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

173 Participants Needed

Trial Summary

What is the purpose of this trial?

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 therapy in treating patients with malignancies that have spread to other places in the body (advanced). Immunotherapy with monoclonal antibodies, such as avelumab, utomilumab, and anti-OX40 antibody PF-04518600, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high-energy rays to kill tumor cells and shrink tumors. It is not yet known how well avelumab works in combination with these other anti-cancer therapies in patients 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. 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.

What data supports the effectiveness of the treatment Avelumab + Utomilumab + Anti-OX40 + Radiation for Advanced Cancers?

Research shows that combining OX40 agonists with other treatments can enhance the immune system's ability to fight cancer, as seen in studies where OX40 agonists improved the function of immune cells and showed potential in preclinical models. Additionally, combining OX40 agonists with other immune therapies has been shown to improve survival in cancer patients. ^{1 2 3 4 5}

Is the combination of Avelumab, Utomilumab, Anti-OX40, and Radiation generally safe for humans?

The combination of Avelumab, Utomilumab, PF-04518600 (an OX40 agonist), and radiotherapy has been evaluated for safety in patients with advanced gynecologic cancers, but specific safety outcomes are not detailed in the available research. Other studies on OX40 agonists in combination with different treatments suggest that while they show potential, safety and efficacy can vary, and further research is needed to fully understand their safety profile. ^{1 2 3 4 6}

What makes the drug combination of Avelumab, Utomilumab, and Anti-OX40 unique for treating advanced cancers?

This drug combination is unique because it combines immune checkpoint inhibitors (Avelumab) with costimulatory agonists (Utomilumab and Anti-OX40) and radiation, aiming to enhance the immune system's ability to fight cancer by activating specific immune pathways that are not typically targeted together in standard treatments. ^{1 6 7 8 9}

Research Team

Aung Naing, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

1. United States 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. [2023]

2. England 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). [2023]

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

A Novel Bispecific Antibody with PD-L1-assisted OX40 Activation for Cancer Treatment. [2021]

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

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

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

Anti-OX40 Antibody Directly Enhances The Function of Tumor-Reactive CD8+ T Cells and Synergizes with PI3Kβ Inhibition in PTEN Loss Melanoma. [2020]

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

OX40 Agonist BMS-986178 Alone or in Combination With Nivolumab and/or Ipilimumab in Patients With Advanced Solid Tumors. [2022]

7. England pubmed.ncbi.nlm.nih.gov

First-in-human study of an OX40 (ivuxolimab) and 4-1BB (utomilumab) agonistic antibody combination in patients with advanced solid tumors. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Anti-OX40 monoclonal antibody therapy in combination with radiotherapy results in therapeutic antitumor immunity to murine lung cancer. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety-in analysis of short-course radiation followed by mFOLFOX-6 plus avelumab for locally advanced rectal adenocarcinoma. [2021]