial will evaluate the effectiveness of different treatment combinations for advanced cancers. Studies have shown that avelumab, one of the treatments in this trial, can be effective against certain advanced cancers, such as advanced bladder cancer, where it has helped patients live longer. In this trial, some participants will receive avelumab combined with other treatments. Utomilumab, another treatment option in this trial, has shown promise in treating solid tumors, although results have varied. The anti-OX40 antibody, PF-04518600, also part of this trial, boosts the body's immune system to fight cancer. Early trials suggest it might help with certain cancers like hepatocellular carcinoma, a type of liver cancer. These treatments aim to strengthen the body's natural defenses to target and destroy cancer cells. ^{1 3 6 7 8}

Who Is on the Research Team?

Aung Naing, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced malignancies, specifically prostate cancer or solid tumors that have spread. Participants must have measurable disease, be in good physical condition (ECOG 0-1), and meet specific blood count and organ function criteria. Women of childbearing potential must test negative for pregnancy and agree to use contraception; men also need to commit to using effective birth control.

Inclusion Criteria

I am not pregnant and agree to use birth control during and 90 days after treatment.

I have multiple tumors that can be biopsied and measured for treatment response.

I cannot tolerate or have not responded to standard treatments, or I refuse them.

Exclusion Criteria

My brain tumor condition is currently stable.

Treatment with an investigational anti-cancer study drug within 4 weeks prior to study drug administration date.

I have an autoimmune disease but it's not worsening with immune-stimulating treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive avelumab in combination with other therapies such as utomilumab, anti-OX40 antibody PF-04518600, and radiation therapy. Treatment cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

28 days per cycle

Radiation

Patients undergo radiation therapy on days -5 to -1 or -14 to -1 depending on the arm assignment.

1-2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment completion. Follow-up occurs at 30 days post-treatment and then every 12 weeks.

Up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Anti-OX40 Antibody PF-04518600
• Avelumab
• Radiation Therapy
• Utomilumab

Trial Overview The study is testing the effectiveness of avelumab combined with utomilumab, anti-OX40 antibody PF-04518600, and radiation therapy on advanced cancers. It's a phase I/II trial aiming to see how well these treatments work together in stopping cancer growth by aiding the immune system.

How Is the Trial Designed?

Group I: Arm F (avelumab, PF-04518600, radiation therapy) Experimental Treatment 4 Interventions

DISCONTINUED AS OF AMENDMENT 9 (02/11/2020) Patients undergo radiation therapy on days -14 to -1. Patients receive avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1, utomilumab IV over 60 minutes on day 1, and anti-OX40 agonist monoclonal antibody PF-04518600 IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm E (avelumab, PF-04518600, radiation therapy) Experimental Treatment 3 Interventions

DISCONTINUED AS OF AMENDMENT 9 (02/11/2020) Patients undergo radiation therapy on days -14 to -1. Patients receive avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1 and anti-OX40 agonist monoclonal antibody PF-04518600 IV over 60 minutes on days 1 and 15, and. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group III: Arm D (avelumab, utomilumab, radiation therapy) Experimental Treatment 3 Interventions

Patients undergo radiation therapy on days -5 to -1. Patients receive avelumab IV over 60 minutes on days 1 and 15 of beginning day 15 of cycle 1 and utomilumab IV over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group IV: Arm C (PF-04518600, utomilumab, avelumab) Experimental Treatment 3 Interventions

Patients receive anti-OX40 agonist monoclonal antibody PF-04518600 IV over 60 minutes on days 1 and 15 of each cycle, utomilumab over 60 minutes on day 1, and avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group V: Arm B (PF-04518600, avelumab) Experimental Treatment 2 Interventions

Patients receive anti-OX40 agonist monoclonal antibody PF-04518600 IV over 60 minutes on days 1 and 15 of each cycle and avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group VI: Arm A (utomilumab, avelumab) Experimental Treatment 2 Interventions

Patients receive utomilumab IV over 60 minutes on day 1 of each cycle and avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 1/2 trial involving 40 patients with recurrent gynecologic cancers, the combination of avelumab and utomilumab was found to be safe, with no serious immune-related adverse events reported.

The objective response rate (ORR) was low at 2.9% overall, but patients with cervical cancer showed a promising ORR of 11% and a disease control rate (DCR) of 78%, suggesting potential for further investigation in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1/2 trial of avelumab combined with utomilumab (4-1BB agonist), PF-04518600 (OX40 agonist), or radiotherapy in patients with advanced gynecologic malignancies. Knisely, A., Ahmed, J., Stephen, B., et al.[2023]

Combining anti-OX40 and anti-CTLA-4 monoclonal antibody immunotherapy enhances the survival of cancer patients by boosting the expansion and function of effector T cells.

Blocking IL-4 alongside this combination therapy further improves anti-tumor effectiveness, suggesting that targeting multiple pathways can enhance cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined OX40 ligation plus CTLA-4 blockade: More than the sum of its parts. Linch, SN., Redmond, WL.[2021]

The phase I/IIa study of BMS-986178, an OX40 agonist, showed a manageable safety profile with low rates of severe treatment-related adverse events (5% for monotherapy and up to 15% for combination therapy), indicating it is safe for use in patients with advanced solid tumors.

Despite the safety, the study did not find significant efficacy for BMS-986178 alone or in combination with nivolumab and/or ipilimumab, with no objective responses observed in monotherapy and low response rates (0% to 13%) in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and/or Ipilimumab in Patients With Advanced Solid Tumors. Gutierrez, M., Moreno, V., Heinhuis, KM., et al.[2022]

The phase I study of the OX40 agonistic monoclonal antibody GSK3174998, alone or with pembrolizumab, was well tolerated among 138 patients with advanced solid tumors, with treatment-related adverse events occurring in 51% of patients in Part 1 and 64% in Part 2, but no maximum-tolerated dose was reached.

Despite demonstrating target engagement and some immune response changes in the tumor microenvironment, GSK3174998 showed limited clinical activity, with a disease control rate of only 9% in Part 1 and no significant improvement when combined with pembrolizumab, indicating it may not be viable for further development in advanced cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1). Postel-Vinay, S., Lam, VK., Ros, W., et al.[2023]

In a study using a murine lung cancer model, the combination of anti-OX40 monoclonal antibody and radiotherapy significantly prolonged survival and was more effective than either treatment alone, indicating a promising therapeutic strategy for lung cancer.

The effectiveness of this combination therapy was found to be primarily dependent on CD8(+) T-cells, which were enhanced in the lymph nodes of irradiated mice, suggesting that this approach not only targets tumors but also boosts the immune response against cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer. Yokouchi, H., Yamazaki, K., Chamoto, K., et al.[2022]

Citations

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First-in-human study of an OX40 (ivuxolimab) and 4-1BB ... This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03217747

NCT03217747 | Avelumab, Utomilumab, Anti-OX40 ... This phase I/II trial studies the side effects of avelumab when given in different combinations with utomilumab, anti-OX40 antibody PF-04518600, and radiation ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.4_suppl.523

Analysis of OX40 agonist antibody (PF-04518600) in ... PF-8600 was given to patients (pts) with advanced/metastatic hepatocellular carcinoma (HCC) in dose expansion of a phase 1 study (NCT02315066).

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12164209/

Anti-OX40 antibody BAT6026 in patients with advanced ... BAT6026 is a fully human IgG1 OX40 monoclonal antibody. This was a multicenter, open-label, dose escalation, and dose expansion phase I study of BAT6026 ...

5. jitc.bmj.com jitc.bmj.com/content/8/Suppl_1/A9

P860 Results from a combination of OX40 (PF-04518600) ... Conclusions The combination of PF-8600 and uto had a tolerable safety profile and demonstrated clinical benefit, including in an NSCLC patient ...

6. patlynk.com patlynk.com/trial/NCT03217747

Avelumab, Utomilumab, Anti-OX40 Antibody PF-04518600, ... This phase I/II trial studies the side effects of avelumab when given in different combinations with utomilumab, anti-OX40 antibody ...

7. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.35063

Phase 1/2 trial of avelumab combined with utomilumab (4 ... The authors sought to evaluate the safety and efficacy of avelumab combined with utomilumab (a 4-1BB agonist), PF-04518600 (an OX40 agonist), ...

8. fightcolorectalcancer.org fightcolorectalcancer.org/clinical-trial/nct03217747/

Avelumab, Utomilumab, Anti-OX40 Antibody PF-04518600, ... * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. * Platelets >= 100 x 10^9/L (For patients with hepatocellular carcinoma, platelets >= 70 ...