Immunotherapy + Radiation for Colorectal and Lung Cancer

Not currently recruiting at 49 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Investigational agents

Disqualifiers: Untreated brain metastases, Active infection, Autoimmune disorders, 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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 4

Duration: 16 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether combining the immunotherapy drugs durvalumab (Imfinzi) and tremelimumab with varying doses of radiation therapy can more effectively treat colorectal and non-small cell lung cancer that has metastasized. The researchers aim to evaluate the efficacy of these combined treatments and understand their side effects. Suitable participants have colorectal or non-small cell lung cancer that has progressed after prior treatments. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial requires that at least 21 days have passed since your last systemic therapy (like chemotherapy or radiation) before starting the study treatment. If you are currently on any investigational agents or immunosuppressive medications, you will need to stop those before participating.

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

Research has shown that durvalumab and tremelimumab have been tested for safety both alone and with radiation therapy. In previous studies, a notable side effect was a lung condition called immune-mediated pneumonitis, occurring in about 1.3% of patients. Although some cases were serious, they were rare.

When used together without radiation, durvalumab and tremelimumab caused immune-mediated colitis (inflammation of the colon) or diarrhea in about 6% of patients, with some cases being serious.

Researchers are now combining these treatments with radiation to assess their combined effectiveness. While some risks exist, they are uncommon. Discuss any concerns or questions about these treatments with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine immunotherapy with radiation to enhance cancer-fighting effects. Unlike standard treatments like chemotherapy, which directly attack cancer cells, durvalumab and tremelimumab work by boosting the body's immune system to target and destroy cancer cells more effectively. Additionally, the trial explores different radiation doses—both high and low—to see how they can best complement the immunotherapies. This combination approach has the potential to offer a more targeted and potent attack on colorectal and lung cancer cells, potentially leading to better outcomes for patients.

What evidence suggests that this trial's treatments could be effective for metastatic colorectal or non-small cell lung cancer?

Research has shown that using the drugs durvalumab and tremelimumab with radiation therapy might help treat colorectal and non-small cell lung cancer. In this trial, participants will receive either high-dose or low-dose radiation therapy combined with durvalumab and tremelimumab, or the drug combination without radiation. Studies suggest that radiation can enhance the immune system's ability to fight tumors when used with these drugs. In some trials, patients with colorectal cancer who received this combination treatment lived for an average of 6.6 months, compared to 4.1 months for those who did not receive it. Specifically, in a particular group, 8.3% of patients experienced tumor shrinkage. While these results are encouraging, they indicate the treatment's potential rather than guaranteed outcomes. ^{6 7 8 9 10}

Who Is on the Research Team?

Jonathan D Schoenfeld

Principal Investigator

Dana-Farber - Harvard Cancer Center LAO

Are You a Good Fit for This Trial?

This trial is for adults with metastatic colorectal or non-small cell lung cancer who've had disease progression after prior therapy. They must have measurable disease, be in good physical condition (ECOG <=1), not pregnant, and willing to use birth control. Exclusions include recent chemotherapy, known allergies to trial drugs, uncontrolled illnesses, HIV-positive status, and certain previous treatments.

Inclusion Criteria

I have been diagnosed with non-small cell lung cancer or colorectal cancer.

My body weight is over 30 kg.

I can have a new biopsy for this study.

Exclusion Criteria

You are currently taking any other experimental drugs.

I haven't had chemotherapy, biologic therapy, or radiotherapy in the last 3 to 6 weeks.

I have not received radiation that would harm my healthy tissues.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tremelimumab and durvalumab with or without high or low-dose radiation therapy

16 weeks

Every 4 weeks

Radiation

Participants receive high or low-dose radiation therapy starting at week 2

10 days for high dose or multiple sessions for low dose

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Durvalumab
• Radiation Therapy
• Tremelimumab

Trial Overview The study tests the effectiveness of durvalumab and tremelimumab immunotherapies with or without radiation therapy on metastatic cancers. It's a phase II randomized trial where patients are assigned by chance to receive either high/low-dose radiation combined with the drugs or the drugs alone.

How Is the Trial Designed?

Group I: Cohort 2, Arm B (tremelimumab, durvalumab, LD-RT) Experimental Treatment 3 Interventions

Patients receive tremelimumab IV and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. Beginning at week 2, patients receive low dose radiation therapy every 6 hours BID on weeks 2, 6, 10 and 14.

Group II: Cohort 2, Arm A (tremelimumab, durvalumab, HD-RT) Experimental Treatment 3 Interventions

Patients receive tremelimumab IV and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses. Beginning at week 2, patients receive high dose radiation therapy QD over 10 days for up to 3 fractions.

Group III: Cohort 1, Arm C (tremelimumab, durvalumab) Experimental Treatment 2 Interventions

Patients receive tremelimumab IV and durvalumab IV over 60 minutes every 4 weeks for up to 16 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive durvalumab IV over 60 minutes 4 weeks after last combination dose for up to 9 additional doses.

Group IV: Cohort 1, Arm B (tremelimumab, Durvalumab, LD-RT) Experimental Treatment 3 Interventions

Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive low dose radiation therapy every 6 hours BID on weeks 2, 6, 10 and 14.

Group V: Cohort 1, Arm A (tremelimumab, durvalumab, HD-RT) Experimental Treatment 3 Interventions

Patients receive tremelimumab and durvalumab and as in Arm C. Beginning at week 2, patients receive high dose radiation therapy QD over 10 days for up to 3 fractions.

Durvalumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination of durvalumab and tremelimumab showed improved disease control rates in patients with head and neck squamous cell carcinoma compared to tremelimumab alone, indicating its potential efficacy in this cancer type.

The combination therapy had a tolerable safety profile, with no significant increase in treatment-related adverse events compared to monotherapy, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab and tremelimumab combination therapy versus durvalumab or tremelimumab monotherapy for patients with solid tumors: A systematic review and meta-analysis. Wang, BC., Li, PC., Fan, JQ., et al.[2022]

Tremelimumab, a CTLA-4 blocking antibody, was approved in the USA in October 2022 for treating unresectable hepatocellular carcinoma (uHCC) in combination with durvalumab, marking a significant advancement in cancer therapy.

In November 2022, tremelimumab was also approved for metastatic non-small cell lung cancer (mNSCLC) when combined with durvalumab and platinum-based chemotherapy, indicating its broad potential in treating various malignant tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tremelimumab: First Approval. Keam, SJ.[2023]

In a safety run-in phase of the DURIGAST PRODIGE 59 study involving 11 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, 63.6% experienced significant adverse events, primarily neutropenia, indicating a notable safety concern with the treatment combination.

The combination of FOLFIRI with Durvalumab and/or Tremelimumab showed an expected safety profile, allowing progression to the randomized phase II study, although careful monitoring for serious adverse events is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of FOLFIRI + Durvalumab +/- Tremelimumab in Second Line of Patients with Advanced Gastric Cancer: A Safety Run-In from the Randomized Phase II Study DURIGAST PRODIGE 59. Evrard, C., Aparicio, T., Soularue, E., et al.[2022]

In a study of 68 patients with locally advanced non-small cell lung cancer treated with intensity-modulated radiotherapy (IMRT), the administration of durvalumab significantly improved distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS), with hazard ratios of 0.31, 0.33, and 0.32 respectively.

The study also found that while grade 2 or higher radiation pneumonitis (RP) was associated with worse DMFS, reducing the incidence of RP could enhance patient outcomes, highlighting the importance of managing treatment-related side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after chemoradiotherapy for locally advanced non-small cell lung cancer prolonged distant metastasis-free survival, progression-free survival and overall survival in clinical practice. Yamamoto, T., Tsukita, Y., Katagiri, Y., et al.[2022]

This phase II study aims to evaluate the safety and efficacy of combining the chemotherapy regimen FOLFOX (5-Fluorouracil, oxaliplatin, and leucovorin) with the immune checkpoint inhibitors durvalumab and tremelimumab in 48 patients with metastatic colorectal cancer (mCRC).

The study hypothesizes that this combination will improve progression-free survival (PFS) rates, expecting a PFS of 70.7% at 6 months, compared to a historical benchmark of 50%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer. Fumet, JD., Isambert, N., Hervieu, A., et al.[2023]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

In a phase 2 trial involving 90 patients with non-small-cell lung cancer resistant to PD-1/PD-L1 therapy, the combination of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) with radiotherapy did not show improved overall response rates compared to the therapy alone, leading to the trial's early termination due to futility.

The most common serious adverse events were manageable, but one patient in the low-dose radiotherapy group died from respiratory failure potentially related to the treatment, highlighting the need for careful monitoring in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial. Schoenfeld, JD., Giobbie-Hurder, A., Ranasinghe, S., et al.[2023]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

The DUART trial is a Phase II study investigating the safety and tolerability of durvalumab in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) who cannot undergo chemotherapy due to poor performance status or other health issues.

This study aims to evaluate whether durvalumab can improve survival outcomes for these patients compared to the current standard of care, which is radiotherapy alone, based on promising results from the PACIFIC trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy. Filippi, AR., Dziadziuszko, R., García Campelo, MR., et al.[2022]

Durvalumab, a PD-L1 blocking antibody, has shown clinical efficacy and a manageable safety profile in treating advanced non-small-cell lung cancer, especially in patients with ≥25% PD-L1 expression.

The drug is being evaluated in various treatment settings, including as a monotherapy and in combination with other therapies, showing promising results particularly after chemoradiation, although lower response rates were noted in patients with EGFR and ALK mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab in non-small-cell lung cancer patients: current developments. Mezquita, L., Planchard, D.[2018]

Citations

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Phase II Single Arm Study of Durvalumab and ... We enrolled 24 patients, and report outcomes after a median follow up of 21.8 (range: 15.9 to 26.3) months. The ORR was 8.3% (2 patients) (95% confidence ...

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small Cell Lung Cancer This randomized phase II trial studies the side effects of durvalumab and tremelimumab and to see how well they work with or without high or low-dose ...

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Durvalumab plus Tremelimumab Immunotherapy ... 26 clinical trial, patients with advanced CRC refractory to all available therapy had a median OS of 6.6 months with durvalumab plus tremelimumab versus 4.1 ...

4. annalsofoncology.org annalsofoncology.org/article/S0923-7534(21)03183-5/fulltext

First results of efficacy at one year for phase II MEDITREME ... The aim of single arm phase II MEDITREME trial was to evaluate efficacy and safety of mFOLFOX6 (6 cycles) in combination with durvalumab (750mg/q2W) and ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S109830152502323X

Cost-Utility Analysis of Durvalumab and Tremelimumab ... Combined durvalumab and tremelimumab is not cost-effective in refractory metastatic colorectal cancer per conventional cost-effectiveness thresholds.

6. imfinzihcp.com imfinzihcp.com/hcc/unresectable/safety.html

Safety Profile of IMFINZI® (durvalumab) & IMJUDO® ... Immune-mediated colitis or diarrhea occurred in 6% (23/388) of patients receiving IMFINZI and IMJUDO, including Grade 3 (3.6%) adverse reactions. Intestinal ...

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK599983/

Tremelimumab (Imjudo) in Combination With Durvalumab ... Imjudo in combination with Imfinzi should only be covered to treat adult patients who have confirmed liver cancer that cannot be removed by surgery, are ...

8. imfinzi.com imfinzi.com/

IMFINZI® (durvalumab) | Immunotherapy for Certain Cancers IMFINZI is used to treat adults with a type of cancer called BTC, including cancer of the bile ducts (cholangiocarcinoma) and gallbladder cancer.

9. clinicaltrials.gov clinicaltrials.gov/study/NCT03122509

NCT03122509 | A Clinical Trial of Durvalumab and ... It will be conducted to determine the efficacy and safety of (1) durvalumab and tremelimumab plus RT in subjects with metastatic CRC who are undergoing RT as ...

10. nature.com nature.com/articles/s41591-023-02497-z

First-line durvalumab and tremelimumab with ... The single-arm, phase 1b/2 MEDITREME trial evaluated the safety and efficacy of durvalumab plus tremelimumab combined with mFOLFOX6 chemotherapy in first line.