Immunotherapy + Chemotherapy for Rectal Cancer

(PANTHER Trial)

Recruiting at 2 trial locations

Overseen By Dakota Trick, M.S.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Weill Medical College of Cornell University

Must not be taking: BCRP substrates, P-gp substrates, CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Recurrent rectal cancer, Unresectable tumor, T4 tumor, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

43 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial uses a combination of radiation therapy, medication, and chemotherapy to treat patients with advanced pelvic tumors. The goal is to shrink the tumors, kill cancer cells, and enhance the overall effectiveness of the treatment.

Do I have to stop taking my current medications for the trial?

The trial requires that you stop taking certain medications that could interact with the study drugs. Specifically, you must not have taken certain drugs like BCRP substrates, P-gp substrates, strong CYP3A4 inducers, and inhibitors within 4 weeks or 5 half-lives of the drug before starting the trial. If you're on these medications, you may need to stop them before participating.

Is the combination of immunotherapy and chemotherapy for rectal cancer generally safe in humans?

Research suggests that combining immunotherapy with radiotherapy (a type of treatment using radiation) generally does not lead to excessive harmful effects, although there can be immune-related side effects. It's important for doctors to monitor for these side effects when using these treatments together. ^{1 2 3 4 5}

How is the treatment of Immunotherapy + Chemotherapy for Rectal Cancer unique?

This treatment is unique because it combines immunotherapy (which helps the immune system fight cancer) with radiation therapy, potentially enhancing the body's ability to attack both the primary tumor and distant cancer cells, a phenomenon known as the abscopal effect. This approach is novel as it leverages the synergy between these therapies to improve outcomes in rectal cancer, which is not commonly seen in standard treatments. ^{6 7 8 9 10}

What data supports the effectiveness of combining immunotherapy and chemotherapy for rectal cancer?

Research suggests that combining immunotherapy with radiation therapy can improve outcomes for gastrointestinal cancers, and radiotherapy has been shown to decrease local relapse rates and improve survival in rectal cancer. Additionally, combining radiotherapy with immunotherapies has shown promising results in other cancers, indicating potential benefits for rectal cancer treatment. ^{1 9 10 11 12}

Who Is on the Research Team?

Encouse Golden, M.D., Ph.D.

Principal Investigator

Weill Medical College of Cornell University

Are You a Good Fit for This Trial?

Adults with rectal cancer that hasn't spread or been treated yet can join this trial. They need to be in good health, not have had prior pelvic radiation or chemotherapy for rectal cancer, and agree to use contraception. Pregnant women, those with recent severe illnesses or allergies to similar drugs, and patients on certain medications are excluded.

Inclusion Criteria

I am not pregnant and agree to use birth control during the study.

I agree to use effective birth control methods.

Hgb >8.0 gm/dL, PLT > 150,000/mm3, total bilirubin ≤ 1.5x upper limit of normal, AST ≤ upper limit of normal, ALT ≤ 3x upper limit of normal

Exclusion Criteria

I have had a blood clot in an artery in the last 6 months.

I haven't taken any specific heart medication that affects drug transport in my body within the last 4 weeks.

I have 4 or more large lymph nodes in my pelvis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants receive short-course radiotherapy to gross pelvic disease (25Gy in 5 fractions) in combination with AB928

1 week

1 visit (in-person)

Chemotherapy

Consolidation chemotherapy with mFOLFOX x9 cycles in combination with AB928 and AB122

18 weeks

Assessment

Therapeutic responses assessed with digital rectal examination, pelvic MRI, and endoscopy

2 weeks

3 visits (in-person)

Surgery

Total mesorectal excision (TME) by transabdominal resection for pathologic evaluation

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

60 months

What Are the Treatments Tested in This Trial?

Interventions

• AB122
• AB928
• FOLFOX regimen
• Radiation therapy

Trial Overview The study tests a combination of new drugs (Zimberelimab and Etrumadenant) with standard chemo (FOLFOX regimen) after initial short-course radiation therapy. The goal is to see if this combo is safe and works better for treating rectal cancer.

How Is the Trial Designed?

Group I: Radiation therapy and etrumadenant (AB928) Experimental Treatment 4 Interventions

Enrolled patients will receive Radiation therapy of 25 Gy in 5 fractions along with etrumadenant 150mg oral drug taken once daily. this will then be followed by 9 cycles of FOLFOX in combination of etrumadenant and zimberelimab investigational drugs.

Who Is Running the Clinical Trial?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Arcus Biosciences, Inc.

Industry Sponsor

Trials

44

Recruited

7,500+

Published Research Related to This Trial

The RTOG 3505 study is investigating the effectiveness of combining concurrent chemoradiation with the immune checkpoint inhibitor nivolumab in patients with locally advanced non-small-cell lung cancer, aiming to improve overall survival and progression-free survival.

With a planned enrollment of 660 patients, the study is designed to have sufficient power to detect significant differences in survival outcomes, ensuring robust results regarding the efficacy of nivolumab compared to placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment Design and Rationale for a Randomized Trial of Cisplatin and Etoposide Plus Thoracic Radiotherapy Followed by Nivolumab or Placebo for Locally Advanced Non-Small-Cell Lung Cancer (RTOG 3505). Gerber, DE., Urbanic, JJ., Langer, C., et al.[2018]

Combining radiotherapy with immunotherapies appears to be safe, as it does not lead to increased toxicity, even at definitive doses of radiotherapy.

Recent clinical trials, like the PACIFIC trial, have shown promising results regarding the safety and efficacy of these combinations, suggesting potential benefits such as abscopal effects, where treatment at one site affects distant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation Therapy and Immune Modulation. Leeman, JE., Schoenfeld, JD.[2020]

Radiotherapy (RT) significantly reduces local relapse rates and improves survival in patients with stage II and III rectal cancer, with preoperative RT being more effective and better tolerated than postoperative RT.

Combining RT with chemotherapy (5FU or capecitabine) enhances local control, but does not show clear benefits in overall or disease-free survival, highlighting the need for further research into neo-adjuvant chemotherapy to address distant relapses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant radiotherapy for rectal cancer: recent results, new questions. Rivera, S., Villa, J., Quero, L., et al.[2011]

Brachytherapy combined with immunostimulatory monoclonal antibodies (anti-PD1 and anti-CD137) can induce abscopal effects, meaning it can shrink tumors that are not directly irradiated, as shown in a mouse model with colorectal cancer.

The study indicates that this combination therapy could be a promising approach for clinical applications, enhancing the effectiveness of radiotherapy in treating cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brachytherapy attains abscopal effects when combined with immunostimulatory monoclonal antibodies. Rodriguez-Ruiz, ME., Rodriguez, I., Barbes, B., et al.[2018]

Immunotherapy is a promising new approach in cancer treatment, but its effectiveness can vary widely among patients, even those with tumors that are expected to respond well.

Combining immunotherapy with radiation therapy may enhance treatment outcomes for patients with gastrointestinal cancers, supported by strong preclinical evidence and ongoing research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy and radiation therapy for gastrointestinal malignancies: hope or hype? Badiyan, S., Kaiser, A., Eastman, B., et al.[2023]

A 74-year-old woman with lung adenocarcinoma developed fatal immune thrombocytopenia after receiving pembrolizumab following radiotherapy, highlighting a potential risk of severe immune-related adverse events (irAEs) when combining these treatments.

Flow cytometry analysis showed increased PD-1 and Ki-67 expression in T cells post-radiotherapy, suggesting that radiotherapy may enhance immune activation and contribute to the development of irAEs in patients undergoing anti-PD-1 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy. Tamanoi, D., Saruwatari, K., Imamura, K., et al.[2022]

In a study of 133 patients with metastatic cancers receiving immune checkpoint inhibitors and radiation, 34.6% experienced immune-related adverse events (ir-AEs), with higher rates observed in those receiving both CTLA-4 and PD-1 inhibitors (71% vs 29%).

The combination of palliative radiation and immune checkpoint inhibitors was generally well tolerated, with most ir-AEs being mild, suggesting that this treatment approach can be safely integrated in clinical practice for patients needing both therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy. Bang, A., Wilhite, TJ., Pike, LRG., et al.[2022]

Concurrent immunoradiotherapy, combining immune checkpoint inhibitors with radiotherapy, showed a 30% overall response rate in 16 patients with metastatic melanoma who had progressed on nivolumab, with a notable 68.8% response rate in lesions within the radiation fields.

Nivolumab combined with radiotherapy demonstrated a 100% response rate inside the radiation fields, suggesting it may be more effective than ipilimumab in this setting, although some patients experienced grade 3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab. Nomura, M., Otsuka, A., Yoshimura, M., et al.[2019]

The 'Synergy between Immunotherapy and Radiotherapy' (SITAR) strategy has shown promising antitumor activity and a favorable toxicity profile in both preclinical and clinical trials, indicating its potential as an effective treatment approach.

Currently, about one in seven radiation therapy studies is exploring SITAR, highlighting the growing interest in this combination therapy, while also emphasizing the need for caution regarding potential toxicities when combining immunotherapy with radiotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical evidence for synergy between immunotherapy and radiotherapy (SITAR). Gill, S., Nowak, AK., Bowyer, S., et al.[2022]

The combination of local radiation therapy (RT) and ipilimumab, an immunotherapy, was well-tolerated in 22 patients with stage IV melanoma, showing no unexpected toxicities.

Half of the patients (50%) experienced clinical benefits, with some achieving ongoing complete responses, suggesting that this combination therapy may enhance systemic immune responses against melanoma and warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma. Hiniker, SM., Reddy, SA., Maecker, HT., et al.[2022]

The trial demonstrated that combining programmed death protein ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibition with radiotherapy is feasible, achieving an 82% feasibility rate for patients entering radioimmunotherapy (RIT) after initial treatment.

Patients with stage III-IVB head and neck squamous cell carcinoma showed promising progression-free survival (PFS) rates of 78% at one year and 72% at two years, particularly benefiting HPV-positive patients who had a 2-year PFS rate of 94%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer. Hecht, M., Eckstein, M., Rutzner, S., et al.[2022]

In patients with locally advanced rectal cancer, a higher proportion of CD4+ regulatory T (Treg) cells in biopsies before neoadjuvant radiotherapy was linked to poorer prognosis, suggesting that Tregs may hinder effective antitumor immunity.

Combining radiotherapy with anti-CD25 or anti-CTLA4 monoclonal antibodies significantly enhanced the immune response by increasing CD8+ T cells and reducing Tregs, leading to improved local tumor control and a notable abscopal effect on distant metastases, ultimately improving overall survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer. Ji, D., Song, C., Li, Y., et al.[2021]

Citations

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

Treatment Design and Rationale for a Randomized Trial of Cisplatin and Etoposide Plus Thoracic Radiotherapy Followed by Nivolumab or Placebo for Locally Advanced Non-Small-Cell Lung Cancer (RTOG 3505). [2018]

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

Radiation Therapy and Immune Modulation. [2020]

3. France pubmed.ncbi.nlm.nih.gov

Adjuvant radiotherapy for rectal cancer: recent results, new questions. [2011]

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

Brachytherapy attains abscopal effects when combined with immunostimulatory monoclonal antibodies. [2018]

5. China pubmed.ncbi.nlm.nih.gov

Immunotherapy and radiation therapy for gastrointestinal malignancies: hope or hype? [2023]

6. Japan pubmed.ncbi.nlm.nih.gov

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy. [2022]

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

Multicenter Evaluation of the Tolerability of Combined Treatment With PD-1 and CTLA-4 Immune Checkpoint Inhibitors and Palliative Radiation Therapy. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Efficacy and safety of concurrent immunoradiotherapy in patients with metastatic melanoma after progression on nivolumab. [2019]

9. Australia pubmed.ncbi.nlm.nih.gov

Clinical evidence for synergy between immunotherapy and radiotherapy (SITAR). [2022]

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

A Prospective Clinical Trial Combining Radiation Therapy With Systemic Immunotherapy in Metastatic Melanoma. [2022]

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

Induction chemoimmunotherapy followed by CD8+ immune cell-based patient selection for chemotherapy-free radioimmunotherapy in locally advanced head and neck cancer. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Combination of radiotherapy and suppression of Tregs enhances abscopal antitumor effect and inhibits metastasis in rectal cancer. [2021]